Synthetic Approaches to the 2002 New Drugs Jin Li *

Transcription

Mini-Reviews in Medicinal Chemistry, 2004, 4, 207-233
207
Synthetic Approaches to the 2002 New Drugs
Jin Li* and Kevin K.-C. Liu*
Pfizer Global Research and Development, Pfizer Inc., Groton CT 06340, USA
Abstract: New drugs are introduced to the market every year and each individual drug represents a privileged
structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights
into molecular recognition, but also serve as drug-like leads for designing future new drugs. Therefore, it is
important to be acquainted with these new structures as well as their syntheses. To these ends, this review
covers the syntheses of 28 NCEs marketed in 2002.
Keywords: Synthesis, New Drug, New Chemical Entities, Medicine, Therapeutic Agents.
INTRODUCTION
Dozens of new drugs are registered and launched every
year around the world. Although thousands of drugs have
been marketed historically, the structure similarity among
some drugs is obvious and even more so for drugs targeting
in the same gene family. Furthermore, it has been
demonstrated that molecules which share the same or similar
chemical template can be further modified for different
therapeutic indications against the similar gene family.
Therefore, medicinal chemists, being aware of these new
drug structures, can strike and adopt ideas for their own
innovations. In addition, preparation of these drug molecules
has been studied extensively to make it concise due to the
cost of goods consideration and to ensure environmentfriendliness. Having such robust and reliable synthetic
methods in hand to access these core structures will steer
synthetic efforts more effectively toward the most promising
compounds and help focus the optimization toward other
challenging properties such as ADME.
In 2002 alone, 33 NCEs including biological drugs, and
two diagnostic agents reached the market [1-5]. This review
article will focus on the syntheses of the 28 new drugs
marketed last year (Figure 1), but excludes new indications
for known drugs, new combinations and new formulations.
The syntheses of these new drugs were published
sporadically in different journals and patents. It is our
intention to compile the syntheses of new drugs yearly into
an annual review for the readers’ advantage. The synthetic
routes cited here represent the most scalable methods
according to the best of the authors’ knowledge and appear
in alphabetical order by generic name.
Adefovir Dipivoxil (HepseraTM)
Adefovir dipivoxil (1), discovered by Gilead, became the
first nucleoside analogue to gain FDA approval for the
treatment of chronic hepatitis B infection [6]. Adefovir
works by blocking viral replication [6]. The synthesis [7,8]
of adefovir dipivoxil (1) involves a four-step process [9,10]
as depicted in Scheme 1. Adenine (29) was condensed with
ethylene carbonate (30) in hot DMF to afford intermediate 9*Address correspondence to these authors at the Pfizer, Groton, CT
06340, USA; Tel: 1-860-7153552; E-mail: [email protected];
[email protected]
1389-5575/04 $45.00+.00
(2-hydroxyethyl)-adenine 31 in 83-95% yield. Alkylation of
31 was carried out using diethyl-p-toluenesulfonyloxymethanephosphonate (32) and sodium t-butoxide in DMF.
Phosphonate ester 33 was then cleaved with
bromotrimethylsilane to furnish 34 and esterification of the
phosphoric acid to append the pivaloyloxymethyl group
provided adefovir dipivoxil (1).
Amrubicin Hydrochloride (Calsed)
This drug is the first anthracycline anticancer antibiotic
produced by purely synthetic methods. It was discovered by
Sumitomo Pharmaceuticals, and is for the treatment of nonsmall cell lung cancer and small cell lung cancer [11].
Tetralone 35 was treated with ammonium carbonate and
potassium cyanide (Strecker reaction) to give the
corresponding aminonitrile intermediate, which was
hydrolyzed under basic conditions to afford amino acid 36 in
excellent yield [12]. The carboxylic acid in 36 was esterified
with HCl in methanol to the corresponding methyl ester,
which was treated with D-(-)-mandelic acid in toluene to
give optically pure levorotatory ester 37 in 33% yield.
Sodium methylsulfinylmethide treatment of 37 followed by
reduction with zinc yielded amino ketone 38, which was
acylated to give amido ketone 39 in 81 % yield from 37.
Compound 39 was converted to tetracyclic amido ketone 40
in one step (90% yield) by heating with phthalic anhydride
in the presence of AlCl3 -NaCl at 170° C. Ketone 40 was
protected as its ketal 41 in order to provide for subsequent
regiospecific bromination. Treatment of 41 with 1,3dibromo-5,5-dimethylhydantoin (DDH) under illumination
in refluxing benzene formed oxazine 42 in 89% yield.
Hydrolysis of the oxazine ring and deketalization were
simultaneously affected by heating 42 with 3N sulfuric acid
to give cis-amino alcohol 43 in 82% yield. Modified
Arcamone conditions (AgOSO2CF3 in ether/tetramethylurea
/DCM) were employed for the stereoselective glycosidation
of 43 with 2-deoxy-3,4-di-O-acetyl-D-erythro-pentopyranosyl
bromide (44) [13] to give the protected β-glycoside in 86%
yield. Basic hydrolysis of the protected coupling product
followed by HCl salt formation gave amrubicin
hydrochloride (2) in 90% yield.
Aripiprazole (AbilifyTM)
This atypical antipsychotic agent was originally
discovered by Otsuka and was co-developed and co-marketed
© 2004 Bentham Science Publishers Ltd.
208 Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2
Li and Liu
O
O
OH
O
O
N
N
O
O
N
N
HCl
NH2
NH2
O
O
O
OH
O
P
O
O
Cl
O
N
HO
Cl
N
Adefovir dipivox il (1)
NH
O
OH
F
H
H
S
N
HCl
H
H
F
Dex methylphenidate HCl (4)
O
N
O
S
O
O
Ertapenem sodium (6)
Dutasteride (5)
NC
NH
OH
F
O Na
N
H
O
F
N
H H
O
O
H
O
N
H
Aripiprazole (3)
F
F
O
O
NH
O
OH
Amrubicin hydrochloride (2)
O
OH
OH
Cl
CO2H
CO2H
N
F
N
O
N
F
Escitalopram oxalate (7)
F
Ezetimibe (9)
Etoricoxib (8)
O
Na+ O
O
O
+
Na O
O
O
+
Na O
O
S
O
O
O
HO
OH O
N
OH
S
O
O
O
ONa +
O
O
O
H
N
O
O
O
NH2
H
H
H
O O O O
N
OH S
S
O
O
ONa+
Na +
H
O
Na+ O
O
Na + O
O
O
S
O
S
OH O
O
S
O
OH O
N
N
H
S
O
ONa+
O
Na +
Frovatriptan (1 1)
O
Fondaparinux sodium (10)
N
OH
OMe
O
H
O
H
HO
H
F
F
N
S
7
Fulvestrant (12)
F
F
F
N
NH
Gefitinib (13)
Cl
F
Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 209
(Fig. 1). contd.....
O
O
O
O
H
N
O
O
N
N
H
Landiolol (14)
OH
O
OH
OH
H2 N
HO
OH
O
O
O
HN
O
OH
O
N
O
O
OH
OH
OH
OH
P
N
H
O
HO
P
H2N
O
N
O
O
O
O
HN
S
H
N
O
N
O
NaO
OH
HN
HO
OH
OH
Neridronate (16)
OH
Micafungin sodium (15)
OH
O
O
N
O
O
O
NO2
N
O
O
N
N
O
O
N
N
O
S
Na
O
NH
N
F
F
O
F
Nitisinone (17)
Olmes artan medoxomil (18)
Parecoxib sodium (19)
Cl
O
O
O
O
O
N
OH
CH 3S O3H
H 2N
N
O
OH
F
F
OO
O
OH
O
O
O
O
O
P az ufloxacin me silate (20)
O
O
O
Pimecrolimus (21)
N
N
Prulifloxacin (22)
OH
N
S
Li and Liu
(Fig. 1). contd.....
HO
O
O
OH
O Na
HN
F
Ca2+
O
N
N
H
N
O
N
Br
O
O
S
O
O
S
4H2O
O
O
HO
O
S
N
S
O
O
2
Tiotropium bromide (25)
Sivelestat sodium hydrate (24)
Rosuvastatin calcium (23)
O
OH
H 2N
S
O
F
N
O
OH
HO
F
N
N
N
N
O
Na O
N
O
Treprostinil (26)
F
Valdecoxib (27)
Voricona zole (28)
Fig. (1). Structures of 28 new drugs marketed in 2002.
Dexmethylphenidate Hydrochloride (FocalinTM)
by Bristol-Myers Squibb. The compound is a partial agonist
at dopamine D2 and 5HT1a and an antagonist at 5-HT2a
receptors [14]. It is indicated for the treatment of
schizophrenia. Hydroxyl quinolinone 45 was alkylated with
1,4-dibromobutane in the presence of potassium carbonate in
DMF to give 46 in 78% yield [15]. Bromide 46 was
condensed with 1-(2,3-dichlorophenyl)piperazine [16] (47) in
the presence of NaI and TEA to give aripiprazole (3) in 87%
yield.
O
NH2
N
N
NH2
O 30
N
N
H
Dexmethylphenidate (4) is the more pharmacologically
active d-threo-enantiomer of methylphenidate which was
marketed for the treatment of attention deficit/hyperactivity
disorder (ADHD) in 1954 [17]. In addition, it has been
shown that there are significant metabolic differences
between the two enantiomers. This drug was discovered by
Cangene and is marketed by Novartis. To date, several
methods have been disclosed in the literature for preparing
O
NaOH, DMF
O
EtO
N
N
N
N
N
N
NaOBut, DMF
OH
83-95%
NH2
32
OEt
120o C
O
33
31
Cl
N
OEt
OEt
NH2
O
N
N
TMSBr
N
P
O
NH2
N
O
N
N
35-48%
29
CH3 CN, ∆
80-90%
OTs
P
O
N
O
P
OH
OH
34
Scheme 1. Synthesis of adefovir dipivoxil.
TEA, NMP
N
O
N
O
40%
1
P
O
O
O
2
OCH3
OCH3
O
OCH3
CO2H
1) KCN, (NH4) 2CO3, 50% EtOH, ∆, 99%
NH2
2) Ba(OH)2 , H2O, ∆, 92%
OCH3
35
CO2 CH3
1) HCl, MeOH, 95%
NH2
2) D-(-)-mandelic acid
toluene, IPA, 33%
OCH3
OCH3
36
37
O
OCH3
O
CH3
1) NaH, DM SO, THF
NH2
2) Zn, NaOH/H2O, toluene
O
80% from 37
38
39
OH
O
CH3
NHAc
TsOH, toluene, ∆
88%
DDH, benzene, hv
∆, 89%
OH
O
40
41
O
OH
O
O
CH3
O
OH
O
OH
CH3
3N H2 SO4, ∆
NH2
82%
N
O
O
O
ethylene glycol
OH
O
AlCl3, NaCl, 170oC
90%
OCH3
NHAc
O
NHAc
OCH3
CH3
O
CH3
Ac 2O, pyridine, toluene
O
OH
O
O
OCH3
O
CH3
OH
OH
43
42
O
O
Br
O
OH
CH3
NH2
AcO
OAc
44
AgOSO2CF 3, ether
tetramethylurea, CH2 Cl2
86%
1) KOH, CH2Cl 2
MeOH,
2) HCl, MeOH, 90%
HCl
O
OH
O
O
HO
OH
2
Scheme 2. Synthesis of amrubicin hydrochloride.
the d-threo-enantiomer of methylphenidate, most involving
with enzymatic resolution [18], or crystallization/
recrystallization methods [19,20]. An asymmetric synthesis
[21] route is depicted in Scheme 4. R-Pipecolic acid (48)
was reacted with (Boc)2O to afford N-Boc pipecolic acid 49.
Treatment of 49 with N,O-dimethylhydroxylamine in DCM
provided the Weinreb amide 50 in 93% yield. Reaction of
amide 50 with phenyllithium at –23°C in Et2 O furnished
enantiopure ketone 51 in 73% yield. Ketone 51 was
converted to chiral aromatic alkene 5 2 using
methylenetriphenylphosphorium ylide in THF at rt. The
transformation of olefin 52 to diastereomeric alcohols 53 and
54 was achieved using BH3-THF complex in 89% overall
yield. Diastereomerically pure alcohol 53 was subjected to
PDC-mediated oxidation in DMF followed by treatment
with excess ethereal diazomethane. The resulting N-Bocmethylphenidate was deprotected with 3N methanolic HCl
to give dexmethylphenidate (4) as a white solid in 67%
yield.
Li and Liu
Cl
Cl
Br(CH2)4Br, K2CO3
HO
N
H
DM F,
O
60oC,
N
78%
Br(CH2)4O
N
H
46
45
Cl
O
47
Nal, TEA
CH3CN, 87%
Cl
N
NH
N
O
N
H
3
O
Scheme 3. Synthesis of aripiprazole.
OH
N
H
(Boc) 2O, TEA
MeOH, rt, 97%
O
OH
N
N, O-dimethylhydroxylamine
O
PhLi, Et2O
BOP, TEA, DCM, rt, 93%
N
-23oC, 73%
O
Boc
Boc
49
48
N
Boc
O
50
O
51
1) BH3 THF, THF
methyltriphenylphosphorium bromide
KOBut , THF, rt, 93%
N
2) NaOH , H2O2, rt
N
Boc
N
N
Boc
Boc
OH
OH
52
53
6 4%
54
25%
1) PDC/DMF
2) CH2N2
N
Boc
OH
3) HCl/MeOH
67%
53
N
H
O
OMe
4
Scheme 4. Synthesis of dexmethylphenidate.
Dutasteride (AvodartTM)
Ertapenem Sodium (InvanzTM)
This steroid 5α-reductase type 1 and 2 inhibitor was
patented by GlaxoSmithKline. It is used for the treatment of
symptomatic benign prostatic hyperplasia in men with an
enlarged prostate to improve urinary symptoms, reduce the
risk of acute urinary retention and BPH-related surgery [22].
Steroidal dutasteride (5) was synthesized from 3-oxo-4androstene-17β−carboxylic acid (55) [23]. Oxidation of 55
with potassium permanganate, sodium periodate and sodium
carbonate in refluxing t-butyl alcohol and water gave secosteroid 56 which was cyclized with ammonium acetate in
acetic acid to give 4-aza-steroid 57 in good yield. Stereoselective hydrogenation of 57 with H2 over PtO2 in hot
acetic acid and in the presence of ammonium acetate yielded
saturated azasteroid 58, which was dehydrogenated with
DDQ in the presence of bis(trimethylsilyl)trifluoroacetamide
(BSTFA) 59 in refluxing dioxane to give 60. Treatment of
60 with thionyl chloride gave the corresponding acyl
chloride intermediate, which was then condensed with 2,5bis(trifluoromethyl)aniline (61) by means of DMAP in
heated toluene to give dutasteride (5) in 57% yield from
intermediate 60.
Ertapenem sodium (6) was introduced in the U.S. and
Europe by Merck & Co. as a once daily injectable
carbapenum antibiotic drug. Ertapenem (6) is indicated for
the treatment of moderate to severe infections in adults
caused by susceptible strains of a range of Gram-positive and
Gram-negative aerobic and anaerobic bacteria [24].
Following a conventional carbapenem synthetic strategy,
ertapenem sodium (6) can be assembled from 4-nitrobenzylprotected β-methyl carbapenemenolphosphate 71 and 2aminocarbonylpyrrolidine-4-ylthio-containing side chain 70.
Many efficient approaches to 71 have been reported in the
literature [25], and this compound is now commercially
available on a large scale [26]. The synthesis of 70 is
outlined in Scheme 6 [27,28]. Protection of the amino group
in trans-4-hydroxy-L -proline (6 2 ) with diisopropyl
phosphite followed by NaClO oxidation gave N-DIPP
protected hydroxyl proline 63 in 80% yield. The carboxyl
group in 6 3 was activated v i a reaction with
diphenylphosphinic chloride (DPPC) in the presence of
diisopropylethylamine (DIPEA). This intermediate 64 was
directly reacted with methanesulfonyl chloride in the
CO2H
CO2H
CO2H
H
KM nO4, NaIO4, Na 2 CO3
H
H
t-BuOH, H2O, 100oC
58-66%
H
NH4OAc, HOAc
H
H
120oC, 85-95%
H
HO2C
O
H
O
N
H
O
57
56
55
CO2H
CO2H
H
F 3C
H
PtO2 , H2
H
HOAc, 60o C
NH4OAc, 75-85%
O
H
N
H H
DDQ,
NSiMe3
59
Me 3SiO
dioxane,
100o C,
70-85%
H
O
O
H
N
1) SOCl2, toluene, pyridine, DMF
H
NH2
O
o
toluene, DMAP, 100 C, 57%
CF3
H
CF3
61
H
N
H H
60
58
F3 C
H
N
H H
CF3
H
5
Scheme 5. Synthesis of dutasteride.
presence of pyridine to furnish mesylate 65. Mesylate 65
was then quenched with aqueous sodium sulfide yielding 66
instantaneously, which then slowly cyclized to 6 7 .
Aminolysis of 67 with m -aminobenzoic acid (68) and
subsequent deprotection of the DIPP group with
concentrated HCl provided 70 in 90-95% yield in a one-pot
process. The coupling reaction between 70 and 71 followed
by deprotection of PNB group was completed in one
reaction vessel to furnish ertapenem sodium (6) (yield was
not disclosed) [28].
Escitalopram Oxalate (Cipralex®)
Escitalopram (7) is a selective serotonin reuptake
inhibitor (SSRI) and was launched first in Switzerland. It is
the more active S-enantiomer of citalopram which is a wellknown antidepressant drug that has been on the market for
some years [29]. It is for the treatment of major depressive
episodes and panic disorder with or without agoraphobia.
The synthesis of escitalopram was carried out in several
different routes [30-33]. 5-Cyanophthalide (72) was treated
with Grignard reagent 73 at 0°C to provide intermediate 75
which was reacted in situ with another Grignard reagent 76
to afford the diol in a one-pot process. Racemic diol 77 was
resolved using (+)-p-toluoyltartaric acid to afford desired S
isomer 78 in 55% yield. The ring closure reaction was
carried out at 0°C using methanesulfonyl chloride in toluene
to furnish escitalopram (7) in 60% yield.
Etoricoxib (ArcoxiaTM)
Merck & Co.’s etoricoxib (8) was launched for the first
time in the U.K. last May as a new COX-2 inhibitor.
Etoricoxib (8) is indicated for the symptomatic relief of
osteoarthritis and rheumatoid arthritis, treatment of acute
gouty arthritis, relief of chronic musculoskeletal pain
including low back pain, relief of acute pain associated with
dental surgery and treatment of primary dysmenorrhea [34].
The synthesis of etoricoxib (8) was explored extensively by
the Merck process research group [35]. Key intermediate 85
was synthesized through at least three different routes. In the
Horner-Wittig approach, 6-methyl methylnicotinate (79) was
converted into Weinreb amide 80 in 95% yield. Amide 80
was then converted to aldehyde 81 via a DIBAL-H mediated
reduction. Subsequent treatment of a solution of aldehyde 81
in isopropyl acetate with aniline and diphenyl phosphite
provided N,P-acetal 82 in 87% yield. The Horner-Wittig
reaction of N , P -acetal 8 2 with 4-methanesulfonylbenzaldehyde (83) furnished enamine 84, which was
hydrolyzed to ketosulfone 85. A Grignard approach was also
developed in the preparation of ketosulfone 85. Addition of
Grignard reagent 86 to Weinreb amide 80 in toluene/THF
provided ketosulfide 85 in 80% yield. Tungstate-catalyzed
oxidation of ketosulfide 87 using hydrogen peroxide
provided ketosulfone 85 in 89% yield by simple filtration.
Ketosulfone 85 was prepared through Claisen condensation
protocol as well. Thus, reaction of 4-methanesulfonyl phenyl
acetic acid (88) with methyl nicotinate 79 under Ivanoff
condition, i.e., the magnesium dianion in THF, resulted
58% yield of ketosulfone 85. Treatment of ketosulfone 85
with a three-carbon electrophile, 2-chloro-N , N dimethylaminotrimethinium hexafluorophos-phate (89) in
the presence of potassium t-butoxide at ambient temperature
resulted adduct 90. Inverse quench of adduct 90 into a
mixture of HOAc /TFA led to the putative intermediate 91.
Ring closure of the pyridine ring occurred upon heating at
Li and Liu
H
O
HO
P
O
1)
80%
S
P
DIPP =
O
COOH
DIPP
63
O
2) NaClO
0-5 o C, PH=9
O
P
N
2) DIPEA
-20oC, DCM
DIPP
P
N
O
DIPP
S
_
S
aq. Na 2S
O
O
OiPr
MsO
O
O
64
OiPr
MsO
Cl
Pyridine
-20 oC
HO
O
N
62
O
P
COOH
N
H
Cl
1)
HO
O
25oC, 2h
N
O
DIPP
65
N
O
DIPP
67
66
one pot process , 90-95% from 63 to 67.
CO2H
HS
HS
H2N
68
AcOH, rt
H
N
CO2 H
HCl conc, rt
N
H _ H
Cl
N
DIPP
O
69
H
HO
H
N
H
O
CO2H
O
N
O
71
OPh
OPh
O
70
P
O
OPNB
one pot process, 90-95% from 67 to 70
H
HO
H
1) Pd/C, NaOH, NEP, TMG
O
2) H2
S
N
O
OH
NH
O
ONa
N
H
O
6
Scheme 6. Synthesis of ertapenem sodium.
reflux in the presence of an excess of aqueous ammonium
hydroxide to give desired etoricoxib (8) in 97% yield in a
one-pot process from 85.
Ezetimibe (Zetia)
Ezetimibe (9) was approved as the first hypolipidemic
drug to act by blocking the absorption of dietary cholesterol.
This drug was discovered by Schering-Plough and is codeveloped and co-marketed by Merck and Schering-Plough
for the treatment of hypercholesterolemia and also two less
common forms of hyperlipidemia: homozygous familial
hypercholesterolemia and homozygous sitosterolemia [36].
The synthesis of ezetimibe (9) begins with the one-step
diastereoselective and practical synthesis [37] of the trans βlactam from commercially available (S)-3-hydroxy-γ-lactone
(92). Lactam 95 was obtained by generation of a dianion of
lactone 92 with LDA in THF followed by addition of the
imine and N,N’-dimethylpropyleneurea (DMPU) to give
predominately adduct 93 (93:94 = 79:21). However,
intermediate 93 and 94 did not cyclize to their respective
lactams due to formation of stable lithium aggregates.
Addition of lithium chloride/DMF was employed to cyclize
the intermediates into trans-lactam 95 as the major product
(trans:cis = 95:5) in a one-pot process from 92 in 64%
yield. The 95:5 ratio of compound 95 was oxidatively
cleaved with NaIO4 to give aldehyde 96. Mukaiyama aldol
condensation was adopted to elaborate the 4-fluorophenylpropyl side chain to give alcohol 98. Without
isolation, the reaction mixture was subjected to dehydration
using p-TSA to give enone 99 in 75% yield from compound
96. Reduction of the double bond in 99 with Wilkinson’s
catalyst yielded ketone 100, which was subjected to the
highly enantioselective CBS reduction to give alcohol 101
with a 98:2 selectivity of S:R at the benzylic position.
Catalytic hydrogenation of compound 101 gave ezetimibe
(9) in 79% yield. Alternatively, a palladium-catalyzed
double reduction in EtOAc/MeOH of both the double bond
and the benzyl protecting group in enone 99 produced free
phenol 107 in 90% yield. A three-step one-pot procedure
was subsequently developed to transform 107 into ezetimibe
(9) in 79% yield. That is, free phenol 107 was protected in
situ as its TMS ether using BSU followed by a highly
selective CBS reduction of the ketone group to give the
NC
NC
OMgBr
O
MgBr
O
OMgBr
NC
THF
O
O
0oC, 3h
rt, overnight
F
F
F
73
72
75
74
OH
NC
N
MgCl
OH
76
N
10oC, 6h
33% from 72
F
77
OH
NC
NC
O
OH
(+)-p-toluoyltartaric acid
resolution
N
TEA, MeSO2 Cl
N
60%
55%
F
78
F
7
Scheme 7. Synthesis of escitalopram.
desired alcohol in 97% ee. The TMS group was removed
during acidic workup to give ezetimibe (9). A more
convergent approach to this drug was also developed by
preparing the (S)-hydroxy side chain before the ring
construction [38]. Therefore, p-fluorobenzoylbutyric acid
(102) was reacted with pivaloyl chloride and the acid
chloride thus obtained was acylated with chiral auxiliary 103
to give the corresponding amide. The ketone group in the
amide was reduced with (R)-MeCBS/BH3-THF (104) in the
presence of p-TSA to give desired alcohol 105 in high yield
(99%) and stereoselectivity (96 % d.e.) [39]. Chiral alcohol
105 was then mixed with the imine in the presence of
TMSCl and DIPEA to protect the alcohols as TMS ethers.
In the same pot, TiCl 4 was added to catalyze the
condensation reaction and gave compound 106 in 65% yield.
Compound 106 was reacted with TBAF and a fluoridecatalyzed cyclization took place to give the corresponding
lactam. Finally, the TMS protecting group was removed
under acidic conditions to give ezetimibe (9) in 91% yield
over two steps.
Fondaparinux Sodium (ArixtraTM)
Fondaparinux sodium (Arixtra; formerly fondaparin
sodium, 10) is a synthetic pentasaccharide heparinoid Factor
Xa antagonist and thrombokinase inhibitor launched
extensively by Sanofi-Synthélabo (formerly Sanofi) and
Organon as a treatment and prophylaxis for deep vein
thrombosis (DVT) and symptomatic pulmonary embolism
following hip or knee surgery. It is also being developed as
a potential treatment for coronary artery diseases [40].
Fondaparinux has a complex structure. Starting from Dglucose, D-cellobiose, and D-glucosamine, the production
process for the synthesis of the pentasaccharide involves
about 55 steps. The synthesis was accomplished by
preparing a fully-protected pentasaccharide, and then
converting it into the final product. The choice of protecting
groups was dictated by two factors: the need to introduce
sulfate substituents (O- as well as N-linked), carboxylate
groups and hydroxyl groups, in the proper positions on the
target molecule, and the constraints of current methods for
oligosaccharide synthesis, particularly the use of 2-azido
glucose derivatives to achieve stereoselective introduction of
α-D-linked glucosamine units. All the monosaccharide
synthons were obtained from glucose or from glucosamine
[41,42], and the synthesis [42-44] is outlined in Scheme 10.
Trisaccharide 108 and disaccharide 109 are the two key
building blocks in the synthesis. Coupling 108 and 109 was
carried out at -20°C in DCE. Fully protected pentasaccharide
110 was then converted into the target compound 10 using
traditional methods: saponification, O-sulfation, cleavage of
benzyl ethers with simultaneous reduction of azido into
Li and Liu
O
CO2Me
OMe
HNMe(OMe), i-PrMgCl
Toluene,
Me
O
-7o C,
DIBAL-H, toluene
N
95%
Me
N
Me
N
H
<-15o C, 92%
Me
81
80
79
N
O
P(OPh)2
aniline
diphenyl phosphite
IPAC
NHPh
Me
87%
N
82
O
MeO2S
CHO
CO2H
M eO2S
CO2 Me
KOBut , IPA/THF
NHPh
t-BuMgCl
THF, <50o C
58%
N
2N HCl
83
87% in two steps
MeO2 S
85
N
SO2Me
Me
N
88
79
84
0.1% Na2WO4
H2O2, MeOH
89%
O
O
MgCl
S
Me
Me
N
toluene/THF
N
<-15oC, 80%
S
87
80
86
Cl
N+
N
85
OMe
N
SO2Me
NMe 2
Cl
Cl
NH4OH, ∆
AcOH/TFA
(89) PF6
t-BuOK, THF
SO2Me
M e2N
O
Me 2N
SO2 Me
Cl
97% from 85
O
N
N
N
N
90
91
8
Scheme 8. Synthesis of etoricoxib.
amino functions and finally N-sulfation. Preparation of
trisaccharide building block 108 started from 1,6-anhydrocellobiose (111). Selective protection at 4’,6’ position was
achieved through benzylidenation to provide crude 112
which was converted into epoxide 113 by treatment with
sodium methoxide and benzylation. Compound 113 was
isolated after filtration on silica gel and crystallization (m.p.
184-5°C). Trans-diaxial opening of the epoxide yielded the
2-azido derivative (66%) which was acetylated to give 114
(99%). The benzylidene was cleaved (92%) and the diol was
then converted into 115 by successive tritylation,
levulinoylation, detritylation, oxidation, methylation and
β− mixture with α as the predominant isomer, 76%). The
preparation of the other building block 109 is described as
following. Selective 6-acetylation of 118 by N acetylimidazole in DCE gave 119 in 60% yield. Treatment
of 119 with 120 using DCE/pyridinium perchlorate and
followed dechloroacetylation using hydrazinedithiocarbonate
afforded the crystalline disaccharide 109 [43].
hydrazinolysis (60% over the 6 steps). Imidate 116 was
prepared in the usual way from its hydroxyl precursor and
coupled with 115 to give O-linked trisaccharide 117 in 78%
yield. Compound 117 was acetolysed (91%), the anomeric
acetate was cleaved by benzylamine in ether (100%) and
imidate 108 was obtained by reaction with potassium
carbonate and trichloroacetonitrile at room temperature (α,
OBn
OBn
1) 2eq. LDA/THF/DMPU
2) 4-BnOPh-CH=N-Ph-4F
DMF, -40o C to -15oC
O
LiO
OLi
OH
N
O
F
N
O
Li
Li
O
O
O
92
94
93
OBn
OX
OBn
OH
LiCl/DMF
-15oC
64%
F
OBn
O
HO
NaIO4
CH3CN
90%
N
O
F
TMSCl
N
O
OH
O
97
X = Li
X = TMS
TiCl4
N
F
F
O
F
95
OBn
OBn
O
O
(PPh3 )3 RhCl/H2
DCM
71%
F
p-TSA
75% from 96
N
F
O
F
99
OBn
OH
Pd/C/H2
F
N
EtOH, 79%
O
F
101
F
98
96
CBS/DCM
70%
N
O
100
F
Li and Liu
F
OH
O
1) BSA/t-BuOMe
TBAF 3H2O
OH
HO
P
O
h-C
H= N
-P h
-4F
DIP
, TM
EA
SCl
,
TiC
OTMS
65%
l4
OH
Ph
106
O
HN
N
2) 2N H2SO4 , IPA
91% two steps
N
F
O
TMSO
9
O
N
F
F
O
O
F
1) BSU, DCM
2) CBS
3) HCl, MeOH, 79%
105
1) pivaloyl chloride
TEA, DCM
2) DMAP, DMF, 92%
OH
O
N
F
O
O
N
107
F
B
CH3
104
O
THF, p-TSA, BH3-THF
99%, 96% de
Pd/C/H2
EtOAc/MeOH, 90%
O
HN
O
O
OH
99
F
102
103
Scheme 9. Synthesis of ezetimibe.
Frovatriptan Succinate (FrovaTM)
The serotonin 5-HT1D receptor agonist frovatriptan
succinate (11) was launched last year in the U.S. for the
acute treatment of migraine attacks. This drug was
discovered at Vernalis and is marketed by UCB Pharm and
Elan. Frovatriptan treats migraine by constricting blood
vessels in the brain [45]. The synthesis of frovatriptan (11)
appeared in a patent in multi-kilo scale [46].
Cyclohexanedione monoketal (121) was converted to amine
122 by reductive amination. The Fischer indolization of
amine 122 with hydrazine 123 furnished indole nitrile 124
in 72% yield. The desired R isomer of the indole nitrile was
obtained via a chiral salt formation/recrystallization process
using chiral lactam 125 and isolated as a L-pyroglutamic
acid salt 126. Hydrolysis of the nitrile functional group in
126 provided carboxamido indole 127, which was converted
to succinate 11 in situ.
Fulvestrant (Faslodex®)
Fulvestrant (12) was launched for the first time in the
U.S. for the treatment of hormone receptor-positive
metastatic breast cancer in postmenopausal women with
disease progression following antiestrogen therapy. As an
estrogen antagonist with no known agonist effects, it is the
only compound in its class to be proven effective after
tamoxifen failure [47]. It is administered as a once a month
i. m. injection. Several routes for the synthesis of fulvestrant
(12) were published [48,49]. One of the best routes [50] is
depicted in Scheme 12. The conjugate addition of Grignard
reagent derived from bromide 130 with dienone 129 gave
adduct 131 as a mixture of 7α- and 7β-isomers in a ratio of
2.5:1 in 90-95% yield. Aromatization of the A-ring with
copper bromide/lithium bromide in acetic acid followed by
hydrolysis of the ester group provided diol 132 in 80-85%
yield. Oxidation of the side chain from sulfite to sulfone
followed by crystallization provided fulvestrant (12) in 30%
overall yield from dienone 129.
Gefitinib (Iressa)
Gefitinib (1 3 ) is the first drug in a new class of
anticancer agents known as epidermal growth factor receptor
(EGFR) inhibitors. It was discovered by AstraZeneca and is
for the treatment of inoperable or recurrent non-small cell
lung cancer [51]. A mixture of 4,5-dimethoxyanthranilic acid
(133) and formamide was heated to generate the cyclized
quinazoline 134 [52]. The quinazoline was selectively mono-
OAc
OAc
OAc
CO2Me
O
OBn
NH
OAc
O
O
O
OH
OBn
108
O
OAc
O
CCl3
OBn
N3
O
OBn
MeO2 C
O
O
OBn
OMe
NHCbz
OAc
N3
109
OAc
OAc
OAc
CO2Me
TMSOTf/DCE
70%
O
O
O
OBn
OBn
O
O
O
O
OBn
MeO2C
OAc
OBn
O
O
OBn
N3
N3
OBn
OSO3H
OSO3H
CO2H
O
1) LiOOH/OH
2)Et3N SO3
O
OH
HO2C
O
OSO3 H
O
OSO3H
O
OH
O
OH
NHSO3H
NHSO3H
OH
OMe
NHSO3H
OSO3H
10
OH
O
O
O
O
OH
OH
OH
O
3) H2/Pd
4) pyridine SO3
72%
O
O
OH
OMe
NHCbz
OAc
110
OH
O
OH
111
O
OBn
Ph
O
O
O
O
OBn
1) NaN3, DMF, 66%
Ph
2) Ac 2O, pyridine, 99%
O
O
O
OTs
112
O
O
OAc
O
O
OBn
113
OBn
114
OAc
1) MeONa, 80%
OH
O
2) BnBr, DMF, 76%
O
OH
O
O
OH
Ph
2) TsCl, pyridine, -20oC, 60%
OH
O
O
1) C6H5CH(OCH3) 2, TsOH, 80%
N3
1) H+ , 92%
4) CrO3 , H2SO4
acetone/H2 O
2) TrCl, pyridine, then
levulinic anhydride
3) HClO4
5) MeI, KHCO3
6) NH2 NH2, H2O
60%
NH
CO2Me
O
OBn
OH
O
OBn
O
OBn
OAc
O
116
N3
OBn
O
N3
O
OAc
O
OBn
CCl 3
O
OAc
OH
O
N-acetylimidazole
DCM , 60%
OMe
NHCbz
118
N3
O
OBn
N3
108
O
OBn
OBn
3) CCl3CN, K2CO3
69%
NH
MeO2C
N3
117
O
OAc
O
O
OBn
OBn
O
OBn
1) Ac2O, TFA
2) C6H5CH2NH2, Et2O
O
OAc
CO2 Me
O
O
OBn
N3
OAc
O
CO2Me
O
TMSTf, DCM, -20oC, 78%
115
OH
OAc
CCl3
O
OBn
OBn
O
OBn
OH
Scheme 10. Synthesis of fondaparinux sodium.
OMe
NHCbz
119
O
O
120
O
OBut
Cl
1) DCE, pyridinium, perchlorate, 45% MeO2C
OAc
O
OBn
O
2) hydrazinedithiocarbonate, 85%
O
OBn
OMe
OH
OAc
109
NHCbz
O
Li and Liu
NHMe HCl
CN
1) MeNH2, 5% Pd/C
H2, EtOH
O
O
NC
1) HCl/H2O
2) NaOH
O
2) Concentrated HCl
85.5%
O
NHMe
72.2%
N
H
NNH2 HCl
124
123
122
121
OH
O
N
H
MeOH, >98%ee
26.5%
O
125
NC
MeHN
NHMe
AcOH, BF 3 Ac OH
o
90-95 C
CONH2
N
H
77.2%
N
H
126
L-pyroglutamic acid salt
127
O
EtOH/H2O
85.9
HO
OH
128
O
MeHN
CONH2
N
H
succinic acid salt
11
Scheme 11. Synthesis of frovatriptan.
OAc
OAc
H
H
o
A
H
H
Br
S
O
CF 2CF 3
A
90-95%
7
7
Mg, CuCl, -34 C
H
H
7
S
O
CF 2CF 3
7
130
129
7α/β ratio about 2.5: 1
OH
OH
H2O2
H
1) CuBr 2, LiBr, Ac2 O
2) NaOH
80-85%
H
H
7
HO
131
S
crystallization
30% overall
from 129
CF 2CF3
H
H
S
HO
CF 2CF 3
7
7
132
O
H
7
12
Scheme 12. Synthesis of fulvestrant.
demethylated with methionine in refluxing methanesulfonic
acid to afford 135 in 47% yield [53]. Compound 135 was
acylated to give acetate 136, which was treated with
refluxing thionyl chloride to yield chloropyrimidine 137.
Chloride 137 was condensed with 3-chloro-4-fluoroaniline
(138) in refluxing IPA to yield anilinoquinazoline 139 in
56% yield from 136. The acetate protecting group in
compound 139 was hydrolyzed with ammonium hydroxide
in methanol, and the free phenol was alkylated with 3-(4morpholinyl)propyl chloride (140) to give gefitinib (13) in
55% yield.
O
MeO
MeO
CO2H
O
o
MeO
NH
methionine
o
190 C, 18%
NH2
HO
NH
HCONH2
MeO
MeSO3H/100 C
N
M eO
N
135
134
133
F
F
O
AcO
MeO
Cl
H2N
AcO
NH
Ac 2O
pyridine
100oC
75%
Cl
N
SOCl2
DMF, 90 C
MeO
136
NH
AcO
N
138
o
N
Cl
IPA, 95oC
56% from 136
N
M eO
137
N
139
O
F
N
O
N
HN
Cl
Cl
O
30%NH4OH
N
140
MeOH, 95%
MeO
N
13
Scheme 13. Synthesis of gefitinib.
Landiolol Hydrochloride (Onoact®)
Landiolol hydrochloride (14) was launched in Japan by
Ono for the treatment of intraoperative tachyarrhythmia. It
improves tachyarrhythmia by selectively blocking β 1
receptors located mainly in the heart and by inhibiting the
action of catecholamine [54]. The synthesis of landiolol
appeared in an earlier patent in 1990 [55]. Esterification of 3(4-hydroxyphenyl)propionic acid (141) with 2,2-dimethyl-
1,3-dioxolan-4-ylmethyl chloride (142) in DMSO gave
desired ester 143 in 57% yield. Treatment of phenol 143
with bromo epoxide 144 in the present of K2CO 3 afforded
ether 145 in 76% yield. Epoxide 145 was then reacted with
free amine 146 via a neucleophilic ring opening process to
provide landiolol (14).
Micafungin Sodium (Funguarg®)
O
O
1) K2CO3 , KI, DMSO, 100oC, 30 min
HO
2)
OH
141
O
O
Cl 100oC, 15h
O
O
O
OH
143
142
57%
O
O
K2CO3,Br
144
O
aceton, ∆
76%
O
H2N
O
O
H
N
N
O
O
145
146
IPA, 30o C, 16h
43%
O
O
O
O
O
14
Scheme 14. Synthesis of landiolol.
O
O
N
H
OH
H
N
N
O
Li and Liu
O
O
MeO
HON
CO2Me
H
O(CH2)4CH3
TEA, THF
84%
Cl
N
148
147
N
O
149
O
N
N
O
1) 1N NaOH, EtOH/THF, 98%
2) HOBt, WSC-HCl, CH2Cl2, 95%
N
O
150
HO
OH
HN
HO
HO
H
N
R
HN
N
DMF, 53%
O
H2N
O
OO
OH
OO
O
HO
N
NH
OH
OH
S
O
FR90 137 9
acylase
O
OH
O
HO
O
HO
OH
NH
O
S
O
HN
OH
HO
N
O
H 2N
N
O
HO
O
N
HO
HN
O
O
HN
HO
15 0, DMAP
O
H
N
O
O
HO
HO
HN
HO
O
OH
O
HO
15
R = CO(CH2) 14CH3
151: R = H
Scheme 15. Synthesis of micafungin sodium.
The semi-synthetic echinocandin antifungal agent,
micafungin sodium (15), is a 1,3-β-glucan synthase inhibitor
discovered by Fujisawa. It is for the treatment and
prevention of infections caused by Aspergillus and Candida
such as fungemia, respiratory mycosis and gastrointestinal
mycosis [56]. The key intermediate for the side chain of
micafungin (15) was prepared by regioselective 1,3-dipolar
cycloaddition reaction of 4-methoxycarbonylbenzhydroxamic
acid chloride (147) and 4-pentyloxyphenylacetylene (148)
with TEA in THF [57]. Basic hydrolysis of thus obtained
ester 1 4 9 , followed by condensation with 1hydroxybenzotriazole (HOBT) gave the corresponding
1) PCl3, H3PO3,
OH
152
Scheme 16. Synthesis of neridronate.
Neridronate (Nerixia®)
This bisphosphonate compound was developed, and is
marketed, by Abiogen Pharma. This drug is the first
treatment ever for osteogenesis imperfecta [58]. 6Aminohexanoic acid (152) was reacted with phosphorus
trichloride and phosphorous acid at 85oC, and then water
O
O
H2 N
activated ester 150 in 95% yield. The cyclic peptide core
151, obtained by acylase-catalyzed hydrolysis of the natural
product F R 9 0 1 3 7 9 , was acylated with 1 5 0 to give
micafungin (15) in 53% yield.
85o C
OH
P
OH
OH
H2 N
2) H2O, 78%
HO
16
HO
P
O
O
F3 C
NO2
O
O
or Et3N, CHCl3, Me
89%
Me
NC
O
NO2
TEA, CHCl 3, TMSCN, 91%
Cl
153
O
F
O
OSiMe 3
Nitisinone
17
154
F
F
Scheme 17. Synthesis of nitisinone.
Olmesartan Medoxomil (Benicar TM)
was added to generate free diphosphonic acid 16 in 78%
overall yield [59].
