Resolution of α-(4-Fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol (BMS 181100) and α-(3-Chloropropyl)-4-Fluorobenzenemethanol Using Lipase-Catalyzed Acetylation or Hydrolysis

Article abstract of DOI:10.1016/S0957-4166(00)86268-0

α-(3-Chloropropyl)-4-fluorobenzenemethanol, a possible intermediate for synthesis of a potential anti-psychotic agent α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMS 181100), was resolved by acetylation using isopropenyl acetate and lipase PS-30 in heptane.S-alcohol was obtained in 42percent yield with >99percent optical purity.R-acetate was obtained with 92.6percent optical purity by stopping the reaction after 46percent conversion.The enzymatically produced acetate was hydrolyzed by lipase PS-30 to give R-alcohol with >99percent optical purity after 62-72percent conversion.BMS 181100 acetate ester was treated with lipase GC-20 in buffer containing 10percent toluene to give the R-alcohol with 97.9percent optical purity after 47.6percent conversion.The rate and enantioselectivity of hydrolysis by lipase GC-20 were very dependent on the organic solvent.E values ranged from 1 in the absence of organic solvent to >100 with dichloromethane and toluene.