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Synthetic method of atorvastatin calcium intermediate

A technology of atorvastatin calcium and synthesis method, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalyst, physical/chemical process catalyst, etc., can solve the problem that the volume ratio of catalyst and raw material is too different , continuous operability is not strong, poor mixing effect and other problems, to achieve the effect of low production cost, short reaction time, high degree of automation

Active Publication Date: 2021-01-22
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent CN107602527A reports that compound II and 2,2-dimethoxypropane are used as raw materials, and p-toluenesulfonic acid is used as a catalyst, but the reaction time of this process is relatively long, and industrial production mostly adopts a kettle-type process, and the continuous operability is not strong
If it is changed to a tubular reactor or a microreactor, the volume ratio of the catalyst to the raw material is too different, the mixing effect is not good, and the yield is low

Method used

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  • Synthetic method of atorvastatin calcium intermediate
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  • Synthetic method of atorvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Under nitrogen protection, add 1000g of compound II and 700g of 2,2-dimethoxypropane into a 2L three-necked flask, start stirring, and cool down to about 10°C after compound II is dissolved. 75 g of Amberlite-15 acidic resin was filled in fixed bed reactor 1, and 75 g of Amberlite IRA-93 basic resin was filled in fixed bed reactor 2 . Use a metering pump to pump the mixture of compound II and 2,2-dimethoxypropane into the fixed-bed reactor 1 filled with acidic resin for catalytic reaction, the reaction temperature is 15°C, and the time is 40s. After the reaction is completed, the The obtained reaction liquid was pumped into the fixed-bed reactor 2 filled with basic resin for quenching, the quenching temperature was 15°C, and the quenching time was 40s. During the reaction, take a sample of the TLC control (take the reaction solution, add a small amount of triethylamine to adjust the pH to alkaline, spot the plate, KMnO 4 Color development), when compound II disappears ...

Embodiment 2

[0025] Under the protection of nitrogen, add 1000g of compound II and 900g of 2,2-dimethoxypropane into a 2L three-necked flask, start stirring, and cool down to about 10°C after compound II is dissolved. Fixed-bed reactor 1 was filled with 40 g of Amberlite-15 acidic resin, and fixed-bed reactor 2 was filled with 40 g of Amberlite IRA-93 basic resin. Use a metering pump to pump the mixture of compound II and 2,2-dimethoxypropane into the fixed-bed reactor 1 filled with acidic resin for catalytic reaction, the reaction temperature is 25°C, and the time is 20s. After the reaction is completed, the The obtained reaction liquid was pumped into the fixed-bed reactor 2 filled with basic resin for quenching, the quenching temperature was 25°C, and the quenching time was 20s. During the reaction, take a sample of the TLC control (take the reaction solution, add a small amount of triethylamine to adjust the pH to alkaline, spot the plate, KMnO 4 Color development), when compound II d...

Embodiment 3

[0027]Under the protection of nitrogen, add 1000g of compound II and 500g of 2,2-dimethoxypropane into a 2L three-necked flask, start stirring, and cool down to about 10°C after compound II is dissolved. Fixed-bed reactor 1 was filled with 90 g of Amberlite-15 acidic resin, and fixed-bed reactor 2 was filled with 90 g of Amberlite IRA-93 basic resin. Use a metering pump to pump the mixed solution of compound II and 2,2-dimethoxypropane into the fixed bed reactor 1 filled with acidic resin to carry out the catalytic reaction, the reaction temperature is 5°C, and the time is 60s. After the reaction is completed, the The obtained reaction solution was pumped into the fixed-bed reactor 2 filled with basic resin for quenching, the quenching temperature was 5°C, and the quenching time was 60s. During the reaction, take a sample of the TLC control (take the reaction solution, add a small amount of triethylamine to adjust the pH to alkaline, spot the plate, KMnO 4 Color development),...

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Abstract

The invention relates to a synthesis method of an atorvastatin calcium intermediate, which comprises the following steps: by using a compound II and 2, 2-dimethoxypropane as raw materials, carrying out catalytic reaction in a fixed bed reactor filled with acidic resin, and pumping the obtained reaction solution into the fixed bed reactor filled with basic resin to carry out quenching reaction after the catalytic reaction is finished, and obtaining crude product of the compound I, Wherein the synthetic route is shown in the specification. The synthetic method disclosed by the invention is shortin reaction time, relatively high in yield and purity, continuous in reaction, high in automation degree, simple in process step, low in production cost and suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to an atorvastatin calcium pharmaceutical intermediate (4R-cis)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid Synthesis method of tert-butyl ester. Background technique [0002] Atorvastatin calcium (Atorvastain calium), the chemical name is (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl ) Calcium pyrrol-1-yl]-3,5 dihydroxyheptanoate, which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Launched by Pfizer of the United States in 1997, it is the third generation of statin blood lipid regulating drugs, which are widely used in clinical practice to prevent and treat hypercholesterolemia. This effect is exerted by reducing total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels in dyslipidemic patients. In addition, atorvastatin calcium also has anti-inflammatory effec...

Claims

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Application Information

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IPC IPC(8): C07D319/06B01J31/10
CPCC07D319/06B01J31/10
Inventor 陈本顺石利平叶金星李大伟徐春涛马骧张维冰程瑞华钱若灿何义郭炳华王欢
Owner JIANGSU ALPHA PHARM CO LTD
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