This Angiotensin II antagonist was discovered by
Sankyo and licensed to Forest for the treatment, alone or in
combination with other antihypertensive agents, of high
blood pressure [62]. The imidazole ring of olmesartan (18)
was constructed with diaminomaleonitrile 155 a n d
trimethylorthobutyrate (156) in CH3CN then xylene to give
157 in 96% yield [63]. Acid hydrolysis of 157 in 6N HCl
gave the dicarboxylic acid intermediate. After esterification
of the diacid in ethanol in the presence of HCl, diester 158
was treated with MeMgCl to give 4-(1-hydroxyalkyl)
imidazole 159 in 95% yield. Alkylation of 159 with
biphenyl bromide 160 in the presence of potassium tbutoxide afforded 161 in 80% yield. Ester 161 was then
hydrolyzed to free carboxylic acid 1 6 2 under basic
Nitisinone (Orfadin®)
This reversible inhibitor of 4-hydroxyphenylpyruvate
dioxygenase was discovered by Swedish Orphan and is comarketed by Apoteket AB and Rare Disease Therapeutics. It
is used as an adjunct to dietary restriction of tyrosine and
phenylalanine in the treatment of hereditary tyrosinemia type
1 (HT-1) disease [60]. Nitisinone (17) was synthesized in
one step by reacting 2-nitro-4-trifluoromethylbenzoyl
chloride (153) with cyclohexane-1, 3-dione (154) in the
presence of TEA and trimethylsilylcyanide or 2-cyano-2(trimethylsilyloxy)propane [61].
H2 N
NH2
NC
CN
1) CH3CN, ∆
PrC(OMe) 3
CN
N
H
CN
Pr
2) HCl(g), EtOH, 86%
N
H
157
Br
CO2Et
N
1) 6N HCl, ∆, 80%
Pr
2) xylene, ∆
96%
156
155
N
CO2Et
158
OH
Me
Me
MeMgCl
Et2 O, CH2 Cl2
95%
N
N
N
OH
Pr
N
N
H
CO2Et
N
EtO
ButOK/AcNMe 2
N
80%
N
N
O
N
CPh3
159
N
N
CPh3
161
160
OH
N
HO
N
N
LiOH, dioxane/H2 O
O
N
N
N
CPh3
162
OH
O
CH3
Cl O
O
O
N
O
O
163
O
N
N
O
N
N
25% AcOH( aq )
O
N
N
81%
164
Scheme 18. Synthesis of olmesartan medoxomil.
O
N
CPh3
K2 CO3, AcNHMe
88% from 161
N
O
O
N
O
OH
18
N
NH
Li and Liu
O
NOH
N
1) n-hexLi, THF, -15-10oC
NH2OH HCl, NaOAc
o
EtOH/H2O, 70 C
95%
165
2) EtOAc,
59%
166
O
-15o C
OH
167
1) ClSO3H, TFA, 5-25oC
N
N
2) NH4OH,
65% (2 steps)
O
H2N
O
1) (CH3 CH2CO) 2O, H2SO4, 80oC
O
10-15oC
Na
2) NaOH, EtOH, 50oC
64% (2 steps)
S
O
O
O
S
N
O
19 parecoxib sodium
27 valdecoxib
Scheme 19. Synthesis of paracoxib sodium.
conditions, and 162 was treated with chloride 163 in the
presence of K2CO3 to give ester 164 in 88% yield from 161.
F
Lastly, the trityl group was removed with 25% aqueous
acetic acid to give olmesartan (18) in 81% yield.
F
F
F
1) EtBr,
CO2H
K2CO3 , DMSO
ButO
2C
F
170
169
F
O
F
NC
H2O2, NaOH
CO2Et
PhCH2N+ Et 3Cl10 N NaOH
F
Ac 2O
81% from
F
F
CO2Et
170
F
F
CO2Et
F
174
2) EtO2CCH2CO2-K+
MgCl2, TEA, DMF
CH3
175
HN
F
F
F
K2CO3, DMSO
H
F
CO2Et
H
N
100oC
80% from 174
N
O
CH3
O
CO2Et
H
O
177
O
O
F
2) NaOH, EtOH/H2O, 98%
2) 6N HCl, 90%
3) CH3SO3 H, EtOH, 94%
OH
H2N
N
O
20
CH3SO3H
Pazufloxacin mesilate
Scheme 20. Synthesis of pazufloxacin mesilate.
173
1) Me 2NCH(OMe) 2
Ac 2O, CH2Cl 2
CH2CO2Et 2) (S)-2-amino-1-propanol
EtOH
F
O
HO
CO2Et
F
1) SOCl2, imidazole, TEA
2N NaOH, 97%
H2N
F
NH
F
2.5 N NaOH, 96%
F
HN
176
13% NaOCl (aq)
172
O
F
F
H2N
171
O
NH
CO2Et
F
168
F
NC
Toluene, reflux
90% from 168
F
O
PTSA H2O
CO2Et
t
2) NCCH2CO2Bu , K2CO3
BrCH2CH2Br
F
F
NC
O
Parecoxib Sodium (Dynastat®)
from commercially available 2,3,4,5-tetrafluorobenzoic acid
(168) by an 11-step process with an overall yield 48% [68].
Starting material 168 was first treated with ethyl bromide
and then with t-butyl cyanoacetate in the presence of
potassium carbonate in DMSO in one flask to give acylated
cyanoacetate 169. Intermediate 169 thus obtained without
purification was refluxed in toluene with p-TSA to yield 4cyanomethylbenzoate 1 7 0 in 90% yield from 1 6 8 .
Cyclopropanation at the benzylic position of 170 was
performed by α,α-dialkylation with two equiv. of 1,2dibromoethane under phase-transfer conditions to give
cyanocyclopropyl compound 171. Cyano compound 171
was subjected to hydration with alkaline H2 O 2 to afford
carboxamide 172 in 81% yield from 170. Subsequently,
carboxamide 172 was treated with NaOCl for Hofmann
rearrangement to give primary amine 173, which was
protected as its N-acetyl derivative 174 for the next reaction.
Treatment of 174 with imidazole in the presence of thionyl
chloride and TEA generated an imidazolide intermediate,
which was converted to β-keto ester 175 by reacting with
potassium ethyl malonate and MgCl2 . Enamine 176 was
obtained without purification by successive treatment of 175
with DMF-dimethylacetal and (S)-(+)-2-aminopropanol.
Crude 1 7 6 was heated in DMSO in the presence of
potassium carbonate to efficiently give tricycle product 177
in 80% yield from 1 7 4 . Finally, the ethyl ester and
Parecoxib sodium (19) is a cyclooxygenase 2 (COX-2)
inhibitor and was introduced by Pharmacia (now Pfizer) as
an injectable formulation for short-term treatment of
postoperative pain [64]. Parecoxib is a water-soluble prodrug
of valdecoxib (27) that undergoes biotransformation in vivo
to release valdecoxib (27). The synthesis (Scheme 19) of
parecoxib sodium (19) started from commercially available
deoxybenzoin (165). Deoxybenzoin (165) was treated with
hydroxylamine in EtOH/H2O (3:1) to give deoxybenzoin
oxime 166 in 95% yield. Deprotonation of oxime 166 with
two equivalents of n-hexyllithium followed by condensation
with ethyl acetate afforded isoxazoline 167 in 59% yield.
Treatment of isoxazoline 167 with chlorosulfonic acid
followed by reaction of the incipient sulfonyl chloride with
aqueous ammonia furnished valdecoxib (27). Acylation of
isoxazole sulfonamide 27 with propionic anhydride afforded
parecoxib, which was converted to its sodium salt by
titration with aqueous sodium hydroxide (64%) [65,66].
Pazufloxacin Mesilate (Pazucross, Pasil)
This fluoroquinolone was co-developed by Toyama and
Mitsubishi Pharm and was launched for the intravenous
therapy of respiratory, urinary, surgical, gynecological and
systemic infections [67]. The drug is elegantly synthesized
TIPSO
HO
HO
32
O
O
O
OTIPS
OTIPS
24
O
O
O OH
O
N
N
OO
O
TIPS-triflate
lutidine, DCM
o
0 C, 16 h
OH
O
N
OO
O
O
O
OO
p-TSA, MeOH/MeCN
OH
O
OH
rt, 2h, 88%
O
O
94%
178
O
O
O
O
O
179
O
180
Cl
NO2 O
O
S
O
O
O
OH
OTIPS
NO2
181
O
SO2Cl
N
1) LiCl, DMF, 70o C
N
5h, 50%
OO
DIPEA, DM AP, DCM, rt, 18 h
78%
O
O
O
O
2) 48% HF, 2h, 37%
OH
OO
O
OH
O
O
182
21
O
Scheme 21. Synthesis of pimecrolimus.
O
O
O
Li and Liu
acetamide in 177 were hydrolyzed under basic and acidic
conditions, respectively, to give the free amine. Pazufloxacin
mesilate (20) was obtained in 94% yield by treatment of its
corresponding free amine with methanesulfonic acid in
ethanol.
macrolide 178 with triisopropylsilyl trifluoromethanesulfonate (TIPS-triflate) in the presence of lutidine in DCM
at 0°C afforded di-protected compound 179 in 94% yield.
Selective deprotection of the TIPS group at position 32
using p-TSA in MeOH at rt gave mono-protected macrolide
180 in 88% yield. Reaction of the hydroxyl group at
position 32 with o-nitrobenzenesulfonyl chloride (181) in
the presence of DMAP and DIPEA in DCM provided 182 in
78% yield with 20% recovered starting material 180.
Displacement of the sulfate with chloride using LiCl in
DMF furnished the chlorinated compound, which was
treated with aqueous HF to remove the TIPS group to
provide pimecrolimus (21).
Pimecrolimus (Elidel®)
Pimercrolimus (21) is the first non-steroid agent for the
treatment of mild to moderate atopic dermatitis lunched by
Novartis. It selectively blocks the production and release of
cytokines from T-cells. These cytokines cause inflammation,
redness and itching associated with eczema. Long-term
therapy with pimecrolimus (21) was more effective than
conventional treatment in reducing the incidence of disease
flares and the use of corticosteroids. This drug is also safe
and effective in pediatric patients and is approved for use in
children as young as two years [69]. The syntheses of
pimecrolimus (21) appeared in several patent applications
[70-73]. Starting material 178 was prepared by either
fermentation [74] or modification of a previously described
synthetic method in the literature [75]. Treatment of
F
Prulifloxacin (Sword)
This fluoroquinolone antibacterial prodrug was originally
discovered by Nippon Shinyaku and subsequently codeveloped and co-marketed by Meiji Seika. The drug is used
in the treatment of systemic bacterial infections including
acute upper respiratory tract infection, bacterial pneumonia,
cholecystitis, prostatitis, internal genital infections, bacterial
F
1) CS 2, TEA, 4 o C
NH2
F
CH2 (CO2Et)2, KOH
NCS
184
EtO2C
F
F
N
H
98%
F
SEt
CO2Et
F
N
CHCl3, 93%
SEt
187
OAc
F
CO2Et
H
N
O
CO2Et
NaOAc
SO2 Cl2
N
SEt
hexane, 79%
F
N
188
189
O
F
CO2Et
THF, 70%
F
S
Me
N
Cl
190
O
O
F
OEt
O
F
OH
KOH, t-BuOH/H2 O = 3: 1
N
N
S
92%
HN
N
N
S
HN
192
191
O
O
O
F
OH
O
O
Br
163
KHCO3, DMF
62%
O
O
O
N
N
22
Scheme 22. Synthesis of prulifloxacin.
_ +
SK
AcCl, TEA
OAc
F
N
H
CO2Et
185
xylene
∆, 79%
186
F
F
OH
CO2Et
(EtO) 2SO2
EtOH, 92%
o C,
dioxane, 4
2) ClCO2Et, CHCl3
74%
183
EtO2C
F
F
Prulifloxacin
N
S
S
Me
N
H
DMF
84%
enteritis, otitis media and sinusitis [76]. The synthesis of
prulifloxacin (22) [77] started with the treatment of 3,4difluoroaniline (183) with carbon disulfide in the presence of
TEA to give the triethylammonium dithiocarbamate, which
by reaction with ethyl chloroformate and TEA in
chloroform, was converted into isothiocyanate 184 in 74%
yield. Reaction of 184 with diethyl malonate in the presence
of KOH in dioxane yielded methylenemalonate 1 8 5
potassium salt, which was ethylated with ethyl sulfate in
ethanol to give compound 186 in excellent yield. 6,7Difluoroquinoline 187 was obtained with the highest yield
and regioselectivity when precursor 186 was heated in
refluxing xylene [78]. To suppress the side reaction in the
subsequent chlorination, quinoline 187 was acylated to give
188 with acetyl chloride in chloroform. Chlorination of 188
with sulfuryl chloride gave compound 189 in 79% yield.
Compound 189 was treated with sodium acetate in THF to
afford cyclized compound 190, which was condensed with
HN
O
CHO
piperazine in DMF to give compound 191. The hydrolysis
of ester 191 with KOH in hot t-butanol gave free acid 192,
which was finally condensed with 4-(bromomethyl)-5methyl-1, 3-dioxol-2-one (163) by treatment of potassium
bicarbonate in DMF to give prulifloxacin (22).
Rosuvastatin Calcium (Crestor®)
The HMG-CoA reductase inhibitor, known as Crestor®
(2 3 ), was originally discovered by Shionogi and
subsequently co-developed and co-marketed by AstraZeneca.
The drug is for the treatment of patients with primary
hypercholesterolemia (type IIa including heterozygous
familial hypercholesterolemia) or mixed dyslipidemia (type
IIb) as an adjunct to diet when response to exercise and diet
is inadequate. Crestor (23) is also used in patients with
homozygous familial hypercholesterolemia either alone or as
an adjunct to diet and other lipid-lowering treatments [79].
AcOH
CO2Et
O
benzene, ∆
87%
F
1) (S)-methylisothiourea H2SO4
HMPA
F
CO2Et
193
194
195
F
F
F
m-CPBA, CHCl3
CO2 Et
N
MeS
2) DDQ, CH2 Cl2
50%
90%
CO2Et
N
MeO2S
N
1) DlBAL-H, toluene, -78o C
1) MeNH2 , EtOH
2) MeSO2Cl, NaH
DM F 58%
N
MeN
2) TPAP, CH2 Cl2
58%
N
SO2Me
197
196
CO2Et
N
198
F
F
O
OTBDMS
CO2Me
Ph3P
CHO
N
O
200
CO2Me
N
MeCN, 71%
MeN
OTBDMS
N
MeN
SO2 Me
1) HF, M eOH
2) Et2 BOMe, NaBH4
THF 85%
N
SO2Me
199
201
F
F
OH
CO2Me
N
MeN
OH
OH
1) NaOH, EtOH, 95%
N
2) CaCl2 , 95%
SO2 Me
202
Scheme 23. Synthesis of rosuvastatin calcium sodium.
N
MeN
SO2Me
N
23
OH
_
CO2
Ca
NO2
O
H 2N
COCl
Li and Liu
TsOH
O
HN
O
O
204
TEA, CH2Cl2
90%
O
Fe, 2N HCl
THF/H2O = 2/1, rt
O
81%
NO2
203
O
207
O
pyridine, 0oC to rt
87%
206
O
HN
SO2Cl
O
O
O
O
2) 5N NaOH, THF
99%
O
_ +
O Na
HN
1) 10% Pd/C, H2
1 atm, rt
MeOH, 96%
S
N
H
O
NH2
205
O
O
HN
N
H
O
O
O
4 H 2O
S
O
O
O
24
Sivelestat sodium hydrate
208
Scheme 24. Synthesis of sivelestat sodium hydrate.
The synthesis of optically pure rosuvastatin (23) begins from
the Knoevenagel reaction of p-fluorobenzaldehyde (193) with
ethyl isobutylacetate (194) to give unsaturated ketoester 195
[80]. Compound 1 9 5 was condensed with (S ) methylisothiourea and then aromatized in situ using DDQ in
methylene chloride to give pyrimidine 196 in 50% yield.
Pyrimidine sulfide 196 was then oxided by m-CPBA to give
sulfone 197 in 96% yield. Sulfone 197 was reacted with
methylamine in methanol followed by treatment with
methanesulfonyl chloride to give the N methanesulfonylamino pyrimidine 198 in 58% yield.
Reduction of ester 198 with DIBAL-H followed by TPAP
oxidation afforded aldehyde 199 in 58% yield. Aldehyde
199 was subjected to Wittig reaction with optically pure
ylide, (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidenehexanoate (200) [81], to give heptenoate
compound 2 0 1 in 71% yield. Compound 2 0 1 was
deprotected with HF in acetonitrile, and stereoselective
N
HCl
O
S
OMe
S
chelation-controlled reduction with Et2BOMe and NaBH4 in
THF-MeOH mixed solvent gave methyl (3R, 5S, 6E)dihydroxyheptenoate 202 in 85% yield. Diol 202 was
hydrolyzed with aqueous NaOH to afford the corresponding
sodium salt. Rosuvastatin calcium salt (23) was obtained as
white powder from the sodium salt on treatment with
aqueous CaCl2.
Sivelestat Sodium Hydrate (Elaspol®)
A neutrophil elastase inhibitor, introduced by Ono
Pharmaceutics as an injectable formulation, is for the
treatment of acute lung injury accompanying systemic
inflammatory response syndrome [82]. The synthesis [83] of
sivelestat (24) started with the amide formation between 2nitrobenzoyl chloride (203) and glycine benzyl ester p-tolene
sulfonic acid salt (204) in the presence of TEA to give amide
205 in 90% yield. Amide 205 was then reduced with iron
1) NH3, toluene 2) NaH
70oC
N
S
O
83%
OH
OH
209
O
210
OH S
211
1) H2 O2 NH2CONH2
V2O5, DMF
2) NaHSO3
N
N
MeBr, DMF, rt
S
O
S
O
88% from 211
O
25
O
Br
O
OH S
Scheme 25. Synthesis of tiotropium sodium.
212
O
OH S
OH
t-BuMe2SiCl, Imd.
OSiMe 2But
OSiMe 2But
n-BuLi/hexane, rt
TBAF/THF
36% yield
from 213
CH2Cl2, rt
Br
OMe
213
OMe
OM e
214
215
OMe
216
O
OH
H
(COCl)2/DMSO/TEA
O
CH2Cl2, -78oC
86%
OM e
217
1) EtMgBr/THF/∆
O
2) 217, 0oC-rt, 3h
52%
N
H
O
O
219
1)
PCC
CH2Cl2, rt
71%
O
OMe
218
O
Ph
O
OH
Ph
B
B
O
OTBDMS
O
B
2) BH3 , Me2S/THF, 70%
3) TBDMSCl, Imid, DMF, rt, 88%
O
OMe
O
OMe
O
221
220
THPO
THPO
4
4
TBDMSO
H
1) Co2(CO) 8, CH2Cl2
rt, 0.5 h
H2, Pd/C, K2CO3
O
O
2) CH3 CN, ∆, 2h
96%
NaBH4, NaOH, EtOH
EtOH, rt, 13h
H
OCH3
OCH3
222
-10oC, 6h, 98%
H
223
THPO
HO
HO
4
4
4
H
H
H
Ph2PH, n-BuLi
CH3OH, p-TSA
OH
OH
OH
THF, 75%
rt, 2h, 78%
OCH3
OH
H
OCH3
224
H
OH
226
225
HO
HO
HO
4
4
H
aq KOH, M eOH
OH
OCH2CN
4
H
H
ClCH2 CN, K2 CO3
acetone, ∆, 95%
H
OH
∆, 3h, 95%
H
227
H
OCH2COOH
228
NaOH
OH
H
OCH2COONa
26
Scheme 26. Synthesis of treprostinil sodium.
power under acidic conditions to give corresponding amine
206 in 81% yield. Alternatively, the mixture of activated
Raney nickel, nitro compound 205, acetic acid and 1,3dimethyl-2-imidazolinone (DMI) under 25 atmospheric
pressure of hydrogen at 40oC in an autoclave can give the
same free amine 206 in 88% yield. Free amine 206 was
treated with p-pivaloyloxybenzenesulfonyl chloride [84]
(207) in pyridine to yield sulfonamide 208 in 87% yield.
Benzyl ester 208 was converted to its free carboxylic acid
under hydrogenation, and the carboxylic acid was
subsequently basified to give sivelestat sodium (24).
Li and Liu
Tiotropium Bromide (Spiriva®)
Treprostinil Sodium (RemodulinTM)
Boehringer Ingelheim’s once-daily inhaled chronic
obstructive pulmonary disease (COPD) therapy tiotropium
bromide (2 5 ) was launched for the first time in the
Netherlands and Philippines in 2002. Tiotropium (25),
which acts through prolonged M3 receptor blockade, is
approved as a bronchodilator for the maintenance treatment
of COPD [85]. At least two synthetic paths have been
disclosed in the patent and literature [86-88]. The synthesis
of tiotropium is depicted in Scheme 25. Tropenol
hydrochloride 209 was first neutralized with ammonia in
toluene and then the free base was reacted with methyl di-(2thienyl)glycolate (210) in the presence of sodium hydride to
furnish desired tropenol ester 211 in 83% yield. The
vanadium-catalyzed oxidation of tropenol ester 211 using
hydrogen peroxide-urea complex gave epoxide 212, which
was converted into its quaternary salt 25 with methyl
bromide. The last two steps were carried out in a one-pot
process in 88%yield.
The prostacyclin analog, treprostinil sodium (26), was
launched in the U.S. in June 2002 for the treatment of
pulmonary hypertension. Developed and marketed by United
Therapeutics, treprostinil is specifically approved for the
treatment of pulmonary arterial hypertension in patients with
NYHA class II-IV symptoms, to reduce symptoms
associated with exercise [89]. The synthesis of treprostinil
[90,91] starts from commercially available 3-methoxybenzyl
alcohol (213). The hydroxyl group in 213 was protected as a
t-butyldimethylsilyl ether via reaction with TBDMS
chloride in DCM at rt. A regiospecific introduction of the
allylic chain and deprotection of the silyl group in situ
provided alcohol 216 in 36% yield in a three-step sequence.
Swern oxidation of alcohol 216 using oxalyl
chloride/DMSO furnished aldehyde 217 in 86% yield.
Acetylene 218 was first treated with magnesium ethyl
bromide and then reacted with aldehyde 217 to provide
adduct 219 in 52% yield. The alcohol functional group in
Cl
F
Cl
OH
Cl
N
F
F
N
95oC,
N
F
N
POCl 3, N,N-dimethylaniline
Mg/THF, EtBr
o
15h, 95%
N
OH
0C
Cl
N
2HCl, NH4Cl, rt.
N
Pd/C, H2
80%
F
Cl
N
O
N
F
NBS, AIBN
DCM,
95%
OMe
80-90%
236
Cl
N
O
F2 (g)
234
N
O
O
OMe
NaOMe
50-70%
N
233
POCl3, Et3N
DCM, 90%
Cl
232
O
N NH=CH-NH2 AcOH
Cl
F
N
231
F
F
75%
OH
ONH4
1) NaOH, 90o C
N
I 2, Et3N, <15o C
Cl
MgBr
230
229
234
N
F
235
N
Zn, Pb, I2 , THF
90%
N
Br
N
F
237
HO
N
N
CH3
238
F
Cl
N
N
F
N
N
N
HO
239
Me
F
HO
Cl
N
N
F
N
1) Pd/C, H2, 85%
N N
2) resolution, 80%
SO3H
N
Me
F
N
F
O
F
240
racemate
Scheme 27. Synthesis of voriconazole.
240 : 241 : 1 : 10.3
F
241
racemate
242
F
28
optical pure
N
219 was then transformed into a carbonyl group in 220 via a
PCC-mediated oxidation. Ketone 220 was then reduced
again using chiral boron reagent to give the chiral alcohol
which was protected with TBDMS chloride in situ (221).
Optically pure intermediate 221 underwent cobalt-mediated
Pauson-Khand reaction to furnish tricyclic compound 222 in
excellent yield. Catalytic hydrogenation was employed to
reduce the double bond and the hydroxyl moiety to give
ketone 223. Sodium borohydride mediated reduction of the
carbonyl group in 223 gave single diastereomer 224. The
THP and methyl ether protecting groups were then removed
in a two-step process to give triol 226. The more reactive
hydroxyl group on the phenyl ring was then reacted with
chloroacetonitrile to furnish nitrile 227. A base mediated
hydrolysis of the nitrile provided free acid, treprostinil
(228), which was converted to its sodium salt 26 by titration
with sodium hydroxide (no yield reported).
hydrogen) to give the racemate of voriconazole. The racemic
voriconazole was resolved using (1R)-10-camphorsulfonic
acid (242) and crystallization of the required diastereomeric
salt provided optically pure voriconazole (28) in 80% yield.
ACKNOWLEDGEMENT
The authors would like to acknowledge the critical
evaluation of this review by Dr. M. Y. Chu-Moyer and Dr.
S Sakya.
ABBREVIATIONS
ADME
=
Absorption, distribution, metabolism,
excretion
AIBN
=
2,2’-Azobisisobutyronitrile
BOP
=
Benzotriazole-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate
BSA
=
Bistrimethyl acetamide
BSTFA
=
Bis(trimethylsilyl)trifluoroacetamide
BSU
=
Bistrimethylsilyl urea
CBS
=
Tetrahydro-1-methyl-3,3-diphenyl-1H,3HPyrrolo[1,2-c][1,3,2]oxazaborole
DCE
=
Dichloroethane
DCM
=
Dichloromethane
DDH
=
1,3-Dibromo-5,5-dimethylhydantoin
DDQ
=
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DIBAL-H
=
Diisobutylaluminum hydride
DIPEA
=
Diisopropylethylamine
DIPP
=
Diisopropylphosphoryl
DMAP
=
4-Dimethylaminopyridine
DMF
=
N,N-Dimethylformamide
DMPU
=
N,N’-dimethylpropyleneurea
DMSO
=
Methyl sulfoxide
DPPC
=
Diphenylphosphinic chloride
HOBT
=
1-Hydroxybenzotriazole hydrate
I.M.
=
Intramuscularly
IPA
=
Isopropyl alcohol
IPAC
=
Isopropyl acetate
LDA
=
Lithium diisopropylamide
NBS
=
N-Bromosuccinimide
NCE
=
New chemical entities
NEP
=
N-Ethylpyrrolidinone
NMP
=
1-Methyl-2-pyrrolidinone
NYHA
=
New York Heart Association
PCC
=
Pyridinium chlorochromate
PDC
=
Pyridinium dichromate
Voriconazole (Vfend®)
Voriconazole was launched by Pfizer in both oral and
injectable formulations for the treatment of fungal infections
in patients intolerant of, or refractory to, other therapy and
for the treatment of invasive aspergillosis [92]. It is a
triazole antifungal agent whose major mechanism of action
is the inhibition of fungal cytochrome P450-mediated 14αlanosterol demethylation [93]. The synthesis [94-96] of
voriconazole is an excellent example of process research. As
depicted in Scheme 27, 5-fluorouracil (229) was chlorinated
in both the 2- and 4- positions using a mixture of
phosphorus oxychloride and N,N-dimethylaniline at 95° C to
afford 230 in 95% yield. Dichloro pyrimidine 230 was
reacted with ethyl magnesium bromide to give
dihydropyrimidine adduct 231. Adduct 231 was oxidized
prior to quenching using a mixture of iodine and TEA in
THF to give 2,4-dichloro-6-ethyl-5-fluoro pyrimidine (232)
in 75% yield. Reaction of 232 with two equiv of aqueous
NaOH at reflux gave selective displacement of the chloro
functionality at 4-position. Acidification of the reaction and
extraction with DCM gave 2-chloro-6-ethyl-5-fluoro-4(3H)pyrimidine which was conveniently isolated as its ammonia
salt 233. Dechlorination of 233 was achieved using catalytic
hydrogenation at 50 ˚ C to provide 234 in 80% yield.
Alternatively, 4-fluoro-6-ethyl-5-fluoropyrimidine (234) was
prepared in a two-pot process in which methyl 3oxopentanoate (235) was fluorinated with fluorine gas to
give methyl 2-fluoro-3-oxopentanoate (236) in 80-90% yield
[97]. This ester was then cyclized [98] with formamidine
acetate in the presence of NaOMe to give 234 in a moderate
yield (50-70%). Reaction of 2 3 4 with phosphorus
oxychloride and TEA afforded 4-chloro-6-methyl-5fluoropyrimidine (237) in 90% yield. Reaction of 237 with
NBS in the presence of AIBN initiator provided bromide
238 in 95% yield. A Reformatsky protocol was employed in
the condensation of 238 with ketone 239 which was an
intermediate in the commercial synthesis of Diflucan [99]. A
solution of iodine in THF was added to a slurry of zinc and
lead at rt and then a mixture of bromide 238 and ketone 239
were added to the above mixture at 5°C for 30 min. This
provided the best diastereomeric selectivity and the ratio of
241 and 240 enantiomeric pair reached approximately 10 to
1. Adduct 2 4 1 was de-chlorinated using standard
hydrogenation condition (5% w/w Pd on carbon /15 psi
Li and Liu
TBAF
=
t-Butyl ammonium fluoride
[37]
TBDMS
=
t-Butyldimethylsilyl
[38]
TEA
=
Triethyl amine
[39]
TFA
=
Trifluoroacetic acid
THF
=
Tetrahydrofuran
THP
=
Tetrahydropyran
TIPS
=
Triisopropyl silyl
TPAP
=
Tetrapropylammonium perruthenate
TMG
=
1,1,3,3-Tetramethylguanidine
[44]
p-TSA
=
para-Toluene sulfonic acid
[45]
[46]
WSC-HCl
=
1-Ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride
[47]
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[1]
[2]
[3]
[4]
[5]
[6]
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1105
Kevin K.-C. Liu*, Jin Li* and Subas Sakya*
Pfizer Global Research and Development, Pfizer Inc, Groton CT 06340, USA
into molecular recognition, but also serve as drug-like leads for designing new future drugs. To these ends,
this review covers the syntheses of 23 NCEs marketed in 2003.
Keywords: Synthesis, New Drug, New Chemical Entities, Medicine, Therapeutic Agents.
INTRODUCTION
“The most fruitful basis for the discovery of a new drug
is to start with an old drug.” Sir James Whyte Black,
winner of the 1998 Nobel prize in physiology and medicine
[1].
Inaugurated last year, this annual review presents
synthetic methods for molecular entities that were launched
or approved in various countries for the first time during the
past year. The motivation to write such a review is the same
as stated in the previous article [2]. Briefly, drugs that are
approved worldwide tend to have structural similarity across
similar biological targets. We strongly believe that
knowledge of new chemical entities and their syntheses will
greatly enhance our abilities to design new drug molecules
in short period of time. With this hope, we continue to
profile these NCEs that were approved for the year 2003.
In 2003, 30 NCEs including biological drugs, and two
diagnostic agents [3,4] reached the market. This review
article will focus on the syntheses of 23 new drugs marketed
last year (Figure 1), but excludes new indications for known
drugs, new combinations and new formulations. Drugs
synthesized via bio-processes (i.e., daptomycin and
talaporfin sodium) and peptide synthesizers (i.e., abarelix
and enfuvirtide) will be excluded as well. The syntheses of
these new drugs were published sporadically in different
journals and patents. The synthetic routes cited here
represent the most scalable methods based on the author’s
judgment and appear in alphabetical order by generic names.
Alfuzosin Hydrochloride (Uroxatral™)
Alfuzosin (SL-77499) (I), a quinazoline derivative which
is a uroselective alpha-1 adrenoreceptor antagonist, has been
developed and launched worldwide by Sanofi-Synthelabo,
for the treatment of benign prostate hyperplasia (BPH) [5].
In November 2003, alfuzosin (I) was launched as an
extended release formulation in the US as Uroxatral utilizing
Skyepharma’s oral controlled release technology. Although
syntheses of alfuzosin (I) have appeared in several reports [68], an optimized route used for the manufacture of the
*Address correspondence to these authors at the Pfizer, Groton, CT
06340, USA; KKL: Tel: 1-860-441-5498;
E-mail: [email protected]; JL: Tel: 1-860-715-3552,
E-mail: [email protected]; SMS: Tel: 1-860-715-0425,
E-mail: [email protected]
1389-5575/04 $45.00+.00
compound does not appear in the literature. The synthesis
reported by the Sanofi group for alfuzosin will be described
and is shown in Scheme 1. The commercially available 4amino-2-chloro-6,7-dimethoxyquinazoline (1) was treated
with 3-methylaminopropionitrile (2) in isoamyl alcohol and
refluxed for 5 hrs. Filtration of the precipitated product and
washing with ethanol gave nitrile 3 in 62% yield.
Hydrogenation of the nitrile was done in 15% ammonia
solution in ethanol with Raney nickel as catalyst at 70o C
and 1000 psi to obtain the corresponding amine free base.
Conversion of the free base to the hydrochloride salt was
done in ethanol to give the HCl salt 4 in 52% yield. The
final acylation of amine 4 was done with the imidazolyl
anhydride of furan 5. Thus, 2-carboxyfuran was treated with
carbonyldiimidazole in THF at 40°C for 1 hr and then
cooled to 10°C. Addition of amine 4 in THF in the presence
of triethylamine at 10°C, then refluxing the reaction for 1 hr,
and aqueous workup gave the alfuzosin free base. After
conversion to the hydrochloride salt and recrystallization
from 2-propanol alfuzosin hydrochloride (I) was obtained in
44% yield.
Aprepitant (Emend™)
Aprepitant (MK-869, L-754030) (II), a functionalized
morpholine acetal derivative with potent neurokinin receptor
1(NK-1) antagonist activity, has been developed and
launched in April, 2003 in the US and February, 2004 in the
UK for the treatment of chemotherapy-induced nausea and
vomiting (CINV) [9] under the trade name Emend™. Several
variations to the synthesis of aprepitant (II) have been
published by the Merck group [10-16]. The latest optimized
synthesis utilizing a novel crystallization-induced
diastereoselective synthesis of aprepitant is highlighted in
Scheme 2 [11]. The synthetic approach entailed (1) the
synthesis and coupling of the key pieces, N-benzyl lactam
lactol 13 and sec-phenethyl alcohol 7, to provide lactam
acetal 1 4 , (2) stereoselective elaboration to the key
intermediate 14, and (3) conversion to the final compound
via either intramolecular cyclization or intermolecular
coupling with triazolinone chloride 24. The intermediate secphenethyl alcohol 7 was synthesized in 97% yield and 95%
e.e. (improved to 99% e.e. after recrystallization) via the
enantioselective borane reduction of ketone 6 in the presence
of 2 mol % of (S)-oxazaborolidine catalyst 8. The optimized
conditions involved the slow addition of ketone 6 to a
Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 10
1106
Liu et al.
N
O
N
H
N
N
N
O
O
HCl O
O
NH
Alfuzosin HCl (I) NH2
H2SO4
O
HN
O
N
O
F
O
H
N
N
H
O
N
H
O
F
N
H
N
N
F
O
OH
O
F
Aprepitant (II)
F
NO2
H
N
O
Atazanavir sulfate (III)
F
F
O
O
N
O
O
N
H
N
HCl
O
OH
H
N
B
OH
O
N
Bortezomib (VI)
Azelnidipine (V)
NH2
N
H
Atomoxetine hydrochlo ride (IV)
O
OH
H
NH2
N
H
NH2
HCl
N
F
N
N
N
O
O
HCl
O
O
O
O
OH
H
O
O
H
O
H
OH
S
HO
O
Epinastine HCl (VIII )
Emtricitabine HC l (VI I)
O
O
Everolimus (IX)
Ca
O
2+
O
P
O
O
NH2
O
O
N
N
S
O
O
P
O
OH
F
N
N
O
F
N
N
H 2N
N
N
N
MeSO3H
N
N
O
Fos amprenavir calcium (X)
F
Fosfluconazole (XI)
O
O
N
P
O
P
OH
OH
OH
OH
HO
Gemifloxacin mesylate (XII)
NH2
HCl
Cl
H
N
OH
Ibandronate Sodium (XIII)
O
OH
O
H
N
O
HO
F
Lumiracoxib (XIV)
Memantine HCl (XV)
Fig. (1). contd.....
O
OH
O
N
ONa
N
HO
O
HO
OH
F
O
H
HCl
H
Palonosetron HCl (XVIII)
O
Mycophenolate sodium (XVII)
OH
Miglustat (XVI)
N
Cl
OH
O
N
N
N
CO2H
Cl
O
OH
1/2 Ca
2+
HO2C
N
O
O
Sertaconazole nitrate (XXI)
Rupatadine fumarate (XX)
N
Cl
S
Cl
Pitavastatin calcium (XIX)
N
H
N
O
N
N
H
O
N
N
H
N
N
S
O
N
O
Tadalafil (XXII )
O
Vardenafil HCl (XXIII )
O
O
N
solution containing catalyst 8 and BH3•PhNEt2 complex in
MTBE at –10 to 0°C. The synthesis of lactam 12 was done
by reacting N-benzylethanolamine (9) with slight excess of
aqueous glyoxylic acid (10, 2.3 equivalent of 50% aqueous
solution) in refluxing THF. Adjustment of the solvent
composition from predominantly THF to predominantly
water resulted in the crystallization of lactam 12 directly
from 11 in the reaction mixture in 76% yield. Lactam 12
was treated with trifluoroacetic anhydride (1 equiv) to give
trifluoroacetate 13, which was reacted in situ with chiral
alcohol 7 in the presence of BF3·OEt2 to give, after workup,
a 55:45 mixture of the acetals 14 and 15 in 95-98% overall
yield. To obtain the desired diastereomer from the 55:45
mixture of 14 and 15, an optimized crystallization sequence
was developed. To a solution of the crude mixture in
heptane, 3,7-dimethyl-3-octanol (17) (0.9 equiv) was added,
cooled to –10 to –5°C and, after seeding the mixture with
pure 14, potassium salt of 3,7-dimethyl-3-octanol (16) (0.3
equiv) was added to initiate the crystallization-induced
O
Cl HN
N
isoamyl alcohol,
∆
62%
N
O
1
NH 2
O
O
O
i.
5
THF, TEA, ∆
ii. HCl/ IPA
44%
2
CN
O
epimerization of 15 to 14. After 5 hr, the mixture was
transformed into a 96:4 mixture from which 14 was isolated
in 83-85% yield and >99% e.e. Under an optimized
condition, the lactam 1 4 was reacted with 4fluorophenylmagnesium bromide (18) (1.3 equiv) in THF at
ambient temperature followed by methanol quench and
addition of p -toluenesulfonic acid (1.8-2.2 equiv).
Immediate hydrogenation of this mixture in the presence of
5% Pd/C gave the addition product 19, which was isolated
as hydrochloride salt in 91% yield. Under these conditions,
no cleavage of the benzylic ether group was seen, even after
extended hydrogenation periods. Elaboration to aprepitant
(II) was done by the initial alkylation of 19 in the presence
of a base with amidrazone chloride 20, which was prepared
from chloroacetonitrile, to give the intermediate 21.
Thermolysis of 21 in toluene provided aprepitant (II) in
85% overall yield. Alternatively, the hydrochloride salt 19
has also been alkylated directly with the triazolinone
chloride 24 to give aprepitant (II) [17].
N
N
N
i . H2 /Raney Nickel
N
O
3
15% EtOH/NH 3
70oC, 1000psi
ii. HCl/EtOH
52%
NH 2
O
O
N
N
N
H
N
N
N
O
H Cl
O
Scheme 1. Synthesis of alfuzosin hydrochloride (I).
O
NH2
Al fuzosi n HCl (I)
O
N
N
N
O
4
NH 2
NH2
●
HCl
1108
F
F
F
F
O
OH
NH
8 (S)- oxazaborolidine catalys t
O
OH
O 10
2.3 equiv.
CO2H
N
O
H 2O
N
crystallization
76%
THF, ∆
9
O
O
Bn
BF 3 OEt 2
O
F
Bn
+
F
O
DCM
95-98%
O
F
F
F
HCl
OH
HN
O
CF3
O
16
(0.3 equiv.)
17
(0.9 equiv.)
F
F
F
O
MgBr
O
O -K +
O
15 45%
F
N
13
F
F
14 55%
Bn
DCM
100%
OH
F
N
F
N
O
(CF 3CO)2O
O
12
11
7
O
B
F
F
7 99%ee after recrystallization
OH
HO
Ph
Me
F
F
F
H Ph
N
MTBE,-10 -0oC
97%
F
OH
F
catalyst (2 mol %) 8
BH3 PhNEt2
F
6
Liu et al.
F F
O
heptan e, -10 to 4oC
crystallization
83-85%
F
18
(1.3 equiv.)
i. THF, rt
14 99% ee
ii. MeOH
p TsOH (1.8-2.2 equiv.),
H2/ 5% Pd/C
iii. HCl/4-methyl-2-pentanone
F
19
F
F
F
H 2N
MeO 2CHN
Cl
N
91%
20
O
24
1 .0 3 equiv.
NH
HN
Pr2NEt, DMF (wet)
99%
N
O
N
F
O
H 2N
●
HCl
22
+
N
F
O
F
N
O
F
toluene, ∆
F
F
21
F
F
Cl
NH2
NH
F
F
F
F
F
F II Aprepitant
O
H2N
MeO2CHN
MeOH
M eO
o
MeO OMe20 C, 3 days
98%
23
H
N
O
HN
N
Cl
24
Scheme 2. Synthesis of aprepitant (II).
Atazanavir Sulfate (ReyatazTM)
Atazanavir (BMS-232632, III), an azapeptide HIV
protease inhibitor, has been developed and launched by
Bristol-Myers Squibb (BMS), under worldwide license from
Novartis, for the treatment of HIV infection [18]. Atazanavir
was launched in the US as Reyataz™ in July 2003. The
synthesis of atazanavir (III) appeared in several reports [1922]. The synthetic route depicted in Scheme 3 was one of
the best routes which was suitable for large scale production
[22]. The commercially available chiral diol 25 was
converted to its silyl mesylate 26 in one pot via selective
silylation and subsequent mesylation. This oily intermediate
26 was carried into the next step without further purification.
