Preparation method of ezetimibe intermediate

Abstract

The invention discloses a preparation method of an intermediate 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluorophenylamino)(4-R-oxophenyl)methyl]-5-hydroxyvaleryl]-(4S)-phenyl-2-oxazolidinone (represented by general formula I) for synthesizing ezetimibe. The method is characterized in that the intermediate is prepared by using (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyvaleryl]-4-phenyl-1,3-oxazolidin-2-one and 4-R-oxophenylmethylene-4-fluoroaniline as initial raw materials. The method has the advantages of no need of an expensive reagent, simple operation, high product yield, high product purity and the like, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to an ezetimibe pharmaceutical intermediate 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluoroanilino) (4-Roxyphenyl)methyl]-5-hydroxypentanoyl]-(4S)-phenyl-2-oxazolidinone preparation method. Background technique [0002] Ezetimibe, English name Ezetimibe, alias Ezetimibe, trade name ZETIA, chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluoro Phenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone (structural formula VI), CAS Registry No. 163222-33-1, manufactured by Schering-Plough and Merck A new class of selective cholesterol absorption inhibitors jointly developed has excellent blood lipid-lowering effects. Ezetimibe inhibits the absorption of cholesterol in the diet and transported to the intestinal tract through bile by the small intestine by binding to the membrane protein on the brush border membrane vesicles of the small intestine, and reduces the cholesterol content in...

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Problems solved by technology

[0007] WO2009140932 discloses a method for preparing the intermediate, which uses (S)-3-[4-(4-fluorobenzoyl)-1-oxybutyl]-4-phenyloxazolidine-2 - Ketone as the starting material, protected by carbonyl group, condensed with 4-benzyloxycarbonyloxybenzylidene-4-fluoroaniline, and then decarbonyl protected, by BH 3 / CBS asymmetric reduction to obtain compound I, this preparation method requires carbonyl protection and deprotection, the steps are long, the yield is 44.7%, resulting in high cost, and the asymmetric reduction is in the last step, it is not easy to purify, resulting in low purity of the product High, only 97.3%

[0008] CN1130342 discloses a method for preparing similar intermediates, which is based on (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1 , 3-oxazolane-2-one (II) and 4-hydroxybenzylidene-4-fluoroaniline were used as starting materials, and the hydroxyl protecting group of the synthesized ezetimibe intermediate was protected by silane. The rate is 65%. The post-treatment of this method is complicated, and due to the instability of silane protection, the product is not easy to purify, and some silane protection groups are easy to fall off. It needs to be silane protection again in the later stage, and the operation is repeated.

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