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Novel method for preparing ezetimibe key intermediate

A technology of ezetimibe and a new method, applied in the production of bulk chemicals, organic chemistry, etc., can solve problems such as increased costs and long routes, and achieve the effects of cost saving, simple processing, and convenient purification

Active Publication Date: 2012-07-04
PHARMA SHANGHAI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The method solves the inconvenience of eliminating the industrial production caused by zinc reagent and palladium catalyst, and the yield is relatively stable; but there is still the problem that the route is too long, which increases the cost of industrialization

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  • Novel method for preparing ezetimibe key intermediate
  • Novel method for preparing ezetimibe key intermediate
  • Novel method for preparing ezetimibe key intermediate

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Embodiment Construction

[0042] The present invention will be described in further detail below through the examples, and the purpose of the examples is to illustrate rather than limit.

[0043] The present invention relates to the method for preparing compound I as shown in Scheme 1:

[0044] plan 1

[0045]

[0046] Specifically, compound II reacts with 4-fluorophenyl Grignard reagent in toluene under the action of triethylamine to obtain compound I. Compound II is a known compound and can be prepared by known methods.

[0047] (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-benzyloxyphenyl-2-azetidine Preparation of ketone (I)

[0048] method one:

[0049] Add 10 mL of dry toluene to a dry three-necked flask under nitrogen protection, cool to -30 degrees, slowly add 4-fluorophenyl Grignard reagent (2M ether solution, 2.08mL, 4.16mmol, 2eq), and then slowly add triethyl Amine (1.73mL, 12.5mmol, 6eq), dropwise completed, stirred for 15 minutes.

[0050] 5 mL of toluene solutio...

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Abstract

The invention discloses a novel method for preparing an ezetimibe key intermediate, which uses an intermediate (II) as a raw material. The intermediate (II) is directly reacted with a 4-fluorine phenyl grignard reagent under effects of alkali, and the key intermediate (3R and 4S)-1-(4-fluorine phenyl)-3-[3-(4-fluorine phenyl)-3-oxo propyl group]-4-substituted phenoxy-2-nitrogen heterocyclic cyclobutanone (I) is obtained by one step. Compared with the existing synthetic route, the method shortens three steps of reaction, does not use a zinc reagent or a palladium catalytic agent, and greatly saves cost of industrial production. By means of the method, processing is simple, purification is convenient, one-step yield can achieve more than 60%, and the novel method has great industrialization production prospects.

Description

technical field [0001] The invention discloses a key intermediate for preparing ezetimibe (3R, 4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl A new method for ]-4-substituted phenoxy-2-azetidinone belongs to the field of drug synthesis. Background technique [0002] Ezetimibe is a selective cholesterol absorption inhibitor developed by Schering-Plough and launched in November 2002 for the treatment and prevention of atherosclerosis and high blood cholesterol. [0003] [0004] Compound I is the key intermediate for the synthesis of ezetimibe. U.S. Patent No. 5,767,115 first discloses a synthesis process of ezetimibe. The synthesis of its key intermediate I uses II as a raw material, which is first hydrolyzed into acid III under alkaline conditions, further made into acid chloride IV, and then combined with the prepared The obtained 4-fluorophenyl zinc reagent is reacted under the catalysis of Pd(PPh3)4. [0005] [0006] This route starts from intermediate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08
CPCY02P20/55
Inventor 安荣昌王伟华董学军李因強彭少平蒋胜力蔡振伟
Owner PHARMA SHANGHAI
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