PROJE NEDİR?

PROJE NEDİR?
Proje belli bir amacı olan ve bu amacı
gerçekleştirmek için çeşitli bilimsel deney ve
faaliyetlerin bir bütçe dahilinde belli bir süre
içerisinde sonuçlandırılmasıdır. Eğer proje başarı ile
sonuçlanmış ise ya bir makale olarak yayınlanır
yada patent ile korunma altına alınır.
PROJENİN ÖNEMİ
-Yaratıcılığı geliştirir
-Kişinin filozofisini değiştirir
-Problem çözme, mantıksal düşünme, iletişim gibi
yetenekleri geliştirir
HAMUR MAYASI KULLANARAK ORGANIK SOLVENT DE
-KETO ESTER REDUKSİYONU VE ESTER HİDROLİZİ
O
OH
O
O
O
O
O
O
H am ur M ayasi
O
OH
O
O
Is o p ro p ilpa lm ita t
O
O
OH
Preparative -Ketoesters Reductions and Ester Hydrolyses by Yeast.
Using Free Cells in Organic Media T. Haag, T. Arslan and D. Seebach.
Chimia 1989, 43, 851.
ANTİSENS NÜKLEOSİD ANALOGLARI
SULFON PROJESİ
ODNA
O
NH
ODNA
B
B
B
O
N
O
O
CH2
O P
-O O
O
B
O S
O CH2
O
O
NH
B
B
N
ODNA
Normal DNA
ODNA
Sulfon Analog
O
Peptide Analog
Redesigning Nucleic Acids. S. A. Benner, T. R. Battersby, B. Eschgfaeller, D. Hutter, J.T Kodra, S.
Lutz, T. Arslan, D. Baeschlin, M. Blaettler, C. Y. Switzer, S. E. Moroney, J. Voegel, L. MacPherson, U. von
Krosigk, C. Hammer, C. Richert, Z. Huang, J. Horlacher, M. Koenig , B. Hyrup, M. Egli, E. Mueller, J.
Schmidt, J. Piccirilli, A. Roughton, H. Held, S. Jurczyk, S. Lutz, , K. P. Nambiar K. C. Schneider, J
Stackhouse. Pure Appl. Chem. 1998, 70, 263.
ANTİSENS NUKLEOSİDLERİN YAPI TAŞLARININ SENTEZİ
O
O
O
O
O
O
O
O
O
O
O
O
O
Su
O
O
O
O
H amur M ayasi
O
O
OH
OH
O
O
O
O
OH
HO
O
OH
O
OR
Reduction of 2 -Substituted 3-Oxoglutarates Mediated by Baker's Yeast. Variation
in Enantioselectivity without Corresponding Variation in Diastereoselectivity. T.
Arslan and S. A. Benner. J. Org. Chem. 1993, 58, 2260.
Determination of the Absolute Configuration of Dimethyl (2S,3S) 2-allyl-3hydroxyglutarate: A Chiral Building Block for Preparing Branched-chain
Nucleoside Analogs. T. Arslan, B. Herradon, W. B. Schweizer and S. A. Benner. Helv.
Chim. Acta. 1993, 76, 2969.
DNA-TOPISOMERASE PROJESİ
Structurally Modified
Substrates for DNA
Topoisomerase I.
Effect of Inclusion of
a Single 3' Deoxynucleotide
within the Scissile Strand.
T. Arslan, A. T. Abraham
and S. M. Hecht.
Nucleosides and
Nucleotides 1998, 17, 515.
Effect of 3' - Deoxynucleotides on DNA Topoisomerase I Binding and Activity.
T. Arslan, T. Abraham and S. M. Hecht. J. Biol. Chem. 1998, 273, 12383.
ATEŞBÖCEĞİ LUCİFERASE’A DOĞAL OLMAYAN AMİNOASİTLERİN
SPESİFİK OLARAK YERLEŞTİRİLMESİ
Misacylated Transfer RNAs as a Source of Synthetic Enzymes. V Karginov; S Mamaev,
H An, A Laikhter, T Arslan, C Crasto, G Short, S M.Hecht,. Book of Abstracts,
212th ACS National Meeting, Orlando, FL, August 25-29 (1996)
Firefly Luciferase: Alteration of the Color of Emitted Light. S. V. Mamaev,
A. L. Laikhter, T. Arslan and S. M. Hecht. J. Am. Chem. Soc. 1996, 118, 7243.
ATEŞBÖCEĞİ LUCIFERASE’IN KİMYASAL ENERJİYİ
IŞIĞA ÇEVİRME MEKANİZMASI
Structurally Modified Firefly Luciferases Effect of Amino Acid.
