METHOD OF PRODUCING (3R,4S)-L-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)- HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE

摘要

Method of producing (3R,4S)-l-(4-fiuorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) of formula I, in which alcohol-oxazolidide of general formula II, wherein PG is a phenol protecting group, such as a carbonate group, for instance benzyloxycarbonyl or tert-butyloxycarbonyl, or an arylmethyl group, for instance benzyl, benzhydryl or trityl, or a silyl group, for instance tert- butyldimethylsilyl or thexyldimethylsilyl, is silylated by silylation agents in an inert organic solvent in the temperature range of -10 0C to the boiling temperature of the mixture; the obtained silylether-oxazolidide of general formula III, wherein PG is as defined above and X is a silyl group of general formula SiR1R2R3, wherein R1 to R3 are identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, is cyclized by action of bis(trimethylsilyl)acetamide and a base in an inert organic solvent in the temperature range of -20 to 40 0C; and, finally, the obtained protected azetidinone of general formula IV, wherein PG is as defined above and Y is hydrogen or the group X as defined above, is deprotected by action of deprotecting hydrogenolytic agents and/or acidic agents in an inert organic solvent.