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

• Published in: Synthetic communications Vol. 40; no. 11; pp. 1566 - 1573
• Main Authors: Reddy, Y. Thirupathi, Reddy, P. Narsimha, Reddy, M. Nikhil, Rajitha, B., Crooks, Peter A.
• Format: Journal Article
• Language: English
• Published: PHILADELPHIA Taylor & Francis Group 11.05.2010; Taylor & Francis; Taylor & Francis Ltd
• Subjects: Bromination; bupropion hydrochloride; Chemistry; Chemistry, Organic; N-bromosuccinimide; Pharmaceutical industry; Physical Sciences; Science & Technology; solvent-free; N-bromosuccinimide; bupropion hydrochloride; solvent-free; MECHANISM; Bromination; WELLBUTRIN(R)
• ISSN: 0039-7911; 1532-2432
• DOI: 10.1080/00397910903097351

A convenient, scalable, and commercially viable process for the production of the antidepressant drug bupropion hydrochloride (1) is reported. The process relies upon an improved, large-scale synthesis of the key intermediate, m-chloro- α -bromopropiophenone (4). During process development, bromine was replaced with N-bromosuccinimide (NBS) in the presence of para-toluene sulfonic acid (p-TSA), for the bromination of m-chloropropiophenone (3), in either a very low volume of acetonitrile or under solvent-free conditions, to furnish 4. Intermediate 4 was further reacted with t-butylamine in N-methyl-2-pyrrolidinone (NMP) to afford bupropion free base (5), followed by treatment with a saturated solution of hydrochloric acid in isopropyl alcohol (IPA-HCl) to afford bupropion hydrochloride (1). This improved process provides pure bupropion hydrochloride (1) in good yields and at considerably lower cost than existing processes, and it does not involve the use of hazardous reagents.