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Abstract
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.
Notes
a 1.0 mol 3, 1.1 mol NBS, 0.1 mol p-TSA.
b 50% w/v of 3 in the appropriate solvent.
c Reactions were run at 60–65 °C.
d Area percentage by GC analysis.
a 1.0 mol 3, 1.1 mol NBS, 0.1 mol p-TSA.
b Reactions were run at 60–65 °C.
c Area percentage by GC analysis.
a 1.0 mol 3, 1.1 mol NBS, 0.1 mol acid catalyst.
b 50% w/v of 3 in acetonitrile.
c Reactions were run at 60–65 °C.
d Area percentage by GC analysis.
a 1.0 mol 3, 1.1 mol NBS, 0.1 mol p-TSA.
b 50% w/v of 3 in acetonitrile.
c Area percentage by GC analysis.
a 1.0 mol of (3), 1.1 mol of NBS, 0.1 mol of p-TSA.
b Reactions were run at 60–65 °C.
c 50% w/v of 3 in acetonitrile.
d Area percentage by GC analysis.
e Based on overall isolated yield of the bupropion hydrochloride (1) from m-chloropropiophenone (3).