The desilylation of 26 was achieved by using inexpensive
ammonium fluoride. The resulting solid product 27 was
readily isolated and further purified through recrystallization
from IPA/H2O in 80% yield. The epoxide formation from
2 7 was affected by KO t Bu in THF/IPA to provide
O
OH
BocHN
OMs
i. TBSCl, TEA, DMAP,
BocHN
OH PhM e, 50oC
ii. MsCl, 0oC
100%
25 Bn
CHO
OMs
NH4F, HOAc
OTBS
BocHN
rt
80%
Bn 26
BocHN
KOtBu, IPA
28 Bn
rt
88%
OH
Bn
27
N
N
Br
N
30
PhMe/EtOH, ∆
80%
29
Pd/C, HCO2Na
EtOH, ∆
78%
∆
Pd(PPh3) 4, Na 2CO3
B(OH)2
N
NH2NHBoc, PhMe/IPA
85%
NHNHBoc
CHO 31
33
NNHBoc
32
N
N
28, IPA
∆
85%
i. THF/HCl (12N), 50oC
ii. WSC, HOBT, DIPEA, DCM, rt
Bn
O
BocHN
N
OH
Bu
OH
N
H
35
O
t
O
N
O
O
O
H
N
N
H
82%
N
H
H
N
O
O
O
NHBoc
N
34
36
H2SO4
O
H2SO4,
EtOH/heptane,
rt
85%
N
O
O
H
N
N
H
N
H
H
N
O
O
O
III atazanavir sulfate
Scheme 3. Synthesis of atazanavir sulfate (III).
enantiomerically pure epoxide 28 in 88% yield. Suzuki
coupling of boronic acid 29 with bromopyridine (30)
provided pyridyl benzaldehyde 31 in 80% yield after
crystallization. The subsequent condensation of aldehyde 31
with t-butylcarbamate was carried out by refluxing in
toluene/IPA and Shiff base 32 was collected by filtration
upon cooling. Reduction of hydrazone 32 to hydrazine 33
was accomplished by employing a catalytic phase-transfer
hydrogenation protocol (Pd/C, HCOONa) to furnish
hydrazine 33 in 78% yield after crystallization. Coupling of
the hydrazinocarbamate 33 with epoxide 28 was performed
in refluxing IPA, followed by the addition of water to
precipitate the crude product. Subsequent recrystallization
from MeCN/H2O furnished 34 in 85% yield. Treatment of
34 with concentrated HCl in THF at 50ºC removed the two
Boc groups in 34 to give the product as an oil, which was
then dissolved in a mixture of DCM/DIPEA and slowly
transferred into a premixed solution of N-methoxycarbonylL-tert-leucine (35), HOBT, and WSC in DCM. After
removal of the solvent the crude product was crystallized
from IPA/EtOH to furnish the freebase 36 in 82% yield. The
sulfate III was obtained by stirring the free base 36 with
concentrated H2SO4 in EtOH at ambient temperature. Direct
crystallization by addition of n-heptane provided the sulfate
salt III as an easily filterable solid in 85% yield.
Atomoxetine (StratteraTM)
This is a selective norepinephrine reuptake inhibitor for
the treatment of attention deficit hyperactivity disorder
(ADHD) and was discovered and launched by Lilly.
Although it is a prescription drug, it is not classified as a
controlled substance because the drug does not appear to
have the potential for abuse [23]. The 3-aryloxy substituent
was introduced utilizing a chiral alcohol by either the
Mitsunobu reaction or by nucleophilic aromatic
displacement. Because of the expense and difficulty of the
Mitsunobu reaction on large scale, the commercial process
adopts the nucleophilic aromatic substitution method. 3Chloropropiophenone (37) was asymmetrically reduced with
borane and catalytic amount of (S)-oxazaborolidine (8) in
THF at 0°C to give chiral alcohol 38 in 99% yield and 94%
1110
Liu et al.
O
Cl
37
HO
0.6 eq. BH3, THF, 0oC
Cl
HO
99%, 94% e.e.
O
38
B
8
Cl
O
N
O
O
N
NaH, DMSO,
15oC-30o C
98%
39
Ph
N
41
N
EtOH, ∆, 90%
Ph
H
40% dimethylamine
O
N
N
i. NaBH4, M eOH, 0oC
AcOH, H2O
ii. SOCl2, DCM
0oC -rt
0oC, 96%
43
44
42
O
O
N
TEA, toluene
Zn, AcOH/H2O
12M HCl
●
HCl
EtOAc, ∆
phenyl chloroformate
60-65oC
95%, 94% e.e.
H
N
98%, 99% e.e.
45
IV atomoxetine hydrochloride
t-BnNH2
F
F
DCM , MS 4A, rt
N
O
40
41
Scheme 4. Synthesis of atomoxetine hydrochloride (IV).
e.e. The chiral alcohol was further purified by recrystallization to greater than 99% e.e. [24]. Subsequent treatment
of chloride 38 with excess dimethylamine (40% in water) in
ethanol gave dimethylamine alcohol 39 in 90% yield.
Alcohol 39 was then subjected to nucleophilic aromatic
displacement [25] in the presence of NaH in DMSO with 1fluoro-2-(t-butylimino)benzene (41), which was prepared in
high yield from 2-fluorobenzaldehyde (4 0 ). The
displacement product 42 was obtained in 98% yield, and the
imine 42 was subsequently hydrolyzed with acetic acid in
water at low temperature to give the corresponding aldehyde
43 in 96% yield. Sodium borohydride was employed to
reduce aldehyde 43 to alcohol in cold methanol and the
intermediate alcohol was converted to chloride 44 with
thionyl chloride. Chloride 44 was then reduced with zinc
metal under acidic conditions to give methyl adduct 45 in
95% yield and 94% e.e. Finally, phenyl chloroformate and
triethylamine was used to transform dimethylamine 45 to
monomethyl amine, which was subsequently treated with
HCl in EtOAc under reflux to give atomoxetin
hydrochloride (IV) in 98% yield and 99% e.e. from 45.
Azelnidipine (CalblockTM)
It is a calcium channel antagonist, co-developed by
Sankyo and Ube. It is a long-acting (slow onset), once-daily
drug for the treatment of hypertension, and is only available
in Japan now. Unlike other anti-hypertension drugs in its
class, it does not produce an associated increase in heart rate
when dosed chronically [26]. A solution of benzhydrylamine
(46) and epichlorohydrin (47) was mixed without adding
solvent to give azetidinol 48 in 57% yield [27]. DCC
coupling between cyanoacetic acid (49) and azetidinol 48 in
hot THF gave ester 50 in 93% yield. Cyanoester 50 was
treated with ethanol and HCl gas in chloroform to give
imidate HCl salt 51, which was treated with ammonia gas in
chloroform and ammonium acetate in acetonitrile to give the
corresponding amidinoacetate 52. A modified Hantzsch
reaction was employed to construct the 2-amino-1,4dihydropyridine core structure. Compound 5 2 was
condensed with 2-(3-nitrobenzylidene)acetic acid isopropyl
ester (55) in the presence of NaOMe in refluxing isopropanol
to give the cyclized product, azelnidipine (V) in 74% yield.
Benzylideneacetoacetate 55 was obtained through the
Knoevenagel reaction employing 3-nitrobenzaldehyde (53)
and isopropyl acetoacetate (54) in isopropanol containing a
catalytic amount of piperidinium acetate at 45-55oC in 65%
yield.
Bortezomib (VelcadeTM)
Millennium (formerly LeukoSite) has developed and
launched bortezomib VI (Velcade; formerly known as MLN341, LDP-341 and PS-341), a ubiquitin proteasome
inhibitor, for the treatment of multiple myeloma (MM) in
the US. Although the synthesis of dipeptidyl boronic acids
have appeared on several reports [28-30], the synthetic
details for bortezomib were not revealed. The synthetic route
for the preparation of bortezomib is depicted in Scheme 6.
O
Cl
O
NC
47
N
rt, 3 days
reflux 3 days, 57%
NH2
OH
46
EtOH, HCl (g)
OH
49
DCC, THF, 55oC
93%
50
1)NH3(g), CHCl3
HCl
2) NH4OAc, CH3CN
HCl
O
O
N
NH
NH
O
OEt
55
NaOMe
IPA, ∆
74%
51
NO2
NH2
52
O
O
O
O
N
H
IPA, 45-55oC
O
N
O
NO2
NO2
CHCl3
CN
O
48
N
O
N
NH2
V azelnidipine
O
+
H
O
HOAc
54
53
O
O
N
H
6 5%
O
55
O
Scheme 5. Synthesis of azelnidipine (V).
The pinanediol ester of leucine boronic acid (56) [31] was
coupled with N-Boc phenylalanine (57) in the presence of
TBTU followed by deprotection of the Boc group to provide
58. N-Acylation of 58 then furnished the dipeptide boronate
ester 60. Deprotection of the boronic ester functionality was
achieved by bi-phase transfer esterification with isobutyl
boronic acid. Bortezomib (VI) was isolated by extractive
workup.
Emtricitabine (EmtrivaTM)
Emtricitabine (BW-524W91, (-)-FTC) (VII), cis-5fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, a
novel enantiomerically pure oxathiolanyl nucleoside analog
was recently approved in the US in July, 2003, for the
treatment of HIV infection [32]. This novel HIV nucleoside
reverse transcriptase inhibitor (NRTI) was developed and
marketed under the trade name Emtriva T M by Gilead
Pharmaceuticals. Emcitritabine (VII) was discovered by
researchers at Emory University and licensed to Triangle
Pharmaceuticals, which started the development work before
being acquired by Gilead. Because emcitritabine (VII)
belongs to an important structural class of nucleosides with
marketed drugs, such as 3TC, several processes for the
manufacture of this class of oxathiolane nucleosides have
appeared in patents and scientific literature [33-41].
However, only the synthesis described in the latest patent
filed for the manufacture of emcitritabine (VII) and one other
efficient synthesis from the Liotta group will be described
(Scheme 7) [38,39]. The synthesis started with diacylation
with butyryl chloride (62) of the 2-butene-1,4-diol (61) in
methyl t-butylether at 0°C to room temperature in the
O
O
H
N
O
CF3COO
H3N
B
i. TBTU, IPDEA, DMF,
O
+
56
H3N
B
N
O
58
57
N
O
H
N
N
H
B
O
O
N
60
Scheme 6. Synthesis of bortezomib (VI).
OH
O
i-BuB(OH) 2, aq HCl
N
MeOH/hexane, rt
N
59
TBTU, IPDEA, DMF, 0o C
O
O
OH
N
O
Cl
ii. 4N HCl/dioxane
OH
BocHN
0oC
H
N
N
H
O
VI bortezomib
B
OH
1112
62
OH
O
O
OH
i. O3, -10oC
ii. thiourea
O
Cl
O
TEA, DMAP
MeO
O
64
O
t
resolution
S
O
O
THF
0 - 19oC
87%
O
S
66
o
i. LiAl(O Bu) 3, 5 C
ii. Ac 2O, DMAP
O
O
54%
O
85oC, toluene,
OH
O
O
HSCH2CO2H,
O
63
95%
O
O
MeOH,
0oC - rt
97%
O
TBME, rt
61
Liu et al.
S
67
65
NHTMS
F
N
F
N
N
O
TMSO
N
68
TMSI, DCM,
0oC - rt
69
DOWEX SBR (- OH) HO
resin
MeOH, 0o - rt
S
N
F
N
N
H
O
VII emcitritabine
F
N
TMSO
71
i. O3, DCM
-78oC- rt
N
68
O
HSCH2CO2H
ii. DMS, -78o to rt
96%
73
(NH4)2SO4
HMDS, ∆
F
OTBDMS
NHTMS
NH2
81%
OH NaH, TBDMSCl
THF, 0oC
72
94%
69
NH2
N
S
O
70
O
N
O
O
O
O
S
O
crystallizatio n
O
O
F
N
N
O
+
S
O
F
N
O
O
NH2
NH2
NH2
OAc
OTBDMS
H
O
O
toluene, ∆
74
88%
TBDMSO
S
NHTMS
O
o
1. Dibal, -78 C
2. Ac2O
toluene,
-78oC - rt
64%
TBDMSO
S
OAc
i.
TMSO
(6:1 anomeric mixture)
76
75
F
N
N
68
VII
SnCl4, DCM, rt
91%
ii. TBAF, THF, rt
98%
Scheme 7. Synthesis of emcitritabine (VII).
presence of triethylamine to give diacylated product 63 in
95% yield. Ozonolysis followed by reduction with thiourea
provided a mixture of hemiacetal 64 mixed with acetals,
dimers and trimers in 97% yield, which was used in the next
step directly. The hemiacetal mixture was reacted with
thioacetic acid in toluene at 85°C for 3 hr to give the crude
keto oxathiolane mixture, which was purified by vacuum
distillation in a 2-in Pope Scientific wiped film still to
remove impurities and collect about 92% pure 66 in 54%
yield. Also mentioned in the patent is the potential use of
enzymatic resolution of the isomers as reported previously
[37]. This keto oxathiolane 66 was reduced at 5°C with
lithium aluminum t-butoxide, which was prepared in situ
via reaction of LAH and t-butanol, and the resulting lactol
was trapped with acetic anhydride in the presence of DMAP
in the same reaction vessel to give, after workup, 87% yield
of the key intermediate acetate 67. The bis-silyl protected 5fluorocytosine 6 8 , prepared in situ by reacting 5fluorocytosine (71) with HMDS, was reacted with acetate 67
in the presence of trimethylsilyliodide at 0°C to room
temperature to give a 1:1 mixture of alpha and beta-anomers
69 and 70. Pure 69 could be isolated by recrystallization
from toluene. Cleavage of the butyryl group with a strongly
basic DOWEX SBR resin in methanol at room temperature
gave emcitritabine (VII) in 81% yield. An alternate concise
synthesis reported by Liotta et al is worth mentioning [39].
This synthetic route accessed the key thioxalane acetate 76 as
the TBDMS ether in four steps from allyl alcohol 72. The
NH2
N
O
Cl
N
i. NH2OH
NaCN
N
THF, < 40oC
DMSO, 90o C
ii. PCl5
77
79
N
i. BrCN, EtOH/THF, RT
ii. NaOH
67%
70%
78
NH
LAH, H2 SO4
80
NH2 HCl
N
iii. HCl/Et2 O
79%
VI II epinastine HCl
Cl
N
O
O
HN
,K2 CO3
N
81
AcOH, < 30oC
O
O
96%
N
CH3CN, ∆
i. NH2NH2 H2 O
O
NaBH4
N
O
NH
ethylene glycol,
110oC
ii. Fumaric acid
90%
95%
HO2 C
CO2H
82
NH2
83
N
NH2
NH
i. BrCN
HCl
N
ii. CH3 NHCH2Ph
80 fumaric acid salt
iii. HCl, DMF
VIII epinastine HCl
Scheme 8. Synthesis of epinastine (VIII).
key step to the preparation of the final compound was the
coupling of the bis-silyl 5-fluorocytosine (68) with acetate
76 with tin tetrachloride in a stereoselective manner, after
cleavage of the silyl groups and recrystallization, to give
pure cis isomer emcitritabine (VII) in excellent yield.
Epinastine (AlesionTM)
Epinastine (WAL-801), a non-sedating, histamine H1
antagonist, was developed by Allergan, after licensing from
Boeringer Ingelheim, and approved in the US in October,
2003 as an ophthalmic formulation for the prevention of
itching associated with allergic conjunctivitis [42]. This
drug was first introduced in Japan in 1993 and followed
shortly by an introduction in several Asian and South
American markets. Several patents on the synthesis of
epinastin (VIII) have appeared in Europe and Japan [43-48].
The synthesis described below is taken partly from the US
patent [43] and a Japanese patent [44]. All the syntheses
utilized 6-aminomethyl-6,11-dihydro-5H-dibenzo[b.e]azepine
(80) as the key intermediate which was converted to the final
guanidine epinastine by reacting with cyanogen bromide.
The solution of 80 in ethanol was treated with a solution of
cyanogen bromide in THF at room temperature and stirred
overnight. The hydrobromide salt was collected in 79%
yield after adding ether to the reaction mixture. The salt was
free based with a solution of sodium hydroxide and then
treated with an ethereal solution of HCl to obtain the
epinastine hydrochloride salt VIII. For the preparation of the
key intermediate, chloroimine 78, presumably obtained from
ketone 77 via Beckmann rearrangement [49,50], was reacted
with sodium cyanide in DMSO to give the nitrile 79 in 70%
yield. Reduction of the imino nitrile was carried out in THF
in the presence of an acid with LAH to give the key
intermediate 80 in 67% yield.
An alternate approach to preparation of 80 is shown in
Scheme 8 as well. Reaction of the commercially available
chloride 81 with phthalimide [46,48] in the presence of a
base gave the phthalimide 82. Reduction of the imine with
sodium borohydride gave 83, which was then reacted with
hydrazine hydrate to free up the amine in 90% yield. The
amine intermediate was isolated as the fumarate salt.
Everolimus (Certican™)
Everolimus (I X ) (SDZ-RAD), was developed by
Novartis as an immunosuppressant [51] to be used in
conjunction with cyclosporin in transplantation allograft
rejection and was recently approved in the US in 2003.
Another natural product that had been approved for use in
transplantation is rapamycin (sirolimus) as an inejectable
agent. In an attempt to develop an orally bioavailable
1114
Liu et al.
OH
H
H
N
O
O
H
2,6-lutidine
O
HO
O
O
O
H
O
H
O
TBDMSO
N
OTf
O
H
toluene, 60o C
OH
O
HO
O
O
O
O
O
O
O
OTBS
O
H
O
2N HCl
H
MeOH, rt
OH
O
O
84
O
H
H
N
O
O
HO
O
O
85
O
H
O
OH
O
H
OH
O
O
O
I X everolimus
Scheme 9. Synthesis of everolimus (IX).
immunosuppressant agent, many companies attempted
modification of rapamycin itself [52]. Everolimus (IX) was
discovered by Sandoz (Novartis) scientists by modifying
rapamycin drug in the 40-hydroxyl position [53]. Thus,
treatment of rapamycin (84) with t-butyldimethylsilyloxy
ethyl triflate in the presence of 2,6-lutidine at 60°C for 3.5
hrs gave ether 85. Deprotection of the silyl group was done
by treating silyloxy ether 85 in methanol with 2N HCl to
give the product IX (everolimus), which was purified by
chromatography. No yields were given for the reactions.
Fosamprenavir Calcium (LexivaTM)
Fosamprenavir is an amprenavir (APV, Agenerase;
Vertex Pharmaceuticals Inc/GlaxoSmithKline plc) prodrug
for the treatment of HIV infection. Fosamprenavir (X) was
developed to overcome adherence barriers, such as pill size
and burden, and food and water restrictions, which are
common amongst all current FDA-approved protease
inhibitors (PI). Fosamprenavir (X) can be administered
without any food or water restrictions as two 700 mg tablets
twice-daily; one 700 mg tablet plus one 100 mg capsule of
ritonavir twice-daily; or two 700 mg tablets plus two 100
mg capsules of ritonavir once-daily. Ultimately,
fosamprenavir (X) will offer patients and physicians a
flexible and convenient PI backbone [54]. The synthesis of
fosamprenavir (X) started with a known amino alcohol 91
[55,56]. N,N-Dibenzyl-L-phenylalaninal (87) was prepared
by reduction of L-phenylalanine (86) to L-phenylalaninol
followed by N,N-dibenzylation and oxidation to the
aldehyde 87 using pyridine-sulfur trioxide complex at room
temperature. A large excess of lithium shot was stirred in a
solution of aldehyde 87 and bromochloromethane in THF at
-65°C. The reaction mixture was subsequently allowed to
warm up to room temperature to provide the diastereomeric
epoxide mixture (6:1) which was quenched with 6N aqueous
HCl and set standing overnight to provide the salt
precipitate. Recrystallization from methanol gave optically
pure dibenzylaminochlorohydrin hydrochloride (88) in 3845% yield. Hydrogenolysis under standard conditions gave
deprotected aminochlorohydrin hydrochloride 89 as a
crystalline white solid. Conversion to desired N -Bocepoxide 90 was accomplished by the introduction of the Boc
group followed by cyclization [55]. N-Boc-epoxide 90 was
then converted to amino alcohol 91 by refluxing with isobutylamine in EtOH [57]. Treatment of the amino alcohol
i. NaBH4, H2SO4
ii. BnBr, K2CO3, EtOH, 60oC
O
H 3N
iii. Py SO3, TEA, DMSO, rt
99%
Bn2N
O
1 atm, rt
OH
88
NHBoc
i-BuNH2
EtOH, ∆
>98%
then KOH/MeOH
HCl
N
H
OH
BocHN
97%
H2N
Cl
89
O
90
OH
NO2
91
O
Cl
i.
Cl
O
Boc 2O, TEA, THF, 5oC
Pd(OH) 2/C, H2, MeOH
Bn2N
ii. HCl
38 - 45%
H
87
86
HCl
i. Li, BrCH2Cl, THF, -65oC
O
S
O
NH2
9 2 , TEA, Toluene, 80oC, 1h
O
NO2
S
O
N
N
O
ii. HCl (concentrate), ∆, 1h
N
HCl
O
94
EtOAc, ∆, 22 h
82%
OH
73%
NO2
O
HN
O
S
O
NH2
93
O
O
i. POCl3, Py, 3h
ii. HCl, ∆, 3h
O
HN
iii. Pd/C, H2, 30oC, 8h O
iv. Ca(OAc) 2, 40 -50oC
N
S
92 %
O P
Ca 2+ O
95
O
N
O
OH
O
O
O
X fosamprenavir calcium
Scheme 10. Synthesis of fosamprenavir calcium (X).
91 with p-nitrobenzene sulphonyl chloride in toluene at
80°C followed by acid hydrolysis of the Boc group
furnished sulphonamide 93 in 73% yield. The carbamate 95
was prepared by refluxing 93 with (S)-tetrahydrofuryl
imidazole carboxylate (94) in EtOAc. Treatment of the
sulphonamide 95 with POCl3 followed by aqueous HCl
hydrolysis provided the phosphate intermediate, which was
then reduced by hydrogenation and converted to
fosamprenavir calcium salt X in a one-pot process in 92%
yield.
Fosfluconazole (Profif™)
Fosfluconazole, a phosphate prodrug of fluconazole (96),
was recently approved for intravenous use in Japan in
October 2003. The drug was developed as a water-soluble
prodrug by Pfizer as an enhancement to the injectable
infusion formulation of fluconazole (96), a very potent
antifungal agent, that could be used intravenously in bolus
doses requiring smaller volumes of fluid and sodium. The
disclosed manufacturing route of synthesis utilized
O
O
OH
N
N
N
F
N
N
N
1. PCl3,-13-13oC, 2hrs
2. BnOH, 14 -16oC, 2hr
3. H2O2, 20oC, 1hr
pyridine, DCM
BnO
P
HO
OBn
NaOH
O
N
N
N
F
N
N
N
OH
O
N
H2 (60psi), 5% Pd/C
H2O, rt
P
N
N
N
F
88%
6 6%
F
F
96 fluconazole
Scheme 11. Synthesis of fosfluconazole (XI).
97
F
XI fosfluconazole
N
N
1116
HCl
EtO
O
H2N
+
O
CN
i. (t-Boc) 2O, CHCl3, rt, 17h
O
KOH, H2O
CN
50-60oC, 5h
48%
O
99
Liu et al.
ii. EtONa, EtOH, 1h
>98%
N
H
100
98
CN
i. NaBH4, MeOH, 0oC, 0.5h
ii. LiAlH4, THF, -5oC, 0.5h
iii. (t-Boc) 2O, dioxane/H2O, rt, 0.5h
83%
N
Boc
101
HO
NHBoc
O
DMSO, rt, 3h
>98%
N
Boc
EtOH/THF/H2O, 40oC, 1h
N
88%
Boc 103
O
O
F
OEt
Cl
N
NH2, 5-10oC, 1h
ii.
Cl
N
Cl
NH
2CF3COOH
105
O
105
PhCHO, Et3N, CH3CN/H2O
rt, 3h
95%
O
OH
ii. HCl, ∆, 5h Cl
N
N
N
52% one-pot from 106
107
O
O
F
F
N
O
i. Et3N, Et2O
108
106
O
F
OEt
Cl
NH2
N
H
O
F
i. (EtO) 3CH, Ac 2O, ∆, 3h
84%
104
N
Boc
102
O
O N
NHBoc
TFA, rt, 20 min
NHBoc
O N
CH3ONH2 HCl, NaHCO3
Pyridine SO3, Et3N
OH
N
40-45oC, 0.5h
95%
N
OH
MeSO3H, H2O
H 2N
N
N
N
MeSO3H
N
N
O
O
109
XII gemifloxacin mesylate
Scheme 12. Synthesis of gemifloxacin mesylate (XII).
fluconazole (96) as a precursor and was prepared in two steps
using inexpensive starting materials [58]. Fluconazole [59]
was dissolved in dichloromethane with pyridine and was
treated sequentially with phosphorus trichloride at –13°C
and reacted at 13°C for 2 hr followed by an addition of
benzyl alcohol at 14-16°C and reacted for 2 hrs at 10-15°C.
The mixture was then cooled to 0°C and 30% hydrogen
peroxide was added over three hours, maintaining the
temperature below 20°C. After stirring the reaction at 20°C
for 1hr, the intermediate 97 was isolated in 66% yield.
Hydrogenation of the benzyl phosphate at 60 psi in water
with 5% palladium on carbon gave the desired phosphate
prodrug, fosfluconazole (XI) in 88% yield.
Gemifloxacin (ZymarTM)
LG Life Sciences (formerly LG Chemical) has developed
gemifloxacin (SB-265805, LB-20304a), a fluoronaphthyridone active against both Gram-positive and Gram-negative
H
i. Pd/C, H2 , 74%
ii. H2CO, HCO2H, 95%
NH2
N
O
110
bacteria, including methicillin-resistant staphylococci, as a
treatment for bacterial infection [60]. By December 2002, the
drug had been approved in Korea. Oral gemifloxacin was
approved by the FDA in April 2003. Two key intermediates,
3-aminomethyl-4-methoxyiminopyrrolidine (105) and 7chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (108) were involved in the synthesis
of gemifloxacin (XII). Michael addition of glycine ethyl
ester hydrochloride (98) to acrylonitrile (99) in the presence
of KOH furnished cyanoester 100 in 48% yield. Protection
of the amino group and Dieckmann cyclization were
accomplished in a one-pot process to furnish 4-cyano-1-(N-tbutoxycarbonyl)-pyrrolidine-3-one (1 0 1 ) in almost
quantitative yield. The conversion of ketone 101 to alcohol
102 was achieved via three reaction sequences in a one-pot
process in 83% yield. The hydroxy group was oxidized to
ketone 103 with pyridine-sulfur trioxide complex in DMSO.
Treatment of ketone 103 with methoxyamine in the presence
of NaHCO 3 provided methyloxime 104 in 88% yield.
N
111
94%
112
OCH3
Pd/C, H2, 49%
NH
113
114
i. 1N NaOH
ii. H3PO3/POCl3
iii. H2O, NaOH
O
N
toluene
93%
115
Scheme 13. Synthesis of ibandronate sodium (XIII).
OCH3
O
HO
N
34% overall
XIII ibandronate sodium
HO
O
P O Na
OH
P
O
Na
O
F
Cl
H2N
NaOtBu
Pd(dba)2 , (t-Bu) 3P
+
Br
O
Cl
HN
Cl
F
O
Cl
Cl excess
F
N
Cl
119
toluene
116
neat, 90oC
117
120
118
F
O
O
AlCl3
N
HO
NaOH
Cl
neat, 160-170o C
Cl
H
N
EtOH/H2O, ∆
F
XIV lumiracoxib
121
Scheme 14. Synthesis of lumiracoxib (XIV).
Deprotection of the Boc groups in 104 by TFA afforded
pyrrolidine 105 in 84% yield [61]. Quinolone acid 108 was
employed in the synthesis of ciprofloxacin and can be
readily prepared according to literature methods [62,63]. A
four step sequence/one-pot process [63,64] is depicted in
Scheme 12. Nicotinoyl acetate 106 was converted to
enaminoester 107 by reaction with ethyl orthoformate and
acetic anhydride, followed by reaction with the cyclopropyl
amine. 1,8-Naphthyridine 108 was obtained through baseassisted cyclization, followed by acid hydrolysis of the ester
function via a one-pot process in 52% overall yield. The
coupling reaction of quinolone 108 with pyrrolidine 105 was
carried out in CH3CN-H2O in the presence of benzaldehyde
and triethylamine. The benzaldehyde served as an important
reagent to protect the primary amine selectively and therefore
the desired gemifloxacin derivative 109 was obtained in high
yield and purity, otherwise a 10% by-product was observed
[65]. The deprotection and salt formation reactions were
carried out in one step by treatment of 109 w i t h
methanesulfonic acid at 40-45ºC in water. The gemifloxacin
mesylate (XII) was collected by filtration upon cooling in
95% yield [65].
injectable and oral formulations [66]. In collaboration with
GlaxoSmithKline, the ibandronic acid was also developed in
both iv and oral formulations for the treatment and
prevention of postmenopausal osteoporosis. The synthesis of
ibandronate sodium (XIII) is shown in Scheme 13 [67].
However some reaction details are not available in the
literature. N -pentylamine (1 1 0 ) was reacted with
benzaldehyde to give oily Schiff base 111 in 94% yield.
Hydrogenation with palladium/charcoal gave N-benzyl-Npentylamine as oil in 74% yield. The secondary amine was
reductively alkylated with formaldehyde and formic acid to
give the tertiary amine 112 in 95% yield. Hydrogenolytic
cleavage of the benzyl group of 112 with palladium/charcoal
gave secondary amine 113, which was reacted with methyl
acrylate (114) in toluene to give compound 115 in 93%
yield. Methyl ester 115 was then saponified with 1N NaOH
to give carboxylic acid. The acid was then heated to 80oC
with phosphorous acid. The melt was mixed with
phosphorus oxychloride at the same temperature for 16
hours. Water was then added and the reaction mixture was
stirred at 100°C for 24 hours to give free diphosphonic acid.
The free diphosphonic acid was finally treated with sodium
hydroxide to give ibandronate sodium (XIII).
Ibandronate (BonivaTM)
This bisphosphonate, a calcium metabolic inhibitor and
osteogenesis inhibitor, was developed and launched by
Boehringer Mannheim (now Roches) for the treatment of
tumor-induced hypercalcemia (TIH) and is available in both
Lumiracoxib (PrexigeTM)
Lumiracoxib, a selective COX-2 inhibitor discovered and
developed by Novartis, was approved in September, 2003 in
the UK for the symptomatic relief of osteoarthritis and short
NH2 HCl
NCl3, AlCl 3
98%
O
NH2 HCl
XV Memantine HCl
HN
Br
Br2
122
H2SO4
neat, ∆
CH3CN, rt
100%
86%
123
Scheme 15. Synthesis of memantine (XV).
NaOH
diethylene glycol, ∆
96%
HCl,Et2 O
73%
124
XV Memantine HCl
1118
Liu et al.
HCl
O
HO
OH n-BuNH , 12N HCl
2
H2, Pd/C, EtOH HO
OH 60oC, 90%
HO
HO
HO
125
HN
HCl
OH
NH
O
HO
N
HO
Pd/C , H2
HO
80%
45% from glucose HO
HO
OH
HO
D-Glucose
Gluconobacter
oxidation
OH
OH
HO
127
XVI miglustat
126
Scheme 16. Synthesis of miglustat (XVI).
Memantine HCl (NamendaTM)
term relief of moderate to severe acute pain associated with
primary dysmenorrhea, dental surgery and orthopedic surgery
[68]. After an initial not approvable letter issued by FDA in
September 2003, Novartis expects to re-submit a NDA by
early 2006 following the completion of several studies
requested by FDA. Since the original patent on the
discovery of lumiracoxib (XIV) disclosed the first synthesis
of this compound [69], several approaches to the synthesis
of lumiracoxib (XIV) have been detailed in the subsequent
process patent [70]. In all the routes, the key to the synthesis
was the ring opening of lactam 121. Coupling of pbromotoluene (116) with 2-chloro-6-fluoroaniline (117) in
the presence of palladium catalyst Pd(dba)3 , tributyl
phosphine and sodium t-butoxide in toluene provided
a n i l i n e i n t e r m e d i a t e 1 1 8 . Acylation with
chloroacetylchloride (119) at 90°C neat gave chloride
intermediate 120. Cyclization in the presence of aluminum
chloride at 160 to 170°C gave the key lactam 121, which
was subsequently opened with sodium hydroxide in boiling
ethanol water mixture to provide lumiracoxib (XIV).
O
MeO2C
Memantine, a NMDA receptor antagonist [71,72], was
co-developed by Forest Laboratories with Merz
Pharmaceuticals and marketed under the trade name
Namenda for the treatment of Alzheimer’s disease in the US
after its approval in October, 2003. This drug has been
available in many European and Asian markets before
getting approval in the US. Memantine (XV) or 1-amino3,5-dimethyladamantane hydrochloride was first synthesized
by Lilly as an anti-diabetic agent but was ineffective in
lowering blood sugar [73]. Several syntheses have been
detailed in the literature [73-76]. However the simplest
synthesis of the drug was done in one step from the
commercially available 3,5-dimethyl adamantine (122).
Treatment of 122 with nitrogen trichloride (CAUTION: very
explosive gas!) in the presence of aluminum trichloride (ratio
of 1.5:1.2) gave the desired amino adamantine in 86% yield.
However, a much safer alternative has been reported by Lilly
scientists. Heating the commercially available 3,5O
Cl
CO2Me +
NaH, THF, rt, 14h
CO2Me
82%
129
128
OPiv
OHC
OH
O
131
CO2Me +
NaH, THF, 2h
CO2Me
OPiv
HO
132
133
NaOH
OMe
O
CO2Me K2CO3, MeOH,
iii. TEA, MeSO2Cl, DCM, rt, 2.5h,
iv. NaBH4, DMF, 77% in two steps
ii. CrO3, H+, acetone, -30o C,
then CH2 N2 , AcOEt, 54%
62%
OMe
i. NaH, DMF, MeI, 3h, rt, 88%
ii. NaBH4, MeOH, 0.5h, 89%
i. O3, DCM, Py, DMS,
-78o C, 52%
OPiv
HO
CHO
33%
132
CO2Me
130
OPiv
M eO
O
6h, rt, 100%
MeO
134
135
OM e
iii. BCl3, DCM,
-78o-rt, 86%
O
O
O
OMe
iv. LiOH, H2O,
rt, 6h, 93%
MeO
136
OH
O
O
ONa
XVII mycophenolate sodium
O
MeO
Scheme 17. Synthesis of mycophenolate sodium (XVII).
OH
O
O
OH
O
MeO
137
dimethyladamantane 122 in bromine gave the bromo
derivative 123 (86%) which was then reacted with sulfuric
acid in acetonitrile to provide quantitatively acetyl amino
derivative 124 after aqueous workup. Hydrolysis of the
acetyl group was done by heating 1 2 4 with sodium
hydroxide in diethylene glycol to give 1-amino -3,5adamantane (96%), which was then made into the
hydrochloride salt in ether and recrystallized from ether and
alcohol mixture to provide the final product memantine
hydrochoride XV.
acid (137) was originally synthesized by Birch and Wright
[81] and has been the subject of several total [82-88] and
formal syntheses [89-95]. The large production in industry is
done via fermentation [96]. A concise synthesis of
mycophenolic acid published recently is depicted in Scheme
17 [88]. Reaction of dimethyl 1,3-acetonedicarboxylate (128)
with commercially available geranyl chloride (129) in the
presence of NaH gave ketoester 130 in 82% yield. Treatment
of ketoester 130 with 4-(pivolyloxy)-2-butynal (131) in the
presence of NaH provided resorcinol 132 in a single step
with all substituents in place in 33% yield along with two
more compounds represented by 133 (62%). Resorcinol 132
was transformed into 134 via a four step sequences:
methylation with NaH and MeI in dry DMF, reduction of
the formyl group with NaBH4, mesylation of the resulting
alcohol and subsequent reduction of the mesylate. The
preparation of phthalide 135 was affected in quantitative
yield on treatment of 134 with K2 C O 3 in dry MeOH.
Selective ozonolysis of compound 135, followed by Jones
oxidation and esterification afforded ester 1 3 6 .
Demethylation with BCl3 in DCM followed by hydrolysis
of the ester function gave the mycophenolic acid (137). The
mycophenolic acid was then converted to its sodium salt
XVII (no conditions and yield available).
Miglustat (Zavesca™)
This orally active glucosylceramide glucosyltransferase
inhibitor, was launched for the treatment of type I Gaucher’s
disease [77]. Miglustat (XVI) has been developed and
launched by Oxford GlycoSciences (OGS; now Celltech) and
Actelion. The drug was originally discovered at Searle (now
Pfizer) and an enzymatic oxidation was employed in the
synthesis [78]. D-Glucose (125) was subjected to reductive
amination with n-butylamine in ethanol under 4 atm of
hydrogen in the presence of Pd/C catalyst at 60 ºC to give
N -butylglucamine HCl salt (1 2 6 ) in 90% yield. N butylglucamine (126) then was submitted to a selective
microorganism oxidation by Gluconobacter Oxidans (DSM
2003) cell paste in water to give 6-(butylamino)-6-deoxy-aL-sorbofuranose HCl salt (127) in 80 % yield. Finally,
compound 127 was cyclized and reduced in situ with
hydrogen over Pd/C at 4000 atm in ethanol/water to give
miglustat (XVI) in 45% overall yield from D-glucose (125).
Palonosetron (AloxiTM)
This selective and conformationally restricted 5-HT3
receptor antagonist was approved for the treatment of
chemotherapy-induced nausea and vomiting [97]. The drug
was originally developed by Syntex Corp (now Roche
Bioscience) and is currently being developed by Helsinn and
MGI Pharm. (S)-3-Aminoquinuclidine was condensed with
inexpensive 1,8-naphthalic anhydride (138) to furnish imide
139 in 93% yield and isolated as its TFA salt [98]. Imide
139 was hydrogenated at 5 psi to give intermediate 140 with
one of the reduced aromatic ring. The less hindered C-3
carbonyl group in 140 was selectively reduced to a hydroxy
group by using sodium borohydride in ethanol under
nitrogen at low temperature to give intermediate 141.
Intermediate 141 was not isolated because of the formation
of a tight boron complex. Subsequently, acid was added to
141 in i-PrOH to decompose the boron complex and
dehydrate intermediate 141 to 142, which was conveniently
Mycophenolate Sodium (Myfortic™)
Novartis has developed and launched an enteric-coated
formulation of mycophenolate sodium (Myfortic; ERL-080),
an IMP dehydrogenase inhibitor, as an oral
immunosuppressive agent for the prevention of kidney
rejection during transplantation [79]. In November 2002, its
first approval was gained in Switzerland; additional
approvals were subsequently received in Brazil, India,
Australia. By January 2004, approval had been received in
36 countries, and by March 2004, approval had been granted
in the EU and US. Mycophenolic acid (137), a natural
product, was discovered 107 years ago [80]. Mycophenolic
N
O
O
N
O
O
N
(S) -3-aminoquinuclidine
N
O
propanol, 93%
H
5psi H2, Pd/C
H
O
O
EtOH, 50oC
●
N
O
NaBH4, EtOH
-78oC to -45oC
139
N
O
N
N
OH
141
Scheme 18. Synthesis of palonosetron (XVIII).
●
142
N
THF, 50oC, 57%
H
81% from
139 to 142
N
O
H
5 psig H2, Pd/C
HCl, i-PrOH
H
TFA
TFA
140
138
●
H
●
HCl
HCl
XVIII palonosetron
1120
Liu et al.
i. TsCl, Na 2CO3, H2O, 78oC, 78%
N
H
Cl
O
HO
i. AlCl3, fluorobenzene, 80oC
O
ii. PCl5, o-dichlorobenzene, 85oC
NH2
S
O
O
CH3
NH2
o
ii. H2O, 80 C, 64%
144
O
F
F
F
145
14 3
i. KOH, dioxane-H2O
OEt
(EtO) 2CO
85%
O
O
148
N
N
149
, THF, -78oC
i.
ONa
CHO
O
151
O
i. NaOH, 92%
CO2Et
150
ii. Et2BOMe, then NaBH4
iii. 2,2-dimethoxypropane, TsOH, 99% from 150
O
O
I
OEt
OLi
TMS
ii. PhI(OAc) 2, I 2, CCl4
CO2Et 500 W halog en-lamp, ∆
74% from 148
Toluene, ∆
Dean-Stark
90%
O
147
146
PTSA, 145
ii. (R)-naphthylethylamine
recrystallization, 31%, 97% e.e.
152
O
O
NH3
i. HCl
O
CO2Et
ii. EtI, DBU 70%
153
O
i. disiamylborane
O
O
CO2Et
ii. NaOEt, EtOH
CH3
Sia 2B
155
154
F
F
OH
O
O
O
OH
O
_
O
OEt
149
PdCl2, CH3CN, 99%
i. HCl(aq)
ii. NaOH
iii. CaCl 2
1/2 Ca+ 2
N
N
156
XI X pitavastatin calcium
Scheme 19. Synthesis of pitavastatin calcium (XIX).
isolated as its HCl salt in 75% yield from 139. Palonosetron
(XVIII) was obtained in 57% yield by palladium-catalyzed
hydrogenation of 142.
Pitavastatin Calcium (Livalo™)
Pitavastatin calcium, another HMG-CoA reductase
inhibitor in the statin family, is marketed by Kowa and
Sankyo for the treatment of hyperlipidemia. Pitavastatin
(XIX) is a liver-selective drug with higher cholesterollowering potency and longer action than pravastatin or
simvastatin [99]. The convergent synthesis [100-102] was
achieved by cross-coupling of aryl halide 149 with (E)alkenyl borane 155 which was derived from terminal
acetylene 154 by via hydroboration [102]. Anthranilic acid
(143) was treated with TsCl and sodium carbonate in hot
water to give N-tosylated intermediate in 78% yield, which
was converted to the corresponding acid chloride 144 with
PCl 5 in o-dichlorobenzene at 85°C. Intermediate 144,
without isolation, was reacted with fluorobenzene in the
presence of AlCl3 at 80°C to give the Friedel-Crafts product
which was then hydrolyzed in hot water to give
fluorobenzophenone free aniline 145 in 64% yield from the
N-tosyl anthranilic acid. Acetyl cyclopropane (146) was
reacted with diethyl carbonate to give the corresponding
ethyl ester 147. The quinoline core structure was obtained by
condensing fluorobenzophenone 145 with 147 under acidic
conditions with a Dean-Stark trap to give quinoline-3carboxylic ethyl ester 148 in 90% yield. Ester 148 was
hydrolyzed with potassium hydroxide, and the free
carboxylic acid thus obtained was subsequently photoiododecarboxylated with iodine and PhI(OAc)2 to give aryl
i. n-BuLi, THF, -20 to -30oC, 1h
EtOCOCl, TEA, DCM
O p-chloroaniline, -10 to -20oC
N
H
N
N
91%
ii.
Cl
158
157
Cl
Cl , -20 to -30oC, 1h
159
O
OH
Cl
91%
H
N
N
O
Cl
160
Cl
Cl
i. PCl 5, DCM, 5oC to rt
N
ii. AlCl3
iii. H2 O, 80o C
71%
N
N
O
161
162
Cl
Cl
OH
OH
HN
HO2C
OH
N
DCC, HOBT, TEA, DM F
18h, 70%
O
163
N
then NaBH4, rt
89%
164
N
SOCl2, CHCl3, ∆, 30 min
POCl 3, CHCl3 , rt
166
165
51%
167
N
i. Mg/THF
+
167
N
N
Cl
162
N
Cl
Fumaric acid
EtOH
N
ii. H2SO4
CO2H
N
70%
42%
N
HO2C
N
N
XX rupatadine fumarate
N
168
Scheme 20. Synthesis of rupatadine fumarate (XX).
iodide 149 in 74% yield. 3-Trimethylsilylpropynal (150)
was used as the starting material to prepare the chiral side
chain. Compound 150 was reacted with di-anion 151 in
THF at low temperature to give the corresponding diol ester
which was first reacted with Et2BOMe and then reduced to
acetylene with sodium borohydride. The free diol was
protected as ketal with 2,2-dimethoxypropane in the presence
of TsOH to give dimethylketal acetylene 152 in 99% yield.
