A kind of preparation method of (s)-tert-butyldimethylsiloxy-glutaric acid monobenzyl ester monoamide

A technology of tert-butyldimethylsiloxy glutaric acid monobenzyl monoamide and methanol, which is used in the blood lipid-lowering drug HMG inhibitor, tert-butyldimethylsiloxy-glutaric acid monoamide monomethyl In the field of ester preparation, it can solve problems such as difficult industrialization, chiral isomerization, and difficult separation, and achieve the effects of easy industrialization, less waste, and low process cost

Active Publication Date: 2017-11-14
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the shortcomings of the prior art that the route is long, there is chiral isomerism, separation is difficult, and it is not easy to industrialize, and a kind of (S)-tert-butyldimethylsilyloxy-glutaric acid monobenzyl ester monobenzyl ester is provided The preparation method of amides

Method used

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  • A kind of preparation method of (s)-tert-butyldimethylsiloxy-glutaric acid monobenzyl ester monoamide
  • A kind of preparation method of (s)-tert-butyldimethylsiloxy-glutaric acid monobenzyl ester monoamide
  • A kind of preparation method of (s)-tert-butyldimethylsiloxy-glutaric acid monobenzyl ester monoamide

Examples

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Effect test

example 1

[0040] Dissolve 14.3g of (S)-3-hydroxy-4-cyanobutyric acid methyl ester (IV), 20g of benzyl alcohol in 250ml of toluene, NOVO-4353g, heat to 60°C, and reflux under reduced pressure for 12 hours, during which time remove and distill out A small amount of toluene, cooled, filtered, added 50ml of water to wash twice, concentrated organic phase, evaporated under reduced pressure to remove low waste point material to obtain (S)-3-hydroxy-4-cyanobutanoic acid benzyl ester, yield 96.5% (purity 92.4%).

example 2

[0042] Dissolve (S)-3-hydroxy-4-cyanobutanoic acid ethyl ester (IV) 15.7g, benzyl alcohol 20g, cyclohexane 250ml, NOVO-4353g, heat to 80°C, and reflux under reduced pressure for 16 hours, during which the Remove a small amount of cyclohexane that evaporated, cool, filter, add 50ml of water to wash twice, concentrate the organic phase, and evaporate the low-waste material under reduced pressure to obtain (S)-3-hydroxy-4-cyanobutyric acid benzyl ester , yield 98.2% (purity 90.6%).

example 3

[0044] Dissolve (S)-3-tert-butylsilyloxy-4-cyanobutanoic acid methyl ester (IV) 25.7g, benzyl alcohol 20g, toluene 250ml, heat NOVO-435 to 60°C, and reflux under reduced pressure for 12 hours. During this period, a small amount of cyclohexane evaporated was continuously removed, cooled, filtered, washed twice by adding 50ml of water, the organic phase was concentrated, and the substances with low waste points were evaporated under reduced pressure to obtain (S)-3-tert-butylsilyloxy-4 - Benzyl cyanobutyrate, yield 91.2% (purity 86.6%).

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Abstract

The invention discloses a preparation method of (S)-tert-butyldimethylsiloxy-glutaric acid monobenzyl monoamide, which belongs to the field of medicine. The method uses the compound (S)-4-cyano-3-hydroxybutyrate as a raw material, catalyzed by Novozymes lipase 435, and benzyl alcohol is transesterified to obtain (S)-4-cyano-3-hydroxybutyrate Benzyl ester, combined with TBSCl again, obtains TBS protection (S)-4-cyano-3-tert-butyldimethylsiloxane monobenzyl butyrate, and then oxidizes to obtain S)-3-tert-butyldimethyl Siloxyglutarate monobenzyl monoamide. Using NOVO‑435 to carry out transesterification to obtain benzyl ester has a higher yield than the original process, less waste, and avoids the pollution of titanium tetrachloride. Use hydrogen peroxide and alkali or catalytic oxidation of amides, less waste, and avoid the high-pollution oxidation method of manganese dioxide, and avoid the high-cost method of catalytic oxidation with Wilkinson precious metals. The process cost is lower and industrialization is easier.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a preparation method of an intermediate (S)-tert-butyldimethylsilyloxy-glutaric acid monoamide monomethyl ester of a blood lipid-lowering drug HMG inhibitor vastatin. Background technique [0002] Rosuvastatin (also known as rosuvastatin, English name: rosuvastatin). Rosevastatin Calcium was developed by Shionogi (Osaka Shionogi Company) in Japan. In February 1999, Phase I, Phase II, and Phase III clinical trials of the drug were completed in the United States. From its existing clinical verification results and comparison with similar products, high-dose rosuvastatin calcium (80 mg) can reduce LDL up to 65%, which is higher than atorvastatin and simvastatin, rosuvastatin calcium Worthy of being called a "super statin", its lipid-lowering effect is very good, and it is the most powerful lipid-lowering drug on the market so far. In the next few years, rosuvastatin calcium is li...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
Inventor 王志华洪华斌颜剑波林义
Owner ZHEJIANG LEPU PHARMA CO LTD
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