Wellbutrin/Zyban synthesis

Transcription

Wellbutrin/Zyban synthesis
CH421 Experiment 7
Synthesis of Bupropion Hydrochloride
Adapted from: Perrine, D. M.; Ross, J. T.; Nervi, S. J.; Zimmerman, R. H. A Short, One‐Pot Synthesis of Bupropion (Zyban®, Wellbutrin®). J. Chem. Ed.
2000, 77, 1479‐1480.
Reading: Organic Chemistry by John McMurry, 8e, Ch11.2‐11.3 (SN2 reaction) and Chapter 22.1‐22.3 (α‐halogenation of ketones)
Techniques: salt formation, melting point, IR, NMR
Introduction
Bupropion (Wellbutrin®, Zyban®) is an aminoketone drug structurally similar to other known stimulants such as
cathinone and amfepramone. More generally, these compounds are phenethylamines; perhaps the best known
example is amphetamine (Adderall®, Figure 1). The aminoketone class of compounds is generally known for its stimulant
effects, but researchers also found other uses for these compounds to treat a variety of conditions including depression,
ADHD, tobacco addiction, and even obesity.
O
Cl
H
N
buproprion
O
O
NH2
cathinone
NH2
N
amfepramone
amphetamine
Figure 1. Structures of some aminoketone drugs and amphetamine.
Bupropion was first synthesized and patented by researchers at Burroughs Wellcome (now GlaxoSmithKline, GSK) in
1969, and it was approved for clinical use in 1989. Bupropion is a dopamine reuptake inhibitor as well as a
norepinephrine reuptake inhibitor. It is mainly prescribed to treat depression under the brand name Wellbutrin®, but
it’s also marketed as smoking cessation aid under the trade name Zyban®. Other antidepressants have not shown
efficacy in smoking cessation, and this is attributed to bupropion’s nicotinic acetylcholine receptor antagonist activity.
While bupropion has advantages in its side effect profile in that it does not cause weight gain or sexual dysfunction as
with selective serotonin reuptake inhibitor (SSRI) antidepressants, a known severe side effect is increased risk of
seizures. The seriousness of this particular side effect caused bupropion to be withdrawn from the market for a period of
time although it has subsequently returned to clinical use at a reduced dose.
In this two‐week experiment, bupropion hydrochloride is synthesized in three steps from 3’‐chloropropiophenone
(Scheme 1). The ketone α‐bromination and SN2 reactions are performed in the same flask, albeit with a solvent switch,
so the reaction sequence is referred to as a “one‐pot” procedure. The free base of bupropion is subsequently converted
to the more stable hydrochloride salt for isolation and characterization.
Scheme 1: Overall 3‐step procedure to synthesize bupropion hydrochloride
Experiment 7: Synthesis of Bupropion Hydrochloride
In Week 1, you will perform the α‐bromination of 3’‐chloropropiophenone using bromine (Scheme 2). α‐Halogenation
reactions can occur under acidic or basic conditions. In this experiment, the bromination occurs under acidic conditions
and proceeds via the enol form of the ketone, which reacts with bromine. The keto‐enol tautomerization is catalyzed by
acid, and since one equivalent of HBr is generated in this reaction, the process is autocatalytic. Following the
bromination, the methylene chloride and HBr are removed in vacuo.
Scheme 2: Week 1 α‐bromination
In Week 2, the SN2 reaction with tert‐butylamine is performed directly on the crude α‐bromoketone (Scheme 3 below).
The polar aprotic solvent NMP (N-methyl‐2‐pyrrolidinone) is used for this step, and as you may recall from CH250, polar
aprotic solvents accelerate the rate of SN2 reactions versus polar protic or nonpolar solvents. Excess tert‐butylamine is
used, which also accelerates the reaction rate, since the rate of this SN2 reaction is dependent on the concentration of
both the electrophile (the bromide) and the nucleophile (tert‐butylamine). Additionally, since tert‐butylamine is more
basic than bupropion, the excess tert‐butylamine reacts with the HBr that is produced and affords bupropion as its free
base. Bupropion is then isolated from the excess tert‐butylamine, tert‐butylamine hydrobromide, and NMP via
extraction into diethyl ether. In the final step, the diethyl ether extract of bupropion is directly treated with a 2 M HCl
solution in ether to afford bupropion hydrochloride, which precipitates from ether.