The ester functionality was hydrolyzed with sodium
hydroxide to give the acid in 92% yield. The racemic free
acid was resolved with (R)-(1-naphthyl)ethylamine to give
the pure diastereomeric salt 153 which crystallized out in
31% yield and 97% e.e. Esterification of the free carboxylic
acid liberated from the crystalline salt with ethyl iodide gave
optically pure acetylene 154 in 70% yield. Hydroboration of
acetylene 154 with disiamylborane gave (E)-alkenyldisiamylborane 155 and the excess borane reagent was
quenched with sodium ethoxide in ethanol. After
evaporation of all volatile material, the residue was directly
subjected to the cross-coupling reaction. Palladium (II)
chloride and aryl iodide 149 were mixed in acetonitrile to
give coupling product 156 in 99% yield. After the ketal in
156 was hydrolyzed under acid conditions and the ester was
hydrolyzed with sodium hydroxide, the resulting carboxylic
sodium salt was reacted with calcium chloride to yield
pitavastatin calcium (XIX) with 99% e.e.
Rupatadine Fumarate (Rupafin™)
Uriach’s rupatadine fumarate, a novel antiallergic drug
with a dual mechanism of action, was launched for the first
time in Spain in 2003. Rupatadine, which acts as a nonsedating histamine H1 antagonist and platelet-activating
factor antagonist, represents a novel approach to the
treatment of allergic rhinitis [103]. One of the convergent
syntheses [104-109] for rupatadine (XX) involved two key
intermediates, tricyclic ketone 162 and chloropiperidine
derivative 167. 3-Methylpicoline acid (157) was reacted with
p-chloroaniline in the presence of acid chloride and TEA to
provide amide 158 in 91% yield. Amide 158 was then
1122
O
O
O
Cl
Liu et al.
N
Br
Cl
Br2 , Et2O/dioxane = 2/1
N
Cl
HO
5 eq. imidazole
Cl
Cl
5-10 C, 1hr
∆, 1 hr, 78%
Cl
170
169
Cl
171
N
(-) -DIP-chloride
172
Cl
N
Cl
N
Cl
o
MeOH
71% from 169
5-10oC
N
NaBH4, MeOH
S
N
H
●
HNO3
N
OH
Et2O/THF
80%
Br
Cl
KOt Bu,
173
Cl
60%HNO3
174
H
EtOH, 89%
DMF, MS 4A
68%
Cl
O
Cl
S
XXI sertaconazole
Scheme 21. Synthesis of sertaconazole (XXI).
treated with n-BuLi at -20°C for 1h, followed by addition of
3-chlorobenzyl chloride (159) to furnish amide 160 in 91%
yield after an aqueous workup. The cyclization of amide 160
was accomplished by treatment with 160 PCl5 first followed
by AlCl3 mediated Friedel-Crafts cyclization. The cyclic
intermediate 161 was directly subjected to hydrolysis
without isolation and tricyclic ketone 162 was obtained in
71% yield via a one-pot process [107]. N-acylation of 5hydroxypiperidine (164) with 5-methylnictonic acid (163)
was accomplished by using HOBT, DCC to furnish amide
1 6 5 . The carbonyl group in 1 6 5 was reduced by
chlorination/reduction sequence using POCl3 and NaBH4.
Alcohol 166 was then converted to the chloride 167 by
refluxing with SOCl2 in CHCl3. Coupling tricyclic ketone
162 and chloride 167 via a Grinard protocal followed by
dehydration furnished the rupatadine 168. Treatment of
rupatadine with fumaric acid in EtOH gave rupatadine
fumarate (XX) in 70% yield [109].
Sertaconazole (DermofixTM, ErtaczoTM)
This drug has been developed and launched for the
treatment of dermatological fungal infections by Ferrer
Internacional S. A.[110]. Mylan received FDA approval for
sertaconazole nitrate cream for the treatment of athlete's foot
(tinea pedis) at the end of 2003. 2,4-Dichloro acetophenone
169 was brominated at low temperature to give bromide
intermediate 170, which was used without isolation. To the
same pot, five-fold excess of imidazole was added to give
imidazolylacetophenone 171 in 71% yield from 169.
Sodium borohydride was employed to reduce ketone 171 to
alcohol 172 in 78% yield. Racemic alcohol 172 w a s
CO2Me
CO2Me
H
O
CO2Me
NH
TFA, CH2Cl2
NH2
NH
+
O
N
H
O
175
N
H
N
H
176
O
177, 42%
O
178, 27%
O
O
CO2 Me
O
Cl
N
H
O
N
N
NaHCO3, CHCl3
NH
Cl
O
CH3
O
CO2 Me
Cl
33% CH3 NH2/EtOH
∆, 77%
N
H
O
N
O
N
H
O
179 93%
O
O
177
Scheme 22. Synthesis of tadalafil (XXII).
180
O
XXII tadalafil
OEt
OH
CNH2
i. K2CO3, ethyl bromide
acetone, reflux, 97%
CN
O
O
O
N
H
THF, reflux
O
O
O
186
O
O
O
70oC
186
NH
HN
N
N
O
O
POCl 3
ClCH2CH2Cl
N
28%
N
HN
N
91%
N
188
O
O
HN
N
187
ClSO3H
OEt
O
185
184
183 +
NH2
O
OEt
Cl
N
H
183
DMAP, pyridine
OH
+
C
NH2NH2.H2O
182
O
N
H
NH
OEt
ethanol
ii. NH4Cl, toluene, Al(Me)3
80oC, 76%
181
NH
O
N
N
H
190
N
SO2Cl
DCM
0 C, 66%
N
S
N
N
N
o
189
N
H
N
O
O
O
XXIII vard enafil
Scheme 23. Synthesis of vardenafil (XXIII).
resolved with (-)-DIP-chloride to give its corresponding
chiral R-alcohol 173 in 80% yield. Compound 173 was then
alkylated with 3-bromomethyl-7-chlorobenzo[b]thiophene
(174) in dry DMF in the presence of potassium t-butoxide to
give the alkylation product in 68% yield. Finally, 60%
nitric acid was used to make sertaconazole mononitrate
(XXI) in 89% yield [111].
Tadalafil (Cialis™)
Tadalafil is an orally active and structurally distinct
phosphodiesterase (PDE) type 5 inhibitor. This drug has
been developed and launched widely in several markets by
Lilly ICOS LLC (a joint venture established in 1998) for the
treatment of erectile dysfunction. Compared to Viagra,
tadalafil (XXII) is more selective against PDE6 , has a
significantly longer duration of action (24 hr vs. 2-4 hr) and
has no food effect on its absorption [112]. Pictet-Spengler
reaction was applied in the synthesis of tadalafil (XXII)
[113]. D -(-)-Tryptophan methyl ester (175) and 1,3benzodioxole-5-carboxaldehyde (176) were subjected to a
modified Pictet-Spengler reaction to form cis- and transtetrahydro-β-carboline tricyclic compounds. The ciscompound 177 was isolated as a white solid in 42% yield.
The basic nitrogen in the piperidine ring of 177 was acylated
with chloroacetyl chloride (179) to give compound 180 in
93% yield. Finally, the diketonepiperazine ring was formed
by adding 180 to 33% methylamine in ethanol under
refluxing conditions and yielded tadalafil (XXII) in 77% as
a white solid.
Vardenafil (LevitraTM)
This is another orally active phosphodiesterase (PDE)
type 5 inhibitor with better potency and selectivity for the
P D E 5 isoform than Viagra. Vardenafil (XXIII) was
originally discovered by Bayer and co-developed by Bayer
and GlaxoSmithKline for the treatment of erectile
dysfunction [114]. The synthesis [115] started with 2hydroxybenzonitrile. 2-Hydroxybenzonitrile (181) was
alkylated with ethyl bromide to give 2-ethoxybenzonitrile in
97% yield as a liquid which was subsequently treated with
AlMeClNH 2, prepared from AlMe3 and NH4 Cl, to give
corresponding 2-ethoxybenzamidine (182) in 76% yield as a
solid. Compound 182 was treated with hydrazine hydrate in
ethanol to give hydrazide 183, which was used in the next
step without isolation. Dakin-West reaction of 2butyrylaminopropionic acid (184) with ethyl oxalyl chloride
(185) in the presence of DMAP in refluxing pyridine/THF to
give corresponding α-oxoamino-acid ester 186 which was
also used for next step without isolation. Hydrazide 183 was
condensed with ester 186 in refluxing ethanol to give
triazinone 187 intermediate which was then cyclized to the
final core structure, imidazo[5,1-f][1,2,4]triazin-4-one, using
POCl3 to give 188 in 28% yield from 183. Compound 188
was sulfonylated with chlorosulfonic acid to give sulfonyl
chloride 189 in 91% yield. Finally, 189 was condensed with
1124
N -ethylpiperazine (190) in dichloromethane to give
vardenafil (XXIII) in 66% yield.
ACKNOWLEDGEMENT
evaluation of this review by Dr. M. Y. Chu-Moyer.
Liu et al.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
ABBREVIATIONS
ADME
=
absorption, distribution, metabolism,
excretion
Boc
=
t-butyloxycarbonyl
Dba
=
dibenzylideneacetone
DBU
=
1,8-diaza-7-bicyclo[5.4.0]undecene
DCC
=
N,N'-dicyclohexylcarbodiimide
[13]
[14]
DCM
=
dichloromethane
[15]
DIBAL-H
=
diisobutylaluminum hydride
[16]
DIP-chloride
=
B-chlorodiisopinocampheylborane
DIPEA
=
diisopropylethylamine
DMAP
=
4-dimethylaminopyridine
DMF
=
N,N-dimethylformamide
DMSO
=
methyl sulfoxide
HOBT
=
1-hydroxybenzotriazole hydrate
HMDS
=
hexamethyldisilazane
[20]
IPA
=
isopropyl alcohol
LDA
=
lithium diisopropylamide
[21]
[22]
LAH
=
lithium aluminum hydride
MTBE
=
t-butylmethyl ether
NCE
=
new chemical entities
TBAF
=
t-butyl ammonium fluoride
TBDMS
=
t-butyldimethylsilyl
TBTU
=
2-(1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium tetrafluoroborate
TEA
=
triethyl amine
TFA
=
trifluoroacetic acid
THF
=
tetrahydrofuran
TMS
=
tetramethylsilyl
Ts
=
tosyl
p-TSA
=
WSC-HCl
=
1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride
[12]
[17]
[18]
[19]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
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1133
Jin Li* , Kevin K.-C. Liu* and Subas Sakya*
Pfizer Global Research and Development, Pfizer Inc, Groton CT 06340, USA
into molecular recognition, but also serve as leads for designing future drugs. To this end, this review covers
the syntheses of 12 NCEs marketed in 2004.
Keywords: Synthesis, New Drug, New Chemical Entities.
INTRODUCTION
“ The most fruitful basis for the discovery of a new drug
is to start with an old drug.” — Sir James Whyte Black,
winner of the 1998 Nobel prize in physiology and medicine
[1].
Inaugurated two years ago, this annual review presents
in various countries for the first time during the past year.
The motivation to write such a review is the same as stated
in the previous article[2-3]. Briefly, drugs that are approved
worldwide tend to have structural similarity across similar
biological targets. We strongly believe that knowledge of
new chemical entities and their syntheses will facilitate our
ability to design new drug candidates.
In 2004, 23 NCEs including biological drugs, and two
diagnostic agents [4] reached the market. Among them,
some products were approved for the first time in 2004 but
were not launched before year end. The synthesis of those
drugs will be covered in the next review. The current article
will focus on the syntheses of the 11 new drugs and one
diagnostic agent (gadoxetic disodium) marketed last year
(Fig. 1), but excludes new indications for known drugs, new
combinations and new formulations. Drugs synthesized via
bio-process and peptide synthesizers will also be excluded as
well. Syntheses of these new drugs were published
sporadically in different journals and patents. The synthetic
routes cited here represent the most scalable methods based
on the authors’ judgment on available publications and
appear in alphabetical order by generic names.
Azacitidine (Vidaza TM)
Azacitidine, an inhibitor of DNA methyltransferase, was
approved by the US FDA for the treatment of
myelodysplastic syndromes in May, 2004 [4]. It is the first
drug to be approved by the FDA for treating this rare family
bone-marrow disorders, and has been given orphan-drug
status. It is also a pioneering example of an agent that targets
“epigenetic” gene silencing, a mechanism that is exploited
by cancer cells to inhibit the expression of genes that
counteract the malignant phenotype [5]. The triazine ring of
*Address correspondence to these authors at the Pfizer, Groton, CT
06340, USA; Tel: 1-860-4415498; E-mail: [email protected]; Tel: 1860-7153552; E-mail: [email protected]; Tel: 1-860-715-0425; E-mail:
[email protected]
1389-5575/05 $50.00+.00
azacitidine is sensitive to water [6]; this characteristic has
made the synthesis of azacitidine a challenge, especially in
manufacturing at commercial scale. A number of reports have
appeared in order to avoid the use of water; however, these
methods all have additional problems that render them
undesirable for the large scale synthesis [7-12]. A recent
improved synthesis [13] is depicted in Scheme 1. 5Azacytosine (1) was bis-silylated with HMDS in the
presence of (NH4)SO4 to furnish trimethylsilylated
azacytosine (2) in greater than 90% yield. Coupling of
silylated azacytosine 2 with 1,2,3,5-tetra-O-acetyl-β-Dribofuranose (3) in DCM in the presence of TMS-triflate
provided protected 5-azacitidine 4. The acetyl groups were
then removed by using NaOMe in MeOH at rt. The crude
azacitidine was crystallized from DMSO/MeOH to provide
pure azacitidine (I).
Belotecan Hydrochloride (Camtobell ®)
The DNA topoisomerase I inhibitor, belotecan
hydrochloride (II), developed by Chong Kun Dang
Pharmaceuticals, was launched for the first time last year in
the Republic of Korea as an injectable formulation, where it
is indicated for the treatment of non-small-cell lung cancer as
well as ovarian cancer. The initial discovery synthetic route
involved over 12 steps. The large scale synthesis was
developed later [14-15]. Treatment of commercially available
camptothecin (5) with tert-butylhydroperoxide in the
presence of FeSO4, AcOH and conc. H2SO4 gave (S)-7methylcamptothecin (6). Mannich reaction of compound 6
with isopropylamine hydrochloride in DMSO as a
formaldehyde source gave belotecan hydrochloride (II).
The total synthesis route is depicted in Scheme 2.2. The
known pyridinone 7 [16] was converted to the bicyclic
pyridinone 8 by treatment with methyl acrylate and K2CO3
in DMF. Hydrolysis and decarboxylation of 8 to ketone 9
was effected by refluxing in a mixture of HOAc and conc.
HCl under nitrogen. Ketalization was performed in a two
phase system of toluene and ethylene glycol to provide ketal
10 in 90% yield. Functionalization of the methyl group in
10 using diethyl carbonate in the presence of KH furnished
the ester 11 in 76% yield. Ethylation of 11 was
accomplished by use of KOBut and EtI in DME. Catalytic
hydrogenation of 12 using Raney Ni in a mixture of Ac2O
and HOAc gave the amide 13. Removal of the catalyst by
filtration followed by addition of NaNO2 to the filtrate gave
the N-nitroso amide. Decomposition of the nitroso amide by
1134
Li et al.
NH2
N
N
H
N
O
O
H
N
N
N
CF 3
N
OH
O
HCl
O
HO
HCl
HO
OH
O
Cinicalcet
hydrochloride (III)
Belotecan
hydrochloride (II)
Azacitidine (I)
CO2
CO2
Gd 3+
S
NaO2C
N
HN
O
N
H
O
O
HCl
N
CO2 Na
N
N
CO2
HCl
O
O
N
OEt
Duloxetine
hydrochloride (I V)
Erlotinib
hydrochloride (V)
O
N
O
H
N
O
N
H2N
O
N
H
O
HN
N
O
N
H
Gadoxetic acid
disodium (VI)
N
N
H
1/2 Ca
N
2 HCl
Indisetron
hydrochloride (VI I)
H2N
O
O
Pregabalin (X)
Pemetrexed
disodium (IX)
Mitiglinide calcium
hydrate (VIII)
N
O
O
CO2H
O
O
Na
O Na
H2 O
HO2C
OH
O
O
N
H
H
N
O
H
N
N
O
HO
N
Solifenecin
succinate (XI)
NH
Ximelagatran (XII)
Fig. (1). Structures of 12 NCEs marketed in 2004.
heating in an inert solvent (CCl4) gave the acetate 14 [17].
The diester 14 was lactonized by LiOH in MeOH/H2O to
give lactone 15 in 92% yield [18]. The carbonyl group in 15
was then reduced with DIBAL-H in THF to give lactol,
which was dehydrated via its mesylate to afford 16 [19]. The
asymmetric dihydroxylation of 16 gave diasteromeric
mixtures in favor of the desired isomer 17 (81% d.e.).
Compound 16 was then oxidized directly with iodine in the
presence of CaCO3 to give α-hydroxy lactone 18. The
deketalization was accomplished by HCl in THF/H2O to
provide the ketone 19 [19]. Condensation of ketone 19 and
the amine 20 [20] in the presence of p-TSA followed by
hydrolytic removal of Cbz group provided the free base
Which was convert to its corresponding HCl salt as
belotecan hydrochloride (II).
NH2
N
NHSiMe 3
N
O
N
HMDS, (NH4 )2SO4
N
H
∆, 8h
>90%
1
Me3 SiO
AcO
H
N
+
O
H
OAc
N
OAc
H
H
OAc
2
3
NHSiMe3
N
AcO
TMS-Triflate
N
O
O
H
DCM, rt
H
NH2
N
N
NaOMe, MeOH
HO
H
H
H
OAc
OAc
O
H
OH
4
O
N
N
H
H
OH
azacitidine (I)
Scheme 1. Synthesis of azacitidine (I).
Cinacalcet Hydrochloride (Sensipar
TM,
Mimpara ®)
reuptake inhibitor, as a treatment for depression [24] and
urinary incontinence [25]. The balanced dual NE and
serotonin reuptake inhibitor increases neurotransmitter
concentration, which is believed to enhance the tone and
contraction of the urethral sphincter and help to prevent
accidental urine leakage due to physical activity . The
synthesis from Lilly’s group [26] is depicted in Scheme 4.
Friedel-Crafts acylation of thiophene (24) by 3chloropropanoyl chloride (25) with SnCl4 as Lewis acid
gave ketone 26 which was then enantioselectively reduced
with
(R
)-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2c][1,3,2]oxazaborole (27) in the presence of borane in THF
to
give
(S)-3-chloro-1-(2-thienyl)-1-propanol (28).
Compound 28 was subjected to Finkelstein reaction to give
(S)-3-iodio-1-(2-thienyl)-1-propanol which was reacted with
methylamine in THF to give compound 29. The alcohol 29
was then used in a nucleophilic displacement reaction with
1-fluoronaphthalene (30) in the presence of sodium hydride
in DMA to give duloxetine free base in 88% yield. Finally,
the free base was treated with HCl to yield duloxetine
hydrochloride (IV).
Amgen’s cinacalcet (III) was licensed from NPS
Pharmaceuticals as a first-in-class oral calcimimetic for the
treatment of secondary hyperparathyroidism (HPT) in
chronic kidney disease patients on dialysis and the treatment
of hypercalcemia in patients with parathyroid carcinoma [21].
Cinacalcet’s (III) mechanism of action is via inhibition at an
allosteric site on the calcium-sensing receptor. The drug
increases the sensitivity of the calcium receptor in the
parathyroid gland to extracellular calcium and thereby
reduces the levels of parathyroid hormone [22]. General
syntheses of this class of compounds have been published
[23], however, the specific synthesis of cinacalcet (III) has
not been available to date. The synthesis of cinacalcet, based
on a patented procedure, is depicted in Scheme 3. A mixture
of 1-acetonaphthone (21), 3-trifluoromethyl-1-propylamine
(22) and titanium (IV) isopropoxide were stirred at rt to form
the enamine intermediate which was reduced with
methanolic sodium cyanoborohydride at rt to give
corresponding racemic α-methyl amine (23). Compound 23
was resolved and then treated with HCl etherate to give
cinacalcet hydrochloride (III) as a white solid.
Erlotinib Hydrochloride (TarcevaTM)
Duloxetine
Ariclaim ®)
Hydrochloride
(Cymbalta TM,
Yentreve®/
Erlotinib hydrochloride (V), a quinazoline derived small
molecule inhibitor of epidermal growth factor receptor
(EDGFR) tyrosine kinase, was approved in November,
2004, for the treatment of advanced or metastatic non-smallcell lung cancer [4]. It belongs to the same class as gefitinib,
Lilly, in collaboration with Boehringer Ingelheim and
Shionogi, has developed and launched duloxetine (IV), an
orally active dual norepinephrine (NE) and serotonin
N
H
t-BuOOH, FeSO4
AcOH, H2SO4
O
N
N
rt, 60h, 86%
O
N
140oC,
N
O
1h, 47%
N
N
O
HO
5
O
i-PrNH2, HCl, DMSO
O
HO
O
Scheme 2.1. Synthesis of belotecan hydrochloride (II ).
6
HO
O
belotecan I I
O
1136
Li et al.
O
O
CN
HN
N
CO2Me , DM F
HCl, HOAc
∆, 89%
HO
O
7
8
9
O
O
CN
N
OH, toluene
HO
O
toluene, ∆
76%
O
O
KOBut, EtI
O
CN
Raney Ni, H2
N
O
i. (Ac) 2O, HOAc, NaNO2
N
O
CO2Et
ii. CCl4, ∆
O
O
O
100%
12
14
13
O
O
N
LiOH, MeOH/H2O
92%
O
O
i. DIBAL-H, THF, -78o, 2h
O
ii. MsCl, TEA, THF, rt, 24h
O
N
O
90%
O
O
16
15
O
N
O
O
N
I2, CaCO3, M eOH/H2O
(DHQD) 2-PHAL, K3Fe(CN) 6
O
OH
O
K2OsO4, 89%, 81% d.e.
rt, 24h, 48%
OH
O
O
O
OH
O
18
17
O
N
HCl, THF/H2O
60o,
N
H
NH2
O
3h, 100%
O
+
O
19
Cbz
N
OH
O
OAc
N
0o , 2h
CO2Et
45o, 50 psi
100%
O
-78o to rt, 98%
NHAc
Ac 2O, HOAc
CO2 Et
O
11
10
O
O
CN
N
(EtO) 2CO, KH
CO2Et
∆, 90%
CN
N
MeO2C
K2CO3, 45oC
75%
EtO2C
O
CN
20
i. toluene, pTSA, ∆
O
N
ii. Pd/C, H2, HAc
40%
iii. HCl
N
HCl
belotecan II
O
HO
O
Scheme 2.2. Total Synthesis of belotecan hydrochloride (II ).
another quinazoline approved for treatment of advanced lung
cancer, but with improved pharmacokinetic properties [2728]. The molecule was originated by Pfizer and development
initiated in collaboration with OSI, which assumed full
rights to the drug when Pfizer merged with Warner Lambert.
Subsequently, Genentech/Roche went into licensing
agreement with OSI to develop and market the drug in the
US and Worldwide [29]. The synthesis of this agent is
based on the original patent and is shown in Scheme 5 [3032]. The 3,4-dihydroxy benzoate 31 was reacted with
bromoethyl methyl ether in the presence of potassium
carbonate and tetrabutyl ammonium iodide to give 32 in
93% yield. Nitration followed by hydrogenation provided 34
in 88% yield, which was then cyclized in formamide with
ammonium formate to provide quinazolone 35. . Subsequent
reaction with oxalyl chloride gave quinazoline chloride 36,
which was then reacted with 3-ethynyl aniline (37) in
isopropanol in the presence of pyridine to give the desired
product erlotinib, which was isolated as the HCl salt (V).
An alternate synthesis, that used protected 3-trimethylsilyl
ethynyl aniline to couple to the quinazoline chloride 36, has
also been published [32].
O
+
ii. NaCNBH3/MeOH
i. titanium (IV) isopropoxide
NH2
F 3C
rt
rt
22
21
H
N
i. chiral resolution
H
N
CF3
ii. HCl etherate
CF3
HCl
Cinacalcet hydrochloride (III)
23
Scheme 3. Synthesis of cinacalcet hydrochloride (III).
O
Cl
+
S
Cl
24
BH3 THF
Cl
rt, 40%
S
OH
O
SnCl4
benzene
H
Ph
Ph
26
25
N
Cl
S
O
28
27
B
S
OH
i. NaI, acetone
ii. NHM e, THF
N
H
S
NaH, DM A
CH3
HCl
O
N
H
HCl
29
F
30
Duloxetine hydrochloride (IV)
Scheme 4. Synthesis of duloxetine hydrochloride (IV).
Gadoxate Disodium (Primovist ®)
Schering AG’s liver imaging product , gadoxate
disodium (VI) was approved and launched last year in
O
HO
OEt
O
Br
O
K2CO3, TBAI
31
O
O
O
Acetone, ∆
64 hrs
93%
HO
Sweden. Gadoxate is designed for the detection and
characterization of liver lesions. Owing to its structural
properties, gadoxate is specifically taken up by the
hepatocytes, so that lesions with no or minimum hepatocyte
O
OEt
HOAc,
O
H2, PtO2 /H2O
O
EtOH
88%
NH2
HCOONH4
CHONH2,
HCl
86%
165oC
O
O
O
O
N
33
O
NH
O
cat DMF,
(COCl) 2
CHCl 3, ∆, 1.5h
N
92%
H2N
N
NO2
35
34
O
O
O
OEt
O
Cl
OEt
32
O
O
O
24hr
O
1 equiv HCl
O
O
HNO3
5oC-rt,
O
HN
, pyridine
37
iPrOH, ∆, 4 hr
36
Scheme 5. Synthesis of erlotinib hydrochloride (V).
CHCl3, Et2O, 1M HCl/Et 2O
O
71%
O
O
N
HCl
O
N
Erlotinib
hydrochloride (V)
1138
Li et al.
function remain un-enhanced and are therefore more readily
detected and localized [33-35]. A scalable synthesis of
gadoxate (VI) has appeared [36] (Scheme 6). The
commercially available N a -benzyloxy-carbonyl-L-tyrosine
methyl ester (38) was O-alkylated at the phenolic hydroxyl
group with ethyl iodide in DMF to yield the ethyl ether 39
in 98% yield. Ester 39 was reduced to corresponding alcohol
40 using sodium borohydride in MeOH. Mesylation of 40
and further reaction with excess of ethylendiamine and
addition of aqueous HCl afforded the mono-protected
triamine dihydrochloride 41 in 81% yield. Catalytic
hydrogenation afforded chiral triamine 42 as the
dihydrochloride salt in 93% yield. Triamine 42 was then
treated with t-butyl bromoacetate in THF/H2O using K2CO3
as a base. The resulting crude product was subjected to
preparative chromatography on reverse-phase silica gel
yielding the oily penta-t-butyl ester 43 in 73% yield. The
penta-t-butyl ester 43 was then hydrolyzed by sodium
hydroxide. After cleavage of the t-butyl groups, the excess of
sodium ions was removed by addition of cation-exchange
resin Amberlite IR 120 to yield the sodium salt, which was
then reacted with Ga2O3 in water at 80˚C to give gadoxetic
acid disodium (VI) after neutralization with NaOH.
Indisetron Hydrochloride (SinseronTM)
Indisetron is a dual serotonin 5HT3/5HT 4 receptor
antagonist co-developed by Nisshin Pharma and Kyorin. It
was approved for the first time in Japan for the treatment of
prophylaxis of chemotherapy-induced nausea and vomiting
[37]. The synthesis [38-39] is highlighted in Scheme 7.
Bromoacetaldehyde dimethyl acetal (44) was condensed with
methylamine with KOH in refluxing ethyleneglycol for 3 hr
to give 33% yield of bis(2,2-dimethoxyethyl)amine (45),
which was cyclized with acetonedicarboxylic acid (46) and
methylamine to generate 3,9-dimethyl-3,9-diazabicyclo[3.3.1]nonan-7-one (47) in 12% yield. Compound 47 was
reacted with hydroxylamine in refluxing pyridine and ethanol
mixture to give corresponding oxime 48 in 88% yield,
which was subsequently reduced with hydrogen over Raney
Ni in hot ethanol in the presence of ammonium acetate at 50
kg/cm2 to give amine 49 in 89% yield. Compound 49 was
OH
O
O
O
EtI, K2CO3, DMF
rt, overnight
98%
O
N
H
O
O
NaBH4, THF/MeOH
<30o C, 1h
92.5%
O
N
H
O
O
38
39
O
O
O
O
OH
N
H
O
i. MeSO2Cl, TEA, THF
rt, 30 min
ii. ethylenediamine, 50oC, 4h
iii. HCl
O
Pd/C, H2, MeOH
H
N
N
H
NH2
15 bar, 1h.
92.5%
2HCl
81%
41
40
O
O
But O2 C
H2N
Br, K2CO3, THF/H2 O
But O2 C
∆, 20h, 73%
H
N
NH2
N
N
CO2But
But O2C
2HCl
43
42
COO
NaO2 C
Gd
N
i. NaOH, MeOH/H2O, ∆, 5h
80oC,
ii. Gd2 O3 ,
80%
1h
Scheme 6. Synthesis of gadoxate disodium (VI).
COO
3+
N
N
EtO
COO
Gadoxetic acid
disodium (VI)
CO2Na
N
CO2 But
CO2But
H3CO
H3 CO
MeNH2
Br
O
MeNH2
O
OCH3
,∆
OH OH
44
OCH3
N
OCH3 CH3
KOH
OCH3
O
N
O
HO
OH
45
NH2 OH, Py/EtOH
∆, 0.5 hr, 88%
CH3
47
46
3 hr, 33%
CH3
N
12%
O
Cl
HON
CH3
N
N
CH3
48
H2, EtOH, NH4OAc
N
H2N
CH3 i.
N
Raney Ni
70oC, 50 kg/cm2
89%
N
CH3
49
N
H
N
O
N
50
N
H
pyridine, DMAP
N
H
2 HCl
N
rt, 16 hr, 16%
Indisteron hydrochloride (VII)
ii. HCl
Scheme 7. Synthesis of indisteron hydrochloride (VII).
condensed with 1H-indazole-3-carbonyl chloride (50) in
pyridine with catalytic amount of DMAP to give crude
indisteron free base, which was re-crystallized from
chloroform/hexane to give indisteron free base as colorless
crystals in 16% yield. Finally, the free base was treated with
hydrogen chloride to give indisteron hydrochloride (VII).
treatment of type 2 diabetes in Japan in May of 2004 [4].
This secretagogue works by inhibiting ATP dependent
influx of potassium in pancreatic beta cells, which induces
depolarization of the cell and opens voltage dependent
calcium channels that increases calcium levels in beta-cells
and results in insulin release. A number of publications and
patents have disclosed the syntheses of mitiglinide [40-44].
One of the syntheses describing the preparation of
mitiglinide using bis-activated esters to obtain a selective
mono amide is described in Scheme 8. The synthesis starts
with racemic 2-benzylsuccinic acid (51) which was resolved
Mitiglinide Calcium Hydrate (Glufast )
Mitiglinide, an insulin secretagogue developed by Kissei
and co-marketed by Kissei and Takeda, was approved for the
OH
N
O
O
O
O
(R)-1-Phenylethylamine
2X recrystallization
19.8%, 99.5%ee
CO2H
HO2C
SOCl2 , Et 3N,
HO2C
CO2H
O
O
O
97%
52
51
N
CH2Cl2
O
N
O
O
53
O
NH
N
54
O
O
O
N
H2 O
O
CH2Cl2
OH
N
O
O
90%
55 (99:1; mono:bis)
O
N
O
O
1/2 Ca
H2O
Mitiglinide calcium
hydrate (VIII)
Scheme 8. Synthesis of mitiglinide calcium hydrate (VIII ).
56 99.6% ee
2N NaOH
M eOH
CaCl2
H2O:EtOH
91%
1140
Li et al.
into its enantiomer using chiral amine salt formation and
crystallization. Out of several amines used, (R)-1phenylethylamine gave the best results for the chiral
resolution (99.5% ee, 19.5%). Acid 52 was treated with
thionyl chloride and triethylamine followed by Nhydroxysuccinamide to give doubly activated ester 53
(97%). Treatment of this double ester 53 with
tetrahydroisoindoline (54) [45] gave selectively mono amide
to di-amide in 99:1 ratio. Hydrolysis of the activated ester in
55 with water gave desired product 56 in 99% yield.
Subsequent conversion in two steps to the half calcium salt
provided mitiglinide calcium hydrate (VIII) in 91% yield.
have appeared. [46-56]. A practical and scalable synthetic
route [56] is depicted in Scheme 9. Palladium (0) coupling
of methyl 4-bromobenzoate (57) with 3-butyn-1-ol (58) gave
crystalline 59, which was then reduced over palladium on
carbon in DCM to give alcohol 60. Filtration of the catalyst
afforded a DCM solution of alcohol 60, which was utilized
directly in a TEMPO-catalyzed sodium hypochlorite
oxidation, providing known aldehyde 61 without isolation.
Addition of 5,5-dibromobarbituric acid (DBBA) and
catalytic amount of HBr in acetic acid to the DCM solution
of 61 effected the conversion to α-bromoaldehyde 62. After
aqueous work-up, the solution was concentrated and diluted
with acetonitrile to exchange solvents. Addition of
commercially available 2,4-diamino-6-hydroxypyrimidine
(63), aqueous sodium acetate and heating to 45°C resulted in
cyclic condensation and precipitation of pyrrolo[2,3d]pyrimidine 64 from the reaction mixture in 67% yield
based on 60. Saponification of 64 with aqueous sodium
hydroxide followed by acidification afforded the carboxylic
acid derivative 65, which was elaborated to 66 by
chlorodimethoxytriazine active ester coupling method.
Reaction of 65 with 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT) in the presence of N-methylmorpholine in DMF
solution followed by reaction of the resulting dimethoxy-s-
Pemetrexed Disodium (Alimta®)
Pemetrexed is a novel multi-targeting antifolate that
simultaneously blocks at least three separate enzymes
essential to the survival of cancer cells: thymidylate
synthase, dihydrofolate reductase and glycinamide
ribonucleotide formyltransferase. Pemetrexed is broadly
active in wide variety of solid tumors, including
mesothelioma, non-small cell lung cancer, breast, bladder,
head and neck, and ovarian cancers. A number of papers
outlining the syntheses of pemetrexed and related analogs
CO2Me
H2, Pd/C, 50psi
CO2Me
PdCl 2, PPh3, CuI, DEA
+ HO
57
3h, 99.2%
50oC, 4h, 83%
Br
HO
O
59
58
HN
CO2Me
CO2Me
NaOCl, TEMPO, KBr
NaHCO3, DCM , <20oC
H2N
O
NaOAc, acetonitrile
X
HO
40oC, 3h
61 X=H
62 X=Br
60
CO2Me
O
DBBA, HBr, rt
i. CDMT, DM F/NMM, rt, 1.5h
HN
ii. NH2 -L -Glu(OEt) 2, rt
1.5h, 91%
H2N
N
H2N
N
H
64
O
N
H
N
H
N
H
66 free bas e
67 pTSA salt
O
CO2Et
HN
N
N
65
O
H2N
67% from 60
CO2H
O
2N NaOH, 40oC
HN
63
NH2
N
pTSA
pTSA, EtOH, ∆
72% from 65
Scheme 9. Synthesis of pemetrexed disodium (IX).
O
i. 1N NaOH
ii. HCl
CO2Et
iii. NaOH
85%
CO2Na
N
H
HN
H2N
CO2Na
N
N
H
pemetrexed disodium (I X)
CO2Et
CO2Et
CO2Et
CHO
i Pr
2NH
KCN, EtOH
CO2Et
+
CO2Et
68
HOAc
(high yield)
CN
94%
iii. HOAc
73%
71
70
69
CO2 H S-(+)-Mandellic Acid
CO2H
i. IPA/H2O
ii. Recrystallization
NH2
i. KOH, MeOH
ii. H2, Ni
CO2Et
OH
i. THF: H2O
OOC
NH3
NH2
100% S
25-29%
99:1 S:R
72
CO2H
Pregabalin (X)
73
Scheme 10. Synthesis of pregabalin (X).
triazinyl ester with diethyl L-glutamate afforded crude 66,
which was isolated via crystallization as pTSA salt 67.
Saponification of 67 with aqueous sodium hydroxide
followed by acidification with HCl gave pemetrexed as the
free acid, which was crystallized as disodium salt form.
the literature, including process scale-up comparison of
several different routes [57-58]. The most cost efficient route
as described in the publication [56] is shown in Scheme 10.
Condensation of diethyl malonate 69 in the presense of
diisopropyl amine in acetic acid gave α,β-unsaturated diester
70 in high yield. Reaction of the enone diester with
potassium cyanide gave cyano diester 71 in 95% yield. In a
remarkable three step, one pot process, the nitrile in 71 was
hydrolyzed followed by decarboxylation of one of the esters
to provide 72 in 73% yield. Resolution of the two
enantiomers was achieved using (S)-(+)-mandellic acid, one
of the best acid found after many salt screening, to give, after
two recrystallization, a 99:1 ratio of the desired diastereomer.
Pregabalin (Lyrica )
Pregabalin, a GABA mimetic that was developed by
Pfizer (originally Warner Lambert) for the treatment of
epileptic seizures and neuropathic pain, was approved in
European Union in the summer of 2004 and subsquently
received approvable letter in September, 2004, in the US [4].
Several syntheses of pregabalin (X) have been disclosed in
O
NH2
benzoyl chloride
or
TEA, CH3Cl
i. POCl3, P 2O5, xylene, ∆
benzoic acid
N
H
TEA, DPPA
DMF
74
ii. NaBH4, EtOH
75
N
NH
NH
R-(+)-tartaric acid
O
TEA, CH2Cl2
78
77
76
OEt
ClCO2Et
HO
CO2H
HO2C
O
N
N
79
HO2C
O
N
NaH, toluene, ∆
80
Scheme 11. Synthesis of solifenacin succinate (XI).
CO2H
N
O
O
Solifenacin succinate (XI)
N
1142
Li et al.
N(Boc)2
N(Boc) 2 NH2OH, Na 2CO3
Br NaH, (Boc) 2NH
THF, rt
18h, 96%
NC
H2 , Pd-C
H2 O, EtOH, ∆
NC
H2N
80%
81
N
82
AcOH:Ac2 O
86%
83
OH
N(Boc)2
N(Boc)2
ClCO2Bn
4N NaOH
H2N
THF
NH
NCbz
86
85
84
O
O
O
HO
H2N
EtOAc
100%
NH
NHBoc
NH2.HCl
HCl
BnO2CHN
5.2-2.8 MPa
H2, Rh/Al2O3
O
NHBoc
HO
MeO
89
MeOH, 3 days
O
MeO
83%
NHBoc
N
NH
, EDC, DMAP
CH3 CN, 5oC - rt
92%
87
90
88
O
O
HO
LiOH
NHBoc
N
THF, 24 hr
NH2
HCl
EDC,
CbzN
+
86
NH2
-8oC - rt
86%
91
O
CbzHN
DMAP
CH3CN
O
O
HN
NHBoc
N
H2N
H2, Pd/C
O
HN
NHBoc
N
HN
HN
92
93
O
O
93
NO2
O
TEA
O
O
O
O
O
O
NHBoc
HN
77%
95
94
O
O
TFA
O
CH2 Cl2, rt
O
HN
N
CH2Cl2, rt, 16h
+
O
NH
NH
O
O
O
O
F 3C
HN
NH2 .TFA
N
O
O
S
O
HN
O
, K2 CO3
O
CH2Cl2, rt
22%
96
O
O
O
O
HN
O
HN
N
O
H
N
HN
O
95%EtOH, rt
58%
HO
N
H
H
N
NH
97
Scheme 12. Synthesis of xilomelagatran (XII).
O
O
NH2 OH.HCl, TEA
Ximelagatran (XII)
O
H
N
N
O
Removal of the acid was done with wet THF instead of base
separation, to avoid salt impurities, and one recrystallization
in ethanol gave 100% ee diastereomer in 25 – 29% overall
yield.
It’s worth noting that the Pfizer group have come up
with a new process of preparing pregabalin (X) via
enantioselective reduction, that promises to further reduce
cost and waste associated with the manufacture of this drug
[59-60].
Solfenacin Succinate (Vesicare®)
Solifenacin , an orally active selective M3 muscarinic
receptor antagonist, was developed and launched by
Yamanouchi for the treatment of overactive bladder (OAB)
with symptoms of urgency, frequency and urge incontinence
[61]. Solifenacin improves various incontinence associated
with OAB by blocking muscarinic receptors on bladder
smooth muscles [62]. The synthesis of solifenacin [63] is
highlighted in Scheme 11. Phenylethyl amine (74) was
reacted with benzoyl chloride or coupled with benzoic acid
to give corresponding amide 75. Reaction with POCl 3 and
P 2O5 in refluxing xylene followed by reduction with sodium
borohydride
in
ethanol
gave
cyclized
racemic
tetrahydroisoquinoline 76. The racemic 76 was resolved
with (R)-(+)-tartaric acid to give 1-(S)-phenyl-1,2,3,4tetrahydroisoquinoline (77), which was reacted with ethyl
chloroformate and TEA in dichloromethane to give ethyl
ester 78. Compound 78 was transesterified with
quinuclidine-3-(R)-ol (79) with NaH in refluxing toluene to
give solifenacin free base as a yellow oil which was treated
with succinic acid and re-crystallized to yield solifenacin
succinate (XI).
Ximelagatran (Exanta ®)
Ximelagatran (XII), a prodrug of a direct thrombin
inhibitor, melagatrin, was approved in the European Union
in December, 2003, for the prevention of venous
thromboembolic events in patients undergoing major
elective orthopedic surgery, that is, hip or knee replacement
[4-64]. The FDA, however, did not approve the drug in the
US based on the recommendation of the advisory panel.
