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

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.