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Reduction preparation process of ezetimibe and its intermediates

A preparation process, ezetimibe technology, applied in organic chemistry, chemical instruments and methods, organic chemical methods, etc., can solve problems such as difficult industrialization, high flammability, unfriendly environment, etc., to reduce production costs and facilitate operation Safe, high chiral purity effect

Active Publication Date: 2020-04-10
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The technical problem to be solved by the present invention is to overcome the reduction reagent used in the reduction preparation process of ezetimibe and its key intermediate I, which is odorous, environmentally unfriendly, and highly flammable. Therefore, it is not easy to industrialize and other defects

Method used

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  • Reduction preparation process of ezetimibe and its intermediates
  • Reduction preparation process of ezetimibe and its intermediates
  • Reduction preparation process of ezetimibe and its intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1, the preparation of compound II-a

[0036]

[0037] 50ml three-neck bottle, cryogenic thermometer, NaBH 4 (0.18g, 4.88mmol, 2eq) was suspended in 10ml THF and cooled to -5°C. Add I dropwise at this temperature 2 (0.62g, 2.44mmol, 1eq) in THF (10ml). After the addition, stir for 30min until clear, then add (R)-Me-CBS in toluene (0.25ml, 0.1eq), and stir for 15min. Then start to add compound I-a (1g, 2.44mmol, 1eq) solution in THF (10ml) dropwise, and react at -5~0℃ after the addition is complete. TLC detected that the compound I-a was completely consumed, quenched by adding 5 ml of methanol, and stirred for 15 min. Concentrate the reaction solution, add dichloromethane (30ml) and 2N HCl (10ml) to the residue, stir and separate the layers, wash the organic layer with water, wash with brine, dry over anhydrous sodium sulfate, concentrate, and use isopropanol: deionized water for the residue (4.5ml:3ml) crystallized to obtain about 0.6g of the target pr...

Embodiment 2

[0038] Embodiment 2, the preparation of compound II-a

[0039] 50ml three-neck bottle, cryogenic thermometer, NaBH 4 (0.1g, 2.44mmol, 1eq) was suspended in 5ml THF and cooled to -5°C. Add I dropwise at this temperature 2(0.31g, 1.22mmol, 0.5eq) in THF (5ml). After the addition, stir for 30min until clear, then add (R)-Me-CBS in toluene (0.25ml, 0.1eq), and stir for 15min. Then start to add compound I-a (1g, 2.44mmol, 1eq) solution in THF (10ml) dropwise, and react at -5~0℃ after the addition is completed. TLC detected that the compound I-a was completely consumed, quenched by adding 5 ml of methanol, and stirred for 15 min. Concentrate the reaction solution, add dichloromethane (30ml) and 2N HCl (10ml) to the residue, stir and separate the layers, wash the organic layer with water, wash with brine, dry over anhydrous sodium sulfate, concentrate, and use isopropanol: deionized water for the residue (4.5ml:3ml) crystallized to obtain about 0.45g of the target product II-a a...

Embodiment 3

[0040] Embodiment 3, the preparation of compound II-a

[0041] 50ml three-neck bottle, cryogenic thermometer, NaBH 4 (0.18g, 4.88mmol, 2eq) was suspended in 10ml THF and cooled to -5°C. Add I dropwise at this temperature 2 (0.62g, 2.44mmol, 1eq) in THF (10ml). After the addition, stir for 30min until clear, then add (R)-Me-CBS in toluene (0.25ml, 0.1eq), and stir for 15min. Then start to add compound I-a (1g, 2.44mmol, 1eq) solution in THF (10ml) dropwise, complete the addition, and react at 5-10°C. TLC detected that the compound I-a was completely consumed, quenched by adding 5 ml of methanol, and stirred for 15 min. Concentrate the reaction solution, add dichloromethane (30ml) and 2N HCl (10ml) to the residue, stir and separate the layers, wash the organic layer with water, wash with brine, dry over anhydrous sodium sulfate, concentrate, and mix the residue with isopropanol: deionized water ( 4.5ml:3ml) crystallized to obtain about 0.63g of the target product II-a as a ...

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Abstract

The invention provides a preparation process of ezetimibe shown as formula II and its intermediate. The process includes the steps of: in an organic solvent, and under the catalysis of (R)-Me-CBS, subjecting compound I to asymmetric reduction reaction shown as the specification in an NaBH4-I2 reduction system so as to obtain II. Specifically, R is hydrogen atom, benzyl, t-butyldimethylsilyl or trimethylsilyl. In the preparation method, the used NaBH4-I2 reduction system is more environment-friendly than borane dimethylsulfide, the operation is safer and more convenient, also the product cost can be reduced, and the obtained product has high yield and chiral purity. Therefore the preparation process can be used for synthesis of ezetimibe smoothly, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a reduction preparation process of lipid-lowering drug ezetimibe and its intermediate. Background technique [0002] Ezetimibe (English name: Ezetimibe), chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxy Propyl]-4-(4-hydroxyphenyl)-2-azetidinone, also known as ezetimibe, is a new cholesterol inhibitor jointly developed by Merck and Schering, and was released in the United States in 2002. FDA approved the marketing, trade name Zetia. [0003] The structural formula of ezetimibe is as follows: [0004] [0005] In the synthetic preparation of ezetimibe, part of the reported synthetic route involves ezetimibetone or its structural formula on the phenolic hydroxyl group protected with a protecting group (that is: corresponding to the R group in the following reaction formula) derivative I The reduction method, under the assistance of chiral auxiliar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08C07B53/00
CPCC07B53/00C07B2200/07C07D205/08
Inventor 朱怡君潘竞张顺利刘珍仁周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD