New chemical and chemo-enzymatic routes for the synthesis of (RS)- and (S)-enciprazine

The chemo-enzymatic synthesis of racemic and enantiopure (RS)- and (S)-enciprazine 1, a non-benzodiazepine anxiolytic drug, is described herein. The synthesis started from 1-(2-methoxyphenyl) piperazine 3, which was treated with 2-(chloromethyl) oxirane (RS)-4 using lithium bromide to afford a racemic alcohol, 1-chloro-3-(4-(2-methoxyphenyl) piperazin-1-yl) propan-2-ol (RS)-6 in 85% yield. Intermediate (S)-6 was synthesized from racemic alcohol (RS)-6 using Candida rugosa lipase (CRL) with vinyl acetate as the acyl donor. Various reaction parameters such as temperature, time, substrate, enzyme concentration, and the effect of the reaction medium on the conversion and enantiomeric excess for the transesterification of (RS)-6 by CRL were optimized. It was observed that 10 mM of (RS)-6, 50 mg/mL of CRL in 4.0 mL of toluene with vinyl acetate (5.4 mmol) as acyl donor at 30 °C gave good conversion (C = 49.4%) and enantiomeric excess (eeP = 98.4% and eeS = 96%) after 9 h of reaction. Compound (S)-6 is a key intermediate for the synthesis of enantiopure (S)-1. The (RS)- and (S)-enciprazine drug 1 was synthesized by treating (RS)- and (S)-6 with 3,4,5-trimethoxyphenol 5 using MeCN as a solvent and K2CO3 as a base.

Figure optionsDownload as PowerPoint slide

(S)-1-Chloro-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-olC14H21ClN2O2[α]D20=+30.15 (c 1, EtOH)Absolute configuration: (S)Source of chirality: enzymatic resolution

(R)-1-Chloro-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-yl acetateC16H23ClN2O3[α]D20=+36.2 (c 1, EtOH)Absolute configuration: (R)Source of chirality: enzymatic resolution

(S)-1-(4-(2-Methoxyphenyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)propan-2-olC23H32N2O6[α]D20=+2.9 (c 1, EtOH)Absolute configuration:(S)Source of chirality: (S)-1-chloro-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol