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Preparation method for simvastatin

A technology of simvastatin and simvastatin ammonium salt, which is applied in the field of medicinal chemistry, can solve problems such as influence, industrialization risk, and time-consuming extension, and achieve the effects of reducing product impurities, avoiding excessive crystallization speed, and reducing impurities

Active Publication Date: 2016-10-05
SHANGYU JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This type of method not only affects the refining yield of simvastatin, but also produces simvastatin methylated impurity (Ⅲ) and ethylated impurity (Ⅳ) in the non-pharmacopoeia standard, especially the simvastatin dissolved in the workshop to meet medical grade simvastatin The whole process of vastatin is much longer than that of the laboratory, and the amplification effect cannot be avoided, resulting in more impurity simvastatin methyl esterification impurity (Ⅲ) and simvastatin ethyl esterification impurity (Ⅳ) than the laboratory, which poses a threat to industrialization. bring risk

Method used

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  • Preparation method for simvastatin
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  • Preparation method for simvastatin

Examples

Experimental program
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Effect test

example 1

[0041] Example 1: Preparation of crude product of simvastatin

[0042] Put 100g of simvastatin ammonium salt and 750ml of dichloromethane into the reaction bottle, stir and control the temperature at 10-25°C, add 22g of methanesulfonic acid dropwise, react for 3 hours, add 10g of sodium bicarbonate and 5g of activated carbon, and stir for 0.5 hours. After filtration, the filtrate was concentrated to obtain crude simvastatin.

example 2

[0043] Example 2: Preparation of Simvastatin Crude Product

[0044] Put into reaction flask 100g of simvastatin ammonium salt, 500ml of toluene, 1.7g of benzenesulfonic acid, under the protection of nitrogen, heat and reflux for 5 hours, cool to room temperature after the reaction, add 1g of sodium bicarbonate and 5g of gac, stir for 0.5 hour, After filtration, the filtrate was concentrated to obtain crude simvastatin.

example 3

[0045] Example 3: Simvastatin Crude Refining (Ethanol Laboratory)

[0046] Add 10g of ethanol to the crude simvastatin prepared in Example 1 to solidify, then add 520g of ethanol, stir and heat to 25°C to dissolve, slowly add 1200g of water to crystallize, after dropping, slowly cool down to 0-5°C and stir for 3 hours , filter, then rinse with a mixture of 50g ethanol and water (the mass ratio of ethanol and water is 1:2.5), the product is dried under reduced pressure to obtain white powdery solid, the yield is 92.50%, and the total impurities are 0.54%, B The esterification impurity was 0.04%, and the methyl esterification impurity was 0.02%.

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Abstract

The invention discloses a preparation method for simvastatin. The preparation method for simvastatin comprises the following steps: subjecting a simvastatin ammonium salt to cyclization, decoloring and concentration so as to obtain a crude simvastatin product; and then subjecting the crude simvastatin product to refining so as to obtain medical simvastatin. Compared with conventional preparation methods, the preparation method provided by the invention has the advantages of substantial improvement of product yield, effective reduction in impurities in the medical simvastatin and enhancement of product quality; and the preparation method can simplify technological operation and is suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of simvastatin, which belongs to the technical field of medicinal chemistry. Background technique [0002] Simvastatin, as an inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, is one of the most popular blood lipid-lowering drugs on the market. Cerebrovascular disease. At present, organic solvents and water are used as mixed solvents for crystallization in the refining process of simvastatin. [0003] In J.Org.Chem56, 4929-4932 (1991), CN1446088 and CN1771241, after refining with alkane, dissolve it with methanol, and then add dropwise water to crystallize to obtain simvastatin that meets the pharmacopoeia standard. [0004] In CN1101805, the alkane is refined first, and then refined with absolute ethanol to obtain simvastatin that meets the Pharmacopoeia standard. [0005] The study found that medical simvastatin and simvastatin crude products will produce simvastatin methyl ester impur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30
Inventor 华长华方沛东苗应壮
Owner SHANGYU JINGXIN PHARMA