Exp t 421 A Short One Pot Synthesis of Bupropion Wellbutrin Zyban Adapted by R Minard from a procedure by Daniel M Perrine Jason T Ross Stephen J Nervi and Richard H Zimmerman Department of Chemistry Loyola College Baltimore MD J Chem Ed Nov 2000 1479 1481 Introduction Bupropion 3b the hydrochloride salt of 2 t butyl amino 3 chloropropiophenone has a unique pharmacological profile It was first marketed in 1985 by Burroughs Wellcome now Glaxo Wellcome as an antidepressant under the trade name Wellbutrin Unlike selective serotonin reuptake inhibitors such as Prozac Zoloft or Paxil it does not interfere with sexual performance is less likely to cause drowsiness and is as effective as Ritalin in the management of attention deficit hyperactivity disorder ADHD 1 But its most interesting feature was discovered by accident in early clinical trials many smokers taking the drug reported that after one or two weeks their craving for tobacco seemed to fade and they were able to quit smoking with few or no withdrawal symptoms Johnston J A Head of Psychiatry Clinical Development Glaxo Wellcome personal communication 14 Dec 1998 When double blind studies confirmed these anecdotal reports2 bupropion was marketed in 1997 with a new name Zyban for use as an aid in smoking cessation This experiment gives you the opportunity to synthesize a well known pharmaceutical and an anti addiction drug Perrine and coworkers investigated various approaches for the synthesis of Zyban By modifying the published procedures3 4 which require more than 24 hours and give yields below 40 they developed a short one pot really one flask synthesis that can be carried out in less than two hours and gives material 98 pure in an average overall yield of 80 The overall synthetic scheme is as follows Cl CH3 C CH3 Cl NH2 Br2 O C CH2 O C CH CH3 1 2 Cl CH3 Br CH3 Cl O N CH3 NMP O C CH CH3 C CH3 NH CH CH3 3a 3 HCl O C CH CH3 C CH3 NH2 CH3 CH3 Cl 3b The ketone 1 is a brominated to bromoketone 2 SN2 displacement of Br by t butylamine yields 3a as a noncrystalline oil This is converted into the crystalline ammonium hydrochloride salt 3b by reaction with hydrochloric acid The greatest improvement in yield came from using N methylpyrrolidinone NMP also called 2methyl 2 pyrrolidinone in place of dimethylformamide DMF as a solvent for the amination of 2 In DMF the reaction can take many hours3 4 whereas in NMP it is complete in less than 10 min at 50 60 C The short reaction time enhances the yield because the free base of 3 but not its hydrochloride salt is significantly liable to decomposition Additionally this one pot procedure skips the isolation of intermediate 2 and prevents exposure to a lachrymatory halogenated ketone Tear gas is a lachrymatory compound The lab provides a study of halogenation and the influence of a nonprotic polar solvent on competition between nucleophilic substitution and elimination reactions Cautions Wear gloves when handling reactive materials and carry out all steps in a well functioning hood Bromine liquid and vapor are extremely caustic to skin and lungs and should be used only in the hood Avoid breathing dichloromethane vapors which are a probable carcinogen keep this solvent and all mixtures containing it in the hood at all times Ether vapors are extremely flammable any open flame or spark can cause a violent explosion If you spill the contents of the reaction after the addition of the bromine but before the addition of the amine during 2 3a do not try to clean up the spill but tell your instructor immediately the reaction mixture at this stage contains intermediate 2 which is a lachrymator irritates eyes and causes tears like onions Step 1 1 2 Synthesis of 2 From the stockroom obtain a 14 20 50 mL round bottom RB flask and 14 20 side arm addition funnel to fit In a good hood put 1 0 g 5 9 mmol m chloropropiophenone 1 into the 50 mL round bottom RB flask obtain from stockroom clamped above a magnetic stirrer add 5 mL dichloromethane CH2Cl2 and a magnetic stirbar and stir until the solid is dissolved Place the addition funnel on the flask Put 6 0 mL 6 0 mmol of a 1 0 M solution of Br2 in CH2Cl2 in the funnel and add a few drops to the flask If the reaction does not begin immediately as judged by the disappearance of the color of the bromine warm the flask briefly with your hand or a warm water bath Once the reaction begins the color of the bromine will rapidly disappear and the flask should be placed in an ice bath The bromine solution can now be added dropwise to the flask with stirring add the bromine solution just rapidly enough so that the color of the bromine has disappeared before the next drop is added Note 1 Isolation of 2 After all the bromine has been added remove the dropping funnel add two boiling chips and set up a simple distillation apparatus by replacing the addition funnel with a microscale distillation head obtained from the stockroom Insert the special ground joinr thermometer and connect the condenser to the water Distill the solvent from the reaction mixture by placing the stirred flask in a beaker of warm water kept at about 55 70 C by a hot plate When all the CH2Cl2 has distilled over a little less than 10 mL will be collected due to evaporative loses the temperature of the distillate should rise to 40 C the bp of CH2Cl2 and then fall when the CH2Cl2 stops distilling Don t keep heating after this happens remove the distillation apparatus Step 2 2 3a Synthesis of 3a The small amount of dense liquid remaining in t he flask at t his stage is 2 2 bromo 3 chloropropiophenone which is a mild lachrymator see Cautions above Using a funnel add to the flask 10 mL of a 50 50 mixture of 5 mL t butylamine and 5 mL N methylpyrrolidinone NMP and heat the unstoppered flask in a 55 60 C water bath with stirring for 10 minutes Note 2 Isolation of an ether solution of 3a The flask now contains 3a the free base form of bupropion Although most of the lachrymatory 2 has been consumed in forming 3a you should continue to work in the hood There are two other substances besides 3a in the flask the excess t butylamine and the NMP solvent All three substances are soluble in ether but the last two are also soluble in water while 3a as the free base is not We will take advantage of these solubility differences to isolate our product in pure form Transfer the contents of the flask to a separatory funnel add 25 mL water and extract the mixture 3 times with 25 mL portions of ether collecting and combining the