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New synthesis method of ezetimibe

An ezetimibe and compound technology, applied in the field of drug synthesis, can solve the problems of low yield, limited application, many reaction by-products, etc., and achieves the effects of low reaction requirements, not easy to fall off, and simple operation

Active Publication Date: 2014-04-23
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the asymmetric Mannich reaction in the route is due to the active nature of the intermediate, resulting in more reaction by-products and lower yield, which limits its application in industrial production.

Method used

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  • New synthesis method of ezetimibe
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  • New synthesis method of ezetimibe

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of ezetimibe intermediate formula (IV) compound

[0033]

[0034] in N 2 Next, 150 ml of dichloromethane and 21.5 g of the compound of formula (III) were added, stirred and cooled to -20°C. Add 30.6 ml of diisopropylethylamine (DIPEA); slowly add 16.1 ml of trimethylchlorosilane (TMSCl) dropwise, and keep stirring at -15°C for 1.5 hours. Cool the reaction solution to -30°C, add 20.0 g of the compound of formula (II), and stir for 10 minutes. Slowly add 4.1 ml of TiCl dropwise 4 , keep the temperature at -30°C and stir the reaction for 4 hours. Slowly add water to the reaction mixture to quench the reaction, add 60 milliliters of 1N hydrochloric acid aqueous solution, add 200 milliliters of dichloromethane, leave to stand for layering after stirring, wash the organic layer with water, dry over anhydrous sodium sulfate, concentrate to a small amount of solvent, add 15 mL of bistrimethylsilylacetamide, heated to reflux for 30 minutes. The mix...

Embodiment 2

[0035] Example 2: Preparation of ezetimibe intermediate compound of formula (V)

[0036]

[0037] Under nitrogen protection, add 300 ml of methyl tert-butyl ether and 20 g of the compound of formula (II), add 14.3 ml of N,O-bistrimethylsilylacetamide (BSA), and control the temperature at 10°C. 0.48 g of tetrabutylammonium fluoride (trihydrate) (TBAF) was added and the reaction was stirred for 2 hours. The mixture was concentrated to dryness and carried directly to the next step.

Embodiment 3

[0038] Example 3: Preparation of Ezetimibe

[0039] Add 50 milliliters of isopropanol and 15 milliliters of 2N sulfuric acid solution to the product in Example 2, stir at room temperature for 2 hours, precipitate a solid, filter, collect the solid, obtain a white solid after recrystallization in isopropanol and water, and obtain the target after drying The compound of product formula (I) was 14.54 g, and the yield was 93%.

[0040] MS(ESI):432.14(M+Na + ).

[0041] 1 H-NMR(500MHz,DMSO)δ(ppm):1.761-1.804(m,3H),1.823-1.889(m,1H),3.079-3.101(m,1H),4.514-4.535(m,1H),4.804 -4.808(d,1H),5.263-5.272(d,1H),6.772-6.789(d,2H),7.099-7.141(m,4H),7.218-7.249(m,4H),7.306-7.334(m, 2H), 9.504(s, 1H).

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Abstract

The invention relates to a new synthesis method of ezetimibe. Particularly, a new method for synthesizing ezetimibe (as shown in formula (I)) comprises the steps of addition, closed loop, deprotection and the like by using a compound shown in a formula (II) and having good stability as a starting raw material. The new synthesis method has the advantages of strong stability, simple operation, high yield and the like, and is suitable for large-scale industrial production. The formula (I) is described in the specification.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to ezetimibe, namely 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]- A new method for the synthesis of 4(S)-(4-hydroxyphenyl)-2-azetidinone. Background technique [0002] Ezetimibe represented by formula (I), also known as ezetimibe and ezetimibe, is the first choice jointly developed by Schering-Plough and Merck This product is the first selective inhibitor of cholesterol absorption approved by the US FDA, and its trade name is Zetia. The product was approved by the FDA on October 25, 2002 and launched in the United States on November 30, 2002. At present, the FDA-approved indications for ezetimibe include primary hypercholesterolemia (adult, pediatric), homozygous familial hypercholesterolemia (adult, pediatric), homozygous familial sitosterolemia ( adults, pediatrics), mixed hyperlipidemia (adults). [0003] [0004] European patent EP720599 first disclosed t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08C07F7/18
CPCC07D205/08C07F7/1804
Inventor 杨宝海潘必高付勇陈星汶
Owner 连云港恒运药业有限公司
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