Synthesis of (S)-3-(N-Methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's Resolution−Racemization−Recycle Synthesis of Duloxetine for Its Robust Processes

(±)-3-( N, N -Dimethylamino)-1-(2-thienyl)propan-1-ol ( 6 ), prepared from 2-acetylthiophene ( 4 ) in a two-step overall yield of 79%, is resolved into ( S )- 6 of 93% ee as its diastereomeric salt ( 8 ) with ( S )-mandelic acid ( 7 ) according to Eli Lilly's procedures developed for the resolution−racemization−recycle (RRR) synthesis of duloxetine ( 2 ) with some modifications in terms of practicality. On its liberation from 8, ( S )- 6 undergoes N -demethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O -ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N -methyl group. Alkaline hydrolysis then affords ( S )-3-( N -methylamino)-1-(2-thienyl)propan-1-ol ( 1 ) of 100% ee, an alleged penultimate precursor to duloxetine ( 2 ), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t -BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2 .