Method for synthesising ezetimibe intermediate

A synthesis method and a technology for etimibe, which are applied in the field of synthesizing etimibe intermediates, can solve the problems of high production cost and complex synthesis process, and achieve the effects of low cost, high optical purity and mild reaction conditions.

Inactive Publication Date: 2013-03-20
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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Problems solved by technology

[0009] The purpose of the present invention is to provide a method for synthesizing ezetimibe intermediates to solve the problem of (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxo in the prior art. Amyl]-4-phenyl-2-oxazolidinone complex synthesis process, high technical problems of production cost

Method used

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  • Method for synthesising ezetimibe intermediate
  • Method for synthesising ezetimibe intermediate
  • Method for synthesising ezetimibe intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1. In a dry three-neck flask under nitrogen protection, add 1ml of tetrahydrofuran and 1ml of pH6.5, 0.1M phosphate buffer to form a two-phase mixed solution, the pH of the two-phase mixed solution is 5.5.

[0043] 2. Add 1g of (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone into the three-necked flask, 0.005g of carbonyl reductase, stirred and reacted in a water bath at 20°C for 30h to obtain (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4 - Phenyl-2-oxazolidinone solution.

[0044] 3. Filter the (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4-phenyl-2-oxazolidinone solution to obtain The filtrate was concentrated in vacuo, washed with dichloromethane, and dried over anhydrous magnesium sulfate to obtain oily (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4 - Pure phenyl-2-oxazolidinone.

[0045] (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4-phenyl-2-oxazolidinone was detected by mass spectrometry, and the mass sp...

Embodiment 2

[0047] 1. Add 15ml of tetrahydrofuran and 1ml of PH6.5 and 0.1M phosphate buffer to a dry three-neck flask under nitrogen protection to form a two-phase mixed solution. The pH of the two-phase mixed solution is 6.5.

[0048] 2. Add 1g of (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone into the three-necked flask, 0.001g of carbonyl reductase, stirred and reacted in a water bath at 30°C for 20h to obtain (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4 - Phenyl-2-oxazolidinone solution.

[0049] 3. Filter the (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4-phenyl-2-oxazolidinone solution to obtain The filtrate was concentrated in vacuo, washed with dichloromethane, and dried over anhydrous magnesium sulfate to obtain oily (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4 - Pure phenyl-2-oxazolidinone.

Embodiment 3

[0051] 1. Add 10ml of tetrahydrofuran and 1ml of a mixed solution of pH 6.5 and 0.1M phosphate buffer into a dry three-neck flask under nitrogen protection. The pH of the two-phase mixed solution is 6.0.

[0052] 2. Add 1g of (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone into the three-necked flask, 0.01g of carbonyl reductase, stirred and reacted in a water bath at 40°C for 15h to obtain (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4 - Phenyl-2-oxazolidinone solution.

[0053] 3. Filter the (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4-phenyl-2-oxazolidinone solution to obtain The filtrate was concentrated in vacuo, washed with dichloromethane, and dried over anhydrous magnesium sulfate to obtain oily (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxopentyl]-4 - Pure phenyl-2-oxazolidinone.

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Abstract

The invention provides a method for synthesising ezetimibe intermediate, comprising the following steps of: dissolving (4S)-3-[5-(4-fluorophenyl)-1,5-di-oxo-pentyl]-4-phenyl-2-oxazolidone and chiral carbonyl reductase in a two-phase mixed solution which is composed of an organic solvent and phosphate buffer; and performing synthesis reaction for 10-30 hours in an nitrogen protection environment, and then obtaining (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxo-pentyl]-4-phenyl-2-oxazolidone, wherein the temperature of the synthesis reaction is 20-50 DEG C, and the pH of the two-phase mixed solution is 5.5-8.5. Via the method, the technical problems of complex synthesis process and high production cost of (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxyl-1-oxo-pentyl]-4-phenyl-2-oxazolidone in the prior art are solved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing an ezetimibe intermediate. Background technique [0002] Ezetimibe is a new cholesterol absorption inhibitor jointly developed by Merck and Schering-plough. It was listed in Germany for the first time in November 2002, and it was listed in the United States at the same time. [0003] [0004] (4S)-3-[(5S)-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone is the key to the synthesis of ezetimibe intermediate. Its structural formula is: [0005] [0006] A kind of synthetic technique of ezetimibe is disclosed in U.S. Patent US6207822B1, with (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl- 2-Oxazolidinone is used as raw material, under the protection of nitrogen, borane pyridine is added, and the key (4S)-3-[( 5S)-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone. Its synthetic route is: [0007] [0008] The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/14C12P17/00C12P17/10C07D263/26C07D263/16C07D277/14C07D277/16C07D233/38C07D233/42
Inventor 张庆华黄鹏勉徐果果陈波
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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