An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers

✍ Scribed by William J. Wheeler; Fengjiun Kuo

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: French
• Weight: 644 KB
• Volume: 36
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580360303

✦ Synopsis

Abstract

Two ^14^C‐isotopomers of duloxetine HCl (S‐(+)‐N‐methyl‐3(1‐naphthal‐ enyloxy)‐3(2‐thiophene)propanamine hydrochloride), a potent mixed serotonin/norepinephrine uptake inhibitor have been prepared by an asymmetric synthesis. The palladium catalyzed cross‐coupling of 2‐thienoyl chloride (3c) (or its [carbonyl‐^14^C] isotopomer 3d) with vinyl tri‐n‐butylstannane, followed by addition of HCl afforded the key pro‐chiral intermediate chloroketone (5a, b). Chiral reduction with borane in the presence of the appropriate oxazaborolidine catalyst (14a or b) provided the S‐chloroalcohol (7a) and its ^14^C‐labeled counterpart 7b or the analogous R‐chloroalcohol (6). Activation of 7a, b by reaction with NaI/ acetone, followed by reaction of the corresponding iodoalcohol with methylamine yielded the penultimate aminoalcohols (8a, b). Formation of the alkoxide with NaH, followed by reaction with 1‐fluoronaphthalene yielded duloxetine or its ^14^C‐labeled isotopomer 9. Alternatively, reaction of 6 with 1‐naphthol‐[1‐^14^C] under Mitsunobu conditions afforded arylether 10a, b, which was in turn activated by reaction with NaI/acetone. Subsequent reaction of 10c, d with methylamine followed by salt formation yielded duloxetine or its naphthalene‐labeled isotopomer (13) as their HCl salts.