tert-Butyl methyl ether → Cyclohexanethiol

Participants

Reaction Steps

FIG. 4 demonstrates a room temperature enantioselective synthesis of (S)-pregabalin in the presence of catalytic quantities of epimeric quinidine thiourea C2. Thiolysis of 3-isobutylglutaric anhydride with cyclohexane thiol in methyltertbutylether (MTBE), at room temperature (rt) in the presence of catalytic quantities of C2 affords (S)-3-cyclohexylsulfanylcarbonylmethyl-5-methyl-hexanoic acid in quantitative yield and in 92% ee (the ee increased to 94% when the reaction was carried out at 0° C.). Aminolysis of resulting thioester intermediate at 40° C. over 1.6 h afforded (S)-3-Carbamoylmethyl-5-methyl-hexanoic acid in 88% yield. This primary amide intermediate was subjected to a Hofmann rearrangement to afford (S)-pregabalin.

Provenance & Evidence