Scheme 3: SN2 Reaction and hydrochloride salt formation
Safety Precautions
Week 1: Bromine is extremely corrosive to the skin and is toxic if inhaled; thus it must be handled in the hood with
gloves and with the sash down. The α‐bromoketone intermediate is a lachrymator. Safety glasses and gloves are
mandatory, and all chemicals must be handled in the hood.
Week 2: 2M HCl/ether is corrosive. Use gloves and work in the hood with this chemical.
Week 1: a-Bromination of 3’-Chloropropiophenone
Pre-Lab Notebook (to be completed prior to the start of lab in Week 1)
•
•
Enter date, experiment number and title on notebook page and in TOC with corresponding page number.
Copy the Week 1 reaction and the reaction table below (in your own writing) into your notebook and complete
all empty cells in the table. Check your calculations with your instructor before starting the experiment.
Experiment 7: Synthesis of Bupropion Hydrochloride
Name
MW
(g/mol)
mass (g)
3’‐chloro‐
propiophenone
168.62
1.00
bromine
(1.0M in CH2Cl2)
159.81
_____
2‐bromo‐3’‐chloro‐
propiophenone
247.52
theo mass
=
mmol
theo mmol
=
equiv
d (g/mL)
vol
(mL)
mp (°C)
bp (°C)
1.00
____
___
45‐47
____
____
6.00
___
Br2: 59
CH2Cl2: 40
____
____
____
____
____
Week 1 Procedure
Obtain a tare weight of the 50 mL round bottom reaction flask and record this in your notebook (Data section). Weigh
1.0 g of 3’‐chloropropiophenone into the tared 50 mL round bottom flask. Add a stir bar and 5.0 mL of CH2Cl2, and stir
the mixture until dissolved. In your hood with the sash down, carefully measure 6.0 mL of a 1.0 M Br2/CH2Cl2 solution
into a 10 mL graduated cylinder, using a glass pipette to transfer the solution. Carefully add a few drops of this solution
to the reaction flask. The disappearance of the dark color indicates the reaction is initiated. If the color does not
disappear, gently warm the flask in a warm water bath. Once the reaction has begun, place the flask into an ice water
bath, and slowly add the remaining Br2 solution while maintaining the flask at 0 °C. The Br2 solution should be added
dropwise at a rate where the color disappears before the next drop is added.
After all of the Br2 has been added, prepare a TLC plate as follows: mark the TLC plate with 3 tick marks: “sm” on the left,
co‐spot in the center, and “rxn” on the right. Prepare a TLC solution using a speck of 3’‐chloropropiophenone in ~1 mL of
ethyl acetate, and spot on sm and co‐spot lanes. Next, remove an aliquot of the reaction mixture by dipping a glass pipet
in the solution to draw up a small amount using capillary action, dip a microspotter into the solution in the pipet tip, and
spot on the co‐spot and rxn lanes. Develop the TLC plate in 1:1 hexanes:dichloromethane and show your results to your
instructor. Draw this plate and calculate Rf values for all spots in your Data section. Finally, after running the TLC,
transfer the flask to a water bath set to 50‐60 °C, and vigorously stir the mixture until the volatiles are removed (bp
CH2Cl2 is 40 °C; bp HBr is –67 °C). Cover the flask with a Kimwipe, label it, and leave it in the back of the hood until the
next lab period.
Data for Week 1 (collect and record in your notebook during the lab)
•
•
•
Tare weight of the empty 50 mL round bottom flask
Determine the mass of the crude just before you start Week 2 (after it has dried for a week) and record here
Describe product and calculate crude % yield
Week 2: a) SN2 Reaction with tert-Butylamine; b) HCl Salt Formation
Pre-Lab Notebook (to be completed prior to the start of lab in Week 2)
•
•
Enter date, experiment number and title on notebook page and in TOC with corresponding page number.
