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Preparation method of simvastatin side chain

A technology of simvastatin and side chain, which is applied in the field of preparation of simvastatin side chain, can solve the problems of low product purity, many reaction steps, difficulty in large-scale production and the like, and achieves simple post-processing operation, good product quality, the effect of industrialization

Inactive Publication Date: 2017-05-31
河南豫辰药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are many synthetic routes for simvastatin, but there is less information about the synthesis of simvastatin side chain dimethyl butyryl-S-propionate methyl ester, and there are not many domestic and foreign documents. Patent CN 103772248 "A Simvastatin The preparation method of the acyl donor of the side chain of statin >> Synthesize 2,2-dimethylbutyric acid-3-mercaptopropionic acid ethyl ester from 3-mercaptopropionic acid. This method has many reaction steps and the purity of the obtained product is not high. High, high cost, serious environmental pollution, time-consuming, cumbersome post-processing operations, and difficulty in large-scale production; these are not conducive to industrial production and product quality improvement, and it is necessary to develop a catalyst that is easy to obtain, low in cost, and easy to recycle raw materials. The method for preparing simvastatin side chains is simple in processing operation, less in environmental pollution, high in safety in reaction operation, high in reaction yield, good in product quality, and conducive to industrialization

Method used

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  • Preparation method of simvastatin side chain

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] A kind of preparation method of simvastatin side chain

[0016] Specific steps are as follows:

[0017] Add 300kg (2.5kmol) of methyl 3-mercaptopropionate to a 3000L glass-lined reactor, turn on the chilled brine in the condenser and pump 600kg of tetrahydrofuran. At the same time, turn on the chilled brine to cool down, and then pump into 242.5kg of pyridine (the temperature will increase) ), pumped (pumped) 350kg (2.6kmol) 2,2-dimethylbutyryl chloride to 2,2-dimethylbutyryl chloride dripping tank for use; lower the temperature to -5℃~10℃ and start dripping 2,2-Dimethylbutyryl chloride, the dropping rate should be controlled at -5℃~10℃. After the addition, the temperature is raised to 10℃~15℃ and reacted for 3~4 hours. GC detects methyl 3-mercaptopropionate The ester is less than 2% to complete the reaction. Add 600 kg of water dropwise, stir at 25°C~35°C for 2 hours, add about 150 kg of hydrochloric acid dropwise to adjust the pH to neutral, separate the water layer, extr...

Embodiment 2

[0019] A kind of preparation method of simvastatin side chain

[0020] Specific steps are as follows:

[0021] Pump 300kg (2.5kmol) of methyl 3-mercaptopropionate into the 3000L glass-lined reactor, turn on the chilled brine in the condenser and pump 600kg of tetrahydrofuran. At the same time, turn on the chilled brine to cool down, and then pump 242.5kg of pyridine (with heating Phenomenon), pump (pump) 370 kg (2.75kmol) 2,2-dimethylbutyryl chloride to 2,2-dimethylbutyryl chloride dripping tank for standby; cool down to -5℃~10℃, start dripping Add 2,2-Dimethylbutyryl chloride, the dropping rate should be controlled at -5℃~10℃. After the addition, the temperature will be raised to 10℃~15℃ and react for 3~4 hours. GC detects 3-mercaptopropionic acid The methyl ester is less than 2% to complete the reaction, add 600 kg of water dropwise, stir for 2 hours at 25°C to 35°C, add about 150 kg of hydrochloric acid dropwise to adjust the pH to neutral, separate the water layer, extract the...

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Abstract

The invention relates to a preparation method of simvastatin side chain. The preparation method comprises the following steps: by taking methyl 3-mercaptopropionate and 2,2-dimethyl butyric acid chloride as raw materials, generating condensation reaction under the existence of an organic solvent, hydrolyzing, acidifying, extracting, drying and concentrating to obtain a crude product, performing high-vacuum rectification on the crude product to obtain dimethyl butyryl-S-methyl propionate with the purity of 99.0%. The preparation method has the advantages that the raw materials are cheap and easily available, the cost is low, the aftertreatment operation is simple, the environment pollution is small, the reaction operation safety is high, the quality of the product is good, and the preparation method is beneficial to industrialization.

Description

Technical field [0001] The invention belongs to the synthetic preparation field of pharmaceutical side chains, and specifically relates to a preparation method of simvastatin side chains. Background technique [0002] Dimethylbutyryl-S-methyl propionate is a colorless and light yellow liquid, flammable, and has the characteristics of burning danger and irritation when exposed to heat, open flames, and strong oxidants. It is immiscible with water and is used in the synthesis of simvastatin. The structural formula is as follows: [0003] [0004] Simvastatin is a statin lipid-lowering drug used to control blood cholesterol levels and prevent cardiovascular diseases. It is semi-synthesized from Lovastatin (fermented product of Aspergillus terreus). As the starting chiral source compound, Lovastatin always maintains chiral characteristics during semi-synthesis. Simvastatin is obtained by modification of the methyl group of the side chain. Lovastatin has good fat solubility, better c...

Claims

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Application Information

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IPC IPC(8): C07C319/14C07C323/52
CPCC07C319/14C07C323/52
Inventor 傅收石艳彩李锋军贾玉香吴银强
Owner 河南豫辰药业股份有限公司