Preparation of (S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine

The novel triple reuptake inhibitor (S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine monohydrochloride 1 possesses a unique 2-phenyl-2-(piperidin-4-yl)ethanol moiety with a stereogenic center at the benzyl position. To synthesize 1 as the (S)-isomer, three possible routes were investigated; (1) the lipase-catalyzed kinetic resolution of tert-butyl 4-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate 2 utilizing PS-IM from Pseudomonas sp. as the lipase; (2) the asymmetric hydrogenation of tert-butyl 4-(1-(3,4-dichlorophenyl)-2-oxoethyl)piperidine-1-carboxylate 5 utilizing dynamic kinetic resolution; and (3) the resolution of racemic [1-(tert-butoxycarbonyl)piperidin-4-yl](3,4-dichlorophenyl)acetic acid 8 with (S)-phenylethylamine. The design of the asymmetric reaction using retrosynthesis, as well as the extensive exploration of enzymes, asymmetric hydrogenation catalysts, and resolving reagents, were all important to afford the optically active compound 1 in excellent yield.

Figure optionsDownload as PowerPoint slide

[(1S)-(tert-Butoxycarbonyl)piperidin-4-yl](3,4-dichlorophenyl)acetic acid (S)-1-phenylethylamine saltC26H34Cl2N2O4Ee = 99.9% [by HPLC][α]D25 = +36.9 (c 0.931, MeOH)Source of chirality: resolved by (S)-1-phenylethylamineAbsolute configuration: (S)(S)