AN ASYMMETRIC-SYNTHESIS OF DULOXETINE HYDROCHLORIDE, A MIXED UPTAKE INHIBITOR OF SEROTONIN AND NOREPINEPHRINE, AND ITS C-14-LABELED ISOTOPOMERS

Two C-14-isotopomers of duloxetine HCl (S-(+)-N-methyl-3(1-naphthalenyloxy)-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-C-14] 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 of b) provided the S-chloroalcohol (7a) and its C-14-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 C-14-labeled isotopomer 9. Alternatively, reaction of 6 with 1-naphthol-[1-C-14] 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.