Preparation method of ezetimibe intermediate

An ezetimibe and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of easy detachment of silane protective group, difficult product purification, low product purity, etc., and achieves the effects of low cost, easy nature and high purity

Inactive Publication Date: 2014-06-18
天津市医药集团技术发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] WO2009140932 discloses a method for preparing the intermediate, which uses (S)-3-[4-(4-fluorobenzoyl)-1-oxybutyl]-4-phenyloxazolidine-2 - Ketone as the starting material, protected by carbonyl group, condensed with 4-benzyloxycarbonyloxybenzylidene-4-fluoroaniline, and then decarbonyl protected, by BH 3 /CBS asymmetric reduction to obtain compound I, this preparation method requires carbonyl protection and deprotection, the steps are long, the yield is 44.7%, resulting in high cost, and the asymmetric reduction is in the last step, it is not easy to purify, resulting in low purity of the product High, only 97.3%
[0008] CN11

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  • Preparation method of ezetimibe intermediate
  • Preparation method of ezetimibe intermediate
  • Preparation method of ezetimibe intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0037] 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluoroanilino)(4-Roxyphenyl)methyl]-5-hydroxypentyl Acyl]-(4S)-phenyl-2-oxazolidinone (Compound I, R=C 6 h 5 CH 2 )

[0038]

[0039] At room temperature, sequentially add (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazone into a four-neck flask Heterocyclopentane-2-one (II) 30g and 4-benzyloxybenzylidene-4-fluoroaniline (III, R=C 6 h 5 CH 2 ) 30g, 25ml diisopropylacetamide and 500ml dichloromethane. After the system is mixed evenly, add 15ml of trimethylchlorosilane dropwise to the system at an internal temperature of 0°C, and add 15ml of a solution of titanium tetrachloride and isopropyl titanate to the system dropwise at -20°C (mol Ratio: 3:1), and stirred at -15°C for 20 hours after the dropwise addition. After the reaction was completed, 1000 ml of 1N hydrochloric acid aqueous solution was slowly added dropwise to the system, followed by 500 ml of dichloromethane, and the organic phase was obt...

Embodiment 2

[0042] 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluoroanilino)(4-Roxyphenyl)methyl]-5-hydroxypentyl Acyl]-(4S)-phenyl-2-oxazolidinone (Compound I, R = C 6 h 5 CH 2 OCO)

[0043] At room temperature, sequentially add (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazone into a four-neck flask Heterocyclopentane-2-one (II) 30g and 4-benzyloxybenzylidene-4-fluoroaniline (III, R=C 6 h 5 CH 2 OCO) 30g, 25ml diisopropylacetamide and 500ml chloroform. After the system is evenly mixed, add 15ml of trimethylchlorosilane dropwise to the system at an internal temperature of -10°C, and add 15ml of a solution of titanium tetrachloride and isopropyl titanate to the system dropwise at -20°C ( molar ratio: 1:1), and stirred at -15°C for 20 hours after the dropwise addition. After the reaction was completed, 1000 ml of 1N acetic acid aqueous solution was slowly added dropwise to the system, followed by 500 ml of dichloromethane, and extracted to obtain an organic phas...

Embodiment 3

[0046] 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluoroanilino)(4-Roxyphenyl)methyl]-5-hydroxypentyl Acyl]-(4S)-phenyl-2-oxazolidinone (Compound I, R=p-BrC 6 h 5 CH 2 )

[0047] At room temperature, 30 g of compound (II) and 4-p-bromobenzyloxybenzylidene-4-fluoroaniline (III, R=p-BrC 6 h 5 CH 2 ) 60g, 25ml triethylamine and 500ml toluene. When the system is evenly mixed, add 15ml of trimethylchlorosilane dropwise to the system at an internal temperature of 0°C, add dropwise 10ml of titanium tetrachloride solution at -30°C, and stir at -30°C for 10 hours after the addition is complete . After the reaction was completed, 1000 ml of 1N hydrochloric acid aqueous solution was slowly added dropwise to the system, followed by 500 ml of toluene, and the organic phase was obtained by extraction. After the organic phase was dried over anhydrous magnesium sulfate, the organic solvent was removed to obtain a yellow solid, which was crystallized in ethanol to obtain 44 g of a wh...

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Abstract

The invention discloses a preparation method of an intermediate 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluorophenylamino)(4-R-oxophenyl)methyl]-5-hydroxyvaleryl]-(4S)-phenyl-2-oxazolidinone (represented by general formula I) for synthesizing ezetimibe. The method is characterized in that the intermediate is prepared by using (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyvaleryl]-4-phenyl-1,3-oxazolidin-2-one and 4-R-oxophenylmethylene-4-fluoroaniline as initial raw materials. The method has the advantages of no need of an expensive reagent, simple operation, high product yield, high product purity and the like, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to an ezetimibe pharmaceutical intermediate 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-(4-fluoroanilino) (4-Roxyphenyl)methyl]-5-hydroxypentanoyl]-(4S)-phenyl-2-oxazolidinone preparation method. Background technique [0002] Ezetimibe, English name Ezetimibe, alias Ezetimibe, trade name ZETIA, chemical name (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluoro Phenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone (structural formula VI), CAS Registry No. 163222-33-1, manufactured by Schering-Plough and Merck A new class of selective cholesterol absorption inhibitors jointly developed has excellent blood lipid-lowering effects. Ezetimibe inhibits the absorption of cholesterol in the diet and transported to the intestinal tract through bile by the small intestine by binding to the membrane protein on the brush border membrane vesicles of the small intestine, and reduces the cholesterol content in...

Claims

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Application Information

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IPC IPC(8): C07D263/26
CPCC07D263/26
Inventor 王亚江孟红赵平刘宁宁苏艳华李玉荃王琳
Owner 天津市医药集团技术发展有限公司
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