Synthesis of melagatran and ximelagatran has been published
in several patents and is shown in Scheme 12 [65-68]. The
synthesis is based on coupling of key fragment 86 with acid
91 followed by elaboration to provide ximelagatran. The
synthesis of the key intermediate, shown in Scheme 12, was
reported to be scalable in high yields [66]. Reaction of
benzyl bromide 81 with ditertbutylimino dicarboxylate in
the presence of sodium hydride gave 82, which was reacted
with hydroxyl amine in aqueous ethanol to give hydroxyl
amidine 83 in 80% yield. Immediate hydrogenation removed
the hydroxyl group and gave 84, which was protected with
benzyl chloroformate to provide 85. Deprotection of 85 with
acid furnished amidine intermediate 86. Synthesis of
fragment 91 was done by hydrogenation of N-BOC phenyl
glycine (87) in the presence of rhodium in alumina to
provide cyclohexyl amino acid 88 in 83% yield. Coupling of
the acid 88 with azetidine 2-methyl ester (89) using EDC
provided 90 in 92% yield. Hydrolysis of the ester followed
by coupling to a key intermediate benzyl carbamate protected
aminino benzyl amine 86 under EDC coupling conditions
provided 92 in 86%. Subsequent hydrogenolysis removed
the benzyl carbamate and provided intermediate 93. To
complete the synthesis, the intermediate 93 was reacted with
activated double ester 94 to furnish simultaneously protected
and activated amidine 95. Removal of the BOC group
(TFA) followed by reaction
with
ethyl
(Otrifluoromethanesulfonyl)-glycolate in the presence of base
provided esterified intermediate 97. Reaction of 97 with
hydroxyl amine hydrochloride in the presence of base
deprotected and installed hydroxyl amidine product,
ximelagatrin (XII).
ACKNOWLEDGEMENT
evaluation of this review by Robert Chambers.
ABBREVIATIONS
ADME
= Absorption, distribution, metabolism,
excretion
Cbz
= Carbobenzyloxy
CDMT
= 2-chloro-4,6-dimethoxy-1,3,5-triazine
DBBA
= 5,5-dibromobarbituric acid
DCE
= Dichloroethane
DCM
= Dichloromethane
(DHQD)2- = 1,4-Bis(9-O-dihydroquininyl)PHAL
phthalazine
DIBAL-H = Diisobutylaluminum hydride
DIPEA
= Diisopropylethylamine
DIPP
= Diisopropylphosphoryl
DMAP
= 4-Dimethylaminopyridine
DMA
= N, N-Dimethylacetamide
DMF
= N,N-Dimethylformamide
DMSO
= Methyl sulfoxide
DPPA
= Diphenylphosphoryl azide
MsCl
= Methansulfonyl chloride
NCE
= New chemical entities
NMM
= 4-Methylmorpholine
TEA
= Triethyl amine
TFA
= Trifluoroacetic acid
THF
= Tetrahydrofuran
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy
p-TSA
= para-Toluene sulfonic acid
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429
Subas M. Sakya1,*, Jin Li2,* and Kevin K.-C. Liu3,*
1
Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340, USA; 2BioDuro LLC, Beijing, China; 3Pfizer
Global Research and Development, Pfizer Inc., La Jolla, CA 92121, USA
Abstract: New drugs are introduced to the market every year and each individual drug represents a privileged structure
for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of
22 NCEs marketed in 2005.
Key Words: Synthesis, new drug, new chemical entities, medicine, therapeutic agents.
INTRODUCTION
“The most fruitful basis for the discovery of a new drug is
to start with an old drug.” Sir James Whyte Black, winner
of the 1998 Nobel prize in physiology and medicine [1].
Inaugurated four years ago, this annual review presents
in the previous article [2]. Briefly, drugs that are approved
new chemical entities and their syntheses will greatly enhance our abilities to design new drug molecules in shorten
period of time. With this hope, we continue to profile these
NCEs that were approved for the year 2005.
In 2005, 41 NCEs including biological drugs [3], and two
diagnostic agents reached the market. Among them, some
products were approved for the first time in 2005 but were
not launched before year end. Synthesis of those drugs will
be covered in 2006’s review. This review will focus on the
syntheses of 22 new drugs marketed last year (Fig. 1), but
excludes new indications for known drugs, new combinations and new formulations. Natural products, diagnostic
agents and drugs synthesized via bio-process and peptide
synthesizers will also be excluded. The syntheses of these
new drugs were published sporadically in different journals
and patents. The synthetic routes cited here represent either
the most scalable methods based on the author’s judgment or
currently available publications, and appear in alphabetical
order by generic names.
CICLESONIDE (ALVESCO®)
Ciclesonide, a newer generation inhaled corticosteroid
for the treatment of persistent asthma, was discovered and
developed by Altana Pharma and launched in January 2005
in England [3]. Besides being approved in a number of other
*Address correspondence to these authors at the Pfizer Global Research and
Development, Pfizer Inc., Groton, CT 06340, USA; Tel: 1-860-715-0425;
E-mail: [email protected]; BioDuro LLC, Beijing, China; Tel: 861062948830; E-mail: [email protected]; Pfizer Global Research and Development, Pfizer Inc., La Jolla, CA 92121, USA; Tel: 1-858-622-7391;
1389-5575/07 $50.00+.00
countries, Altana and Aventis has received an approvable
letter in the US. It’s novel release and distribution properties
help target the lung specifically, resulting in an efficacious
anti-inflammatory effects. Two separate approaches to the
syntheses of the chiral ciclesonide have been described in the
patent literature [4,5]. The first route involves a chiral resolution step [4] and the second approach highlights a stereoselective trans acetalization approach[5]. The first synthesis of
ciclesonide (Scheme 1) started by reacting (11,16)-11,
16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione (1) with
isobutyric anhydride to make the tri-isobutyl ester in 87%
yield. Reaction of the tri-ester with cyclohexane carboxaldehyde in the presence of HCl and 70% perchloric acid gave
the cyclohexane acetal 3, which was then separated into the
desired isomer ciclesonide (I) by HPLC or recrystallization.
In the second route (Scheme 2), desonide (4) was reacted
with cyclohexane carboxaldehyde in the presence of 70%
perchloric acid in nitropropane, a key solvent required for
selectivity, to give the isomers 5 (R/S in 88:2 ratio). The alcohol was subsequently capped with isobutyric anhydride to
give the desired product ciclesonide (I) in good yields. Enrichment of the desired isomer, if required, was done by either recrystallization or HPLC purification.
CLOFARABINE (CLOLAR®)
Clofarabine, a purine nucleoside analogue, is an anticancer agent approved in December 2004 for the treatment of
refractory or relapsed lymphoblastic leukemia with at least
two years of prior treatment in pediatric patients. The drug
was discovered by Ilex oncology (now Genzyme) and currently marketed by Genzyme [3,6]. Several routes to the synthesis of clofarabine have been published, including a process scale-up chemistry as shown in Scheme 3 [7,8,9]. Treatment of commercially available 2-deoxy-2--fluoro-1,3,5-triO-benzoyl-1-R-D-arabinofuranose (6) with 33%HBr in acetic acid provided the bromo sugar 7 in 88% yield. The bromide 7 was reacted with 2-chloroadenine (8) in optimized
mixed solvent system in the presence of calcium hydride and
potassium t-butoxide to give the desired -anomeric product
9 in 50:1 ratio. Deprotection of the benzoyl groups with sodium methoxide then provided clofarabine (II).
CONIVAPTAN (VAPRISOL®)
Conivaptan, a vasopressin antagonist, was discovered
and developed by Yamanouchi for the treatment of hyponatraeum associated with congestive heart failure [3,10]. After
430
O
O
O
Sakya et al.
NH2
O
N
O
N
HO
O
H
H
HO
N
O
O
Cl
N
CH3
N
H
N
H
H
HCl
HO
F
II. Clofarabine (Clolar)
(Scheme 3)
O
O
I. Ciclesonide (Alvesco)
(Scheme 1 & 2)
III. Conivaptan hydrochloride (Vaprisol)
(Scheme 4)
HO
OH
H
H2N
N
N
H
N
O
N
O
HBr
OH
O
N
N
N
N
Cl
N
N
O
O
Cl
H2N
N
N
NH2
VI. Doripenem (Finibax)
(Scheme 7-9)
O
O
HN
O
S
N
H
NH2
O
O
HO
V. Deferasirox (Exjade)
(Scheme 6)
IV. Darfenacin hydrobromide (Emselex)
(Scheme 5)
O
S
N
N
Cl
N
OH
HO
N
VII. Eberconazole (Ebernet)
(Scheme 10)
IX. Eszopiclone (Lunesta)
(Scheme 12)
VIII. Entecavir (Baraclude)
(Scheme 11)
OH
Cl
O
O
N
N
CN
S
O
NH
O
Cl
Cl
O
O
HCl
X. Ivabradine hydrochloride (Procorala)
(Scheme 13)
F
N
S
N
XII. Lumiracoxib (Prexige)
(Scheme 15)
XI. Luliconazole (Lulicon)
(Scheme 14)
O
O
O
H2N
N
N
F
N
N
NH2
N
N
N
O
N
N
O
H2N
O
N
F
HO
N
OH
N
HO
XIII. Nelarabine (Arranon)
(Scheme 16)
O
XIV Nepafenac (Nevanac)
(Scheme 17)
HO
XV. Posaconazole (Noxafil)
(Scheme 18 & 19)
O
H
N
CH3SO3H
O
Cl
O
O
O
HN
XVI. Ramelteon (Rozerem)
(Scheme 20)
XVII. Resagiline mesilate (Azilect)
(Scheme 21)
F3C
N
H
N
H
XVIII. Sorafenib (Nexavar)
(Scheme 22)
N
H
N
431
(Fig. 1. Contd….)
O
N
H
OH
H
N
N
H
OH
O
H
N
NH2
N
H
O
OH
O
OH
OH
O
O
XX. Tigecyline (Tygacil)
(Scheme 24)
XIX. Tamibarotene (Amnolake)
(Scheme 23)
CF3
OH
H
N
O
S
O
O
O
N
O
N
H
N
N
HN
O
O
S
N
N
O
XXI. Tipranavir (Aptivus)
(Scheme 25)
XXII Udenafil (Zydena)
(Scheme 26)
O
OH
O
70% HClO4
O
CHO
O
O
O
O
OH
HO
O
OH
HO
HCl/Dioxane
O
O
pyridine, RT
1.5 - 2 h
O
rt (190h)
-40oC (12 h)
O
O
87%
1
O
2
100%
O
O
O
O
O
HO
O
HO
Prep HPLC or
O
H
O
Crystallization
H
O
3
O
O
H
I Ciclesonide
Scheme 1. Racemic synthesis of Ciclesonide.
OH
OH
O
O
CHO
O
HO
O
O
HO
70% HClO4
O
1-nitropropane
O
4
Scheme 2. Stereoselective synthesis of Ciclesonide.
I
acetone, reflux,
2.5 h, 99%
0oC - rt, O/N
O
isobutyric anhydride,
K2CO3
5
R/S: 97.8/2.2
432
Sakya et al.
NH2
N
O
OCOPh
PhCOO
PhCOO
PhCOO
O
33% HBr, AcOH
N
H
Br
CaH2; KOBut
rt, overnight, 88%
F
PhCOO
6
Cl
8
F
MeCN:t-Amyl alcohol:DCM(1:2:1)
50oC, 40 min
7
NH2
NH2
N
N
PhCOO
O
PhCOO
N
Cl
HO
NaOMe
O
N
Cl
MeOH, 33oC, 7 h
F
HO
64%
F
50:1 beta:alpha
II Clofarabine
9
Scheme 3. Synthesis of Clofarabine.
looking at several different approaches to the synthesis [1113], a convergent approach, shown in Scheme 4, was developed for large scale synthesis [15]. Bromination of benzazepinone 10 with pyridinium hydrobromide perbromide in
chloroform followed by recrystallization gave bromide 11.
Reaction of bromide 11 with ethaneimidate hydrochloride in
the presence of potassium carbonate in toluene or chloroform
gave the desired imidazole 12 in 69% yield. Although chloCl
O
O
Br
HN
C5H5N HBr Br2
CHCl3, 15-30oC
N
NH2
N
NH
Ts
10
N
3 h, 69%, 2 steps
Ts
NH
80oC
toluene, 95 -100oC
N
N
80% H2SO4
K2CO3
1 h,90%
N
H
13
Ts
12
11
OH
H2N
N,N-dimethylaniline
SOCl2, cat DMF
CO2H
O
COCl
toluene, 40oC
acetone, rt, >2h
N
H
95%
>2h
14
CO2H
O
15
16
O
acetonitrile
N
13
EtOH
toluene
90%
SOCl2
O
N
N
H
N
H
HCl
III Conivaptan hydrochloride
Scheme 4. Synthesis of Conivaptan.
ing the M1 and M2 receptors that are believed to be involved
in central nervous system and cardiovascular function respectively. The compound was originally developed by
Pfizer and licensed to Novartis and Bayer. The synthesis of
darifenacin [17] is depicted in Scheme 5. Commercially
available (2S,4R)-(-)-4-hydroxy-2-pyrrolidinecarboxylic acid
(17), anhydrous cyclohexanol and 2-cyclohexen-1-one were
heated at 154oC to give de-carboxylated compound 18 in 69
% yield. The 3-(R)-hydroxypyrrolidine (18) was N-tosylated
with p-toluenesulfonyl chloride in pyridine yielding compound 19 in 26 % yield . The N-tosylated alcohol 19 was
subjected to Mitsunobu reaction in the presence of methyl ptoluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF to afford N-tosyl-3(S)-(tosyloxy)
pyrrolidine (20) in 70% yield, which was then condensed
with 2,2-diphenylacetonitrile with NaH in refluxing toluene
to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin2(S)-yl]acetonitrile (21). The tosyl group of 21 was removed
with 48% HBr and phenol in refluxing water to yield 2,2diphenyl-2-[2(S)-pyrrolidinyl] acetonitrile as its corresponding hydrogen bromide salt (22), which was coupled to 2-(2,
3-dihydrobenzofuran-5-yl) acetic acid (23) by treatment with
carbonyldiimidazole (CDI) in ethyl acetate to the corresponding amide 24 in a quantitative yield. The amide (24)
was dissolved in toluene and reduced with sodium borohydride in THF with slow addition of boron trifluoride THF
roform provided a slightly better yield, for large scale preparation, toluene was used to minimize halogenated solvent
waste and because the quality of product was similar or better than with use of chloroform. Deprotection of the tosylate
was found to be effective with heating the sulfonamide 12 in
80% sulfuric acid at 80oC. The benzazepinone product 13
was obtained in 90% yield after crystallization from acetonitrile and water mixture.
Synthesis of the coupling partner 16 required to provide
conivaptan was synthesized in 95% yield from biphenyl 2benzoic acid (Scheme 4) via sequential reaction with thionyl
chloride in toluene followed by coupling with aminobenzoic
acid in acetone with N,N-dimethylaniline as a base. High
quality acid 16 was obtained by crystallization from DMF
and water. The acid 16 was activated by converting it into
acid chloride with thionyl chloride in acenonitrile, to which
was added imidazo benzazepine 13 in toluene and, after recrystallization in acidic ethanol, gave conivaptan hydrochloride (III) in 90% yield.
DARIFENACIN HYDROBROMIDE (EMSELEX®)
Darifenacin, an orally active, once a day selective M3
receptor antagonist, was launched for the treatment of overactive bladder in patients with symptoms of urge urinary
incontinence, urgency and frequency [16]. The drug selectively inhibits M3 receptor in the detrusor muscle while sparOH
CO2H
HO
O
HO
HO
TsCl, Pyridine
+
NH
NH
4.5h, 154oC
17
TsOMe, Ph3P, DEAD
Ts
19
18
Ph2CHCN, NaH
TsO
N
THF, 70%
N
16h, 26%
HCl
69%
Ts
HBr, H2O, PhOH
NC
PhMe, reflux 2h
84%
reflux 3h, 79%
N
Ts
20
21
HO2C
O
NC
23
NH
HBr
HBr, MeOH
NaBH4,THF, PHMe
NC
93%
BF3 THF, 88%
N
CDI, EtOAc, 100%
O
O
24
22
1) KOH, 2-methyl-butan-2-ol
NC
reflux, 20h,
crystallization in PhMe, 84%
N
HBr
2) HBr, 2-methyl-butan-2-ol
O
H2N
N
HBr
O
O
25
Scheme 5. Synthesis of Darifenacin.
433
83%
IV Darfenacin hydrobromide
434
Sakya et al.
O
HO
O
NH2
OH
O
O
O
H2N
170oC
N
N
H
29
N
N
Cl
+
55%
OH
N
refluxing EtOH, 2h
O
OH
OH
HO
26
27
28
HO
V Deferasirox
Scheme 6. Synthesis of Deferasirox.
complex to keep the temperature below 10oC to give free
amine in 88% yield. The free amine was converted to corresponding hydrogen bromide salt (25) with 48% HBr in
methanol. Compound 25 was hydrolyzed with potassium
hydroxide in refluxing 2-methyl-butan-2-ol for twenty hours
to give acetamide which was crystallized from toluene as a
toluene solvated form in 84% yield. Finally, the toluene solvated compound was converted to darfenacin hydrobromide
(IV) with 48% HBr in 2-methyl-butan-2-ol.
®
DEFERASIROX (EXJADE )
Deferasirox, an orally active iron chelator, was approved
for the treatment of chronic iron overload because of blood
transfusions in chronic anemia in adult and pediatric patients
iron chelator two years of age and older [19]. Deferasirox,
developed by Novartis, is the only drug administered as a
drink, compared to the current standard treatment which often requires a subcutaneous infusion lasting 8 to 12 hours per
night, for 5 to 7 nights a week for as long as the patient continues to receive blood transfusions or has excess iron within
the patient body. Synthesis of deferasirox [20] (Scheme 6)
HO
DORIPENEM (FINIBAX®)
Doripenem, a carbapenem antibiotic approved in Japan
2005, was developed and marketed by Shionogi Pharmaceuticals in Japan for the treatment of serious infections caused
by both gram positive and negative bacteria including pseudomonas aeruginosa. It is currently being developed in the
U.S. by Peninsula Pharmaceuticals [3]. Two process syntheses have been reported for the preparation of doripenem
(Scheme 7) [21]. Both methods utilize a common commercially available starting material, 3-hydroxy proline (30). In
method A, compound 30 was initially reacted with thionyl
chloride or HCl in methanol to provide methylester 31, which
was immediately protected with p-nitrobenzylchloroformate
(PNZCl) to give PNZ N-protected 3-hydroxy proline ester 33
Route A
N
H
SOCl2 or
HCl/MeOH
started with cyclization of salicylamide (26) with salicyloyl
chloride (27) by heating at 170 C without any solvents to
give 2-(2-hydroxyphenyl)-benz[e][1,3]oxazin-4-one (28) in
55% yield. Compound 28 was reacted with 4-hydrazinobenzoic acid (29) in refluxing ethanol for 2 hours to give
deferasirox V as colorless crystals.
CO2Me
PNZCl, K2CO3
H2O/toluene, 5oC
31
40oC
HO
HO
MsO
MsCl, Et3N
CO2H
N
H
N
PNZ
30
33
PNZCl, K2CO3
H2SO4, MeOH
H2O/toluene, 5oC
HO
reflux
95%
N
PNZ
CO2H
32
Scheme 7. Synthesis of intermediate mesylate 34.
Route B
CO2Me
toluene, rt
N
PNZ
CO2Me
34
30 to 34: 91%
EBERCONAZOLE (EBERNET®)
and finally the alcohol was converted to mesylate 34 before
isolation in 91% overall yield. Alternatively, in method B,
the hydroxyl proline is protected as the PNZ ester 32 first in
95% yield. The protected proline acid 32 was converted to
the methyl ester with refluxing sulfuric acid in methanol
followed by conversion of the alcohol to the mesylate 34 in
91% overall yield from 30. The mesylate ester was reduced
with sodium borohydride to provide alcohol 35, which was
converted without purification to thiol ester 36 by reacting
with potassium thioacetate (Scheme 8). Mitsunobu reaction
of alcohol 36 with BOC-sulfonyl urea 38, which was prepared from chlorosulfonyl isocyanate with ammonia in tbutanol in 90% yield, provided the key thioacetate intermediate 39. Finally, protected doripenem 42 was prepared by
coupling thiol 40, obtained by hyrolysis of thioacetate 39,
with enolphosphate 41 (Scheme 9) in 88% yield [20]. Deprotection of intermediate ester and carbamate protecting groups
via hydrogenation gave the desired carbapenem VI, which
was isolated after crystallization. Final form of the drug
doripenem was prepared by sterilization, crystallization and
granulation.
Eberconazole is an azole antifungal agent developed by
Salvat and approved in Spain in 2005 for the topical treatment of cutaneous fungal infections, including tinea corporis, tinea cruris and tinea pedis [3]. The synthesis
(Scheme 10), started with the Wittig reaction of the phosphonium bromide 43 with the 3,5-dichlorobenzaldehyde to
give the olefin mixture 44. Hydrolysis of the ester followed
by hydrogenation gives acid 46, which was cyclized to tricyclized ketone 47. Completion of the synthesis was accomplished in three steps via reduction of the ketone 47 with
sodium borohydride, chlorination of resulting alcohol 48
with thionyl chloride and alkylation of the chloride 49 with
imidazole to give eberconazole (VII) [23].
ENTECAVIR (BARACLUDETM)
Entecavir, an orally activity nucleoside analogue launched
in the U.S. by Bristol-Myers Squibb, is for the treatment of
chronic hepatitis B in adults with evidence of active viral
replication and either evidence of persistent elevations in
AcS
MsO
38
KSAc
NaBH4
OH
OH
34
N
PNZ
EtOAc/MeOH
36
AcS
Ph3P, DEAD
EtOAc
N
PNZ
DMF-EtOAc
35
BOC
N
N
PNZ
81%
from 32: 71%
from 34: 76%
SO2NH2
39
BOC
t-BuOH, NH3
ClSO2NCO
HN
SO2NH2
EtOAc
37
38
90%
Scheme 8. Synthesis of key intermediate thioacetate 39.
OH
H H
OPO(OPh)2
O
O
H2SO4
39
H
N
MeOH
65oC, 2.5hr
OPNB
OH
H
41
SH
N
PNZ
NHSO2NH2
H
NPNZ
iPr2NEt
S
SO2NH2
EtOAc/DMF
5oC, 18 hr
98%
O
OPNB
O
88%
40
42
OH
H
i. 0.5psi H2, 10%Pd/C
MgCl2.H2O
NHSO2NH2
H
NH
iii. Sterilization
S
H2O:THF
26 - 36oC, 2 hr
iv. Crystallization
O
OH
O
VI Doripenem
Scheme 9. Synthesis of Doripenem.
435
436
Sakya et al.
O
O
O
NaH
OEt
PPH3+Br-
NaOH
OEt
Cl
DMF, rt, O/N
43
OH
Cl
MeOH, Reflux,
14 h
44
45
H2/Pd/C
Cl
Cl
O
NaBH4
OH
Cl
PPA
Cl
MeOH, RT
MeOH, RT,
3h
120oC - 160oC
3h
3.5 h
46
O
Cl
47
Cl
H
N
Cl
Cl
SOCl2,
reflux, 1 h
Cl
OH Cl
48
Cl
Cl
N
N
DMF, reflux,
6h
56% 3 steps
Cl
N
VII Eberconazole
49
Scheme 10. Synthesis of Eberconazole.
serum aminotransferases (ALT or AST) or histologically
active disease [26]. Entecavir is designed to selectively block
the replication of hepatitis B virus (HBV) by inhibiting the
virus’ ability to infect cells. Several syntheses of entecavir
have been reported and the synthesis described below is
based on the most recent patents [25,26] (Scheme 11).
Commercial sodium cyclopentadienide (50) was treated with
phenyldimethylchlorosilane in anhydrous THF at –78oC. The
resulting silane moiety serves as a masked hydroxyl group
that will be revealed later in the synthetic process. The silylated product was subsequently reactive with dichloroacetyl
chloride to a 2+2 cycloaddition reaction to give cyclobutanone 51 as crude dark oil. The cyclobutanone 51 was then
opened under a basic condition, and the resulting intermediate reduced with sodium borohydride at low temperature to
yield racemic free carboxylic acid 52. The racemic 52 was
subjected to chiral resolution with a chiral amine, R, R-(-)-2amino-1-(4-nitrophenyl)-1,3-propanediol (53), to give chiral
salt 54 in 99% e.e. and 28% overall yield from the starting
material 50 as crystals. The chiral salt 54 was de-salted and
converted to corresponding methyl ester 55 with sulfuric
acid in methanol. The double bond in compound 55 was then
expoxidized with titanium(IV) isopropoxide/TBHP at –30oC
in dichloromethane to give an epoxyl ester which was selectively reduced with sodium borohydride in IPA to give epoxyl diol 56 as light yellow oil. Lithium salt of 2-amino-6-Obenzyl-oxypurine (57) was added to the epoxide 56 to give
the ring-opening product 58. The vicinal diol moiety of 58
was converted to an alkene by a two-step procedure. Compound 58 was reacted with diethoxymethyl acetate and PPTS
in dichloromethane to give a mixture of dioxolanes as a viscous brown oil which was subsequently reacted with acetic
anhydride at 120oC for 30 hours to an alkene. Concentrated
HCl was added to the alkene mixture to hydrolyze the 6benzyl-oxy group and an 2-N-acetyl group formed in the
previous acetic anhydride reaction to give compound 59 as a
light brown colored product. Finally, compound 59 was converted to entecavir by protodesilylation of the silane moiety
followed by oxidation to convert the silane moiety to the
hydroxyl group. Therefore, 59 was treated with boron
trifluoride-acetic acid complex in acetic acid at high temperature and followed by basic hydrogen peroxide oxidation
to give entecavir (VIII).
ESZOPICLONE (LUNESTA TM)
Eszopiclone is a non-benzodiazepine hypnotic discovered
by Aventis Pharma and licensed exclusively in the U.S. to
Sepracor. Eszopicolone is the S-isomer of zopicolone. The
parent compound, zopicolone, is a short acting hypnotic
agent of cyclopyrrolone class which has been marketed in
Europe for the treatment of insomnia under the brand name
Imovane® or Amoban®. Therefore, Eszopicolone is for the
treatment of transient and chronic insomnia. The hypnotic
effect of eszopiclone is believed to result from its interaction
with GABA-receptor complexes at binding domains located
close to or allosterically coupled to benzodiazepine receptors
[27]. The synthesis of eszopicolone involves enzymatic resolution of a zopicolone [28] derivative to give the chiral compound as depicted in the Scheme 12 [27]. Pyrazine-2,3dicarboxylic acid anhydride (60) was reacted with 2-amino5-chloropyridine (61) in refluxing acetonitrile to generate 3(5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid
(62) in 95% yield. Compound 62 was cyclized by treating
with refluxing SOCl2 to give 6-(5-chloropyrid-2-yl)-5,7dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (63) in 79% yield.
SiMe2Ph
SiMe2Ph
1) PhMe2SiCl/THF, -78oC
O
2) Cl2CH2C(O)Cl,
Et3N, Hexane
Na
1) ButOH, H2O, Et3N
reflux, 3h
Cl
Cl
OH
O2N
OH
CO2H
2) NaBH4, 10oC
437
H2N 53
EtOH, 50oC, 5h
28% from 50, 99%e.e.
OH
Racemate
50
51
52
OH
SiMe2Ph
SiMe2Ph
O2N
SiMe2Ph
OH
CO2Me
H2SO4, MeOH
CO2H
.
H2N
OH
OH
1) Ti(O-iPr)4, DIPT, CH2Cl2
TBHP, -30oC
OH
2) NaBH4, IPA
Pure chial compound
54
55
56
O
SiPhMe2
OBn
H2N
N
N .
H
Li salt
H2N
57
N
N
DMF, 80oC
N
OH
N
HN
OH
OH
N
N
OH
O
H2N
N
N
1) CH3CO2CH(OC2H5)2, CH2Cl2
PPTS
N
2) Ac2O, 120oC, 30h
3)HCl, H2O, MeOH, 65oC
OBn
58
SiPhMe2
HO
59
O
N
HN
1) CH3CO2H, CH3COOH.BF3
95oC, 4h
H2N
N
N
2) K2CO3, H2O2 (30wt%), MeOH
70oC, 10h
OH
HO
VIII Entecavir
Scheme 11. Synthesis of Entecavir.
Compound 63 was subjected to partial reduction with KBH 4
in dioxane-water at low temperature to give 6-(5-chloro-2pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one
(64) in 64% yield, which was esterified with vinyl chloroformate in pyridine to give corresponding vinyl acetate 65 in
75% yield. The racemic 65 was then subjected to kinetic
resolution by a highly enantioselective enzymatic hydrolysis
process. Chiral vinyl acetate 67 with desired stereochemistry
was obtained when candida antarctica lipase was employed
for hydrolysis of 65 in dioxane/water at 60oC for 2 days.
Interestingly, the enzymatic hydrolysis stopped at 50% conversion and the hydrolyzed alcohol was recovered as the
starting substrate 65 because of spontaneous racemization of
the alcohol in the reaction medium. Therefore, although a
maximum yield of kinetic resolution is 50%, the overall efficiency of this enzymatic process is 100% because of substrate recycling. Finally, the chiral vinyl acetate 67 was condensed with methyl piperazine in acetone to give eszopicolone (IX).
IVABRADINE (PROCORALAN®)
Ivabradine is a first selective and specific If inhibitor that
was approved by EMEA in November for symptomatic
treatment of chronic stable angina pectoris in patients with
normal sinus rhythm. This is the first agent to lower heart
rate by inhibiting the cardiac pacemaker If current. The compound was discovered and developed by Servier and is currently being marketed in Ireland [3,30]. The convergent synthesis of ivabradine was accomplished by coupling the key
benzocylclobutanyl amine 73 with oxadioxalane 76 in an in
situ deprotection and amination as shown in Scheme 13 [29].
For the synthesis of the key amine 73, cyano group of compound 69 is reduced with borane-THF to give amine 70 in
90% yield, which was reacted with ethyl chloroformate to
give carbamate 71 in 80% yield. Complete reduction of the
carbamate was accomplished by refluxing with LAH in THF
to give racemic methyl amine 72 in 92% yield, which was
then resolved by crystallizing with N-acetyl –L-glutamic
438
Sakya et al.
H2N
O
Cl
N
61
O
N
H
reflux, CH3CN,
1.5 h, 95%
N
O
Cl
O
N
N
N
O
N
reflux, SOCl2
N
KBH4
N
79%
63
Cl
O
N
vinyl chloroformate
N
OH
O
H2O
O
O
N
pyridine, 75%
N
N
64%
O
62
N
13oC,dioxan/H2O
N
N
CO2H
60
Cl
Cl
N
N
O
OH
O
O
64
O
65
Candida antarctica lipase
CH3
recycle
O
N
O
O
N
N
O
N
N
N
Cl
+
Cl
N
N
N
N
N
H
N
68
N
acetone
O
O
O
OH
Cl
N
O
N
O
N
66
67
IX Eszopiclone
Scheme 12. Synthesis of Eszopicolone.
OMe
BH3.THF
OMe
NC
69
THF, rt
12h
90%
H2N
OCH3
TEA
EtOCOCl
OCH3
DCM, rt
80%
OCH3
EtOCONH
OCH3
70
71
OCH3
LAH
THF, reflux,
1.5 h
92%
OCH3
optical resolution
H3CHN
OCH3
H3CHN
crystallization
OCH3
72
73
O
MeO
O
Br
O
MeO
H2, Pd/C
O
NH
K2CO3
MeO
N
MeO
O
EtOH, 55oC
O
75
74
O
MeO
O
H3CHN
MeO
N
MeO
O
O
76
Scheme 13. Synthesis of Ivabradine.
H2, Pd/C
85oC
O
N
73
N
MeO
O
X Ivabradine hydrochloride
acid to give chiral salt 73. Prior to the next step, the amine is
converted to the hydrochloride salt.
solid phenylacetic acid 83 was reacted with SOCl2 in refluxing dichloromethane with a few drop of DMF to give corresponding acyl chloride as a yellowish oil, which is treated
with dimethylamine in diethyl ether/THF to yield 2-(2-iodo5-methylphenyl)-N,N-dimethylacetamide (84). Condensation
of compound 84 with 2-chloro-6-fluoroaniline (85) in the
presence of Cu powder, Cu2I2 and K2CO3 in refluxing xylene
afforded
2-[2-(2-chloro-6-fluorophenylamino)-5methylphenyl]-N,N-dimethyl-acetamide (86) as an off white
crystalline solid that was finally hydrolyzed with NaOH in
refluxing butanol/water to yield lumiracoxib (XII).
The coupling partner 76 to make ivabradine was prepared
from the azepinone 74 by first reacting with bromoethyldioxalane to give 75. The olefin in 75 was reduced by hydrogenating with palladium/carbon catalyst at 55oC to give 76.
To the same pot, the amine 73 was added and hydrogenated
to give reductive amination product ivabradine hydrochloride (X) in very good yields.
LULICONAZOLE (LULICON®)
NELARABINE (ARRANON®)
Luliconazole is a topical imidazole related antifungal
agent which was approved for use to treat tinea pedis, candidiasis and pityriasis in Japan [3]. Synthesis of luliconazole
(Scheme 14) started with diol 77, prepared according to literature procedure in 98%ee [32] which was activated by
converting to dimesylate 78 in 99% yield and coupled to
dipotassium enolate 80, prepared in situ by reacting cyano
methylimidazole 79 with carbon disulfide, to give luliconazole (XI), 99% ee in 48% yield [33].
Nelarabine, a novel water soluble nucleoside analog
prodrug of ara-G with T- cell selectivity, was approved by
the FDA in October, 2005 for treatment of T-cell acute lymphobalstic leukemia (T-ALL). After accumulation in cancer
cells, it is converted to its corresponding arabinosylguanine
nucleoide triphosphate (araGTP) which results in inhibition
of DNA synthesis and cytotoxicity [3,36]. The drug was synthesized (Scheme 16) by enzymatic coupling of arabinosyluracil 87, prepared according to literature [37] and 2-amino6-methoxy purine 88 using purine nucleoside phosphorylase
(PNP) and uridine phosphorylase (UP) in phosphate buffer
for 30 days to give the nelarabine (XIII) in 48% yield [38].
LUMIRACOXIB (PREXIGE)
Lumiracoxib, a orally active cyclooxygenase-2 (COX-2)
inhibitor launched by Novartis in Brazil in 2005, is for the
treatment of osteoarthritis and acute pain. In 2004, Novartis
withdrew its application for the European mutual recognition
procedure for the compound to await the outcome of a review from the EMEA of all selective COX-2 inhibitors. Novartis expects to resubmit in 2006 the application with added
safety and efficacy data according to the EMEA's recommendations. In addition, phase III clinical trials of lumiracoxib are still under way in the U.S., Japan and Europe for
the treatment of dysmenorrhea, rheumatoid arthritis (RA)
and gout [34]. Synthesis of lumiracoxib is rather straightforward (Scheme 15) [35]. 2-Iodo-5-methylbenzoic acid (81)
was reduced with BH3/THF in THF to give 2-iodo-5methylbenzyl alcohol as a white solid, which was treated
with 48% HBr under refluxing to yield benzyl bromide 82 as
a yellow solid. The benzyl bromide 82 was reacted with
NaCN in ethanol/water to afford corresponding phenylacetonitrile as a white solid, which was hydrolyzed with NaOH in
refluxing EtOH/water to provide phenylacetic acid 83. The
Cl
Cl
Cl
OH
NEPAFENAC (NEVANACTM)
Nepafenac originated from Wyeth is a non-steroidal antiinflammatory drug (NSAID) that was launched by Alcon in
2005 for the treatment of pain and inflammation associated
with cataract surgery [39]. The drug, which rapidly penetrates ocular tissues, is the first ophthalmic NSAI prodrug to
receive FDA approval. Nepafenac is metabolically converted
to 2-amino-3-benzoylbenzeneacetic acid, amfenac, a potent
cyclooxygenase inhibitor and clinically approved anti-inflammatory drug. The synthesis of nepafenac (Scheme 17) [40]
started with commercially available 2-amino-benzophenone
(89). Compound 89 was reacted with t-butyl hypochrite at –
65oC in DCM to give a mono-N-chloroaniline (90) which
was subsequently treated with methylthioacetamide in THF
at –65oC in the same pot to give an aza-sulfonium salt 91 as
a solid. Compound 91 was slurred in DCM and triethylamine
was added to give sulfer ylide 92 intermediate which underCl
Et3N, MsCl
OMs
0oC-rt,
98%ee
OH
DCM,
2h
77
99%
OMs
78
DMSO, rt,
2h
Cl
+
S
NC
48%, 99% ee
CS2, KOH
KS
CN
DMSO, rt
KS
N
Cl
S
N
N
79
Scheme 14. Synthesis of Luliconazole.
XI Luliconazole
N
80
439
CN
N
N
440
H3C
CO2H
i BH3/THF
I
ii HBr, reflux
Sakya et al.
H3C
H3C
i NaCN, EtOH/H2O, reflux
Br
I
CO2H
I
ii EtOH, NaOH, reflux
83
82
81
NH2
Cl
H3C
N(Me)2
i SOCl2, CH2Cl2, DMF(cat), reflux
I
ii NH(Me)2/THF, Et2O, OoC
O
F
H3C
N(Me)2
NH
85
Cl
Cu, Cu2I2, K2CO3
xylene, reflux
O
F
84
H3C
86
OH
NH
NaOH
O
Cl
F
butanol/H2O
reflux
XII Lumiracoxib
Scheme 15. Synthesis of Lumiracoxib.
went a Sommelet-Hauser type rearrangement to give compound 93 after re-aromatization of the intermediate cyclohexadienone imine. Compound 93 was finally reduced with
Raney nickel to give nepafenac (XIV) in 73% yield as yellow needles.
POSACONAOLE (NOXAFIL®)
Posaconazole, a tetrahydrofuran antifungal agent discovered and developed by Schering Plough, was approved in the
European Union in October, 2005 for the treatment of invasive fungal infections in adult patients, especially those who
have been refractory or are intolerant of other commonly
used antifungal agents [3,41,42]. Several routes to the synthesis of posaconazole have been published in the literature
[43-46]. The most likely route to large scale synthesis uses
convergent synthesis of a key chiral THF subunit 101 and
aryl piperazine amine 102 followed by introduction of the
triazole subunit at the end (Scheme 19) [44,46]. The readily
accessible allyl alcohol 94 (Scheme 18) was brominated
(PBr3) to give bromide 95 which was alkylated with sodium
diethylmalonate and the resulting diester was reduced with
NaBH4 /LiCl, to give the key diol 97 in very good yields.
After scanning many hydrolases to desymmetrize the diol via
selective acylation, hydrolase SP 435 was found to be suitable [47]. Thus reaction of the diol 97 in the presence of SP
435 with vinyl acetate in acetonitrile gave monoacetate 98 in
greater than 90% yield. Iodine mediated cyclization of the
monoacetate 98 with iodine in dichloromethane gave chiral
iodide 99 in 86% yield. The iodide was converted to triazole
(sodiumtriazole, DMF: DMPU) and immediately followed
by hydrolysis of the acetate with sodium hydroxide to provide alcohol 100. Activation of the alcohol to the pchlorobenzene sulfonate 101 proceeded in 76% yield which
was then coupled with commercially available amino alcohol
piperazine 102 with aqueous sodium hydroxide in DMSO to
give amine intermediate 103 in 96% yield. The amine was
O
O
HN
K2HPO4
OMe
+
O
N
OH
H2N
HO
N
PNP, UP
N
H
KH2PO4
K2HPO4
buffer
H2N
N
OH
30days,
87
88
47%
PNP = purine nucleoside phosphorylase
UP = uridine phosphorylase
Scheme 16. Synthesis of Nelarabine.
N
N
N
O
N
N
O
HO
OH
HO
XIII. Nelarabine
441
NHCl
NH2
O
O
CH3SCH2CONH2, THF
Me3COCl,CH2Cl2,
-65oC
-65oC
90
89
Cl
NH
O
S
CH2
NH
CO2NH2
CH3
Et3N
O
S
CH
CO2NH2
CH3
92
91
O
O
H3CS
Sommelet-Hauser rearrangement
H2N
NH2
NH2
Ra-Ni
H2N
THF, 73%
rearomatization, 43% from 89
O
93
O
XIV Nepafenac
Scheme 17. Synthesis of Nepafenac.
reacted with benzoyl chloride to give benzoate 104 (97%),
which was subsequently converted to triazine of posaconazole.
For the preparation of chiral hydrazine 107, intermediate
needed to make the triazolone, lactam 105 was reduced with
Red-Al to give (S)-2-benzyloxy propanal 106 (94%) which
was then reacted with formyl hydrazine to give hydrazone
107 in 81% yield. Addition of EtMgBr directly to formyl
hydrozones 107 gave mixture of (S,S)stereoisomer 109 and
(S,R)-diastereomer 110 in relative good diastereoselectivity
(94:6) in 55% yield. However, protection of the formyl
group as TBDMS ether 108 followed by treatment of the
EtMgCl gave 95% yield of the (S,S)-diastereomer 109 and
(S,R)-diastereomer 110 in 99:1 ratio.
For finishing off the synthesis, the formyl hydrazine 109
was coupled with the phenyl carbamate 104 in toluene at 75
- 85oC for 12 – 24 hrs. After the completion of coupling, the
intermediate was heated at 100 – 110oC for 24 – 48 hrs to
completely cyclize to the benzyloxy triazolone 108, which
was deprotected with 5% Pd/C and formic acid at room temperature overnight and 40oC for 24 h to give posaconazole
(XV) in 80% overall yield.
RAMELTEON (ROZEREM™)
Ramelteon, a melatonin receptor (MT1/MT2) agonist,
was approved in 2005 for the treatment of primary insomnia
characterized by difficulty with sleep onset. Discovered and
developed by Takeda, this drug is one of the first prescription medication in 35 years to reach US market with a novel
mechanism targeting the melatonin receptors in the suprachiasmatic nucleus to modulate the sleep/wake cycle. This drug
has shown no dependence liability and is not designated as a
controlled substance [3,48]. Several routes to the synthesis of
this drug have been published [49,50] including the process
route as shown in Scheme 20 [51].
Vilsmeier-Haack reaction on benzofuran 112 provided
aldehyde 113 (100%), which was converted to olefin 114
(88%) by Horner-Emmons reaction with triethylphosphonoacetate, and was followed by hydrogenation of the olefin to
give ester 115 (100%). In order to avoid the cyclization of
the acid chloride intermediate into the wrong position, the
benzene ring was protected by bromination. Both bromination and hydrolysis of the ester is accomplished in a single
pot to give acid 116. Thus the ester is brominated with bromine in sodium acetate and acetic acid at 0oC and RT for
442
Sakya et al.
