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Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate

A technology of ethyl hydroxybutyrate and atorvastatin, applied in the fields of medicine and chemical industry, can solve the problems of unsatisfactory purity of intermediate I, low stereoselectivity, expensive catalyst, etc., and achieves short reaction process and abundant raw material sources. , the effect of low price of raw materials

Inactive Publication Date: 2010-09-22
HUANGGANG HUAYANG PHARMA
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Problems solved by technology

The shortcoming of this method one is that the catalyst is expensive, and the other is that the stereoselectivity is not high. In addition, the purity of intermediate I can not meet the needs of high-purity atorvastatin synthesis, and it is difficult to use common methods (such as extraction, recrystallization) etc.) for refining

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  • Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate

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Embodiment Construction

[0038] Take the industrialized production of ATS-5 with an annual output of 40 tons as an example:

[0039] The first process is: split epichlorohydrin to obtain S-epichlorohydrin. The R configuration or S configuration of epichlorohydrin reacts with the resolving agent (chiral reagent) B to form complexes R.B or S.B respectively. There is no mirror image relationship between them, and the energy of the two is also different; therefore, the R type When Type S and Type B react with B respectively, their activation energies are different, and their reaction speeds are also different. The relative speed of hydrolysis of S-type and R-type epichlorohydrin is different, and the hydrolysis speed of R-type epichlorohydrin is faster than that of S-type epichlorohydrin, and the hydrolysis speed of epichlorohydrin is proportional to the square of concentration (is a two level reaction kinetics). After a period of reaction, the R-type epichlorohydrin is completely hydrolyzed, and a smal...

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Abstract

The invention relates to a manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate (ATS-5), which solves the problems of high cost, expensive raw material price and the like of the prior art. The manufacturing method is characterized in that the atorvastatin intermediate is prepared from epichlorohydrin as a raw material through ring-opening addition, glycolysis esterification, cyaniding substitution synthesis and refining. The invention has simple synthesis route, abundant raw material resources, low equipment requirements and no high-temperature high-pressure reaction; the content of produced ATS-5 is more than 98 percent, the content of water is lower than 0.2 percent, and the content of enantiomer is less than 1.0 percent. The manufacturing method is a mature production process for manufacturing the intermediate of medicine atorvastatin and is applicable to medium-sized and small enterprises.

Description

1. Technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a preparation method of a drug intermediate, in particular to a chemical drug atorvastatin intermediate (R)-(-)-4-cyano-3-hydroxybutyric acid The preparation method of ethyl ester (hereinafter referred to as ATS-5). 2. Background technology [0002] In recent years, lipid-lowering drugs have become the focus of modern drug research. Since 1999, the world's lipid-lowering drugs have maintained a growth rate of 16% for several consecutive years. Atorvastatin is the drug with the fastest growth rate and the highest sales among blood lipid-lowering drugs in the world. It occupies more than half of the global blood-lipid-lowering market and is the prescription drug with the largest sales in the world. The chemical name of atorvastatin is: [R-(R′, R′)]-2-(4-fluorophenyl)-β·δ-dihydroxy-5-(1-methylethyl)-3- Phenyl-4-[(aniline)carbonyl]-1-hydrogen-pyrrole-1-heptanoic acid ...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/20C07C253/14
Inventor 周拥军熊劲军李中军何年兵
Owner HUANGGANG HUAYANG PHARMA
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