Substitution at Position 286. T. Arslan, S. V. Mamaev,
N. V. Mamaeva and S. M. Hecht. J. Am. Chem. Soc. 1997, 119, 10877.
SILDENAFIL CITRATE
EP 463756 Temel patent Pfizer 1992
O
O
OH
SOCl2
Toluene
O
HN
2
HN
N
2
Cl
N
+
CH2Cl2
Et3N
N
O
N
N
H
2HN
O
4-Amino-1-methyl
-3-n-propyl pyrazole
-5-carboxyamide
2-Ethoxybenzoyl
chloride
2-Ethoxy
benzoic acid
O
O
O
4-(2-Ethoxybenzamido-1-methyl
3-n-propylpyrazole-5-carboxyamide(I)
O
O
O
HN
2
O
N
N
O
NH
(I)
EtOH, H2O2
NaOH
CH2Cl2, NaCO3
NaCO3, NaCl
Ether
O
N
HN
N
N
N
Chlorsulfonic
acid
N
CH2Cl2, H2O, MeOH
O
O
5-(2-Ethoxyphenyl)-1-methyl
3-n-propyl-1,6-dihydro-7Hpyrazole[4,3,d]pyrimidin-7-one
N
HN
O
S
Cl
5-(5-Chlorosulphonyl
2-Ethoxyphenyl)-1-methyl
3-n-propyl-1,6-dihydro-7Hpyrazole[4,3,d]pyrimidin-7-one(II)
O
(II)
N
N-methylpiperazine
EtOH
CH2Cl2, MeOH, NaCO3
N
HN
O
O
Citric acid
O
COOH
N
HN
N
N
N
MeOH
.
HO
COOH
COOH
O
O
O
S
N
Sildenafil base
N
O
S
N
Sildenafil Citrate
N
SODIUM ALENDRONATE TRIHYDRATE
US 4922007 Temel patent Merck 1992
1) PO3H, PCl3
O
HN
2
Sunflower oil
OH
OH
HN
2
2) NaOH, MeOH
PO3H
PO3Na
.3H2O
50-60%
4-Aminobutanoic acid
Sodium Alendronate Trihydrate
Preparation of 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
EP 1390363 B1, eidem US 7009071
Antihypertensive Drugs
LISINOPRIL
O
O
+
O
O
AlCl3
OH
96%
(CH2)4
CH
*
Trifluoroacetyl
-L-Lysine
l
hydrochloride
EtO
(I) + (II)
Et3N/LiOH
NaI
O
Ethyl-2-chloro-4-oxo-4phenylbutyrate (I)
NH2.HCl
Benzyl
alcohol
NH2.HCl
O
OEt
-Benzoylacrylic acid
Maleic anhydride
CF3CON
HCl(g)
EtOH
94%
O
O
COOH
CF3CON
CH COOBn
*
N6-Trifluoroacetyl
-L-lysine benzyl ester
hydrochloride(II)
SOCl2
O (CH ) HNOCCF
2 4
3
COOBn
NH
O (CH ) HNOCCF
2 4
3
(S)-1-[N2-(Ethoxycarbonyl-3phenylpropyl)-N6-trifluoroacetyl
-L-lysyl]N2-carboxyl anhydride(III)
N
O
O
O
(CH2)4
EtO
Pd/C
EtOH, HCl
NaOH pH 3
65%
Dioxane
53%
EtO
Cl
O (CH ) HNOCCF
2 4
3
NH
Im2CO
CH2Cl2
COOH
N2-(1-(S)-Ethoxycarbonyl-3phenylpropyl)-N6-trifluoroacetyl
-L-lysine
NH
H Cl
NH
C OOH
C OOMe
S O C l2
M eO H
87 %
L- P rolin e
L- P rolin e m eth yl e s ter
H ydr o c hlo rid e (IV )
E tO
O
(C H 2 ) 4 H N O C C F 3
C H 2 C l2
NH
(III) + (IV )
97 %
O
N
C OOMe
F u ll p ro tec te d
L is ino p r il
HO
N H2
O
M eO H
NH
O
N aO H
N
53 %
2H 2 O
C OOH
Lis ino pr il
Process for the Production of Lisinopril. EP 1513868 B1
Supported by Tübitak-Teydeb
Temel patent EP 308065, SmithKline 1988
DCC
DMAP
DMF
O
N
HN
O
O
O
N
N
2HN
NH
O
O
Protected Valacyclovir
H 2/Pd(5%)
MeOH, 0.5N HCl
O
N
HN
2HN
O
N
N
O
O
NH2 .HCl.H2O
Valacyclovir Hydrochloride Monohydrate
Preparation Novel Polymorphs of Valacyclovir US 0252776
Supported by Tübitak-Teydeb
LOSARTAN POTASSIUM
Temel patent EP 324377Du Pont 1988
NC
MgCl
+
NC
