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Method for preparing ezetimble intermediate

A technology for etimibe and intermediates, which is applied in the field of preparation of etimibe intermediates, can solve problems such as troublesome post-processing, troublesome industrial production, etc., and achieves the effects of low cost, easy implementation and high yield

Inactive Publication Date: 2013-06-12
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this route can obtain the target compound in only one step, it requires the use of expensive peptide condensing agent DCC, and the post-treatment of this process is also troublesome, which brings troubles to industrial production

Method used

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  • Method for preparing ezetimble intermediate
  • Method for preparing ezetimble intermediate
  • Method for preparing ezetimble intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Under the condition of nitrogen protection and stirring, CH 2 Cl 2 20ml and 4g (19mmol) of 4-(4-fluorobenzoyl)butanoic acid, cooled the system to 15°C, slowly added 4.4ml (47mmol) of oxalyl chloride, stirred for 30min, then heated to 39°C for 3h, TLC detected that the reaction was basically After concentrating to dryness, add CH 2 Cl 2 15ml was further concentrated to dryness to obtain 3.5g of light yellow liquid, namely 6-(4-fluorophenyl)-3,4-dihydropyran-2-one, which was directly used in the next reaction without purification. The structure detection data of 6-(4-fluorophenyl)-3,4-dihydropyran-2-one prepared in this step are as follows:

[0025] 1 H NMR (500MHz, CDCl 3 )δ2.47-2.51(m, 2H), 2.65-2.68(t, J=7.5Hz, 2H), 5.73-5.74(t, J=4.7Hz, 1H), 7.00-7.04(m, 2H), 7.53 -7.56(m, 2H);

[0026] 13 C NMR (125MHz, CDCl 3 )δ19.3, 28.3, 100.2, 115.4, 115.6, 126.4, 126.5, 128.9, 129.0, 150.2, 162.1, 164.1, 168.6;

[0027] MS(ESI): m / z=193.2 (M+H + )

[0028] Under the ...

Embodiment 2

[0035] Under the condition of nitrogen protection and stirring, CH 2 Cl 2 20ml and 4g (19mmol) of 4-(4-fluorobenzoyl)butanoic acid, cooling the system to 15°C, slowly adding SOCl 2 2.7ml (37mmol), stirred for 30min, then added and heated to 39°C, reacted for 3h, TLC detected that the reaction was basically completed, concentrated to dryness, added CH 2 Cl 2 15ml was further concentrated to dryness to obtain 3.6g of light yellow liquid, namely 6-(4-fluorophenyl)-3,4-dihydropyran-2-one, which was directly used in the next reaction without purification.

[0036] Add toluene 15ml, (S)-4-phenyl-2-oxazolidinone (3.1g, 19mmol) and triethylamine 4ml (28.5mmol) successively to another 50ml there-necked flask under nitrogen, the above obtained 6 -(4-Fluorophenyl)-3,4-dihydropyran-2-one liquid was stirred and dissolved with 10ml of toluene, then slowly added to the above reaction system, the system was stirred for 30 minutes, then heated to 75°C and stirred for 6 hours, and the reacti...

Embodiment 3

[0041] Under nitrogen protection and stirring conditions, add 20ml of toluene and 4g (19mmol) of 4-(4-fluorobenzoyl)butyric acid to a 50ml three-necked flask in sequence, cool the system to 15°C, and slowly add SOCl 2 3.4ml (47.5mmol), stir for 30min, heat up to 70°C and stir for 3h, TLC detects that the reaction is basically completed, concentrate to dryness, add CH 2 Cl 2 15ml was further concentrated to dryness to obtain 3.6g of light yellow liquid, namely 6-(4-fluorophenyl)-3,4-dihydropyran-2-one, which was directly used in the next reaction without purification.

[0042] Add toluene 15ml, (S)-4-phenyl-2-oxazolidinone (3.4g, 21mmol) and triethylamine 3.2ml (22mmol) successively to another 50ml there-necked flask under nitrogen, the above obtained 6 -(4-Fluorophenyl)-3,4-dihydropyran-2-one liquid was stirred and dissolved with 10ml of toluene and slowly added into it. After the system was stirred for 30 minutes, it was heated to 75°C and stirred for 6 hours. After the reac...

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Abstract

The invention discloses a method for preparing an ezetimble intermediate. The method comprises the following steps of: (1) adding 4-(4-fluorobenzoyl)butyric acid to an organic solvent A under the conditions of stirring, adding a chloridizing reagent to carry out a cyclization reaction, and treating reaction products after the cyclization reaction is completely finished to obtain 6-(4-fluorophenyl)-3,4-dihydropyran-2-ketone; (2) dissolving the 6-(4-fluorophenyl)-3,4-dihydropyran-2-ketone to a solvent B, adding a dissolved solution to a reaction system formed by mixing an organic solvent B, (S)-4-phenyloxazolidinone and organic base to carry out a condensation reaction, treating reaction products after the condensation reaction is completely finished to obtain (4S)-3-[5-(4-fluorophenyl)-1,5-oxopentyl]-4-phenyl-2-oxazolidine. Cheap and easily obtained raw materials, such as thionyl chloride, oxalyl chloride, triethylamine and the like, are utilized, thus the cost is low, and the yield ishigh; and the whole preparation method disclosed by the invention is simple, is easy to implement and is convenient to realize the industrialization.

Description

technical field [0001] The invention belongs to the technical field of organic intermediate preparation, and in particular relates to a preparation method of an ezetimibe intermediate. Background technique [0002] Ezetimibe (Ezetimble, chemical name: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -Phenyl)-2-azetidinone) is a new type of cholesterol absorption inhibitor developed by Schering-Plough Pharmaceuticals, which was first listed in the United States in 2002. It is the first cholesterol absorption inhibitor approved by FDA. Mibe is different from bile acid sequestrants, it can selectively inhibit the absorption of cholesterol, and it has been proved to be more effective when combined with simvastatin. In addition, the therapeutic effect of ezetimibe on Alzheimer's disease is in clinical trials . [0003] In view of the better curative effect and good market reflection of ezetimibe, there are many reports on the synthesis of the drug, among ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/26
Inventor 杨健余长泉
Owner ZHEJIANG UNIV