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 anantidepressant, 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 effectiveas Ritalin in the management of attention-deficit hyperactivity disorder (ADHD)1. But its most interesting featurewas discovered by accident: in early clinical trials, many smokers taking the drug reported that after one or twoweeks their craving for tobacco seemed to fade and they were able to quit smoking with few or no withdrawalsymptoms (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 witha new name, Zyban, for use as an aid in smoking cessation. This experiment gives you the opportunity to synthesizea well-known pharmaceutical, and an “anti-addiction” drug. Perrine and coworkers investigated various approachesfor the synthesis of Zyban. By modifying the published procedures3,4, which require more than 24 hours and giveyields below 40%, they developed a short, “one-pot” (really one flask) synthesis that can be carried out in less thantwo hours and gives material 98% pure in an average overall yield of 80%: The overall synthetic scheme is asfollows:
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 2- methyl-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 α -halogenated ketone. (Tear gas is a lachrymatory compound!) The lab provides a study of α- 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 beginimmediately (as judged by the disappearance of the color of the bromine), warm the flask briefly with your hand or awarm-water bath. Once the reaction begins, the color of the bromine will rapidly disappear, and the flask should beplaced in an ice bath. The bromine solution can now be added dropwise to the flask with stirring; add the brominesolution 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 ether extracts in a beaker. Remember to shake the separatory funnel well during each extraction and to wait for the layers to fully separate. (Caution! Ether is very volatile and pressure will develop!) The ether layer(s) will be on top and contain your product, 3a, while the aqueous layer will be at the bottom. The water layer contains the NMP solvent and excess t-butylamine; discard this layer, rinse the funnel with water, and return the combined ether extracts to the separatory funnel. Shake the ether solution five times with new 25 mL portions of water each time, allowing the layers to separate each time and then discarding the water layer. Transfer the ether solution to a clean, dry Erlenmeyer flask and remove any remaining water by stirring it in the beaker with anhydrous Na2SO4. You should add Na2SO4 until new material swirls freely in the solvent without clumping. Remove 2 to 3 mL (a Pasteur pipetful) of this ether solution into a vial and allow the ether to evaporate in your locker until next time so that you can run an NMR on the free amine 3a in CDCl3. Run the C-13 NMR if instructed to do so. Step 3: 3a -> 3b
At this point your beaker contains a solution of the free base of bupropion, 3a, in ether. Like most amines, the
free base of this compound is soluble in ether and insoluble in water. But when 3a is reacted with an acid, it will form a salt which will have opposite solubility properties, being insoluble in ether but soluble in water. Most pharmaceuticals are amines like bupropion, and they are nearly always marketed and administered in their salt form, usually the chloride. Following an ancient convention, amine chlorides in pharmacy and medicine are referred to as the “hydrochloride”: e.g., morphine hydrochloride, fluoxetine (Prozac) hydrochloride. We will form the hydrochloride salt in a solvent mixture consisting mostly of ether, so that it will precipitate out in crystalline form. Synthesis of 3b: Decant the ether solution through a funnel loosely plugged with cotton into a dry beaker chilled in an ice bath. The white powder remaining behind is the drying agent, Na2SO4. Wash any residual 3a from this powder by stirring it with enough fresh ether to cover it, allow it to settle, and decant the ether through the same cotton-plugged funnel into the beaker in the ice bath. You can then discard the cotton plug and the Na2SO4 desiccant. Using a Pasteur pipet, add a 2:10 v:v solution of conc. HCl:isopropyl alcohol dropwise with manual stirring to the chilled ether solution until the contents of the beaker are acid to pH paper. A few pipets-full will be needed (Note 3); test the pH by touching a stirring rod moistened with the solution to a small piece of pH paper moistened with water. About half way to t he equivalence point, sparkling white crystals of bupropion hydrochloride, 3b, will begin to form in the beaker. When the pH of the beaker is < 3 enough acid has been added. Isolation of 3b: Cover the beaker loosely with a watch glass, and allow it to chill thoroughly for 5-10 minutes in the ice bath. Collect the crystals by gentle vacuum filtration, wash them twice with small portions of ether, and let them air dry. (Do not force a rapid stream of air through the crystals during vacuum filtration; if you do, they may develop a static electric charge, and when approached with a spatula will leap around the bench like Mexican jumping beans.) When the crystals are dry, determine the mass, calculate the percent yield, and determine the mp. Run an IR, 1H NMR, 13C NMR, and GC-MS. Experimental Notes
Note 1. You should be able to see small bubbles forming where the bromine solution falls into the flask. What
do you think these bubbles consist of? If the humidity is high enough, you may notice a fog or fumes coming fromthe mouth of the flask as the reaction takes place; what is this? Alpha halogenations are acid-catalyzed; does thisexplain why this reaction is often slow at first but then proceeds rapidly?
Note 2. The displacement of a bromine atom by an amine is usually an SN2 process. Why would you expect
that the reaction you are carrying out, using t-BuNH2 , might be much slower than the same reaction using methylamine? What other reactions would be expected to compete with the SN2 reaction which forms bupropion? Thechoice of solvent in these reactions can be very significant. Try to find a discussion of solvent effects in SN2reactions in your textbook, in the library, or the Web.
Note 3. The HCl solution was made by mixing 2 mL concentrated HCl (12.0 M) with 10 mL isopropyl alcohol.
Assuming there is no contraction or expansion of volume on mixing, what is the molarity of the resulting solution? How many mL should you need if all your starting material (5.9 mmol 1) has been entirely converted to 3a? Cleaning Up:
The aqueous extracts can be washed down the drain with lots of COLD water. Discard the ether filtrate in the
appropriate waste container in the hood. Final Report:
In your discussion, be sure to answer all the questions in the Experimental Notes section. Interpret your spectral
data by drawing the structure on the spectrum and assigning the key features of each spectrum to functional groups,hydrogens, carbons, and molecular ion. Literature Cited
1. Perrine, D. M. The Chemistry of Mind-Altering Drugs: History, Pharmacology, and Cultural Context, American Chemical Society (Oxford
University Press): Washington, DC, 1996; p 237.
2. Hurt, R. D.; Sachs, D. P. L.; Glover, E. D.; Offord, K. P.; Johnston, J. A.; Dale, L. C.; Khayrallah, M. A.; Schroeder, D. R.; Glover, P. N.;
Sullivan, C. R.; Croghan, I. T.; Sullivan, P. M. N. Engl. J. Med. 1997, 337, 1195–1202.
4. Mehta, N. B. Meta Chloro Substituted-α-butylaminopropio-phenones, U.S. Patent 3,819,706, Jun 25, 1974.
5. Hill, J. A.; Scharver, J. D., J. Labelled Compd. Radiopharm. 1988, 25, 1095–1104.
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