RESOLUTION OF L)-4-(5-FLUORO-2-PYRIMIDINYL)-1-PIPERAZINE-BUTANOL (BMS-181100) AND ALPHA-(3-CHLOROPROPYL)-4-FLUOROBENZENEMETHANOL USING LIPASE-CATALYZED ACETYLATION OR HYDROLYSIS

alpha-(3-Chloropropyl)-4-fluorobenzenemethanol, a possible intermediat e for synthesis of a potential anti-psychotic agent orophenyl)-4-(5-fl uoro-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 42% yield with >99% optical purity. R-acetate was obtained with 92.6% optical purity by stopping the reaction after 46% conversion. The enzymatically produced acetate was hydrolyzed by l ipase PS-30 to give R-alcohol with >99% optical purity after 62-72% co nversion. BMS 181100 acetate ester was treated with lipase GC-20 in bu ffer containing 10% toluene to give the R-alcohol with 97.9% optical p urity after 47.6% conversion. The rate and enantioselectivity of hydro lysis by lipase GC-20 were very dependent on the organic solvent. E va lues ranged from 1 in the absence of organic solvent to >100 with dich loromethane and toluene.