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Preparation method for Ezetimibe

A technology of ezetimibe and temperature control, which is applied in the field of biomedicine, can solve the problems of low yield, high impurities, low safety and stability, etc., and achieve the effect of increasing the yield and improving the yield

Inactive Publication Date: 2015-02-18
CHENGDU SENKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a preparation method for preparing ezetimibe to solve the problems of low yield, many impurities, low safety and stability in the existing technology. question

Method used

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  • Preparation method for Ezetimibe
  • Preparation method for Ezetimibe
  • Preparation method for Ezetimibe

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Embodiment

[0041] Mechanically dissolve 40ml of dichloromethane, cool down to -5°C under a nitrogen atmosphere, add 40ml of 10M borane / dimethyl sulfide, stir for 10min, then add 40ml of 1M(R)-MeCBS toluene solution, the temperature rises by about 3 ℃, stir for 30min; control the temperature at -5℃, add dropwise 200gRM1 / 1400ml dichloromethane solution under stirring, about 1.5h to complete the dropwise addition, then continue to stir for 1h, add TLC to monitor the disappearance of raw material RM1; then control the temperature at - Add 40ml of methanol dropwise at 5°C, a large amount of gas escapes, and the dropwise addition is completed in about 1 hour, then continue to stir for 1 hour, and then add 5% H 2 o 2 Mix 13.3ml of aqueous solution and 500ml of pure water for 1 hour; let stand to separate the liquid, add 300ml of dichloromethane to the separated water layer for extraction, then combine the organic phase after liquid separation and the organic phase after extraction, wash with 30...

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Abstract

The invention discloses a preparation method for Ezetimibe. The preparation method comprises the following steps: adding (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxo propyl] azacyclobutane-2-one (RM1 for short) into a borane / dimethylsulfide reaction system, and then adding an oxidant to react to generate an Ezetimibe intermediate; and carrying out hydrogenation reduction on the Ezetimibe intermediate to obtain Ezetimibe with a structural formula III. According to the preparation method, in the preparation process of the Ezetimibe intermediate, RM1 is taken as a raw material, dichloromethane is taken as a raw material solvent and (R)-MeCBS / methylbenzene solution is taken as a reaction catalyst, so that the reaction can be accelerated; the yield of the Ezetimibe intermediate can be improved; in the preparation method of Ezetimibe, methanol is taken as a solvent, 10% Pd / C is taken as a reactant, so that low-temperature reaction is carried out; meanwhile, air oxidation reaction is prevented so as to further improve the yield of Ezetimibe.

Description

technical field [0001] The invention belongs to the technical field of biomedicine and relates to a preparation method of ezetimibe. Background technique [0002] Ezetimibe is a new cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck. It was launched in Germany for the first time in November 2002 and was launched in the United States at the same time. This product is the first selective inhibitor of cholesterol absorption approved by the US FDA. Its chemical name is (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3- (4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone. [0003] Ezetimibe can selectively inhibit intestinal cholesterol transporter, effectively reduce intestinal cholesterol absorption, reduce plasma cholesterol level and liver cholesterol storage. Ezetimibe is an ideal companion to statin therapy, providing better LDL-C treatment target rate than doubling the statin dose or switching to a more potent statin, and is safe and well...

Claims

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Application Information

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IPC IPC(8): C07D205/08
CPCC07D205/08
Inventor 田兴华晏柳清李建惠赵智程罗丹
Owner CHENGDU SENKE PHARMA
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