CO2Et
OH
F
Br
F
DCM, 0oC -rt,
4h
>90%
F
THF, rt,
1.5h
>90%
F
94
F
Sodium
diethylmalonate
PBr3
CO2Et
NaBH4, LiCl
EtOH, rt,
15h
88%
F
96
95
OH
OAc
H
F
SP 435 (hydrolase)
Vinyl acetate
OH
F
I2, NaHCO3
OH
CH3CN, 0oC,
4-6h
>90%, >98%ee
F
OAc
F
CH3CN, 0oC -rt,
3h
86%
F
97
O
I
F
99
98
OCBs
OH
1. Na-Triazole
DMF:DMPU, 100oC,24h,
F
F
80%
Et3N, pClPhSO2Cl
2. NaOH, THF, rt, 90%
N
N
F
O
DCM, RT, 18h
76%
O
N
H
N
101
N
N
100
HO
N
N
N
O
NH2
N
NH2
F
aq. NaOH
102
O
DMSO, RT,
O/N
96%
N
H
N
103
N
O
OPh
N
O
N
NH
F
PhOCOCl
O
DCM, RT
97%
H
N
N
104
N
Scheme 18. Synthesis of key Intermediate 104.
several hours followed by quenching of remaining bromide
by sodium thiosulfate. The resulting acidic solution was
taken up in acetonitrile and refluxed for 2hr to provide the
acid 116 in 73% yield. The conversion of the acid to acid
chloride was done by reacting with thionyl chloride in odichlorobenzene at 40oC for 30 to 40 min after which the
reaction was cooled to 0oC . Aluminum trichloride was
added and the reaction mixture was stirred at 0oC for 30 min
to deliver cyclized ketone 117 in 92% yield. After completion of the cyclization, the bromines are removed by hydrogenation (86%) and resulting ketone 118 was then reacted
under Horner-Emmons condition with diethyl cyano phosphonate to give vinyl nitrile 119 in 84% yield. Selective reduction of the nitrile was accomplished by hydrogenation
under basic condition (sodium hydroxide in toluene) in the
presence of the activated cobalt at 25-50oC for 6.5 hr. The
amine was recovered as hydrochloride salt 120 (99% yield)
by treating the amine with HCl in methanol. In the next step,
the amine salt 120 was taken up in toluene and treated with
sodium hydroxide followed by hydrogenation of the mixture
with [RuCl(benzene)(R)-BINAP]Cl as catalyst to provide
chiral amine 121, after several work up and palladium catalyzed hydrogenations, in 73% overall yield. Final acylation
of the amine with propionyl chloride in the presence of
aqueous sodium hydroxide in THF at room temperature gave
the desired product ramelteon (XVI), after crystallization, in
97% yield.
give corresponding enamine (Scheme 21) which was reduced
with sodium borohydride in ethanol to give racemic Nbenzyl-1-inda-namine (123) in 82% yield [51]. The racemic
benzylamine 123 was resolved with L-tartaric acid and recrystallized from boiling water to give optical pure Rbenzylamine 124 as a tartarate salt. The recovered S-isomer
125 can be racemized under basic condition to give back as
the starting racemic 123. Compound 124 was hydrogenated
and basified to give free amine 126 in 72 % yield which was
alkylated with propargyl chloride and K2CO3 in hot acetonitrile to yield free resagiline. Finally resagiline mesilate
(XVII) was obtained by treating resagiline with methanesulfonic acid in refluxing IPA.
RESAGILINE MESILATE (AZILECT®)
SORAFENIB (NEXAVAR®)
Rasagiline mesylate is a potent and selective irreversible
monoamine oxidase B (MAO-B) inhibitor launched in 2005
in Israel by Teva as monotherapy in patients with early Parkinson's disease and as adjuvant treatment in moderate-toadvanced disease [52]. Lundbeck will market the drug
throughout Europe. Rasagiline is in phase II clinical trials at
Teva and Eisai for the treatment of Alzheimer's type dementia. 1-Indanone (122) was condensed with benzyl amine to
O
Sorafenib, an orally active potent multi-kinases inhibitor,
was approved in the U.S. for the treatment of advanced renal
cell carcinoma [54]. The drug targets both tumor cell proliferation and tumor angiogenesis kinases that include RAF,
VEGFR-2, VEGFR-3, PDGFR-, KIT and FLT-3. Sorafenib
is being jointly developed by Bayer and Onyx in phase III
trials as a single agent for the treatment of advanced hepato-
O
NH2NHCHO
H
-5oC
toluene, -10 to
then 0oC, 8-12h
94%
OBn
NHCHO
N
Red-Al
N
Et3N, TBDMSCl
H
Hexane, rt, 24h
OBn
TBME, rt, 24h
95%
OBn
81%
106
105
107
OTBDMS
N
N
HN
NHCHO
HN
NHCHO
EtMgCl
+
THF: toluene, 0oC - rt,
24h
95%
H
OBn
OBn
OBn
109
108
110
99:1
O
N
O
DBU,
107
+
104
4Ao
Mol Sieves
N
N
111
N
O
HCO2H, RT, O/N; then 40oC,
24h
80% 2 steps
O
N
N
F
O
F
N
N
XV Posaconazole
N
Scheme 19. Synthesis of Posaconazole.
N
O
F
5%Pd/C
N
F
toluene, 75-85oC, 12-24h;
then 100-110oC, 24-48h
443
N
N
N
OH
N
N
OBn
444
O
(EtO)2(O)P
O
POCl3
Sakya et al.
CO2Et
O
t-BuONa
DMF, 70-80oC, 2h;
80-90oC
100%
toluene, rt, 1h
88%
CHO
112
CO2Et
113
ii. aq. Na2SO3, 0oC, 20
min
iii. CH3CN, reflux, 2h
73%
CO2Et
AcOH, 50oC
100%
114
i. Br2, AcONa, AcOH, 0oC, 2h; rt,
4h
O
H2, 5% Pd/C
i. SOCl2, DMF, 42oC, 30-40 min
O
o-dichlorobenzene
Br
ii. AlCl3, 0oC, 30 min
o-dichlorobenzene
92%
CO2H
Br
115
116
O
H2, 5% Pd/C,
AcONa
O
40oC,
MeOH,
86%
Br
O
(EtO)2(O)P
O
CN
CN
O
NaOMe
toluene:MeOH, rt (4h) reflux,1 h
8h
84%
Br
118
119
117
i. NaOH, toluene
i. H2, Activated Co
NaOH
ii. H2, [RuCl(benzene)(R)BINAP]Cl
NH2.HCl
O
iii. aq HCl, 30oC, 30min
iv. NaOH, pH 6
v. H2, 5% Pd/C, 60oC, 6 h
vi. NaOH, H2O
toluene
ii. aq. HCl, MeOH, 2550oC, 6.5h
120
NH2.HCl
O
121
73%
O
i.
O
Cl
NaOH,
THF, rt, 1h
ii. Recrystallization/
pulverization
N
H
O
XVI Ramelteon
Scheme 20. Synthesis of Ramelteon.
cellular carcinoma and in combination with carboplatin and
paclitaxel in patients with advanced metastatic melanoma.
Phase II trials in combination with doxorubicin for the
treatment of advanced hepatocellular carcinoma are also
under investigation. Additional phase II trials are ongoing
for non-small cell lung cancer (NSCLC) and in postmenopausal women with estrogen receptor and/or progesterone
receptor-positive metastatic breast cancer. In addition, the
National Cancer Institute (NCI) is evaluating the compound
both as a single therapy agent and in combination with other
oncology agents in phase II trials for several cancer indications. An improved, four-step synthesis in 63% overall yield
was published recently [55] and is illustrated in Scheme 22.
Picolinic acid (127) was heated with Vilsmeier reagent for
16 hr to give 128 in 89% yield as an off-white solid. The
acid chloride 128 was treated with methylamine in methanol
at low temperature to give amide 129 in 88% yield as paleyellow crystals after its crystallization from ethyl acetate.
445
i. CH3COOH, NH2CH2Ph
benzene, reflux
L-tartaric acid
+
ii. NaBH4, EtOH, 82% two steps
NHBn
O
H2O, 70-80oC
NHBn
.
L-tartaric acid
L-tartaric acid
NHBn
.
122
123
124
tBuOH,
5% Pd/C, H2O
25 atm, 45-50oC
L-tartaric acid
NHBn
.
DMSO, 120oC, 2hr
CH3SO3H
Cl
NH2
NaOH, 72%
NH . HSO3CH3
IPA, reflux
K2CO3, CH3CN
60oC
126
124
125
XVII Resagiline mesilate
Scheme 21. Synthesis of Resagiline Mesilate.
4-Aminophenol anion was generated under a basic condition
and compound 129 was added to the anion solution to give
corresponding addition compound 131 in 87% yield. For an
unknown reason, potassium carbonate used in the reaction
increased the reaction rate significantly. Finally, compound
131 was condensed with isocyanate 132 in methylene chloride to give sorafenib (XVIII) in 92% yield as a white solid.
TAMIBAROTENE (AMNOLAKE®)
Tamibarotene, a retinoic acid receptor- (RAR) agonist,
was approved for the treatment of relapsed or refractory
acute promyelocytic leukemia (APL) in Japan on June, 2005
and is currently marketed by Nippon Shinyaku Co. This
novel drug has shown high remission rate among patients
who have recurrent disease after all trans retinoic acid therapy [3,56]. Several synthesis of tamibarotene have been disclosed in the literature [57] including the process scale synthesis as shown in Scheme 23 [57]. The synthesis started
with preparation of dichloride 134 in 82% yield from diol
133 by treating with concentrated HCL in DCM. Friedal
Crafts reaction of dichloride 134 with acetanilide in the presence of aluminum chloride at -15oC for 2h provided
acetanilide derivative 136 in 78% yield. In a single pot, the
acetanilide was reacted with PCl5 and dimethylaniline at Cl
Cl
SOCl2, DMF
N
CO2H
tBuOH,
CH3NH2/CH3OH
16 hr, 89%
N
. HCl
127
COCl
THF, 3oC, 88%
N
DMF, K2CO3
CONHMe
NH2
80oC, 87%
129
128
HO
130
NH2
CF3
O
CF3
+
CH2Cl2, 92%
Cl
Cl
O
O
N
N
CONHMe
131
Scheme 22. Synthesis of Sorafenib.
NCO
132
N
H
N
H
XVIII Sorafenib
CONHMe
446
Sakya et al.
NHAc
OH
OH
Cl
conc HCl
i. PhNMe2, PCl5,
CH2Cl2, -25oC,
NHAc
1.5 h
135
Cl
AlCl3
CH2Cl2, -15oC, 2 h
RT, 1 h
82%
ii. MeOH, -25oC -RT, 2h
iii. PhNMe2, terepthalic chloride
monomethylester, -20oC --30oC, 1h
81%
78%
133
134
136
O
O
OH
OMe
H
N
H
N
NaOH
MeOH:H2O,
reflux, 1h
92%
O
O
XIX Tamibarotene
137
Scheme 23. Synthesis of Tamibarotene.
25oC for 1.5h followed by quenching the reaction with
methanol for 2h after addition at -25oC. Addition of dimethylaniline and terepthalic chloride mono-methylester at -30 - 20oC for 1 hr provided the tamibarotene methyl easter 137 in
81% yield. Hydrolysis of the ester by heating with sodium
hydroxide in MeOH:water mixture for 1h followed isolation
and crystallization gave tamibarotene (XIX) in 92% yield.
panded broad spectrum of in vitro activity against many
Gram-positive bacteria, Gram-negative bacteria, anaerobes
and methicillin-resistant Staphylococcus aureus (MRSA). It
does not require dosage adjustment in patients with impaired
renal function and is conveniently dosed every 12 hours [59].
Synthesis of tigecycline (Scheme 24) [60] started with nitration of 138 with potassium nitrate and concentrated sulfuric
acid to give 9-nitro derivative 139 in 93 % yield as disulfate
salt, which was hydrogenated over Pd/C in 2-methoxyethanol/2N sulfuric acid at 40 psi to provide 9-aminominocycline
(140). Finally, 9-aminominocycline (140) is acylated directly
with N-tert-butylglycyl chloride in a 1:5 mixture of acetonitrile and N, N-dimethylpropyleneurea (DMPU) with anhydrous sodium carbonate to give tigecycline (XX).
TIGECYLINE (TYGACILTM)
Tigecycline, a new glycylcycline class of antibiotics, was
initially launched in 2005 for the treatment of complicated
skin and skin structure infections (cSSSI) and complicated
intra-abdominal infections (cIAI). Originally discovered and
developed by Wyeth, the intravenous antibiotic has an ex-
N
N
H
H
O
OH
OH
0oC, 1.5 hr, 93%
OH
H2, Pd/C, 2N H2SO4
MeOCH2CH2OH
40 psi, 1.5 hr, 61%
NH2
O2N
OH
O
N
H
KNO3, H2SO4
OH
NH2
OH
H
N
O
OH
O
OH
O
O
.2H2SO4
139
138
N
H
H
H
N
OH
NH2
H2N
OH
O
OH
OH
O
140
Scheme 24. Synthesis of Tigecycline.
N
O
N
O
CH3CN, DMPU
Na2CO3, 76%
Cl
H
H
N
OH
O
H
N
NH2
N
H
OH
O
XX Tigecyline
OH
OH
O
O
OH
OH
OH
O
O
O
OCH2Cl
OLi
i)
THF, 98%
OEt
NH2
OH
(POMCl)
145
OH
143
DIEA, toluene,
ii) NaOH, MeOH, 94%
447
110oC,
73%
CH3CN
141
144
142
O
OPOM
OH
OH
OPOM
N
OH 148
O
DIBAL, toluene
OPOM
OPOM
NaOCl, CH2Cl2
KBr, NaHCO3
99%
78%
149
147
146
AcO
HO
AcO
CH3
Lipase
Amano P30
MTBE
NO2
i) MsCl, DIEA,CH2Cl2
HO
+
ii) NaCH(CO2Et)2, EtOH
NO2
NO2
152
151
150
OH
EtO2C
MeO2C
i) 6N HCl, reflux, 18hr
OPOM
NaHMDS, THF
-78oC, 90%
ii) HCl, MeOH
CO2Et
CO2Me
149
NO2
NO2
NO2
153
155
154
O
OH
PCC, CH2Cl2
H2SO4/MeOH
NaOAc, Florisil
99%
84%
NO2
NaOH, MeOH
CO2Me
75%
OH
NO2
O
156
157
CF3
OH
Cl
NH2
H2, Pd/C
THF, 50 psi,
21hr
O
O
158
Scheme 25. Synthesis of Tipranavir.
O
O
CF3
OH
H
N
N
S
O
O
159
Pyridine, DMSO
78%, from 157
O
O
XXI Tipranavir
S
N
O
448
Sakya et al.
lazide in THF at low temperature gave hydroxyester 155 in
90% yield as a mixture of four diastereomers. This mixture
was oxidized with pyridinium chlorochromate (PCC) in dichloromethane to afford corresponding ketoester which was
subsequently treated with sulfuric acid in methanol to remove the POM protecting group to yield hydroxy ketoester
156 in 84% yield. Compound 156 was cyclized with NaOH
in methanol/water to afford dihydropyranone 157 in 75%
yield. The nitro group of 157 was reduced with hydrogen
over Pd/C in THF to give corresponding aniline 158, which
was finally amidated with 5-(trifluoromethyl)pyridine-2sulfonyl chloride 159 and pyridine in DMSO to give tipranavir (XXI) in 78% yield from compound 149.
TIPRANAVIR (APTIVUS®)
Tipranavir, an HIV protease inhibitor, is for the treatment
of HIV-1-infected patient with evidence of viral replication
who have HIV-1 strains resistant to multiple protease inhibitors or have extensive treatment already. The drug originally
discovered at Pfizer and then developed by Boehringer Ingelheim gained accelerated approval from FDA based on
analyses of plasma HIV-1 RNA levels in two controlled
studies of tipranavir of six months duration [61]. Synthesis
of tipranavir (Scheme 25) was assembled by an aldol condensation between two chiral key intermediates, 149 and 154
[62]. Condensation of 1-phenylhexan-3-one (141) with ethyl
acetate in the presence of butyllithium and diisopropylamine
in THF gave racemic 3-hydroxy-3-(2-phenylethyl)hexanoic
acid ethyl ester, which was directly hydrolyzed with NaOH
in methanol to corresponding free acid 142 in 94% yield.
The racemic 142 was subjected to optical resolution with (1R,
2S)-(-)-norephedrine to yield chiral compound 144 which
was alkylated with 4-biphenylyloxymethyl chloride (POMCl)
and diisopropylethylamine in toluene to give POM protected
ester 146 in 73% yield . The choice of POM protection group
is for the purification since the POM protected intermediates
were highly crystalline compounds. The ester group of 146
was reduced with diisobutylaluminum hydride in toluene to
give corresponding alcohol 147 in 78% yield, which was
oxidized with 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy
radical (TEMPO)/bleach (NaOCl) to yield corresponding
aldehyde 149 in 99% yield. The other chiral intermediate
154 was synthesized as described below. Racemic compound
150 was subjected to kinetic enzymatic resolution with a
lipase and isopropenyl acetate in dichloromethane to give
chiral alcohol 152 which was converted to its mesylate and
reacted with sodium diethyl malonate to give diester 153.
The diester 153 was decarboxylated under an acid condition
and re-esterified to give optical pure intermediate 154. Aldol
condensation of 149 and 154 with sodium hexamethyldisi-
UDENAFIL (ZYDENA®)
Udenafil, an orally active phosphodiesterase 5 (PDE5)
inhibitor with pyrazolopyramidinone core structure, was
launched by Dong-A in Korea for the treatment of erectile
dysfunction (ED). Phase III trials are expected to begin in
the U.S. in 2006. Udenafil has a unique pharmacokinetic
profile with a relatively rapid onset and sufficiently long
duration (Tmax 1-1.5 hr, t1/2 11-13 hr) to make it effective
for up to 24 hours [63]. Synthesis of this racemic compound
(Scheme 26) started with commercially available 2-propoxybenzoic acid (160) [64]. The free acid 160 was converted to
it acyl chloride with thinoy chloride in refluxing dichloromethane, which was condensed with 4-amino-1-methyl-3propyl-1H-pyrazole-5-carboxamide (161) with TEA and
DMAP in dichloromethane to yield carboxamide 162 in 85%
yield from 160. Compound 162 was sulfonated with chlorosulfonic acid to yield benzenesulfonyl chloride 163 in 67%
yield, which was treated with racemic 2-(1-methylpyrrolidin2-yl)ethylamine (164) in dichloromethane to afford sulfonamide 165 in 80% yield. Finally, compound 165 was cyclized
with t BuOK in refluxing tBuOH to give udenafil (XXII) in
81% yield.
CH3
O
CO2H
O
N
N
H2N
i) SOCl2, DCM, reflux
H2N
ClSO3H
N
O
O
CH3
N
N
O
CH3
H2N
67%
N
H
ii) TEA, DMAP, DCM, 0oC
O
N
H
S
Cl
CH3
85%
O
N
O
CH3
O
O
H2N
160
CH3
161
CH3
163
162
CH3
CH3
O
O
N
N
CH3
H2N
NH2
O
O
164
O
tBuOH,tBuOK
N
H
S
N
H
80%
N
reflux
N
CH3
O
81%
O
O
N
H
S
CH3
CH3
CH3
Scheme 26. Synthesis of Udenafil.
165
XXII Udenafil
N
N
O
N
N
HN
ABBREVIATIONS
ADME
=
Absorption, distribution, metabolism,
excretion
CDI
=
Carbonyl diimidazole
DBU
=
1,8-Diazabicyclo[5, 5,0]undec-7-ene
DCE
=
Dichloroethane
DCM
=
Dichloromethane
DEAD
=
Diethylazodicarboxylate
[8]
DIBAL
=
[9]
DIEA
=
DIPP
=
Diisopropylphosphoryl
[10]
DIPT
=
Diisopropyl tartrate
[11]
DMAP
=
[12]
DMF
=
DMPU
=
N, N-dimethylpropyleneurea
[13]
[14]
DMSO
=
Methyl sulfoxide
IPA
=
Isopropyl alcohol
MsCl
=
Methansulfonyl chloride
MTBE
=
tert-Butyl methyl ether
[5]
[6]
[7]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
NaHMDS =
Sodium bis(trimethylsilyl)amide
NCE
=
New chemical entities
O/N
=
overnight
PCC
=
PNP
=
Purine nucleoside phosphorylase
PNZCl
=
p-Nitrobenzylchloroformate
PPA
=
Polyphosphoric acid
Red-Al
=
Sodium bis(2-methoxyethoxy)aluminum
hydride
TBHP
=
tert-Butyl hydrogen peroxide
TEA
=
Triethyl amine
TFA
=
THF
=
Tetrahydrofuran
[30]
[31]
TsCl
=
Toluenesulfonyl chlodire
[32]
p-TSA
=
UP
=
Uridine phosphorylase
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1255
Kevin K.-C. Liu1,*, Subas M. Sakya2,* and Jin Li3,*
1
Pfizer Inc, La Jolla, CA 92037, USA; 2Pfizer Inc, Groton, CT 06340, USA; 3 Shenogen Pharma Group, Beijing, China
for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 16
NCEs marketed in 2006.
INTRODUCTION
Inaugurated five years ago, this annual review presents
in the previous articles [2-5]. Briefly, drugs that are approved
new chemical entities and their syntheses will greatly enhance our abilities to design new drug molecules in shorter
period of time. With this hope, we continue to profile these
NCEs that were approved in 2006.
In 2006, 41 new products including new chemical entities, biological drugs, and diagnostic agents [6] reached the
market. Another nine new products were approved for the
first time in 2006 but were not launched before year end.
Syntheses of those drugs will be covered in 2007’s review.
The current article will focus on the syntheses of 16 new
drugs marketed last year (Fig. 1), while excluding new indications for known drugs, new combinations and new formulations. Drugs synthesized via bio-process and peptide synthesizers will also be excluded as well. The syntheses of
these new drugs were published sporadically in different
journals and patents. The synthetic routes cited here represent the most suitable methods based on the author’s judgment and appear in alphabetical order by generic names.
Anecortave Acetate (Retaane®)
Anecortave acetate, an angiogenesis inhibitor, was launched in Australia by Alcon for the treatment of age-related
macular degeneration (AMD). AMD is the leading cause of
untreatable blindness among people aged 65 to 74 years in
the U.S. Worldwide, approximately 20 to 25 million people
*Address correspondence to these authors at Pfizer Inc, La Jolla, CA 92037,
USA; Tel: 858-622-7391; E-mail: [email protected]
Pfizer Inc, Groton, CT 06340, USA; Tel: 860-715-0425;
Shenogen Pharma Group, Beijing, China; Tel: 8610-8289-8780;
1389-5575/07 $50.00+.00
suffer from AMD, a disease that until recently was untreatable. Anecortave, an angiostatic steroid, down-regulates the
expression MMP-2 and -9 to exert its antiangiogenic effects
[7]. Anecortave has been synthesized by several different
routes, and Pharmacia process patents are cited here [8,9].
The synthesis is depicted in Scheme 1. Compound 1 was
condensed with 2-chlorovinyl ethyl ether with n-BuLi in
THF at low temperature to give a mixture of two isomeric
aldehydes 2 in 91% yield [8]. The mixture 2 was treated with
acetic anhydride and anhydrous potassium acetate in DMF at
106oC to give acetate 3 which was reacted with RhCl(PPh3)3
and triethylsilane in methylene chloride at 45oC for 4 hours
to yield the corresponding triethylsilane ether 4 as a solid
after crystallization in hexane. Finally, compound 4 was oxidized with 40% peracetic acid in toluene at low temperature,
and the reaction was quenched with SO2 in methanol (2M),
and treated with TEA to give anecortave acetate [9].
Darunavir (Prezista™)
Darunavir (TM-114) is a potent HIV protease inhibitor
that has been shown to be efficacious in both wild type and
resistant forms of HIV with low toxicity. With increased use
of both protease inhibitors and reverse transcriptase inhibitors, there has been an increased level of resistance to most
commonly used anti-HIV agents. Darunavir, developed and
marketed by Tibotec, has so far shown excellent efficacy
against the HIV-1 strains that show resistance to other approved protease inhibitors [6,10]. Several routes to the synthesis of darunavir have been reported utilizing the chiral
hexahydro-furo[2,3-b]furan-3-ol carbonate 12 [11-13] and
several chiral syntheses of bisfuranol 12 have been disclosed
as well [12-15]. One route that has been performed on kilogram scale is highlighted in Scheme 2 [13]. Thus 2,3-Oisopropylidene-glyceraldehyde 5 was stirred with dimethyl
malonate at RT for 3 h in tetrahydrofuran followed by addition of pyridine and heating to 45ºC. Then acetic anhydride
was added at 45ºC over 4h and stirred at that temperature for
12 h. Concentration of the reaction followed by basic
workup and extraction with toluene and solvent swap to
methanol gave the products as a 23.6% solution in methanol.
Nitromethane was added to this methanol solution followed
by the addition of DBU over 30 min keeping the reaction
temperature below 25ºC. Stirring the reaction for an additional 3 h afforded intermediate 7. The reaction was cooled
Liu et al.
O
O
O
O
OH
H
O
NH2
Ph
O
O
N
H
O
N
S
O
OH
H
O
Darunavir (II)
Anecortave acetate (I)
O
NH2
N
N
H
N
N
H
S
Cl
N
N
O
N
O
OH
N
N
O
N
O
O
HO
OH
HO
HO
Decitabine (IV)
Dasatinib (III)
F
F
Lubiprostone (V)
HCl
O
O
N
O
OH
O
N
N
H
H
N
N
N
O
Ranolazine (VII)
Mozavaptan hydrochloride (VI)
O
Cl
N
H
N
N
H
N
O
N
N
S
O
N
CF3
Cl
H2N
O
OH
OH
Cl
Silodosin (X)
Rotigotine (IX)
Rimonabant (VIII)
O
F
S
F
NH2
O
O
N
F
H3PO4
O
N
N
N
O O
O
S
O
N
F
N
H
N
Cl
Na
N
N
H
OH
O
HO
OH
O
N
H
O
CF3
Sitagliptin phosphate (XI)
Sunitinib malate (XIII)
Sitaxsentan sodium (XII)
O
HN
O
N
O
O
N
HO
CO2H
NH
HO
N
HO
HO
Telbivudine (XIV)
Varenicline tartrate (XV)
CO2H
H
N
N
H
O
Vorinostat (XVI)
OH
O
Cl
O
H3C
O
H3C
H3C
Cl
OEt
H
H3C
H3C
H3C
H
CH3
H
H
O
O
O
91%
1
H
DMF, 106oC
i. n-BuLi, -45oC
ii. 6N HCl
O
O
Ac2O, AcOK
2
3
O
Si(Et)3
O
H3C
H3C
H
OH
AcOOH(40%)
H3C
H
CH3
Toulene, 0-5oC
H
triethylsilane
CH2Cl2, 45oC
CH3
H3C
O
O
RhCl(PPh3)3
O
O
H
O
O
Anecortave Acetate (I)
4
Scheme 1. Synthesis of Anecortave Acetae.
MeO2C
O
H
CO2Me
O
O
O
ii. AcOH, rt, 2h
+
OMe
O
O
9
1h
7
HO
i. LiBH4, THF,
50oC, 2h
O
OMe
O
8
O2N
O
i. KOH/H2O
reflux, 2h
COOMe
HO
MeOH. 0oC-10oC
3h
6
MeOOC
COOMe
CO2Me
O
MeOH, rt
12h
5
i. NaOMe, 0oC,
0.5h
ii. conc. H2SO4
CO2Me
O
CO2Me
O
45oC
THF, rt -
O
CO2Me
O
Py, Ac2O
CH3NO2,
cat DBU
OMe
O
ii. Conc HCl,
THF, -10 -0oC
O
11
10
O
O
O
O
O
Disuccinimidyl carbonate, Et3N
CH3CN, rt, 3h
O
O
12
BOC
NH2
O
H
N
pNO2C6H4SO2Cl,
aq. NaHCO3
OH
BOC
14
H
N
H
N
23oC,
Ph
13
iPrOH, 84oC
6h. 99%
1 atm H2, 10%Pd/C
H
N
N
O
Ph
17
Scheme 2. Preparation of Darunavir.
BOC
i. TFA, CH2Cl2, rt, 40
min
12h,
Ph
O
O
N
S
16
NH2
OH
H
N
O
N
S
O
ii. 12, Et3N
CH2Cl2, rt, 3h,
89%
O
O
15
NH2
OH
BOC
EtOAc, rt, 11h,
95%
Ph
CH2Cl2,
96%
NO2
OH
H
N
O
O
Ph
Darunavir (II)
S
O
to 0ºC and sodium methoxide was added dropwise over 30
min After stirring the reaction for 30 min, the reaction was
added slowly over 1h to conc. H2SO4 in methanol at 0oC
while ensuring the temperature did not exceed 10oC. This
cooled reaction mixture (0ºC) was then added to a vigorously
stirred mixture of ethyl acetate and 1N sodium hydrogen
carbonate at 0oC. The organic layer was separated, washed
with brine and concentrated to give the residue containing a
mixture of 8 and 9. This mixture was dissolved in methanol
then water and potassium hydroxide were added and the resulting mixture was heated at reflux for 2 h. The reaction
was cooled to 35ºC and acetic acid was added and the resulting mixture concentrated. Additional acetic acid was added
and stirred at room temperature for 2 h. The mixture was
concentrated, diluted with water and extracted with ethylacetate. The ethylacetate layer was washed with 1N sodium bicarbonate three times and the organic layer was concentrated
and diluted with isopropanol. The isopropanol mixture was
then heated to 60-70ºC and further evaporation of isopropanol under reduced pressure to a concentrated volume with
cooling to 0ºC over 4-5 h, allowed for the crystallization of
product 10. After filtration and drying, the intermediate lactone 10 was dissolved in THF and treated over 30 min with a
solution of lithium borohydride in THF. The reaction was
warmed to 50ºC over 1 h and stirred at that temperature for
2h. The resulting suspension was cooled to -10ºC and conc.
HCl was added slowly over 4h, while maintaining the temperature below 0ºC. Solvent swap was done by concentrating
to a small volume and addition of ethyl acetate and further
concentration of the solvent with continuous addition of ethylacetate. Following this procedure, when the final ratio of
THF:ethylacetate reached 4:1 ratio, the mixture was cooled
to 0ºC and filtered off while washing the filter cake with
more ethylacetate. Concentration of the filtrate to dryness
gave the hexahydro-furo [2,3-b]furan-3-ol 11 which was
confirmed by NMR and chiral gas chromatography. Carbonate intermediate 12 was prepared in 66% yield by treating 11
with disuccinimidyl carbonate at RT for 3h in the presence
of triethylamine [13]. Since the process scale synthesis of
darunavir has not been disclosed, the latest reported synthesis is highlighted [13]. The commercially available epoxide
13 was mixed with isobutyl amine in isopropanol at RT and
refluxed for 6h. The reaction was concentrated and purified
by chromatography to provide amine 15 (99%). p-Nitrophenyl sulfonyl chloride was added to a mixture of the amine 15
in dichloromethane and saturated aqueous bicarbonate at RT
and stirred for 12 h to give sulfonamide 16 in 96% yield after
purification. Hydrogenation of 16 with 10% Pd/C under 1
atm hydrogen for 11h at room temperature gave aniline 17 in
95% yield. The BOC group was removed by treating 17 with
TFA in dichloromethane and the resulting amine was reacted
with carbonate 12 in the presence of triethylamine for 3h to
provide the desired darunavir (II) in 89% yield.
Dasatinib (SprycelTM)
Dasatinib, developed and marketed by Bristol Myers, is
the first approved oral tyrosine kinase inhibitor which binds
to multiple conformations of ABL kinase for the treatment of
two leukemia indications: chronic myeloid leukemia (CML)
and Philadelphia chromosome-positive acute lymphoblastic
leukemia (Ph+ ALL) [16]. Dasatinib is a highly potent, ATP-
Liu et al.
competitive kinase inhibitor which, at nanomolar concentrations, inhibits BCR-ABL, SRC family, c-KIT, EPHA2 and
PDGFR-B. A concise and efficient route (Scheme 3) was
developed for the synthesis of dasatinib [17,18]. Reaction of
2-chlorothioa-zole (18) with n-butyllithium at low temperature followed by addition of 2-chloro-6-methylphenyl isocyanate (19) gave anilide 20 in 86% yield. The amide 20 was
protected as corresponding 4-methoxy benzyl (PMB) anilide
22 in 95% yield which was subsequently reacted with 4amino-6-chloro-2-methylpyrimidine (23) in the presence of
sodium hydride in hot THF to give compound 24 in 83%
yield. The PMB protecting group was then removed with
triflic acid to give compound 25 in 99% yield. Compound 25
was reacted with 1-(2-hydroxyethyl)piperazine (26) in refluxing dioxane to give dasatinib (III) in 91% yield.
Decitabine (DacogenlTM)
SuperGen’s decitabine was approved for the treatment of
myelodysplastic syndromes (MDS) and exerts its antineoplastic effects by incorporation into DNA and inhibition of
DNA methyltransferase in rapidly dividing cells. However,
non-proliferating cells are relatively insensitive to this agent
[19]. Silylated 5-aza-cytosine (28) was condensed with 9fluorenylmethoxycarbonyl (Fmoc) protected 2-deoxy-1-chlororibose (27) with tin chloride (IV) in dichloroethane (Scheme
4). The coupled product 29 was de-protected with excess
triethylamine in dry pyridine to give decitabine (IV) in 36%
yield after separation from its corresponding isomer [20].
Lubiprostone (AmitizaTM)
Lubiprostone, developed by Sucampo Pharmaceuticals
and jointly marketed with Takeda, represents a novel pharmacotherapy for the treatment of chronic idiopathic constipation which is a form of constipation characterized by difficult
passage of stools for a period of at least of 3 months. It is the
first selective chloride channel (ClC-2) activator on the market and works by exerting its effects through increasing fluid
secretion and motility in the intestine to alleviate symptoms
associated with chronic idiopathic constipation [21]. Synthesis of lupiprostone started with the tetrahydropyran (THP)
protected (-)Corey lactone 30 [22] (Scheme 5). Desilylation
of 30 with TBAF in THF gave free carbinol in 82% yield
which was oxidized with oxalyl chloride and DMSO to give
corresponding crude aldehyde 31. Aldehyde 31 was condensed with dimethyl 3,3,-difluoro-2-oxoheptylphosphonate
(32) in the presence of thallium ethoxide to give unsaturated
difluoroketone 33 which was hydrogenated with H2 over
Pd/C in ethyl acetate and the resulting ketone was subsequently reduced with sodium borohydride in methanol to
give lactone 34 in excellent yield. The lactone 34 was reduced to lactol 35 with DIBAL at -78oC in toluene and the
crude lactol 35 was condensed with 4-carboxybutyl triphenylphosphonium bromide (36) in the presence of t-BuOK in
THF to yield compound 37. Crude 37 was reacted with benzyl bromide and DBU in dichloromethane (DCM) to give the
benzyl ester in 96% yield. Oxidation of the alcohol with
Collins reagent and removal of the THP protecting group
under acidic conditions gave corresponding prostaglandin E2
benzyl ester 38. Finally, compound 38 was submitted to simultaneous benzyl ester group cleavage and double bond
hydrogenation with H2 over Pd/C in ethyl acetate to give
lubiprostone (V) in 94% yield.
OMe
Cl
S
N
CH3
n-BuLi, THF, -78oC
N
H
N
NCO
18
Cl
Cl
19
NaH, THF, reflux
N
Cl
Cl O
N
S
Cl
CH3
CH3
TfOH, TFA
N
N
H
O
22
95%
N
N
Cl
21
OMe
CH3
S
MeO
O
20
86%
Cl
N
S
CH3
N
CH3
NaH, THF
Cl
NH
CH2Cl2, 99%
Cl
CH3
Cl O
N
N
S
N
N
H
Cl
CH3
N
24
23
H2N
25
83%
CH3
OH
N
NH
dioxane, reflux
HN
CH3
26
Cl O
91%
N
S
N
N
N
H
N
N
Dasatinib (III)
OH
Scheme 3. Synthesis of Dasatinib.
Mozavaptan (Physuline®)
Mozavaptan is a vasopressin V2 antagonist developed by
Otsuka Pharmaceutical Co. in Japan for the treatment of hyponatremia in patients with inappropriate anti-diuretic hormone (ADH) secretion syndrome. This tends to occur in patients with tumors with ectopic ADH production and others
with liver failure, cardiac failure and volume contraction
in 97% yield. Reaction of the resulting benzazepine 41 with
p-nitrobenzoyl chloride (42) in the presence of triethylamine
provided amide 43 which was hydrogenated in the presence
of 10% Pd/C in ethanol at room temperature to give aniline
44. Acylation of aniline 44 with 2-methylbenzoylchloride
(45) in the presence of triethylamine gave mozavaptan (VI)
in 54% yield.
NH2
NH2
N
SiMe3
HN
O
Cl
Fmoc-O
Fmoc-O
+
N
SnCl4
N
O
N
Me3SiO
N
ClCH2CH2Cl
O
Fmoc-O
O
TEA 15 eq
N
O
HO
pyridine, 1 hr
36%
N
N
N
HO
Fmoc-O
27
28
29
Decitabine (IV)
Scheme 4. Synthesis of Decitabine.
[6,23]. The reported synthesis of mozavaptan is shown in
Scheme 6 [24,25]. Readily available benzazepin-5-one 39
[26] was refluxed with 40% methyl amine methanol solution
in the presence of molecular sieves for 5h followed by the
reduction of the resulting imine with sodium borohydride to
give the monomethyl amine. Reductive alkylation of the
monomethyl amine with formaldehyde in the presence of
sodium cyanoborohydride gave the dimethyl amino benzazepine 40. Removal of the tosyl group was facilitated by
heating 40 in polyphosphoric acid at 150oC for 2 h to give 41
Ranolazine (Ranexa™)
Ranolazine, developed by CV therapeutics after licensing
it from Roche (Syntex), is a late stage sodium channel
blocker approved in March 2006 for the treatment of chronic
angina. The compounds anti-angina and anti-ischemic affects
do not depend on reductions in heart rate or blood pressure.
Because of the potential for QT prolongation, the drug is
indicated for treating patients that do not get adequate response with other anti-anginal drugs [6,27]. Two syntheses,
one from the inventors at Roche [28] and other from a group
Liu et al.
O
O
O
i.TBAF, THF, 82%
O
F
MeO
P
O
O
OMe
CHO
ii. (COCl)2, CH2Cl2
DMSO
OTMS
O
C4H9-n
OH
C4H9-n
F
OTHP
O
DIBAL, -78oC
C4H9-n
F
36
F
F
OTHP
F
35
HO
O
OH
toluene
34
OH
CO2H
F
O
i.PhCH2Br, DBU, DCM, 96%
F
ii.CrO3. Py, CH2Cl2, 78%
F
C4H9-n
t-BuOK, THF
37
O
HO
38
O
O
OH
O
O
OH
F
H2, Pd/C, EtOAc
94%
HO
F
O
O
HO
F
F
CH3
Lubiprostone (V)
Scheme 5. Synthesis of Lubiprostone.
O
i. MeNH2, 4Ao MS,
MeOH, reflux, 5h
Me2N
Me2N
ClOC
ii. NaBH4, MeOH,
0-4oC, 1h
N
Ts
PPA
iii. 37% HCHO,
NaBH3CN, AcOH,
MeOH, rt, 1h
39
N
150oC,
41
40
78%
Me2N
Me2N
Et3N/ DCM, 0oC -rt,
1h
N
H
97%
Ts
NO2
42
2h
Me2N
ClOC
N
45
1 atm H2, 10% Pd/C
O
N
N
EtOH, rt, 5h
DCM, Et3N, 0 - 5oC, 0.5h
O
O
43
NO2
Scheme 6. Synthesis of Mozavaptan.
54%
NH2
44
CO2Bn
C4H9-n
iii. AcOH, H2O, THF = 3:1:1
50oC, 93%
OH
THPO
F
33
HO
O
F
OTHP
31
ii. NaBH4, MeOH, 99%
Ph3P Br
O
32
TlOEt, CH2Cl2, 44%
O
i. H2, 5%Pd/C, EtOAc, 98%
CH3
OTHP
OTHP
30
O
F
NH
Mozavaptan (VI)
O
O
Cl
NH2
HN
H
N
Cl
46
O
ii. HCl/MeOH
73%
50
(No yield given)
48
Taken forward as crude
O
Cl
O
N
OH
O
52
NaOH
OH
O
NH
EtOH,
reflux, 2h
O
82%
H
N
i. 53, iPrOH,
reflux, 3h
N
49
Cl
47
CH2Cl2,Et3N
0oC, 4h
H
N
NH
N
O
O
O
H2O,:dixane,
reflux, 3h
O
.2HCl
53
(No yield given)
51
Ranolazine (VII)
(purified by distillation)
Scheme 7. Synthesis of Ranolazine.
Rimonabant (Acomplia®)
in Hungary [29], of Ranolazine have been described in the
patent literature. The original synthesis is highlighted in
Scheme 7. Reaction of 2,6-dimethylaniline 46 with chloroacetyl chloride (47) in the presence of triethylamine for 4h at
0ºC gave amide 48 in 82% yield. This chloro amide 48 was
reacted with piperazine in refluxing ethanol for 2 h to give
piperazinyl amide 50. Reaction of amide 50 with epoxide
intermediate 53, prepared by reacting 2-methoxy phenol 51
with epichlorohydrin, in refluxing isopropanol for 3 h followed by treatment with HCl/methanol gave ranolazine dihydrochloride (VII) in 73% yield.
Rimonabant is a central cannabinoid receptor 1 (CB-1)
antagonist developed by Sanofi-Aventis and approved for the
treatment of obesity in Europe. It’s currently under review in
the US. The inhibition of the endocannabinoid pathway,
which is believed to play an important role in the control of
appetite signals, reduces food intake and thus may aid in
obesity control [6,30,31]. The reported preparation of rimonabant, both in small and large scale, is shown in Scheme
8 [32]. Lithium enolate formation of p-chlorophenyl ethyl
Cl
Cl
i. LiHMDS
O
Cl
THF, -78oC,
45 min
H2NHN
O-Li+
Cl
O
N
OEt
Cl
OEt
O
55
57
Cl
O
SOCl2
Cl
KOH
Cl
AcOH,reflux, 24h
Cl
Cl
N
N
N
toluene,
reflux, 3 h
N
MeOH:H2O,
reflux, 3h
EtO
HO
O
O
58
Cl
59
Cl
Cl
Cl
HN
Cl
EtOH, rt, 16 h
ii. (CO2Et)2,
-78oC - rt, 16 h
54
Cl
56
O
Cl
N
N
i.
H2N
N
CH2Cl2, rt, 3h
ii. HCl/Et2O
O
60
Scheme 8. Synthesis of Rimonabant.