Mn
Cl
THF
4-Tolylmagnesium
Chloride(I)
2-Chloro
benzonitrile(II)
4-Methyl-2'-cyanobiphenyl(III)
N
NC
NH
N
NaN 3
N
Et3NHCl
Toluene
4-Methyl-2'-cyanobiphenyl(III)
5(4-Methyl-1,1-biphenyl2-yl)
1H-tetrazole(IV)
N
N
NH
N
NTr
N
N
TrCl
N
CH2Cl2
Et3N
AcOEt
5(4-Methyl-1,1-biphenyl
2-yl)-1-triphenylmethyl1H-tetrazole(V)
5(4-Methyl-1,1-biphenyl2-yl)
1H-tetrazole(IV)
N
NTr
N
N
5(4-Methyl-1,1-biphenyl
2-yl)-1-triphenylmethyl1H-tetrazole(V)
Br2
AIBN
CH2Cl2
Toluene
Na2SO4
N
NTr
N
Br
N
5(4'-Bromomethyl-1,1biphenyl2-yl)
1H-tetrazole(VI)
N
NTr
N
Br
N
N
+
5(4'-Bromomethyl-1,1biphenyl2-yl)
1H-tetrazole(VI)
N
H
DMF, K2CO3
MeOH, NaBH4
H2O, EtOAc
HO
NTr
Cl
N
N
N
N
N
Trityl Losartan (VIII)
Cl
O
2-Butyl-2-chloro
1H-Imidazole-5carboxaldehyde (VII)
Cl
Cl
OH
N
N
N
N
H O N H 2. H C l
N
N
N
M ethanol
A c etone
W ater
E thyl ac etate
N
Trityl Losartan
N
NH
N
Losartan Acid
Cl
Cl
OH
N
OH
N
OH
N
N
N
KOH, IPA
N
NH
N
Losartan Acid
t-butylmethylether
N
N
N
- +
NK
N
Losartan Potassium
METHOD FOR PRODUCING METAL SALTS OF LOSARTAN WO 2007 / 062675A1
Methoxytriphenylmethane safsızlığının oluşması
Cl
OH
N
OH
N
Cl
N
N
N
N
H O N H 2. H C l
N
N
N
-
N
+
N
M eth anol
A c etone
W ater
N
MeOH
H3O+
Cl
OH
N
N
N
N
NH
N
+
M eO
PROCESS FOR PRODUCING BIPHENYL-TETRAZOLE COMPOUNDS
EP2001869
Hydroxylamine nin Türevlendirilmesi
MeOH
O
H2N
OH
Hydroxylamine
+
1-p-Tolyl-ethanone
Supported by Tübitak-Teydeb
HO
N
1-p-Tolyl-acetoxime
Methoxy safsızlığının retro-Michael Mechanisması Üzerinden Oluşması
Cl
N
H+
Cl
OH
N
M eO H
N+
-H 2 O
N
N
N
N
N
NH
N
NH
re tro -M ic h e a l
p ro d u ct
N
-H +
L o s a rta n A cid
Cl
O Me
N
N
N
N
NH
N
M e th o xy im p u rity
PROCESS FOR PRODUCING USEFUL SALTS FORM OF
BIPHENYL-TETRAZOLE COMPOUNDS PCT/TR2006/000036
IRBESARTAN
Basic Patent EP 454511. Sanofi 1990
N
N
O
O
N
N
H O N H 2 .H Cl
N
N
N
N
M ethanol
A cetone
W ater
E thyl acetate
N
N
NH
N
N
O
O
N
N
Crude
Irbesartan
N
N
Ethanol
N
NH
N
W ater
N
N
NH
N
Irbesartan
METHOD FOR PRODUCING PURE CRYSTALLINE FORMS OF 2-n-BUTYL-3-((2- (1H-TETRAZOLE-5-YL)
(1,1’-BIPHENYL)-4-METHYL)-1,3-DIAZAPSPIRO (4,4’) NON -1- EN-4-ONE PCT/TR2006/000046
Safsızlık A
IRBESARTAN IMPURITIES
- OH
N
HO
O
N
O
N
N
N
N
NaOH
NH
N
W ater
N
NH
N
N
NH
O
HN
O
N
N
NH
N
Safsızlık B
O
N
O
N
O
N
N
O
N
N
NH
N
N
N
N
N
N
O
N
O
O
N
N
O
N
N
N
N
N
N
O-
CANDESARTAN CILEXETIL
Temel patent EP459136 Takeda,
1990
N
N
N
NC
O
O
N
O
N
Ethyl 1-(2'-cyano-biphenyl
-4-ylmethyl)2-ethoxybenzimidazole
-7-carboxylate(III)
1. trimethyltin azide,
toluene
2. NaOH, C 2H 5OH
3. trityl chloride,
N(C 2H 5)3,CH 2Cl2
HO
N
O
N
O
N
Trityl Candesartan(IV)
Trt
N
NTr
N
N
O
IV
+
O
I
O
K2CO3, DMF
O
O
O
O
O
N
O
cyclohexyl 1-iodoethyl
carbonate
N
Trityl Candesartan Cilexetil
