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

摘要: (±)-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 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 duloxetine (2) some modifications terms practicality. On liberation 8, undergoes N-demethylative ethyl carbamate formation two discrete but successive steps an 87% 8:  (1) O-ethyl carbonate and concomitant loss N-methyl group. Alkaline hydrolysis then affords (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol 100% ee, alleged penultimate precursor (2), 75% after single recrystallization ethylcyclohexane. In process thus developed, PhMe substituted successfully t-BuOMe, solvent that has been used favorably origina...