A Short, One-Pot Synthesis of Bupropion (Zyban, Wellbutrin)

Abstract

A one-pot synthesis of (±)-2-(t-butylamino)-3'-chloropropiophenone (bupropion) as its hydrochloride salt (Zyban, Wellbutrin), an important antidepressant drug used in the treatment of nicotine addiction, is described. The procedure, suitable for students in their first year of organic chemistry, can be carried out in less than two hours and provides material of high purity in overall yield of 75-85%. A solution of m-chloropropiophenone in CH2Cl2 is treated with Br2. After removal of the solvent, t-butylamine and N-methylpyrrolidinone are added and the mixture is warmed briefly, quenched with water, and extracted with ether. Concentrated HCl is added to the ether solution to precipitate the product.

Convenient and Scalable Process for the Preparation of Bupropion Hydrochloride via Efficient Bromination of m-Chloropropiophenone with N-Bromosuccinimide

“…In all syntheses of bupropion reported thus far, [6][7][8] bromine is still used as the brominating agent for the preparation of the key intermediate, 4, and up until this current study, no process-development methodologies have ever utilized Nbromosuccinimide (NBS) as a brominating agent for the preparation of 4. In addition, these previous processes are either lengthy, lead to the formation of several process-related impurities, use unacceptable process solvents, or contain operations that are not optimal for safety when adopted for large-scale production.…”

“…In addition, these previous processes are either lengthy, lead to the formation of several process-related impurities, use unacceptable process solvents, or contain operations that are not optimal for safety when adopted for large-scale production. [6][7][8] We now report a convenient, scalable, and commercially viable process for the preparation of the key intermediate 4, starting from commercially available 3. In this process, NBS is utilized as an efficient brominating agent in the presence of p-toluenesulfonic acid (p-TSA) as a catalyst in a very low volume of acetonitrile or under solvent-free conditions at 60-65 C. Intermediate 4 is then reacted with t-butylamine in a mixture of N-methyl-2-pyrrolidinone (NMP) and toluene at 55-60 C to furnish bupropion free base (5).…”

A novel photoaffinity ligand for the dopamine transporter based on pyrovalerone

“…[ 3 H]-Dopamine uptake inhibition potencies in the same cells under the same conditions were also determined (Table 1). Racemic bupropion ( 4 ) and pyrovalerone ( 5 ) were also synthesized28, 29 and pharmacologically evaluated for comparison to the novel compounds. Replacement of the 4-Me group in pyrovalerone with 4-NHAc slightly reduced DAT binding affinity 28.…”

(±)-2-(N-tert-Butylamino)-3′-[125I]-iodo-4′-azidopropiophenone: A dopamine transporter and nicotinic acetylcholine receptor photoaffinity ligand based on bupropion (Wellbutrin, Zyban)

“…Access to target (±)- 3 in its HCl salt form was then achieved using standard methodology for the synthesis of bupropion and its derivatives. 4,5,20 First, ketone 8 was brominated to provide an α-bromo ketone derivative, followed by displacement of the bromide with tert -butyl amine and subsequent HCl salt formation. Although this strategy proved successful, it provided target photoprobe (±)- 3 in rather low yield, 11% over three steps.…”

“…DAT ligand affinities of (±)- 3 and synthesized (±)- 1 20 were determined via inhibition of [ 3 H]-WIN-35,428 (a cocaine analog) binding to hDAT in N2A neuroblastoma cells. The DAT affinity for target compound (±)- 3 (hDAT K i = 3071 ± 497 nM) was sevenfold lower than bupropion (hDAT K i = 441 ± 174 nM), but still bioactive in the range of parent compound (±)- 1 such that further experimentation was justified.…”