N
NTr
N
N
O
O
O
O
O
O
H2SO4
N
O
N
Trityl Candesartan Cilexetil
Aceton
MeOH
Water
O
O
O
N
NH
N
N
O
N
O
N
Crude Candesartan Cilexetil
N
NH
N
N
N
NH
N
N
O
O
O
O
O
O
EtOH
N
O
N
Crude Candesartan Cilexetil
O
O
O
O
N
O
N
Candesartan Cilexetil
CANDESARTAN SAFSIZLIKLARI
O
R
O
O
N
O
O
N
R1
N
O
N
N
H3O+
N
H
O
N
O
N
H
Desethyl Candesartan
O
R
R1
N
O
N
H
+
H2O
Candesartan Cilexetil için yeni bir Proses
N
NH
N
N
N
NTr
N
N
O
O
O
O
O
O
H2SO4
EtOAc
N
O
N
O
O
O
O
N
Water
O
Toluen
Trityl Candesartan Cilexetil
N
Crude Candesartan Cilexetil
A Process for Preparing Candesartan
Cilexetil in High Purity TR2009/07894
Supported by Tübitak-Teydeb
ZOLEDRONIC ACID MONOHYDRATE
EP 0275 821 B1 Basic patent Ciba 1987
Basamak 1:Ham Zoledronic Acid Monohydrate Üretimi
O
PCl3
Sunflower oil
O
N
N
OH.HCl
1H-imidazol-1-yl-acetic
acid hydrochloride
H3PO3
EtOAc
EtOH
MeOH
HO
N
P
N
HO
OH
OH
P
O
OH .H2O
Crude zoledronic
acid monohydrate
Step-2: Zoledronic Acid Monohydrate Kristalizasyonu
O
HO
N
P
N
HO
Water
NaOH
HCl
OH
OH
P
O
O
HO
N
P
N
OH .H2O
Crude zoledronic
acid monohydrate
A General Process For The Preparation of
Bisphosphonic Acids and Salt Thereof
TR 2009/08880
HO
OH
OH
P
O
OH .H2O
Zoledronic
acid monohydrate
X-Ray Diffractogram of Zoledronic acid monohydrate (Batch No: 8M0001)
X-Ray Diffractogram of Form I (US7435827B2)
SODIUM IBANDRONATE MONOHYDRATE
US 4942 157 Basic patent Boehringer 1987
Sodium Ibandronate Monohydrate Step 1
HCl
H3PO3, PCl3
Sunflower oil
Ethyl acetate
O
N
OH
H2O, NaOH
MeOH
C9H20ClNO2
209.72
N-Methylpentyl propionic
acid Hydrochloride
Supported by Tübitak-Teydeb
OH
N
O
P
P
.H2O
OH
OH
OH
O ONa
C9H22NNaO7P2 .H2O
359.21
Crude Sodium Ibandronate
Monohydrate
Sodium Ibandronate Monohydrate Step 2
OH
N
O
P
P
.H2O
OH
OH
OH
O ONa
C9H22NNaO7P2 .H2O
359.21
OH
Ethanol
H2O
N
.H2O
P
P
OH
OH
OH
O ONa
C9H22NNaO7P2 .H2O
359.21
Processes For The Preparation Of Sodium Ibandronate
Monohydrate Polymorphs and Polymophs Mixture
TR 2009/08885
O
X-Ray Diffractogram of Ibandronate Sodium monohydrate A+B
(TA.01.34)
X-Ray Diffractogram of Form A which is taken from literature
X-Ray Diffractogram of Form B which is taken from literature
Teşekkür:
Arkadaşlarıma: Neslihan Çakar, Bedriye Koç, Filiz Sahpaz, Evren Özarslan,
Ayçil Yurdakul,Emre Burmaoğlu, Nurten Rıdvanoğlu, Sait Uluözyurt,
Nihat Arslan, Hasan kaya, Selda Turhan, Melek Köroğlu, Tuba Biçer,
Yıldız Gülkok, Mustafa Tekgezer, Ender Ermiş,
Meral Çolak, Yasemin şahin, Serkan Karaman and Müge Dedeoğlu
Mentors of Pharmaceutical Industry: Sn. Ender Koçak ve Sn. Hasan Ulusoy
Tubitak-Teydeb’e: Sanayi Ar-Ge si Destekleri için
Çanakkale Universitesine: Bu Konuşmayı Olanak Sağladığı için