Copy the Week 2 reaction and the reaction table below (in your own writing) into your notebook and complete
all empty cells in the table. Check your calculations with your instructor before starting the experiment.
Experiment 7: Synthesis of Bupropion Hydrochloride
Name
MW (g/mol)
mass (g)
mmol
2‐bromo‐3’‐chloro‐
propiophenone
247.52
tert‐butylamine
73.14
_____
2M HCl/ether
36.46
_____
5.93
bupropion
hydrochloride
276.20
theo mass
=
theo mmol
(5.93 at most)
=
equiv
d (g/mL)
vol
(mL)
mp
(°C)
bp
(°C)
1.00
____
___
____
___
0.696
5.00
___
43‐47
___
____
233‐
234
___
____
____
____
____
Week 2 Procedure
SN2 Reaction
To the 50 mL round bottom flask containing crude 2‐bromo‐3’‐chloropropiophenone, add 5.0 mL of NMP; then 5.0 mL of
tert-butylamine. Stir the reaction mixture in a water bath set to 50‐60 °C for 15 minutes. After 15 minutes, transfer the
contents of the flask to a 125 mL separatory funnel containing 25 mL of water. Rinse the round bottom flask with a small
amount of ether into the separatory funnel. Extract the mixture 3 times with 25 mL ether, collecting the combined
organic extracts into a 125 mL Erlenmeyer flask (NOTE: ether is the top layer!). Return the combined ether extracts to
the separatory funnel, then wash the organic layer five (5) times each with 25 mL of water, collecting the aqueous
washes into a 250 mL Erlenmeyer flask. Finally, wash the ether layer with 15 mL of brine (saturated NaCl) to help remove
residual water from the organic solution (this can also be drained into the flask containing the aqueous washes). Next,
drain the ether layer into a clean and dry 250 mL Erlenmeyer flask, then dry the organic solution with Na2SO4, adding
enough so that the solids flow freely when swirled. After 5 minutes, filter the organic solution through a glass funnel
with a wad of cotton or glass wool (alternatively a paper funnel cone folded into the funnel) into another clean and dry
250 mL Erlenmeyer flask.
HCl Salt Formation
Add a stir bar to the flask containing the dried ether solution, set it to stir, and in the hood, carefully add the calculated
amount of 2 M HCl in ether solution using a glass pipette. White crystals of the bupropion hydrochloride salt should
form. After addition of the HCl is complete, cool the flask in an ice bath for 10 minutes, and then collect the crystals by
vacuum filtration. IMPORTANT NOTE: use only a gentle vacuum to reduce the amount of static generated, so the crystals
can be more easily handled and collected.
TLC analysis: Dissolve a speck of the HCl salt in ~0.5 mL 95% EtOH, and spot just this solution on a TLC plate. Develop the
TLC plate with CHCl3:NEt3 (19:1 v:v). Draw this plate and calculate Rf values for all spots in your Data section.
Data for Week 2 (collect and record in your notebook during the lab)
• Describe product and calculate % yield of the solid
• TLC data (draw TLC, calculate Rf’s, include mobile phase)
• Obtain melting point (if the material decomposes prior to melting, note the temperature at which this occurs)
• Obtain IR of solid, staple in notebook, and assign major functional group peaks
•
Experiment 7: Synthesis of Bupropion Hydrochloride
Obtain 1H NMR (~20 mg in DMSO-d6; bupropion HCl is not soluble in CDCl3), staple into notebook, and assign all
peaks in the spectrum
Overall Conclusion (record in your notebook)
• One short paragraph for Week 1 results: outcome based on TLC, crude % yield
• One short paragraph for Week 2 results: outcome, % yield, support that the desired product was obtained (refer
to IR and NMR). Also note purity based on TLC analysis.
• One short paragraph on overall results: comment on the overall success of the experiment; provide the overall
yield for the synthesis; possible sources of error, and any other information deemed necessary and relevant.
The IR and NMR data for the 3’‐chloropropiophenone starting material are given below for your reference.
IR of 3’-chloropropiophenone (nujol mull)
1
H NMR of 3’-chloropropiophenone (90 MHz in CDCl3)
t, 3H
q, 2H
m, 2H
m, 2H