Novel ezetimibe synthesis method

A technology of etimibe and a new method, which is applied in the field of synthesizing 1---[3---hydroxypropyl]---2-propiolactam, can solve the problem of limited application, low reaction yield and high reaction yield. Acid waste and other problems, to achieve the effect of convenient purification, high purity and little environmental pollution

Inactive Publication Date: 2011-11-09
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Compared with the earlier route, this route has been greatly optimized, but there are still many defects in the key asymmetric Mannich reaction: as the reaction needs to use a large amount of trimethylchlorosilane (TMSCl), resulting in more acidic waste; and for example, the yield of this step reaction is not high, only 65%
These all limit its application in technology

Method used

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Examples

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Effect test

Embodiment 1

[0062] Example 1: 3-[(5-(4-fluorophenyl)-(5S)-hydroxypentanoyl]-3-{(2R)-[1-(4-acetoxyphenyl)-(1S) Synthesis of -(4-fluoroanilino)]-(4S)-phenyloxazolidinone (IVa)

[0063]

[0064] At room temperature, 30 grams of 3-[(5-(4-fluorophenyl)-(5S)-hydroxypentanoyl]-(4S)-phenyloxazolidinone (II), 22 Gram N-4'-acetoxybenzylidene-4-fluoroaniline (IIIa), 30 milliliters of triethylamine and 600 milliliters of dichloromethane. Add 10 ml of trimethylchlorosilane dropwise, and stir at 25°C for 20 hours after the dropwise addition. Cool down to 10°C, and add 15 ml of titanium tetrachloride solution dropwise to the system within 30 minutes. Stir under low temperature for 12 hours. After the reaction, the internal temperature does not exceed 15°C, slowly add 1 liter of 1N hydrochloric acid aqueous solution dropwise to the system, then add 600 ml of dichloromethane, and extract the organic phase. The organic phase is dried over anhydrous sodium sulfate Finally, the organic solvent was remov...

Embodiment 2

[0065] Example 2: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)- Synthesis of 2-propiolactam (ezetimibe, I)

[0066]

[0067] Add 23 grams of 3-[(5-(4-fluorophenyl)-(5S)-hydroxypentanoyl]-3-{(2R)-[1-(4-acetoxyphenyl)- (1S)-(4-fluoroanilino)]-(4S)-phenyloxazolidinone (IVa), 350 milliliters of toluene and 18.5 milliliters of BSA, followed by reflux for 6 hours. Then add in batches within 1 hour 2 grams of tetra-n-butylammonium fluoride, keep this temperature and continue to react for 6 hours. Cool down to room temperature, add 1 liter of water to this system, and under vigorous stirring, slowly add 55 milliliters of 2N sulfuric acid dropwise, and stir for 2 hours, the solid precipitates 。 Filtrate, dry the solid, and recrystallize in toluene to obtain 12.6 g of white solid with a yield of 82% and a purity of 99.6%.

[0068] Reference Example 1: Synthesis of N-4'-acetoxybenzylidene-4-fluoroaniline (IIIa)

[0069] Add 144 grams of p-h...

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Abstract

The invention discloses a novel ezetimibe synthesis method. The method comprises the following steps: reacting 3-[(5-(4-fluorophenyl)-(5S)-hydroxyvaleryl]-(4S)-phenyl-oxazolidinone (II) with N-4'-substituted acyloxy benzylidene-4-fluoroaniline (III) under the combined action of a tri-substituted chlorosilane and a titanium Lewis acid to generate 3-[(5-(4-fluorophenyl)-(5S)-hydroxyvaleryl]-3-{(2R)-[1-(4-substituted acyloxy phenyl)-(1S)-(4-fluoroanilino)]-(4S)-phenyl-oxazolidinone (IV), and sequentially treating the compound (IV) with BSA (bis(trimethylsilyl)acetamide), a fluoride ion cyclization catalyst and a proton acid solution to obtain a target product 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (I). The method has the advantages of low cost, simple operation, little environmental pollution, high product yield, high product purity and the like, and is especially suitable for industrial production.

Description

technical field [0001] The present invention relates to the synthesis of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)- A new approach to 2-propiolactam (ezetimibe). Background technique [0002] Ezetimibe (I), the English name is Ezetimibe; the trade name is Yishichun, Ezetrol or Aizeting, Zetia; the chemical name is 1-(4-fluorophenyl)-(3R)-[3-(4 -fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-propionolactam, the first selective cholesterol absorber jointly developed by Schering-Plough and Merck Inhibitors are also the first selective inhibitors of cholesterol absorption approved by the US FDA. Since it was launched in the United States in 2002, it has been approved to be listed in more than 40 countries. The results of the study prove that whether ezetimibe (I) is used alone or in combination with statins, it can receive a good lipid-lowering effect, and it can also reduce the level of low-density lipoprotein choleste...

Claims

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Application Information

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IPC IPC(8): C07D205/08C07D263/22C07F7/18
Inventor 马大为甘明华陈宇竺伟樊钱永甘立新
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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