Study on the synthetic process of ezetimibe and its epimer impurities
The synthetic process of ezetimibe was optimized to make it suitable for large-scale production and the synthesis of cis isomeric impurities were provided for quality research.Starting from 4-(4-fluorobenzoyl)butyric acid,the key intermediate 24 and its cis isomer impurities were synthesized through condensation and asymmetric reduction.The above intermediates underwent cyclization reaction under the action of BSA and TBAF,removing trimethylsilyl and benzyl groups to obtain ezetimibe(1)and its cis isomer impurities.The structures of the target compounds obtained were confirmed by MS,1H-NMR and 13C-NMR spectra.Ezetimibe has successfully completed three validation batches,three process stability batches,and kilogram scale amplification validation in the cGMP workshop,proving that the process used is stable,with a chemical purity more than 99.7％and an optical purity greater than 99.8％.
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