Cl
, Et3N
N
N
61
Cl
Cl
.HCl
HN
N
O
Rimonabant (VIII)
Liu et al.
ketone 54 with LiHMDS in THF at -78ºC for 45 min followed by reaction with diethyl oxalate at -78ºC and warming
to room temperature over 16 h provided the lithium enolate
salt of the diketoester 55. Reaction of diketoester salt 55 with
2,4-dichlorophenyl hydrazine (56) in ethanol at room temperature gave intermediate hydrazone 57 which is then cyclized in refluxing acetic acid for 24 h to obtain pyrazole
ester 58. Hydrolysis of ester 58 with KOH in refluxing
methanol:water mixture gave acid 59 which was then converted to the acid chloride 60 with thionyl chloride in refluxing toluene in very good yield. On scale, the synthesis of the
acid chloride was performed in cyclohexane at 83ºC. Reaction of acid chloride 60 with 1-aminopiperidine (61) in the
presence of triethylamine at 0ºC to room temperature over 3h
gave rimonabant (VIII) which was isolated as the HCl salt
by treating it with HCl in ether.
Rotigotine (Neupro®)
Rotigotine is a nonergolinic dopamine D2/D3 receptor
agonist that was developed and approved for marketing in
Europe for the treatment of Parkinson’s disease. It was developed jointly by Aderis Pharmaceuticals and Swartz Pharmaceuticals as a transdermal patch for an once daily application [6]. The synthesis described by the originators at Discovery Therapeutics Inc. (now known as Aderis Pharmaceuticals) is shown in Scheme 9 [33]. The synthesis utilizes the
chiral methoxy tetralin 62 as starting precursor which was
obtained via chiral crystallization procedure described in a
patent literature [34]. Demethylation of tetraline 62 with
refluxing 40% HBr solution for several hours provided phenol 63 in 96% yield [35]. Reaction of the amine 63 with 2thiophenylethyl tosylate 64 in refluxing xylene for 24-32 h in
the presence of 0.6 equiv sodium carbonate gave the desired
rotigotine (IX) without requiring chromatographic purification. The ratio of sodium carbonate to the amine was critical
to achieving good yields (59-84% yield) without requiring
extensive purification. Rotigotine was isolated as the HCl
salt.
Silodosin (Urief)
Silodosin (KMD 3213) is an 1a receptor subtype inhibitor indicated for the treatment of urinary disturbances due to
urethral resistance from enlarged prostate. It was developed
by Kissei and jointly marketed with Daiichi in the Japanese
market since approval in 2006 [6,36]. The synthesis of silodosin has been disclosed in several patents [37-39]. The latest synthetic route disclosed in the 2006 patent is highlighted
in Scheme 10 [38d]. The synthesis started with Grignard
generation from readily available bromoindoline 65 by treating it with Mg in the presence of a catalytic dibromoethane
in THF. After initiation of the reaction with some heat and
refluxing at a steady rate, CBZ protected oxazolidinone 66
[39b] was added over 1 h, refluxed for 4 h and then stirred at
room temperature for 2 days. The reaction was quenched
with 6 M aqueous HCl and stirred for 12 h after which time
the reaction was worked up to provide product 67 in 53%
yield. Ketone 67 was then treated with triethylsilane in TFA
at 0ºC and stirred at room temperature for 10 h to provide
amine 68 in 61% yield. Bromination of the indoline 68 with
bromine in warm acetic acid furnished bromide 69 in 53%
yield which was reacted with copper cyanide in DMF at
130ºC to give the cyano indoline 70 in 82% yield. Selective
deprotection of the benzyloxycarbonyl over the benzyl group
was accomplished by reacting indoline 70 with 1 atm hydrogen in the presence of 5% Pd/C in ethanol at room temperature. The resulting free amine 71 was then reacted with mesylate 72 [37] in t-butanol with sodium carbonate as base at
80-90ºC for 46 h to provide 73 in 67% yield. Removal of the
benzyl ether was accomplished by reacting 73 with 1 atm
hydrogen in the presence of 10%Pd/C to give alcohol 74,
which upon hydrolysis provided the desired silodosin (X).
No yield for the final reaction was given.
Sitagliptin Phosphate (JanuviaTM)
Sitagliptin is the first novel dipeptidyl peptidase IV inhibitor from Merck for the treatment of type 2 diabetes without weight gain and the incidence of hypoglycemia was similar to placebo. Sitagliptin acts by enhancing the body’s incretin system, which helps to regulate glucose by affecting and cells in the pancreas [40]. Synthesis of sitagliptin
[41,42] started with the slow addition of chloropyrazine (75)
to 35% aqueous hydrazine at 60-65oC, controlling this exothermic reaction and making it process-friendly, and the resulting crude pyrazinyl hydrazine was acetylated with trifluoroacetic anhydride to afford bis-trifluoromethylhydrazide
76 in 49% yield from the chloropyrazine (Scheme 11). Compound 76 was treated with superphosphoric acid, a diluted
form of polyphosphoric acid, to give cyclized compound 77
which was hydrogenated with Pd/C and the resulting product
was treated with HCl in IPA to afford compound 78 as its
HCl salt in 51% yield from 76. Compound 78 was used later
on in a coupling reaction to generate sitagliptin. Compound
79, a beta-ketoester, was subjected to asymmetric reduction
with (S)-BinapRuCl2-triethylamine complex in methanol at
80oC, catalytic amount of hydrogen bromide, and 90 psi of
hydrogen atmosphere to give the desired beta-hydroxy ester
S
OTs
NH
40% HBr,
reflux, 2-3h
NH
i.
Na2CO3
N
64
xylene, reflux, 24h
OH
O
62
Scheme 9. Synthesis of Rotigotine.
ii. HCl/MeOH
63
OH
Rotogotine hydrochloride (IX)
S
O
Br
NHCBz
i. Mg, THF
NHCBz
cat (BrCH2)2
Et3SiH
Br2
N
N
ii.
O
N
O
OBn
65
reflux 4h
66
68
NH2
NHCBz
CuCN, NaI
N
DMF,
69
1 atm H2,
5%Pd/C
N
130oC
46h, 82%
BnO
4h, 53%
67
53%
NHCBz
Br
OBn
10h, 61%
OBn
N
CBz
AcOH, 40oC,
TFA, 0oC - rt
CN
BnO
MsO
85%
F3C
CN
EtOH, rt
70
O
N
O
72
Na2CO3
BnO
tBuOH, 80-90oC
71
46h, 67%
OCH2CF3
OCH2CF3
O
OCH2CF3
O
1 atm H2,
10%Pd/C
O
H2O2, NaOH
HN
HN
HN
EtOH, rt, 3h
DMSO, rt
80%
CN
N
CN
N
OBn
73
CONH2
N
OH
74
Silodosin (X)
OH
Scheme 10. Synthesis of Silodosin.
which was hydrolyzed to give carboxylic acid 80 in 94% e.e.
and 83% yield. The carboxylic acid 80 was coupled with
BnONH2-HCl in the presence of EDC and lithium hydroxide
in THF/H2O to give coupled compound 81 which was cyclized to compound 82 with DIAD and triphenylphosphine
in THF in 81% yield from compound 80. Compound 82 was
then hydrolyzed to -amino acid 83 with lithium hydroxide,
and the acid was coupled with compound 78 at 0oC with
EDC-HCl and NMM as base to give compound 84 in excellent yield. Compound 84 was hydrogenated with 10% Pd/C
in an ethanol/H2O mix solvent system. The water was crucial
to complete the reaction and restore catalyst activity. Finally,
the ethanol solution of the hydrogenated product was treated
with phosphoric acid, and sitagliptin (XI) was crystallized as
its anhydrous phosphoric acid salt from aqueous ethanol solution.
Sitaxsentan Sodium (Thelin®)
In November Encysive Pharmaceuticals launched Thelin®
(sitaxsentan sodium) in the U.K. for the treatment of pulmonary arterial hypertension (PAH), following European Commission approval in August 2006. Sitaxsentan is the first
selective endothelin A (ETA) receptor antagonist, and the
first once-daily oral treatment available for patients with
PAH. It is 6,500-fold selective in the targeting of ETA ver-
sus ETB receptors. Sitaxsentan is indicated for improving
exercise capacity in PAH patients classified as World Health
Organization (WHO) functional class III. Efficacy has been
shown in primary pulmonary hypertension and pulmonary
hypertension associated with connective tissue disease. In
the U.S., Encysive has submitted a complete response to an
approvable letter received from the FDA in July. The synthesis of sitaxentan is depicted in Scheme 12. 5-amino-3methylisoxazole 85 was treated with NCS in DCM at 0°C to
give chloroisoxazole 86 in 87% yield. The amine was then
coupled with the commercially available 2-(methoxycarbonyl)-3-thiophenesulfonyl chloride (87) using sodium hydride
in THF at 0°C. The resulting ester was directly hydrolyzed in
1N NaOH to furnish acid 88 in 45% yield [43]. The acid 88
was then coupled with N,O-dimethylhydroxylamine to give
Weinreb amide 89. The amide 89 was then treated with benzylic Grignard reagent followed by acidic workup to give the
sitaxentan XII in 50% yield in two steps. The Grignard reagent 90 was prepared through the following sequence. The
5-methylbenzodioxole 91 was treated with aqueous formaldehyde and concentrated HCl in ethyl ether to give the desired benzyl chloride 93 and condensation product 92. The
mixture of 92 and 93 was used to form the Grignard reagent
without separation [44].
Liu et al.
O
O
35% Hydrazine(aq)
Cl
O
F3C
CF3
O
N
CF3
N
N
60-65oC
N
Superphosphoric acid
NH
N
O
49% (two steps)
N
N
CF3
N
N
CF3
75oC
77
75
76
N
HN
i. H2, 10% Pd/C, EtOH
N
ii. HCl, IPA
HCl
N
CF3
51% from 76
78
F
F
F
O
O
i. (S)-BinapRuCl2, 48%HBr(aq)
H2, MeOH, 80oC, 90 psi
F
OH
O
BnONH2-HCl, EDC
OMe
F
OH
ii.NaOH, MeOH/H2O
LiOH, THF/H2O
F
83%, 94% e.e.
79
80
F
F
F
F
F
HO
OBn
N
O
DIAD, PPh3, THF
O
OBn
F
HN
LiOH
O
OH
THF/H2O
NHOBn
81%
F
F
F
83
82
81
F
F
EDC-HCl, NMM, CH3CN
F
OBn
HN
i. H2, 10% Pd/C
EtOH/H2O
O
0 oC
N
HCl
N
F
N
CF3
99%
NH2
O
N
N
N
N
N
HN
F
N
CF3
ii. H3PO4
82% yield two steps
F
H3PO4
N
N
CF3
XI Sitagliptin phosphate
84
78
Scheme 11. Synthesis of Sitagliptin.
Sunitinib Malate (Sutent®)
Sunitinib, an orally active multi-tyrosine kinase inhibitor
from Pfizer, was approved for the treatment of gastrointestinal stromal tumors (GIST) after disease progression on or
intolerance to imatinib mesylate and advanced renal cell carcinoma (RCC). This was the first time that FDA simultaneously granted two indications for a new oncology drug.
Sunitinib is a potent inhibitor of platelet-derived growth factor receptors (PDGFR and PDGFR), vascular endothelial
growth factor receptors (VEGFR1, VEGFR2 and VEGFR3),
stem cell factor receptor (KIT), Fms-like tyrosine kinase-3
(FLT3), colony stimulating factor receptor Type 1 (CSF-1R),
and the glial cell-line derived neurotrophic factor receptor
(RET). [45]. The commercially available 3-oxobuturic acid
tert-butyl ester (94) was condensed with sodium nitrite in
acetic acid to give corresponding hydroxyimine 96 which
was treated with 3-oxobutyrate ethyl ester in the presence of
zinc dust in acetic acid to give cyclized compound 97 in 65%
yield from 94 (Scheme 13). Compound 97 was subjected to
hydrolytic decarboxylation and formylation with trifluoroacetic acid and triethylorthoformate to give compound 98 in
64% yield which was hydrolyzed with potassium hydroxide
to give corresponding acid 99 in 93% yield. Acid 99 was
coupled with 2-(diethylamino)ethylamine (100) with EDC,
HOBT in DMF to give amide 101. The oxindole 104 was
prepared from 5-fluoroisatin (102) by heating 102 with neat
hydrazine hydrate to give hydrazide 103 which was cyclized
under acid to provide 5-fluorooxindole (104). The crude amide 101 was finally condensed with oxindole 104 in the presence of pyrrolidine in ethanol at 80oC and the resulting product (SU011248) was treated with L-malic acid to provide
sunitinib malate (XIII) [46].
O
Cl
S
Cl
NCS, DCM, 0oC
N
H2N
H2N
87%
O
N
86
O
S
N
O
rt
Cl
N
O
CDI, CH3NHOCH3, THF
88
45%
Cl
N
O
MgCl
+
H
O
S
N
O
O
O
H
CO2H
S
ii. NaOH
85
N
O
87
i. NaH, THF, 0oC
O
O
S
CO2Me
S
N
O
O
Cl
H
O
S
N
O
S
OMe
Mg
89
O
O
XII Sitaxentan
90
Cl
HCHO, HCl, Et2O
+
O
O
O
O
O
O
O
O
91
92
93
Scheme 12. Synthesis of Sitaxentan.
Telbivudine (TyzekaTM in US; Sebivo® in Switzerland)
third of whom have potentially progressive and life-threatening liver disease associated with the infection. Chronic
hepatitis B infection can lead to cirrhosis, liver failure and
There are approximately 400 million people worldwide
with chronic hepatitis B virus (HBV) infection, about one-
O
EtO
NOH
O
CH3
O
O
NaNO2, AcOH
94
O
OEt
H3C
H
O
OH
N
H
100
EDC, HOBT, Et3N, DMF
O
F
104
N
H
L-malic acid
F
N
H
pyrrolidine, ethanol, 80oC
N
H
N
H
101
O
O
F
NH2NH2.H2O
F
O
Sunitinib malate (XIII)
F
O
N
H
NH2
103
104
O
OH
O
NHNH2
reflux
Scheme 13. Synthesis of Sunitinib Malate.
OH
HO
HCl, H2O
O
102
N
N
H
O
N
H
N
H
N
H2N
99
N
H3C
H
N
H
O
O
98
O
O
97
93%
O
OEt
O
MeOH: H2O = 3:10
N
H
TFA, 64%
96
65oC
65% from 94
4N KOH
HC(OCH3)3
H
O
95
O
H3C
O
Zn, AcOH,
<15oC to rt
O
CH3
O
CH3
H3C
Liu et al.
but not human polymerases [47,48]. Of these three compounds, telbivudine was the only one to combine reasonable
oral bioavailability with good anti-HBV activity and so was
progressed to development jointly with Novartis with the
highest priority.
hepatocellular carcinoma. Globally, HBV infection accounts
for over one million deaths annually. At present, lamivudine
and adefovir dipivoxil are the only approved nucleoside/
nucleotide analogs for the treatment of HBV infection. However, resistance to lamivudine is now recognized in 16 to
32% of HBV-infected patients after the first year of monotherapy [47,48] and about 50% of patients after two years.
With adefovir treatment, the resistance rate is much lower, at
about 2.5% after two years of therapy. Experience in treating
chronic HIV infections has proven the advantage of therapy
with a combination of antiviral compounds. Similarly for
HBV, there is a clear need for additional antiviral compounds. Several promising candidates are currently in clinical development. Idenix (then known as Novirio) discovered
that the known beta-L-nucleosides, L-dA, L-dC (torcitabine)
and L-dT (telbivudine), have highly specific activity against
HBV [47]. These L-nucleosides are essentially without activity against any of the other viruses tested and are similarly
without effect in cell culture and in vivo toxicological tests.
However, they are phosphorylated within human cells to
their triphosphates which inhibit the HBV DNA polymerase,
O
OH
The synthesis of telbivudeine is depicted in Scheme 14
[49,50]. The L-arabinose (105) was treated with acid in
methanol to form the semi-acetyl intermediate which was
then reacted with benzoyl chloride to provide 106 in 50%
yield [51]. Acetolysis of 106 with a mixture of acetic acid
and acetic anhydride afforded 107 in 95% yield. The /
mixture was directly condensed with activated thymine to
give 108. The nucleoside 108 was purified by column chromatography and characterized as the -anomer. Debenzoylation of 108 with sodium methoxide in methanol afforded
109. Differentiation of the 2’-OH was achieved by selective
protection of the two other hydroxyl groups with 1,3dichloro-1,1,3,3,-tetraisopropyldisiloxane to form 110. In
order to limit undesired reaction during the deoxygenation
step, 110 was transformed into o-phenylthiocarbonate 111
i. MeOH/H2SO4/CaSO4
ii. PhCOCl/Py, 50oC, 1 h
OH
OMe
O
OBz
OBz
OH
5-10oC, 4h, 95%
50% overall for 4
BzO
BzO
OBz
OBz
OH
107
106
105
O
O
NH
N
NH
O
O
thymine/Me3SiNHSiMe3
N
O
NaOMe,MeOH, rt, 1h
OBz
Me3SiCl/SnCl4/MeCN
reflux 1h, 60%
O
Pri
Pri
O
Si
Cl
Pri
Si Pri
Cl
OH
80%
BzO
OAc
O
Ac2O/AcOH, H2SO4
Py, rt, 1h, 100%
HO
OBz
OH
109
108
O
O
Si
O
Pri
N
O
Si
Pri
O
PhOC(S)Cl, DMAP, Py
Si
O
Pri
Pri
O
Pri
N
Bu3SnH/AIBN, toluene
O
O
reflux, 3h, 83%
O
rt, 16h, 68%
O
Pri
NH
Pri
NH
Pri
Si
O
O
OPh
OH
S
111
110
O
O
NH
NH
Pri
O
Si
Bu4NF, THF
Pri
N
O
O
N
O
rt, 0.5h, 41%
OH
O
Pri
Pri
Si
HO
O
112
Scheme 14. Synthesis of Telbivudine.
Telbivudine (XIV)
O
provided di-aldehyde 117 which was immediately reacted
with benzyl amine in the presence of sodium acetoxyborohydride to give benzyl amine 118 in 85.7% yield. The removal of the benzyl group was effected by hydrogenation of
the HCl salt in 40-50 psi hydrogen pressure with 20%
Pd(OH)2 in methanol to give amine hydrochloride 119 in
88% yield. Treatment of amine 119 with trifluoroacetic anhydride and pyridine in dichloromethane at 0ºC gave trifluoroacetamide 120 in 94% yield. Dinitro compound 121 was
prepared by addition of trifluoroacetamide 120 to a mixture
of trifluoromethane sulfonic acid and nitric acid, which was
premixed, in dichloromethane at 0ºC. Reduction of the dinitro compound 121 by hydrogenation at 40-50 psi hydrogen
in the presence of catalytic 5%Pd/C in isopropanol:water
mixture provided the diamine intermediate 122 which was
quickly reacted with glyoxal in water at room temperature
for 18h to give compound 123 in 85% overall yield. The
trifluoroacetamide 123 was then hydrolyzed with 2 M sodium hydroxide in toluene at 37-40ºC for 2-3h followed by
preparation of tartrate salt in methanol to furnish varenicline
tartrate (XV).
which upon treatment with tributyltin hydride under Barton’s
conditions afforded 112 in good yield. Desilylation of 112
gave Telbivudine (XIV).
Varenicline (Chantix™)
Varenicline, a nicotinic 42 partial agonist, was approved in the US for the treatment of smoking cessation in
May of 2006. It was developed and marketed by Pfizer as a
treatment for cigarette smokers who want to quit. Varenicline partially activates the nicotinic receptors and thus reduces the craving for cigarette that smokers feel when they
try to quit smoking. By mitigating this craving and antagonizing nicotine activity without other symptoms, this novel
drug helps quitting this dangerous addiction easier on the
patients [6,52]. Several modifications [54,55] to the original
synthesis [53,56] have been reported in the literature, including an improved process scale synthesis of the last few steps
(Scheme 15) [57]. The Grignard reaction was initiated on a
small scale by addition of 2-bromo fluorobenzene 113 to a
slurry of Magnesium turnings and catalytic 1,2-dibromoethane in THF and heating the mixture until refluxing in
maintained. To this refluxing mixture was added a mixture
of the 2-bromo fluorobenzene 113 and cyclopentadiene 114
over a period of 1.5 h. After complete addition, the reaction
was allowed to reflux for additional 1.5 h to give the DielsAlder product 115 in 64% yield. Dihydroxylation of the olefin 115 by reacting with catalytic osmium tetraoxide in the
presence of N-methylmorpholine N-oxide (NMO) in acetone:water mixture at room temperature provided the diol
116 in 89% yield. Oxidative cleavage of diol 116 with sodium periodate in biphasic mixture of water: DCE at 10ºC
F
+
OH
1.5 h addition,
1.5h reaction
115
O
NaIO4
H2O:DCE,
OH 10oC, 1h
Acetone:H2O
(8:1)
THF, reflux
114
113
Vorinostat, a histone deacetylase (HDAC) inhibitor from
Merck, was approved for the treatment of cutaneous T-cell
lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.
Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3
and HDAC6 at nanomolar concentrations. HDAC inhibitors
are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers
[58]. Commercially available monomethyl ester 125 was
NMO,
15mol% OsO4
Mg
Br
Vorinostat (ZolinzaTM)
O
116
rt, 60h
117
89%
64%
BnNH2,
NaHB(OAc)3
ii. H2, 20wt% Pd(OH)2
85.7%
O2N
O
94%
119
3 wt% 5%Pd/C,
40-50 psi H2
H2N
CF3
O2N
iPrOH:H2O (4:1)
H2N
28 - 30oC, 4h
2 M NaOH
O
CF3
NH
toluene, 37-40oC,
2-3h
123
Scheme 15. Synthesis of Varenicline.
glyoxal
CF3
H2O, 0-5oC, 2h;
20oC, 18h
84.5%
N
N
N
N
O
122
121
N
120
N
N
CH2Cl2, 0oC
CF3
CH2Cl2, 0oC, 3h
MeOH, 40-50psi,
24h, 88%
118
TfOH, HNO3
N
NH.HCl
NBn
DCE, RT, 30-60min
O
TFAA, Pyridine
i. HCl/EtOAc
L-(+)-tartrate
MeOH
N
124
NH .tartrate
N
Varenicline (XV)
Liu et al.
O
HO
H
N
NH2
126
O
OCH3
O
O
HOBt, DCC, rt, DMF, 4hr
125
OCH3
127
89%
O
H
N
N
H
NH2OH.HCl, KOH, MeOH, rt, 1hr
OH
O
90%
Vorinostat (XVI)
Scheme 16. Synthesis of Vorinostat.
reacted with aniline in the presence of DCC and HOBt in
DMF to give amide 127 in 89% yield [59] (Scheme 16). Methyl
ester amide 127 was then reacted with hydroxylamine HCl
salt and potassium hydroxide in methanol to give vorinostat
(XVI) in 90% yield.
ACKNOWLEDGEMENTS
NEP
=
NMM
=
N-Methylmorpholine
NMP
=
PCC
=
PDC
=
We would like to thank Dr. Takushi Kaneko for helping
with the translation of one of the Japanese patent.
PMB
=
4-methoxylbenzyl
ABBREVIATIONS
PPA
=
Poly phosphoric acid
AIBN
=
TBAF
=
CBZ
=
Benzyloxycarbonyl
TBDMS
=
CDI
=
N,N'-carbonyldiimidazole
TEA
=
Triethyl amine
DCE
=
Dichloroethane
TFA
=
DCM
=
Dichloromethane
TFAA
=
Trifluoroacetic acid anhydride
DIAD
=
Diisopropyl azodicarboxylate
THF
=
Tetrahydrofuran
DIBAL-H =
THP
=
Tetrahydropyran
DIPEA
TIPS
=
Triisopropyl silyl
=
=
DMAP
=
TPAP
DMF
=
TMG
=
DMPU
=
N,N’-dimethylpropyleneurea
p-TSA
=
DMSO
=
Methyl sulfoxide
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IPA
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Isopropyl alcohol
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LDA
=
LIHMDS
=
Lithium bis(trimethylsilyl)amide
MS
=
Molecular sieves
NBS
=
N-Bromosuccinimide
NCS
=
N-Chlorosuccinimide
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1526
Kevin K.-C. Liu1, Subas M. Sakya2, Christopher J. O’Donnell2 and Jin Li3,*
1
Pfizer Inc, La Jolla, CA 92037, USA; 2Pfizer Inc, Groton, CT 06340, USA; 3Shenogen Pharma Group, Beijing, China
for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as
leads for designing future new drugs. This review covers the syntheses of 19 NCEs marketed in 2007.
INTRODUCTION
Inaugurated six years ago, this annual review presents
in the previous articles [2-5]. Generally, drugs that are approved worldwide tend to have structural similarity across
similar biological targets. We strongly believe that knowledge of new chemical entities and their syntheses will greatly
enhance our abilities to design new drugs in shorter periods
of time. With this hope, we continue to profile the NCEs that
were approved in 2007.
In 2007, 30 new products including new chemical entities, biological drugs, and diagnostic agents reached the
market [6]. Six additional products were approved for the
first time in 2007, however they were not launched before
year’s end and therefore, the syntheses of those drugs will be
covered in 2008’s review. This article will focus on the syntheses of 19 new drugs marketed in 2007 (Fig. 1) and exclude new indications for known drugs, new combinations,
and new formulations and drugs synthesized via bioprocesses, or peptide synthesizers. The synthetic routes cited
herein represent the most scalable methods reported and appear in alphabetical order by generic names.
Aliskiren Fumarate (Tekturna®)
Last March, the U.S. became the first country to approve
Tekturna® (aliskiren fumarate; Novartis/Speedel), a first-inclass antihypertensive agent. The once-daily, oral, direct
renin inhibitor received FDA approval for treatment of high
blood pressure as mono therapy or in combination with other
antihypertensive medications. In an extensive clinical trial
program involving more than 6,400 patients, aliskiren provided significant blood pressure reduction for a full 24 hour
period. Furthermore, aliskiren demonstrated increased efficacy when used in combination with other commonly used
blood pressure-lowering medications. Novartis is conducting
*Address correspondence to this author at the Shenogen Pharma Group,
Beijing, China; tel: 8610-8277-4069; E-mail: [email protected]
1389-5575/08 $55.00+.00
a large outcome trial program to evaluate the long-term effects of aliskiren and of direct renin inhibition in general.
The product, which is known as Rasilez® outside the U.S.,
was approved in the E.U. in August. Aliskiren has been synthesized by several different routes [7-11] and a convergent
synthesis of aliskiren by Wuxi PharmaTech was performed
on large scale; however, the yields were not reported [12].
The synthesis of aliskiren by Novartis is depicted in Scheme
1 [9]. Aliskiren (I) was synthesized through a convergent
synthetic strategy by coupling key intermediate chloride 5
with aldehyde 10. Hydrogenation of cinnamic acid 1, followed by generation of the acid chloride of the corresponding acid and reaction with (+)-pseudoephedrine provided
amide 2 in 91% yield. Deprotonation of amide 2 with LDA
followed by alkylation with 2-iodopropane in refluxing THF
gave 3 as a single diastereomer in 52% yield. Reduction of
the amide functionality in 3 using n-butyl lithium boron
trifluoride ammonium complex proceeded without epimerization of the chiral center to give alcohol 4 in 66% yield.
Chlorination of 4 using phosphorus oxychloride gave chloride 5, in 78% yield as the organometallic precursor for the
eventual coupling to aldehyde 10. Synthesis of fragment 10
commenced with (+)-pseudoephedrine isovaleramide 6,
which was efficiently deprotonated with LDA and alkylated
using allyl bromide; diastereomerically pure 7 was obtained
upon crystallization of the crude reaction mixture in 78%
yield. Bromolactonization of 7, using n-bromosuccinimide in
the absence of acetic acid gave amide acetal 8 with a single
configuration at the spirocenter and a 6:1 mixture of
trans:cis ring substituents. Displacement of the bromide using tetrabutylammonium acetate followed by basic hydrolysis provided alcohol 9 in 85% yield. Oxidation of 9 using
dimethyl sulfoxide-sulfur trioxide/pyridine proceeded without epimerization to furnish the masked lactone aldehyde 10
in 60% yield. Coupling of fragments 5 and 10 was achieved
by treatment of 10 with the organocerium reagent of the corresponding Grignard reagent prepared from 5. Hydrolysis of
the crude spirocyclic addition product revealed that the hydroxylactone 11 was formed in 51% overall yield as an inseparable epimeric mixture with a Felkin-Anh selectivity of
85:15. The requisite nitrogen functionality was installed via
the brosylate to give azido lactone 12 in 68% yield. Aminolysis with 3-amino-2,2-dimethylpropionamide led to formation of the open chain azido alcohol 13 in 76% yield. The
OH
O
NH2
O
OH
O
H
N
O
N
NH2
O
O
O
N
O
CO2H
HO2C
I Aliskiren Fumarate
II Ambrisentan
O
OH
H
N
H
HN
H
N
O
O
HO
O
HO
O
H
F
H
O
F
F
CO2H
III Arformoterol tartrate
IV Clevudine
V Fluticasone furoate
O
O
S
OH
N
N
HN
O
CO2H
O
O
O
O
HO
S
HO
N
HO
HO
F
N
HO
N
H2N
NH
O
O
F2HC
O
•CH3SO3H•H2O
VI Garenoxacin mesilate hydrate
OH
O
VIII Ixabepilone
VII Imidafenacin
NH2
O
HN
H
N
S
O
O
F
H
N
Cl
N
2
N
IX Lapatinib ditosylate hydrate
F
O
SO3H H2O
O
NH2
2CSO3H
X Lisdexamfetamine dimesilate
F
N
H
N
F3C
O
N
H
N
O
NH
N
N
N
N
N
N
N
XI Maraviroc
HCl H2O
XII Nilotinib hydrochloride monohydrate
Liu et al.
(Fig. (1). Contd….)
OH
N
O
N
N
N
O
N
H
N
O
F
O
OK
N
N
F
H
N
N
O
O
XIV Raltegravir potassium
HO
XIII Paliperidone
F
O
OH
O HO
O
N
S
O
H
N
F
N
N
O
NH2
O
XVI Rufinamide
XV Retapamulin
O
O
O
OH
OH
O
HN
HO
O
O
O
O
O
OH
O
O
O
O
S
O
O
N
N
XVII Temsirolimus
HO
H
O
O
OH
O
N
N
H
XVIII Trabectedin
O
CN
XIX Vildagliptin
synthesis of aliskiren was completed by azide hydrogenolysis and formation of the hemifumarate salt. Generation of
pure aliskiren was achieved via crystallization which removed the residual minor (R)-epimer carried through from
the Grignard addition step to afford aliskiren (I) in 43%
yield.
Ambrisentan (Letairis )
TM
Ambrisentan (BSF-208075) is an endothelin-1a antagonist developed by Gilead (formerly Myogen) under license
from Abbott Laboratories and received FDA approval for the
treatment of pulmonary arterial hypertension in June 2007
[6,13]. Both the discovery [14] and process routes to the synthesis of ambrisentan have been published and the process
route is described as shown in Scheme 2 [15]. Reacting a
mixture of benzophenone (14) and sodium methoxide in
THF at 0 °C with methylchloroacetate over a four hour period provided glycidate 15 which was taken forward without
purification to the subsequent step. Addition of ptoluenesulfonic acid monohydrate to a solution of glycidate
15 in methanol was followed by heating at reflux and distilling out the solvent until the temperature reached 66oC. While
the solution was still refluxing, 10% potassium hydroxide
was added and the remaining organic solvent was distilled
out until the temperature reached 94oC, providing complete
hydrolysis to acid 16. The reaction was cooled to room temperature and diluted with water and methyl tert-butylether
(MTBE) then acidified with 10% sulfuric acid. The MTBE
layer was separated and taken to the next step. Additional
MTBE and methanol were added to the crude acid 17 and the
resulting mixture was heated at reflux. (S)-1-(4-chlorophenyl)ethylamine was added to the refluxing solution and the
resulting mixture was allowed to cool to 0-5oC slowly at a
rate of 10oC/h which resulted in crystallization of the salt 19
in 33% overall yield from benzophenone and 99% e.e. The
chiral hydroxyl acid salt 19 was mixed with sulfone 20 and
lithium amide in a toluene/DMF mixture and heated at 45 °C
for 12 hours to give, after acidic workup and crystallization,
ambrisentan (II) in 84% yield as a colorless powder with
99.8% e.e.
Arformoterol Tartrate (Brovana™ )
Sepracor’s Brovana™, a nebulized long acting bronchodilator, was launched in the U.S. in April 2007. The 2adrenoceptor agonist is indicated for the twice-daily, longterm maintenance treatment of bronchoconstriction in patients
O
O
O
OH
O
i. H2, Pd/C
ii. (COCl)2, DMF, rt
O
O
iii. (+)-pseudoephedrine, NaOH
toluene-H2O, rt
91%
MeO
Ph
N
OH
MeO
1
2
O
i. LDA, LiCl, THF, 0 oC
O
O
ii. 2-iodopropane, rt-
52%, >95% de
BF3•NH3, n-BuLi, rt
Ph
N
OH
MeO
66%
3
O
O
O
POCl3, DMF, PhMe, 80 oC
OH
MeO
O
Cl
MeO
78%
4
O
5
O
i. LDA, LiCl, THF, 0 oC
Ph
Ph
N
ii. allyl bromide, 0 oC
78%, >95% de
OH
Ph
NBS, DME-H2O
N
N
O
0 oC, 60%
O
OH
Br
6
7
Ph
Ph
i. n-Bu4NOAc, acetone, N
Py•SO3, Et3N
N
O
O
ii. K2CO3, MeOH-H2O, rt
85%
8
O
O
DMSO/DCM, 0 oC
60%
OH
CHO
9
10
O
i. Mg, 1,2-dibromoethane, THF, ii. CeCl3, -78 oC
5
O
O
O
iii. aldehyde 10, -78 oC
iv. AcOH-THF-H2O, 50 oC
51%
OH
MeO
11
O
O
i. p-bromobenzensulfonyl chloride
DMAP, DCM, rt
3-amino-2,2-dimethylpropionamide
MeO(H2C)3O
ii. NaN3, NMP, 60 oC
68%
N3
MeO
2-hydroxypyridine, Et3N, 80 oC
76%
12
HO
O
H
N
O
N3
MeO
13
Scheme 1. Synthesis of Aliskiren Fumarate.
O
i. H2, Pd/C, ethanolamine, MeOH, rt
CONH2
ii. Fumaric acid, H2O, MeCN, MeOH
43%
>98:2 S:R NH2
Aliskiren
Fumarate
I
Liu et al.
O
Cl
O
O
O
NaOMe
O
O
O
p-TsOH.H2O
THF, 0 °C
4 h addition
OH
O
OH
OH
O
MeOH:H2O
16
15
17
N
NH2
O
OH
NH2
S
S
O2
O
N
OH
N
20
18
Cl
O
KOH
MeOH, rt - 14
OMe
Crystallization
OH
O
LiNH2
Cl
MTBE:MeOH
33% (4 steps)
O
O
N
DMF:toluene
45 °C, 12 h
82%
99% e.e.
19
99.8%ee
II Ambrisentan
Scheme 2. Synthesis of Ambrisentan.
enantio/diastereomerically pure (R,R)-formoterol is cited
here (Scheme 3) [21a]. Bromoalcohol 22 was synthesized in
84% yield with 94% e.e. through the catalytic enantioselective reduction of bromo ketone 21[21b]. The nitro functional
group in 22 was reduced in quantitative yield by hydrogena-
with chronic obstructive pulmonary disease (COPD), which
includes chronic bronchitis and emphysema. It is the first
long-acting nebulized bronchodilator approved by the FDA
for this indication [16]. There are several reports on the synthesis of arformoterol [16-24]. A large-scale synthesis of
O
OH
Br
Br
i. PtO2, H2, 45psi, THF, toluene
5% cat, THF, 25 oC
BnO
NO2
H
N
21
ii. HCOOH, Ac2O
75%
BnO
0.7 eq BH3•Me2S
84%
NO2
94% e.e.
BH
22
O
catalyst
OH
H
N
H
OH
i. K2CO3, 26, MeOH, THF
ii. neat, 120 oC, 24 h
Br
O
HO
iii. Pd/C, H2, EtOH
iv. tartaric acid, i-PrOH
70%
BnO
NHCHO
H
N
O
HO
CO2H
HO
CO2H
98-99% e.e.
23
III Arformoterol tartrate
O
PhCH2NH2, Pt/C, H2
OCH3
99%
24
Scheme 3. Synthesis of Arformoterol Tartrate.
(S)-mandelic acid, MeOH
HN
HN
12-14%, 99.5% e.e.
25
OCH3
OCH3
mandelic acid salt
26
tion in the presence of Adams catalyst and the resulting aniline was isolated by filtration of the catalyst and removal of
the solvent. In order to avoid auto-oxidation, the aniline was
treated with a mixture of formic acid and acetic anhydride
immediately after the removal of the platinum catalyst. Upon
concentrating the reaction mixture, bromohydrin 23 crystallized and could be isolated in 75% yield with 98.6% e.e. It
was further enriched to >99.5% e.e. by a single re-crystallization from ethylacetate. Next, a mixture of bromohydrin
23 and amine salt (R)-26-(S)-mandelic acid was treated with
K2CO3 resulting in generation of the corresponding epoxide
of 23 and liberation of the free base of (R)-26. After an
aqueous work up to remove salts and mandelic acid, the reaction mixture was heated to 120 °C to affect epoxide opening with the amine of 26. Removal of the benzyl protecting
groups of the resulting crude product via catalytic hydrogenation followed by salt formation with tartaric acid afforded arformoterol tartrate (III) in 70% yield upon crystallization.
give acetylated arabinose, which was then brominated using
30% HBr in AcOH/Ac2O at room temperature for 36 hours
to afford bromo-sugar 28 as a white solid in 57% yield after
crystallization in ethyl ether. Bromo-sugar 28 was then
treated with Zn dust, CuSO4 and NaOAc in AcOH/H2O, followed by chromatographic separation to give L-arabinal 29
in 60% yield. L-arabinal 29 was converted to the fluoro derivative in 70% crude yield by reaction with Selectfluor® (FTEDA-BF4) in refluxing nitromethane/H2O, and the resulting
fluoroalcohol was deacetylated with NaOMe in MeOH to
give compound 30 in 100% crude yield. Compound 30 was
then treated with H2SO4 in refluxing MeOH to afford methyl
furanoside 31 in 80% crude yield. Furanoside 31 was benzoylated with benzoyl chloride in pyridine to give a mixture
of isomers, from which the -anomer was isolated by chromatography and then brominated with 30% HBr/AcOH in
CH2Cl2 to provide the crude bromo-sugar 32 which was dissolved in chloroform and used without further purification in
the next step. Compound 34 was obtained by treatment of
thymine (33) with HMDS and ammonium sulfate in refluxing
chloroform for 16 hours. The sugar 32 was condensed with
silylated pyrimidine derivative 34 in refluxing chloroform to
afford 3,5-di-O-benzoylclevudine in 42% yield after recrystallization from ethanol. The benzoyl groups were removed upon treatment with n-butylamine in refluxing
methanol to give clevudine (IV) in 82% yield.
Clevudine (Levovir®)
Clevudine, a DNA polymerase inhibitor, was launched in
South Korea for the treatment hepatitis B [25]. The hepatitis
B virus (HBV) belongs to the family of hepadnaviruses. The
HBV genome is a relaxed circular, partially double-stranded
DNA of approximately 3,200 base pairs. The drug was originally discovered at the University of Georgia and Yale University. Bukwang acquired the rights and Eisai in-licensed
clevudine from Bukwang. The synthesis is depicted in
Scheme 4 [26]. L-Arabinose (27) was treated with acetic
anhydride and pyridine at room temperature for four hours to
O
HO
OH
O
i. Ac2O, pyridine
ii. HBr, AcOH, Ac2O
OH
Fluticasone Furoate (Veramyst™)
In April 2007, the FDA approved GlaxoSmithKline’s
once-daily Veramyst™ (fluticasone furoate) nasal spray to
treat seasonal and year-round allergy symptoms in adults and
O
Br
AcO
57%
OAc
OH
OAc
27
OH
O
H2SO4, MeOH
HO
F
OAc
60%
29
OMe
HO
HO
80% crude
ii. NaOMe/MeOH 70% crude
AcO
CuSO4, AcONa
28
O
i. Selectfluor,
NO2CH3/H2O, Zn(dust)
F
O
i. PhCOCl, pyridine
ii. separation
Br
PhCO2
PhCO2
iii. HBr, AcOH
F
OH
30
32
31
O
O
HN
HN
O
HMDS
HN
O
OTMS
N
H
(NH4)2SO4
33
Scheme 4. Synthesis of Clevudine.
O
32
N
TMSO
N
34
CH3Cl, 42% for 2
steps
BuNH2
O
PhCO2
PhCO2
O
N
O
HO
MeOH, 82%
F
3,5-di-Obenzoylclevudine
N
HO
F
IV Clevudine
Liu et al.
children 2 years of age and older. Fluticasone furoate is an
intranasal corticosteroid that works throughout the allergy
process to block an entire range of inflammatory mediators
that may lead to nasal allergy symptoms, although the precise mechanism through which the drug affects allergy
symptoms is not known. The approval of fluticasone furoate
was based on clinical trials in more than 2,900 adults and
children suffering from seasonal or year-round allergies. The
product was launched in May. In October the European
Committee for Medicinal Products for Human Use (CHMP)
issued a positive opinion for fluticasone furoate, which will
be marketed upon approval in Europe under the trade name
Avamys™. The synthesis of fluticasone on large scale was
disclosed in the patent literature [27-29]. The starting 6,9difluoro-11-17-dihydroxy-16-methyl-3-oxoandrosta-1,4diene-17-carboxylic acid 35 [27a] was converted to the
analogous carbothioic acid 36 in 95% yield via activation
with carbonyl diimidazole, followed by reaction with hydrogen sulfide gas (Scheme 5). Conversion of the carbothioic
acid to fluticasone was completed through a three-step sequence in a one pot process in 99% overall yield. Carbothioic acid 36 and DMAP were dissolved in MEK. Tripropylamine (TPA) was then added to the mixture at -8 to -5 °C.
Neat furoyl chloride was then added dropwise over 2-3 minutes and the resulting mixture was then stirred at -5 to 0 °C
for 15 minutes generating a mixture of desired ester 37 and
thioanhydride 38. A solution of N-methylpiperazine in water
was then added dropwise over 2-3 minutes at -5 to 0 °C to
O
the crude reaction mixture and stirred for 10 minutes, which
enabled the conversion of thioanhydride 38 to the ester 37. A
solution of bromofluoromethane in MEK was then added
rapidly at 0 °C and the resulting solution was stirred at 20 °C
for 5 hours. After a simple work-up, fluticasone furoate (V)
was obtained in 99% overall yield from 36 with 97% purity.
