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Preparation method of Ezetimibe isomer

A technology of ezetimibe and isomers, which is applied in the field of medicinal chemistry and can solve the problems of not finding reports of SSR isomers

Active Publication Date: 2015-02-04
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there is no report on the SSR-type isomer of the ezetimibe raw material drug found in the open literature.

Method used

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  • Preparation method of Ezetimibe isomer
  • Preparation method of Ezetimibe isomer
  • Preparation method of Ezetimibe isomer

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 2.1 g of (R)-diphenylprolinol and 30 mL of toluene to a 500 mL reaction flask, vacuumize the system, replace with nitrogen, stir, and add 0.8 g of trimethylboroxane dropwise. After the dropwise addition was completed, stir at room temperature for 30 minutes, then raise the temperature to reflux, evaporate toluene after reflux for 1.5 hours, lower the temperature to -5~0°C under the protection of nitrogen, add 60 mL of dichloromethane, then add 9.3 mL of 10N borane dimethyl sulfide, and stir For 15 minutes, take 30 g of the compound of formula 1, dissolve it in 90 mL of dichloromethane, and add it dropwise to the above catalyst solution. The liquid was rotary evaporated to dryness to obtain a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether=3:7, volume ratio) to obtain 26.2 g of compound 2.

Embodiment 2

[0026] Add 20g of compound 2 and 24g of compound of formula 3 into a 500mL reaction flask, then add 300mL of dichloromethane, vacuumize the system, replace with nitrogen, stir, cool down to -15~-10℃, add N,N-diisopropylethyl Amine 38.3g, drop the temperature to -25~-20℃ after the dropwise addition, add 20g of trimethylchlorosilane dropwise, after the dropwise addition, react at -25~-20℃ for 1 hour, monitor the reaction by TLC, cool down to -35 At ~-30°C, add 12g of titanium tetrachloride dropwise. After the dropwise addition, react at -35~-30°C for 3 hours, and monitor the reaction by TLC. Add dropwise 10 mL of acetic acid to quench the reaction, pour the reaction solution into 280 mL of 7% DL-tartaric acid aqueous solution, stir for 1 hour, then add 100 mL of 20% aqueous sodium bisulfite, stir for 1 hour, separate the organic phase (dichloromethane layer), Concentrate to 160g, add 13.6g of N,O-bistrimethylsilylacetamide, heat up to reflux, add 240ml of n-heptane dropwise unde...

Embodiment 3

[0028] Add 20 g of compound 4, 200 mL of methyl tert-butyl ether, 14.2 g of N,O-bistrimethylsilylacetamide, and 0.09 g of tetrabutylammonium fluoride into a 500 mL reaction flask, react at room temperature for 1 hour, and monitor the reaction by TLC. 1 mL of acetic acid was added dropwise to quench the reaction, and the reaction solution was rotary evaporated to dryness to obtain compound 5.

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Abstract

The invention belongs to the field of medicinal chemistry and discloses a preparation method of an Ezetimibe isomer (SSR-type isomer), namely 1-(4-fluorphenyl)-3(S)-[3-(4-fluorphenyl)-3(S)-hydroxypropyl]-4(R)-(4-hydroxyphenyl)-2-azetidine (azacyclobutane) ketone and a preparation method thereof. The SSR isomer is one of main impurities of an Ezetimibe crude drug. By synthesis of the Ezetimibe SSR isomer, a contrast is provided for test and quantitative and qualitative analysis of Ezetimibe impurities, thus the quality standards of the Ezetimibe are improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and the invention discloses an ezetimibe isomer (SSR type isomer), that is, 1-(4-fluorophenyl)-3(S)-[3-(4- Fluorophenyl)-3(S)-hydroxypropyl]-4(R)-(4-hydroxyphenyl)-2-azetidin(azetidin)one, and a process for its preparation. Background technique [0002] Ezetimibe is a lipid-regulating drug developed by Merck and is the first selective cholesterol absorption inhibitor approved for clinical use. It can selectively inhibit small intestinal cholesterol transporters, effectively reduce intestinal cholesterol absorption, and reduce plasma Cholesterol levels and liver cholesterol stores. The structural formula of ezetimibe is as follows: [0003] [0004] There are three chiral centers and 7 optical isomers in the ezetimibe molecule. These isomers play an important role in the quality research of ezetimibe raw materials. Among them, the SSR type isomer is the raw material of ezetimibe One of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08
CPCC07D205/08
Inventor 黄赟朱墨张晓郭亚兵杨波
Owner WUHAN WUYAO SCI & TECH
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