Garenoxacin Mesilate Hydrate ( Geninax®)
Toyama, Astellas Pharma and Taisho Toyama launched
Geninax® (garenoxacin mesilate hydrate), an orally formulated quinolone, last year in Japan. The product is indicated
for pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infection in chronic respiratory lesion,
otitis media and sinusitis. Garenoxacin is the first synthetic
antibacterial agent indicated for treatment of penicillinresistant S. pneumoniae. Garenoxacin, discovered by Toyama, displays good oral absorption and tissue distribution,
providing for once-daily administration. Several syntheses of
garenoxacin have been reported and the largest scale synthesis is reported herein [30-32]. The synthesis was initiated by
methylation of 2,6-difluorophenol (39) with methyl iodide
and K2CO3 in DMF giving 2,6-difluoroanisole (40) in 90%
yield (Scheme 6). Deprotonation of 40 with n-butyl lithium
and reaction with CO2 yielded 2,4-difluoro-3-methoxybenzoic
acid which was methylated with diazomethane in ether to
afford methyl ester 41 in 69% yield. Liberation of the phenol
was accomplished by reaction with BBr3 in dichloromethane
resulting in 2,4-difluoro-3-hydroxybenzoic acid methyl ester
OH
O
OH
HO
F
OH
HO
i. CDI, DMF, 22 °C, 4 h
H
O
i. DMAP, MEK, 20 °C, 10 min
ii. TPA, -8 to -5 oC
H
ii. H2S, 15 min
95%
H
SH
F
iii. furoyl chloride, -5 to 0 oC, 5 min
H
O
F
35
F
36
O
O
O
SH O
O
O
HO
N-methylpiperazine
O
H
+
F
O
O
HO
O
H
S
H
F
O
-5 to 0 oC, 10 min
H
O
F
F
37
O
F
SH O
O
O
HO
38
O
Br
O
H
F
H
H
O
then 20 to 22 °C, 5 h
99% from 36
F
H
O
F
37
Scheme 5. Synthesis of Fluticasone Furoate.
O
O
HO
F , MEK, 0 °C
S
F
V Fluticasone furoate
i. n-BuLi, THF, -70 oC;
CO2, 1 h
MeI, K2CO3, 50 oC
F
F
2 h, 90%
F
F
ii. CH2N2, 10 min, 69%
OCH3
OH
CO2CH3
ClCHF2, K2CO3, DMF
F
sealed tube, 120-130 oC
2.5 h, 81%
BBr3, DCM
-30 oC
F
2 h, 70%
OCH3
40
39
F
F
CO2CH3
41
CO2CH3
F
CO2CH3
NaN3, DMSO, 70 °C
20 h, 45%
F
N3
F
OCHF2
OH
42
OCHF2
43
44
CO2CH3
H2, Pd/C, EtOH
CO2H
CuBr, NaNO2, HBr
NaOH, EtOH, 40 oC
H2N
rt, 5 h, 37%
F
H2N
4 h, 86%
F
OCHF2
OCHF2
45
46
O
CO2H
Br
O
i. CDI, rt, 2 h
i. Ac2O, (MeO)2CHN(Me)2, DCM, 2 h
OEt
ii. MgO2CCH2CO2Et, 20 h 86%
F
rt, 24 h, 96%
ii.
Br
NH2
F
OCHF2
77%
OCHF2
47
, EtOH
48
O
K2CO3, DMSO, 90 °C
OEt
Br
F
B(OH)2
O
O
30 min, 91%
NH
(Ph)3C
O
N
51
OEt
Br
OCHF2
PdCl2(PPh3)2, xylene, 60%
N
F2HCO
49
O
50
O
O
OEt
O
OH
i. HCl, EtOH, 0.5 h
N
(Ph)3C
N
O
F
F
N
ii. NaOH, 1 h
85%
iii. MeSO3H
52
HN
O
F
F
•CH3SO3H•H2O
VI Garenoxacin mesilate hydrate
Scheme 6. Synthesis of Garenoxacin.
42 in 70% yield. Alkylation of 42 with chlorodifluoromethane and K2CO3 in DMF gave 3-(difluoromethoxy)-2,4difluorobenzoic acid methyl ester 43 in 81% yield, which
was then treated with sodium azide in DMSO, yielding the
azido derivative 44 in 45% yield. Reduction of 44 with H2
over Pd/C in ethanol afforded 3-amino-2,4-difluorobenzoic
acid methyl ester 45 in 37% yield and 45 was hydrolyzed
with NaOH in ethanol, giving the free acid 46 in 86% yield.
Diazotization of 46 with NaNO2 followed by reaction with
HBr yielded 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic
acid 47 in 96% yield. Acid 47 was then condensed with the
magnesium salt of malonic acid monoethyl ester by means of
CDI in THF affording 3-oxopropionate 48 in 86% yield. The
reaction of 48 with dimethylformamide dimethylacetal and
cyclopropylamine by means of acetic anhydride in dichloromethane gave the 3-(cyclopropylamino) acrylate 49 in 77%
yield, and this was followed by cyclization using K2CO3 in
hot DMSO, yielding quinolone 50 in 91% yield. Coupling of
50 with the isoindolylboronic acid derivative 51, which was
obtained by reaction of 5-bromo-1-(R)-methyl-2-tritylisoindoline with triisopropyl borate and n-butyl lithium, in THF
using bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene afforded the protected compound 52
in 60% yield. Removal of the trityl group with HCl in etha-
Liu et al.
O
NH2
H
N
H3C
BrCH2CH2Br
NC
NC
N
NC
70% H2SO4
Et3N, DMF, 150 °C
NaNH2
toluene
N
N
Br
N
N
54
53
55
VII Imidafenacin
Scheme 7. Synthesis of Imidafenacin.
nol, followed by saponification of the ethyl ester and formation of the mesylate salt provided garenoxacin mesilate hydrate (VI).
7). The bromide 54 was condensed with 2-methylimidazole
in the presence of Et3N in hot DMF to afford 2-methylimidazole derivative 55. Hydrolysis of the cyano group of 55
with 70% sulfuric acid provided imidafenacin (VII).
Imidafenacin (Staybla, Uritos®)
Ixabepilone (IxempraTM)
Imidafenacin, an orally active muscarinic M1/M3 antagonist, was launched in Japan for the treatment of overactive bladder (OAB) [33]. Overactive bladder alone incurs
annual costs of $12.6 billion [USD]. The drug was originally
developed by Kyorin and it has selective action on bladder
smooth muscle. Subsequently, Kyorin signed an agreement
with Ono Pharmaceutical for co-development and co-marketing of imidafenacin. To date, the synthesis reported [34],
gives no information on chemical yields. Diphenylacetonitrile (53) was alkylated with dibromoethane in the presence
of NaNH2 in toluene to give bromide compound 54 (Scheme
Ixabepilone is a semi-synthetic analog of epothilone developed by Bristol-Myers Squibb for the treatment of metastatic breast cancer and has a mode of action similar to paclitaxel which involves stabilizing microtubules by promoting
tubulin polymerization [35]. Ixabepilone is indicated for use
as monotherapy in metastatic or locally advanced breast cancer after failure of an anthracycline, a taxane, or capecitabine
treatment. Additionally, ixabepilone is currently undergoing
clinical trials targeting a variety of additonal cancer indications. The synthesis [36] is described in Scheme 8, and was
O
O
S
S
N
HO
OH
N
HO
NH4Cl, THF, H2O
PMe3, Pd2(dba)3
96%
O
O
NaN3, Bu4NCl
O
O
O
O
S
S
N
HO
PMe3
OH
OH
O
OH
NH2
O
OH
57
O
S
N
HO
NH
OH
N
HO
N3
O
O
O
OH
56
O
PdLn
OH
O
VIII Ixabepilone
Scheme 8. Synthesis of Ixabepilone.
K2CO3,
DMF/THF(1:1)
HOBt, EDCI
2h
93%
NaN3
initiated by treating epothilone B (56) with sodium azide,
tetrabutylammonium chloride, ammonium chloride, trimethylphosphine and tris-(dibenzylideneacetone)-dipalladium(0)
chloroform which gave the ring-opened amino acid 57 in
96% yield. It has been proposed that this reaction proceeds
via initial ring-opening -allyl palladium complex formation
followed by trapping with azide and subsequent reduction to
the desired amine [36b]. Lactamization of the acyclic amino
carboxylic acid 57 by reaction with K2CO3, HOBt and EDCI
provided ixabepilone (VIII) in 93% yield. Re-crystallization
from cyclohexane/ethyl acetate afforded ixabepilone in 56%
overall yield from epothilone B.
prior therapy [37]. The drug was discovered and developed
by GlaxoSmithKline and is also currently being evaluated
for several additional cancer indications. The synthesis started
with Williamson ether synthesis between 2-chloro-4-nitrophenol (58) and 3-fluorobenzyl bromide to give ether 59
(Scheme 9); however, no specific yields were provided [38].
Reduction of the nitro group of compound 59 by catalytic
hydrogenation over Pt/C and subsequent condensation of the
resulting aniline with 4-chloro-6-iodoquinazoline (61) in
refluxing i-PrOH afforded compound 62. 4-Chloro-6-iodoquinazoline (61) was prepared by reacting 6-iodoquinazolin4(3H)-one (60) with POCl3 in the presence of triethylamine.
Compound 62 was subjected to Stille coupling with 5dioxolanyl-2-(tributylstannyl)furan (63) in the presence of
PdCl2(PPh3)2 to give 64. Acidic hydrolysis of acetal 64 using
HCl in THF/H2O provided the corresponding aldehyde which
was further subjected to reductive amination with 2-(methan-
Lapatinib Ditosylate (Tykerb®)
Lapatinib, an ErB-1 and ErB-2 dual kinase inhibitor, was
launched for the treatment of advanced or metastatic HER2
(ErbB2) positive breast cancer in women who have received
F
OH
O
Br
O2N
Cl
F
F
O2N
K2CO3, MeOH
Cl
i. H2, Pt/C
O
ii. iPrOH, Cl
58
59
POCl3
I
HN
N I
N
O
I
N
Et3N
NH
Cl
N
61
N
62
60
F
O
O
SnBu3
O
O
i. HCl, H2O, THF
63
HN
O
PdCl2(PPh3)2
iPr2NEt, DMF
O
O
Cl
N
F
64
O
NH
HN
O
Cl
N
N
SO3H H2O
2
IX Lapatinib ditosylate hydrate
Scheme 9. Synthesis of Lapatinib ditosylate.
H3C
O
N
MeO2S
ii.
NH2
S
O
NaBH(OAc)3, AcOH
CH2Cl2
Liu et al.
esulfonyl)ethylamine in the presence of sodium triacetoxyborohydride to yield lapatinib. Lapatinib was treated with ptoluenesulfonic acid solution to give lapatinib ditosylate
(IX).
[42,43]. The preparation of the azabicyclic triazole core of
maraviroc (75) is described in Scheme 11. Cyclization of
2,5-dimethoxytetrahydrofuran 68 with benzylamine 69 and
1,3-acetonedicarboxylic acid 70 under aqueous HCl and
NaOAc produced benzyl protected tropanone 71 in 47%
yield. Reaction of 71 with ammonium hydroxide in pyridine
generated the corresponding oxime in 96% yield which was
reduced using sodium in refluxing pentanol to give exoamine 72 in 92% yield. Acetylation of 72 with isobutyric
acid using EDC gave amide 73 in 53% yield. Triazole 74
was then prepared in a one-pot, two step procedure by first
reacting amide 73 with phosphorus oxychloride followed by
acetohydrazide to affect the desired cyclization in 30% yield.
Removal of the benzyl protecting group of the amine under
standard transfer hydrogenolysis conditions using ammonium formate as the hydrogen source gave azabicyclic triazole intermediate 75.
Lisdexamfetamine Mesilate (Vyvanase®)
Lisdexamfetamine, a prodrug consisting of d-amphetamine conjugated to L-lysine, is a stimulant for the treatment
of ADHD in children. Lisdexamfetamine was discovered,
developed, and launched in the US in 2007 by New River
Pharmaceuticals and marketed by Shire after their merger.
Lisdexamfetamine offers the advantage of prolonged duration of action and reduced abuse potential liability versus
traditional stimulant agents for the treatment of ADHD [39].
The straightforward synthesis of lisdexamfetamine mesilate
was initiated by adding a solution of D-amphetamine (66) to
a solution of Boc-L-Lys(Boc)-OSu (65), N-methylmorpholine and 1,4-dioxane (Scheme 10) [40]. The resulting
mixture was partitioned between isopropyl acetate and an
acetic acid/brine solution, and the organic layer was washed
with aqueous sodium bicarbonate to give Boc-L-Lys(Boc)D-amphetamine (67) in 91% yield. The two primary amine
groups were liberated by reacting a solution of 67 in 1,4dioxane with methanesulfonic acid providing lisdexamfetamine mesilate (X) in 92% yield.
The preparation of the 4,4-difluorocyclohexane carboxylic acid chloride coupling partner 81 is described as follows
(Scheme 11). Difluorination of cyclohexanone-4-carboxylic
acid ethyl ester 76 was accomplished through the reaction
with diethylaminosulfur trifluoride (DAST) to give a inseparable 1:1 mixture of the desired difluorinated product 77 and
undesired fluoroalkene 78 in 85% yield. This mixture was
reacted with osmium tetroxide and NMO to affect complete
dihydroxylation of the alkene functional group of 78 to keto
alcohol 79 with concomitant no reaction of the difluorinated
ester 77. Purification of 77 from the reaction mixture followed
by saponification under basic conditions gave acid 80 in 65%
yield. Reaction of 80 with thionyl chloride produced the 4,4difluorocyclohexane carboxylic acid chloride coupling partner 81 which was carried on without further purification.
Maraviroc (Selzentry®)
Maraviroc, a chemokine CCR5 antagonist, was discovered and developed by Pfizer for the treatment of HIVinfected adults who are infected with only CCR5-tropic
HIV-1 virus and who have HIV-1 strains resistant to multiple
antiretroviral agents [41]. Maraviroc was launched in the
U.S. and the E.U. in 2007. In addition to treating HIV-1,
Pfizer is currently developing maraviroc for the potential
oral treatment of rheumatoid arthritis. Two separate but similar approaches to the synthesis of enantiomerically pure
maraviroc have been described, differing only in the end
game strategy, the largest scale synthesis is reported herein
The endgame strategy to maraviroc is described as follows (Scheme 11). Readily available alcohol 82 was oxidized to aldehyde 83 using sulfur trioxide pyridine complex
[44]. Aldehyde 83 was reacted with azabicylic triazole 75
and sodium triacetoxyborohydride to give the protected
NHBoc
NHBoc
O
N
O
i. NMM, 1,4-dioxane
ii. AcOH/brine, IPAC
NH2
NHBoc
+
O
iii. NaHCO3/H2O
91%
O
65
H
N
66
67
NH2
MsOH, 1,4-dioxane
H
N
NH2
92%
2CH3SO3H
O
X Lisdexamfetamine Mesilate
Scheme 10. Synthesis of Lisdexamfetamine Mesilate.
NHBoc
O
O
MeO
OMe
O
+
BnNH2
68
O
O
+
HO
HCl
OH
69
NaOAc
47%
2. Na, pentanol, 92%
BnN
70
O
1. NH2OH, pyr, 96%
O
NH2
BnN
72
71
O
O
HO
N
H
NH2
N
H
BnN
EDC, 53%
HCO2NH2
N
BnN
N
POCl3, pyr
30%
N
N
HN
Pd(OH)2, 85%
N
N
73
74
O
F
F
F
F
O
F
F
OH
OsO4, NMO
DAST
OEt
O
76
F
NaOH
F
F
SOCl3
+
+
1:1 mix
85%
O
75
acetone/H2O
74%
O
OEt
THF, H2O
65%
OEt
O
78
77
NCBz
O
OEt
O
OEt
79
77
OH
80
O
Cl
81
NCBz
Na(OAc)3BH
SO3•pyr
OH
O
+
N
HN
N
76% for 2 steps
N
82
83
75
F
F
NCBz
N
N
N
N
1. Pd(OH)2, H2, 78%
2. 81, 59%
O
NH
N
N
N
N
84
XI Maraviroc
Scheme 11. Synthesis of Maraviroc.
amine 84 in 76% yield for the two step sequence. Removal
of the CBz protecting group under standard catalytic hydrogenolysis conditions using Pearlman’s catalyst gave the corresponding primary amine in 78% yield which was reacted
with acid chloride 81 to give maraviroc (XI) in 59% yield.
Nilotinib (Tasigna®)
Nilotinib, an orally active signal transduction inhibitor
that selectively inhibits the tyrosine kinase Bcr-Abl, was
discovered and developed by Norvartis and was launched for
the treatment of chronic myeloid leukemia (CML) in patients
with Philadelphia chromosome-positive (Ph+) disease who
are resistant or intolerant to imatinib mesilate [45]. Additional clinical trials are currently underway for the treatment
of acute lymphoblastic leukemia (ALL) and gastrointestinal
stromal tumors (GISTs). A concise synthesis of nilotinib was
recently described (Scheme 12) [46]. 3-Bromo-5-trifluoromethylaniline (85) was condensed with 4-methylimidazole in
the presence of CuI, 8-hydroxyquinoline and potassium carbonate in hot DMSO to give compound 86 in 75% isolated
yield. Aniline 86 was reacted with 3-iodo-4-methylbenzoic
chloride and diisopropylethyl amine (DIPEA) in THF at
room temperature to give amide 87 in 95% yield. Palladium
catalyzed aryl amine coupling between 87 and commercially
available 4-(pyridin-3-yl)pyrmidin-2-amine (89) was effectively carried out by using Pd2(dba)3/Xantphos as the catalyst
system in the presence of cesium carbonate in dioxane/tBuOH to give nilotinib in 89% yield as a while solid which
was treated with aqueous HCl solution to give nilotinib hydrochloride monohydrate (XII).
O
N
F3C
NH2
Liu et al.
F3C
I
NH2
Cl
CH3
8-hydroxyquinoline
CuI, K2CO3, DMSO
120 oC, 15 h, 75%
Br
H
N
F3C
N
H
DIPEA, THF, rt
2 h, 95%
N
I
O
N
N
N
85
1.
86
87
N
N
H2N
N
H
N
F3C
N
89
N
H
N
O
Cs2CO3, Pd2(dba)3
Xantphos, dioxane
t-BuOH, 100 oC, 7 h, 85%
2. HCl(aq)
N
N
HCl H2O
N
XII Nilotinib hydrochloride monohydrate
Scheme 12. Synthesis of Nilotinib.
Paliperidone (InvegaTM)
Paliperidone, a metabolite of the marketed antipsychotic
drug risperidone, is a dual inhibitor of 5HT2 and dopamine
D2 receptors developed by Johnson and Johnson for the
treatment of schizophrenia [6,47]. It is formulated for once a
day dosing with a proprietary OROS extended release formulation [6]. Among a number of publications on the preparation of paliperidone [48], the most recently described improved synthesis of the drug is shown in Scheme 13 [49,50].
2-Amino-3-hydroxypiperidine (90) was treated with benzyl
O
92
BnBr
OH
OBn
40% aq NaOH
cat. TBAB
NH2
N
O
NH2
90
POCl3
N
pTsOH•H2O
N
DCM:H2O, 20 °C
RT, overnight
98%
OBn
O
N
toluene, 30 h, 90%
OH
O
91
93
HN
OBn
OH
3 bar H2
10% Pd/C (5%)
N
N
Cl
N
N
HCl, MeOH
48 °C, 70%
O
94
95
N
N
Cl
O
OH
N
O
XIII Paliperidone
N
Scheme 13. Synthesis of Paliperidone XIII.
O
F
96
N
O
Na2CO3, KI
DMF, 85 °C
8 h, 58%
F
diglyme, 90-92 °C
5.5 h, 89%
bromide, sodium hydroxide and a catalytic amount of t-butyl
ammonium bromide (TBAB) in a biphasic mixture of water
and DCM to afford benzyl ether 91 in 98% yield. Amino
pyridine 91 was reacted with ketolactone 92 in refluxing
toluene and catalytic p-TsOH·H2O with azeotropic removal
of water providing bicyclic pyrimidone 93 in 90% yield.
Subsequent treatment of 93 with phosphorous oxychloride in
diglyme gave the chloride 94 in 89% yield. The pyridine ring
of chloride 94 was reduced by hydrogenation at 3 bar H2 and
48 °C for 7.5 hours in the presence of 10%Pd/C and concentrated HCl giving 95 in 70% yield. Chloride 95 was coupled
with benzisoxazole piperidine 96 in the presence of sodium
carbonate and potassium iodide in DMF to give racemic
paliperidone (XIII) in 58% yield.
HO
NH3, 30 psi
CN
oC,
10
H2N
Reltagravir (Isentress™)
Reltagravir is an HIV integrase inhibitor developed by
Merck and approved in 2007 in the US for treatment of HIV1 disease. Reltagravir is approved for the combination therapy with other antiretroviral agents for patients who have
been exposed to other drugs and experienced resistance or
patients that have growing viral loads [6,51,52]. Reltagravir
was shown to be active in patients who had been unresponsive to other anti retroviral drugs and developed resistance
[52]. Both the discovery [53] and process scale synthesis
[54], have been published and the process synthesis is described in Scheme 14. The synthesis follows a convergent
approach with the preparation of two key intermediates,
pyrimidone 105 and the oxadiazole acid chloride 111, fol-
CBZCl, DIEA
CN
CBZNH
CN
MTBE, rt
16 h, 88%
97%
97
NOH
NH2OH(aq)
CBZNH
NH2
oC
IPA, 60
3 h, 88%
98
99
100
O
DMAD
NOH
MeOH, 20- 30 oC
CBZNH
N
H
~95% conversion
xylene
CO2Me
90-135 oC
52%
CO2Me
DMSO, 20- 60 oC
CBZNH
N
101
N
CBZNH
OH
N
EtOH, 72
90%
CO2Me
N
70%
O
F
OH
CO2Me
102
NH2
O
Mg(OCH3)2, MeI
OH
HN
oC
CBZNH
H2, 40psi
5% Pd/C
F
H
N
N
MeOH, MSA
50 oC, 3-4 h
96%
O
104
103
O
OH
N
NH2
F
H
N
N
O
105
N
NH
N
Et3N
+
N
OEt
Cl
N
N
N
toluene
N
O
106
107
O +
N
KOH
N
EtOH:H2O
91%
N
O
N
O
109
H2N
O
(COCl)2, MeCN
DMF, 5 °C
110
O
OH
F
H
N
N
O
111
-N2
108
N
N
OEt
CO2K
O
COCl
N
CO2Et
O
O
105
Scheme 14. Synthesis of Reltagravir.
1. THF, NMM
0-5 °C, 91%
2. KOH, MeCN
N
OH
N
N
H
N
O
H
N
N
O
XIV Raltegravir potassium
F
O
Liu et al.
lowed by amide coupling to make reltagravir. The synthesis
of pyrimidone 105 began with amination of cyanohydrin 97
with ammonia at 10 °C using pressurized ammonia gas feed
to give amino cyanohydrin 98 in 97% yield. Aminonitrile 98
was protected with benzylchloroformate in methyl tert-butyl
ether (MTBE) at room temperature in the presence of DIPEA
to provide protected aminonitrile 99 in 88% yield. Aminonitrile 99 was then reacted with aqueous hydroxyl amine in
IPA at 60 °C to furnish amidoxime 100 in 88% yield. Initial
reaction of amidoxime 100 with dimethylacetylene dicarboxylate (DMAD) in methanol at 20-30 °C provided clean
conversion to intermediate 101, which upon gradual warming to 90-135 °C in xylene gave pyrimidone 102 in 52%
yield. Deprotonation of pyrimidone 102 in DMSO with
magnesium methoxide, followed by removal of the residual
methanol and treatment with methyliodide provided Nmethyl pyrimidone 103 in 70% yield. Remarkably, there was
less that 0.5% O-methylated side products after workup and
methanol:MTBE (9:1) wash of the crude product. Heating
pyrimidone ester 103 with p-fluorobenzylamine in ethanol at
72 °C followed by crystallization gave amide 104 in 90%
yield. Hydrogenolysis of the CBZ protecting group of amide
104 at 40 psi H2 using 5% Pd/C catalyst in the presence of
methanesulfonic acid at 50 °C gave pyrimidone amine 105,
obtained as a hydrate, in 96% yield.
yltetrazole (106) in the presence of triethylamine in toluene
at 0 °C to give intermediate 108. Slow addition of this intermediate to warm toluene at 50 °C followed by heating the
reaction mixture at 65 °C for 1 hour resulted in loss of nitrogen and provided the oxadiazole ester 109. Crude ester 109
was treated with KOH which resulted in saponification of the
ester to give oxadiazole carboxylic acid potassium salt 110 in
91% yield from 106. The synthesis was completed by first
converting 110 to the corresponding acid chloride 111 using
oxalyl chloride followed by reaction with pyrimidone 105 in
the presence of N-methyl morpholine giving reltagravir in
91% yield after recrystallization from isopropanol/water. The
reltagravir potassium salt XIV was then obtained by mixing
KOH with reltagravir in acetonitrile and precipitating out the
product via slow concentration and filtration of the potassium salt.
Retapamulin (AltabaxTM)
Antibacterial retapamulin is a derivative of the natural
product pleuromutilin and was developed by Glaxo and approved in the US in 2007 for the treatment of skin infections
[6]. It has a unique mechanism of action, inhibiting bacterial
protein synthesis by inhibiting the larger subunit of the ribosome, and thus has no cross resistance to other antibacterial
agents [55, 56]. A number of routes have been disclosed in
the patent literature and all of them start with the natural
product pleuromutilin [57, 58] and the process route is
shown in Scheme 15 [58]. Commercially available tropinol
The synthesis of oxadiazole acid chloride 111 was initiated by reaction of ethyl oxalylchloride (107) with meth-
OH
OMs
S
KSAc
Et3N, MsCl
DCM, -10 to -5 °C
N
pyridine:H2O
35-40 °C, 70%
N
112
EtOH
8-20 °C, 0.5 h
N
113
MsO
NaOMe
O
114
OH
O
O
H
SH
N
S
O
O
N
EtOH, 20-25 °C
0.5-1.5 h
115
HO
OH
O
117
H
O
XV retapaulin
OH
O
O
H
MsO
Et3N (20 min@-15 °C MsCl (added
over 1.28 h)
OH
O
O
H
DCM, -9 to 1 °C
100%, crude
O
O
116
Scheme 15. Synthesis of Retapamulin XV.
117
F
F
Cl
water
N3
CN
F
118
F
N
80 °C
N
F
119
O
NaOH (30%)
CN
N
N
toluene
80 °C 40 min
120
N
F
N
NH2
XVI Rufinamide
Scheme 16. Synthesis of Rufinamide.
112 was mesylated under standard conditions (MsCl, Et3N)
to give mesylate 113. Tropinol mesylate 113 was reacted
with potassium thioacetate in pyridine and water giving intermediate 114 which was treated with sodium methoxide in
ethanol to give intermediate 115. Thiol 115 was reacted with
pleuromutilin mesylate 117, prepared by reacting pleuromutilin with methanesulfonyl chloride and triethylamine in
DCM in 95% yield, giving crude retapamulin in 75% purity.
Purification by crystallization in ethanol afforded retapamulin (XV) in >96-100% purity and 10.6% overall yield
from tropinol mesylate 113.
Rufinamide (Inovelon®)
Rufinamide was developed by Novartis, and licensed by
Eisai, for the treatment of epileptic seizures associated with
Lennox-Gastaut Syndrome (LGS) [6]. Rufinamide is a sodium channel blocker and works by reducing the recovery of
neuronal sodium-dependent action potential [59-62]. Although several different approaches have been reported in
the literature [60, 63], a simple one pot synthesis of rufinamide is shown in Scheme 16 [64]. 2,6-Difluorobenzyl azide
118 was reacted with 2-chloroacrylonitrile 119 in water at 80
°C for 24 hours. The excess acrylonitrile was removed by
heating and upon cooling, toluene was added. The resulting
mixture was heated to 80 °C and sodium hydroxide was
added to affect hydrolysis of the nitrile. After removal of
toluene by distillation, the reaction mixture was cooled and
the resulting product, rufinamide (XVI) was collected by
filtration.
Temsirolimus (Torisel®)
Temsirolimus, a cell cycle inhibitor developed by Wyeth
for the treatment of renal cell carcinoma, was launched in the
US in 2007. Temsirolimus works by inhibiting mTOR
(mammalian target of rapamycin)-driven cell proliferation
[65]. Temsirolimus is also being developed for the treatment
of mantle cell lymphoma (PhIII) and also as mono- or combination therapy for the treatment of ovarian and endometrium cancer (PhII). Additionally, temsirolimus is being
evaluated for the treatment of several other types of cancer
as well as multiple sclerosis and rheumatoid arthritis. The
synthesis of temsirolimus was initiated by bis-silylation at
positions 31 and 42 of rapamycin (121) using trimethylsilyl
chloride and imidazole to give 122 (Scheme 17) [66]. The
silyl ether at positon 42 was regioselectively desilylated using dilute sulfuric acid producing intermediate 123. The C42
position was acylated with the mixed anhydride derived from
the 2-phenyl boronate acid 124 and 2,4,6-trichlorophenyl
carboxylic acid chloride 125 using catalytic DMAP to give
126 [67]. Next, the silyl ether group at position 31 was removed using dilute sulfuric acid in acetone and after work up
with aqueous sodium bicarbonate solution and acetic acid
provided the deprotected intermediate 127. The boronate
ester was removed by reaction with excess 2-methyl-2,4pentanediol 128 and the crude product was precipitated using
ether/heptanes to afford pure temsirolimus (XVII) in 86%
yield.
Trabectedin (Yondelis®)
Trabectedin is a novel marine-derived tetrahydroisoquinoline, an antitumor agent isolated from the colonial tunicate
Ecteinascidia turbinate. Trabectedin binds to the minor
groove of DNA and bends the DNA toward the major
groove, blocking the activation of genes via several pathways. These pathways include selective inhibition of the
expression of key genes (including oncogenes) involved in
cell growth and drug resistance, inhibition of genetic repair
pathways and inhibition of cell cycle progression leading to
p53-independent programmed cell death [68]. Trabectedin
was originally developed by PharmaMar, a subsidiary of
Zeltia. Subsequently, the drug was co-developed and comarketed with Ortho Biotech, a subsidiary of Johnson &
Johnson. Trabectedin was approved as an orphan drug designation for the treatment of advanced soft tissue sarcoma and
ovarian cancer. PharmaMar and Johnson & Johnson are exploring trabectedin for numerous additional cancer indications. Cyanosafracin B (129), available from the optimization of the fermentation of bacteria Pseudomonas fluorescens
on kilogram scale, was used as the starting material for the
synthesis (Scheme 18) [69]. The amino and phenol groups of
compound 129 were protected as their corresponding Boc
and MOM derivatives, respectively giving compound 130 in
67% yield for the 2 steps. Compound 130 was subjected to
NaOH in H2O/MeOH, hydrolyzing the methoxy-p-quinone
to give free hydroxyl compound 131 in 68% yield. Compound 131 was reduced with H2 over Pd/C to give an unstable hydroquinone which was selectively alkylated with bromochloromethane in hot DMF in a sealed tube to give benzodioxolane 132, which was used in the next step without
purification. Compound 132 was subjected to a second alkylation with allylbromide to give allylic adduct 133 as a white
solid in 56% yield from compound 131. Removal of both the
MOM and Boc protecting groups of 133 with TFA gave
compound 134 in 95% yield. Compound 135, the free amine
product, was obtained by Edman degradation of the amide
side chain of compound 134 by treating 134 with excess
phenyl isothiocyanate to form the corresponding thiourea in
87% yield which was subsequently hydrolyzed with HCl in
dioxane to give 135 in 82% yield. To set up the critical conversion of primary amine of compound 135 to its corresponding alcohol, the phenol of the E-ring needed to be protected as its MOM derivative. Therefore, the primary amine
Liu et al.
HO 42
TMSO
O
O
O
O
HO
O
31 OH
O
O
O
O
O
O
O
TMSCl, imid
O
EtOAc
O
HO
O
O
OTMS
O
0.5 N H2SO4
O
O
O
122
121
Rapamycin
Ph
HO 42
B
O
O 42
O
Cl
O
O
O
O
Cl
31 OTMS
O
O
Cl
Cl
O
31 OTMS
O
125
O
O
HO
O
O
O
O
B
O
O
O
O
O
126
124
O
O
CO2H
123
O
B
O
HO
Ph
O
O
Ph
O
DMAP, CH2Cl2
HO
O
HO
O
O
O
OH
i. 0.5N H2SO4
acetone
ii. NaHCO3 (aq)
iii. AcOH
58% from 121
O
O
OH
O
O
OH
128
O
O
HO
O
O
O
O
ether/heptane
86% yield for 2 steps
O
O
O
HO
O
O
127
O
O
OH
O
O
O
XVII Temsirolimus
Scheme 17. Synthesis of Temsirolimus.
was temporary protected as TROC carbamate in 98% yield.
This was followed by reaction with MOMBr in the presence
of DIPEA in 88% yield, and removal of the TROC protecting group with Zn in HOAc to give compound 136 in 83%
yield. Compound 136 was treated with NaNO2 in HOAc to
give key primary hydroxy intermediate 137 in 50% yield
which was coupled with 138 in the presence of EDC and
DMAP to give ester 139 in 95% yield. Compound 139 was
treated with n-tributyl tin hydride and a palladium catalyst
removing the allylic protecting group to give the corresponding phenol in 90% yield which was subsequently oxidized
with benzeneselenic anhydride in methylene chloride at low
temperature to give 140 in 91% yield as a mixture of alcohol
isomers. Compound 140 was converted to lactone 141 in
58% yield by the following transformations as developed by
Corey [70]: a) reaction of compound 140 with in situ Swern
O
O
H2N
BocHN
NH
CN
i. Boc2O, EtOH
rt, 23 h, 81%
O
NH
CN
O
OMe 1M NaOH
OMe
N
N
N
ii. MOMBr, DIPEA
DMAP, CH3CN, 40 °C
6 h, 83%
H
N
MeOH, rt, 2.5 h
68%
H
O
OH
O
OMOM
O
O
129
130
O
O
BocHN
BocHN
NH
CN
i. 1atm H2, 10%Pd/C
rt, 2 h
O
OH
N
N
N
N
56% from 131
H
O
OMOM
OH
OMOM
O
O
131
132
O
O
BocHN
H2N
NH
CN
NH
CN
O
O
O
N
N
TFA, CH2Cl2
rt, 95%
H
H
O
OMOM
ii. HCl, dioxane, 4.3 M
rt, 1 h, 82%
O
OH
O
O
133
134
NH2
CN
NH2
CN
O
i. TrocCl, pyridine, CH2Cl2
0 °C, 1 h, 98%
ii. MOMBr, DIPEA, DMAP
CH3CN, 40 °C, 6 h, 88%
O
N
N
H
iii. Zn, AcOH/H2O
rt, 7 h, 83%
O
O
O
N
OH
O
i. phenyl isothiocyanate
CH2Cl2, rt, 3 h, 87%
O
N
N
allyl bromide, Cs2CO3
DMF, rt, 3 h
O
O
ii. BrClCH2, Cs2CO3
DMF, 110 °C
H
NH
CN
N
NaNO2
H
AcOH/H2O/THF
0 °C, 3 h, 50%
O
OMOM
O
135
136
NHTroc
S
O
OH
CN
HO
O
O
O
S
O
Fm
N
H
CN
NHTroc
O
O
N
Fm
O
N
138
EDC HCl, DMAP, CH2Cl2
rt, 2 h, 95%
N
H
OMOM
O
OMOM
O
O
137
139
i.Bu3SnH, PdCl2(PPh3)2
AcOH, CH2Cl2
rt, 15 min, 90%
ii. (PhSeO)2O, CH2Cl2
-10 °C, 15 min, 91%
Liu et al.
(Scheme 18. Contd….)
NHTroc
NHTroc
S
O
O
Fm
O
O
CN
O
N
N
OH
iii. tBuOH, 0 °C, 5 min
iv. (CH3N)2C=N-t-Bu
rt, 40 min
v. Ac2O, rt, 1 h
O
OMOM
O
N
H
ii. Zn, AcOH
H2O, 70 °C, 6 h
77% from 140
O
OMOM
O
56%
140
O
141
NH2
O
O
O
O
O
S
CN
O
S
CN
OHC
O
N
N
H
HO
O
O
N
i. TMSCl, NaI
CH2Cl2, CH3CN
rt, 30 min
O
O
N
H
S
CN
i. Tf2O, DMSO, CH2Cl2
-40 °C, 35 min
ii. DIPEA, 0 °C, 45 min
O
CH3
I
N
N
H
DBU, (CO2H)2, rt
4 h, 57%
O
MeO
O
O
142
O
143
OH
HN
O
CN
O
O
N
H
HN
O
O
S
O
N
OH
O
O
144
silica gel
EtOH, rt
12 h
90%
O
OH
OH
O
NH2
OH
AgNO3
CH3CN
S
O
O
N
N
H2O
rt, 16 h
90%
H
O
OH
O
OH
O
O
145
O
O
XVIII Trabectedin
Scheme 18. Synthesis of Trabectedin.
reagent in DMSO at low temperature, b) addition of DIPEA
to form the exendo quinine methide, c) quenching with tBuOH to remove excess Swern reagent, d) addition of excess
N-t-butyl-N’, N’, N’, N’-tetramethylguanidine to convert the
9-fluorenylmethyl thioether to the thiolate ion and to initiate
nucleophilic addition of sulfur to the quinine methide to generate the lactone ring, and e) addition of excess acetic anhydride to acetylate the resulting phenoxide group. The MOM
and TROC protecting groups were removed with TMSCl/
NaI and Zn in AcOH/H2O, respectively to give compound
142 in 77% yield for these two steps. The -amino lactone of
compound 142 was oxidized to the corresponding -keto
lactone with the methiodide of pyridine-4-carboxaldehyde in
the presence of DBU to give compound 143 in 57% yield.
Compound 143 was reacted with 144 in the presence of silica gel in ethanol at room temperature to give stereospecifically the spiro-tetrahydroisoquinoline 145 in 90% yield
which was finally reacted with AgNO3 to replace the nitrile
with a hydroxyl group to yield trabectedin (XVIII) in 90%
yield.
Vildagliptan (Galvus®)
Vildagliptin, a dipeptidyl-peptidase IV (DPPIV) inhibitor
discovered and developed by Novartis Pharmaceuticals, was
approved for the treatment of type II diabetes in Mexico,
Brazil and the E.U. Vildagliptin is the second DPPIV inhibi-
ClCOCH2Cl
HN
O
NH2
Cl
N
H
+ Me
N Cl
Cl
Me
O
iPrOAc:DMF
15 - 35 °C 1.5 h
O
146
148
Cl
O
15 - 25 °C
1h
NH2
N
147
CN
149
H
HO
NH2
152
KI, K2CO3
2-butanone
35 - 70 °C, 30 min
HO
N
N
H
H
O
CN
XIX Vildagliptin
KOH
HNO3/H2SO4
H
NH2
0 °C, 2 h;
RT, 30 h
150
O2N
NH2
H2O, 0-80 °C, 45min HO
151
NH2
152
Scheme 19. Synthesis of Vildagliptin.
tor approved after last year’s approval of sitagliptin developed by Merck [6,71,72]. Both the discovery [73] and process routes [74] toward the synthesis of this drug have been
published, and the process route is shown in Scheme 19. A
solution of L-prolinamide 146 in DMF was added to a premixed solution of chloroacetyl chloride in isopropylacetate/DMF at 15 °C. Upon complete addition of 146 the reaction mixture was warmed to 35 °C, which generated intermediate 147. After 1.5 hours, the reaction mixture was cooled
to 15 °C and Vilsmeier reagent 148 was added portionwise
to generate nitrile 149. 3-Hydroxyaminoadamantane 152,
required for coupling with 149, was prepared in two steps
[74]. Aminoadamantane 150 was added in small portions to
an ice cold solution of sulfuric acid and nitric acid. Upon
complete addition, the reaction was stirred for 2 hours at 0
°C and for 30 hours at room temperature generating intermediate 151. Next, the reaction mixture containing 151 was
cooled in an ice-water bath and solid KOH was added portionwise over 45 minutes. After addition was complete, the
reaction had reached 80 °C which resulted in the evolution of
NO2 gas and the reaction turned into a white slurry. After
filtration of the slurry, the solid was washed with DCM,
dried, and concentrated to give the desired 3-hydroxyaminoadamantane 152. The synthesis was completed by adding a
solution of 149, prepared as described above, to a solution of
3-hydroxyaminoadamantane 152, potassium carbonate, and
potassium iodide in 2-butanone generating vildagliptin
(XIX) in 31% crude yield. Pure vildagliptin was obtained
upon re-crystallization from 2-butanone; however the yield
was not reported.
ABBREVIATIONS
AIBN
=
BOC
=
t-Butyloxycarbonyl
CBZ
=
Benzyloxycarbonyl
CDI
=
N,N'-Carbonyldiimidazole
DBU
=
1,8-Diazabicyclo[5.4.0] undec-7-ene
DCE
=
Dichloroethane
DCM
=
Dichloromethane
DIAD
=
Diisopropyl azodicarboxylate
DIBAL-H =
DIPEA
=
DMAP
=
DMF
=
DMPU
=
N,N’-Dimethylpropyleneurea
DMSO
=
Methyl sulfoxide
DPPC
=
EDC
=
N-(3-Dimethylaminopropal)-N'ethylcarbodiimide
HOBT
=
IPA
=
Isopropyl alcohol
IPAC
=
Isopropyl acetate
LDA
=
LIHMDS
=
Lithium bis(trimethylsilyl)amide
MEK
=
Methylethyl ketone
MS
=
Molecular sieves
NBS
=
N-Bromosuccinimide
NCS
=
N-Chlorosuccinimide
NEP
=
NMM
=
N-methylmorpholine
NMP
=
PCC
=
PDC
=
PMB
=
4-Methoxylbenzyl
PPA
=
Polyphosphoric acid
TBAF
=
TBAB
=
t-Butyl ammonium bromide
TBDMS
=
TEA
=
Triethyl amine
TFA
=
TFAA
=
Trifluoroacetic acid anhydride
THF
=
Tetrahydrofuran
THP
=
Tetrahydropyran
TIPS
=
Triisopropylsilyl
TPA
=
Triisopropylamine
TPAP
=
TROC
=
2,2,2-Trichlorethoxycarbonyl
TMG
=
p-TSA
=
Liu et al.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
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Synthetic Approaches to the 2002 New Drugs Jin Li *

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