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A kind of purification method of atorvastatin calcium intermediate ats-9

A technology of atorvastatin calcium and ATS-9, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome operation, unfavorable environmental protection, high cost and unsuitable for industrialization, etc.

Active Publication Date: 2020-09-22
HENAN NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing reports, the method with the purity of ATS-9 reaching 98% is either cumbersome to operate; or uses too many toxic organic solvents, which is not conducive to environmental protection; or the high cost is not suitable for industrialization

Method used

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  • A kind of purification method of atorvastatin calcium intermediate ats-9
  • A kind of purification method of atorvastatin calcium intermediate ats-9
  • A kind of purification method of atorvastatin calcium intermediate ats-9

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 65.4g (1.09mol) of acetic acid to 100mL of acetonitrile, stir to dissolve, add dropwise to 500mL of acetonitrile solution with 300g (1.09mol) of crude ATS-9 dissolved, add dropwise with stirring, after the addition, heat to Dissolve at 40℃, add 6g medical activated carbon, filter, the filtrate is slowly cooled to room temperature under stirring (10℃ in winter, 25℃ in summer) for crystallization, suction filtration, the filter cake is rinsed with mother liquor, and the filter cake is dried with 1000mL water Dissolve, add ammonia water to adjust pH=8-12, stir for 1h, the resulting solution is extracted three times with dichloromethane, the organic phases are combined, the obtained organic phases are washed with 900mL water, dried with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The rate is 96.1%, and the purity is 99.7%.

Embodiment 2

[0026] Add 230.4g (1.09mol) of citric acid to 500mL of tetrahydrofuran, stir to dissolve, add dropwise to a solution of 300g (1.09mol) of crude ATS-9 dissolved in 1000mL of tetrahydrofuran, add dropwise with stirring, after the addition is complete, heat Dissolve at 80°C, add 15g of medical activated carbon, filter, the filtrate is slowly cooled to room temperature (10°C in winter, 25°C in summer) under stirring, crystallization, suction filtration, the filter cake is rinsed with mother liquor, and the filter cake is dried and used 1000mL Dissolve in water, add sodium hydroxide to adjust pH=8-12, stir for 1.5h, extract the resulting solution with chloroform three times, combine the organic phases, wash the resulting organic phases with 900 mL of water, dry with anhydrous sodium sulfate, and distill under reduced pressure After removing the solvent, the yield was 95.3% and the purity was 99.5%.

Embodiment 3

[0028] Add 13g (0.128mol) of trimethylacetic acid to 50mL of dichloromethane, stir to dissolve, and add dropwise to a solution of 35g (0.128mol) of crude ATS-9 in 100mL of acetonitrile, add dropwise while stirring, and the addition is complete Then, heat to 40℃ to dissolve, add 1.4g medical activated carbon, filter, the filtrate is slowly cooled to room temperature under stirring (10℃ in winter, 25℃ in summer) for crystallization, suction filtration, the filter cake is rinsed with mother liquor, and the filter cake is baked After drying, dissolve in 100mL water, add sodium carbonate to adjust pH=8-12, stir for 2h, the resulting solution is extracted three times with ethyl acetate, the organic phases are combined, the resulting organic phases are washed with 50mL water, dried with anhydrous magnesium sulfate, and reduced The solvent was removed by pressure distillation, the yield was 96.7%, and the purity was 99.6%.

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Abstract

The invention discloses a purification method for an atorvastatin calcium intermediate ATS-9, and belongs to the technical field of preparation of high-purity atorvastatin calcium intermediate ATS-9.The method comprises the following steps: dissolving an acid in an organic solvent, and dropwise adding the obtained solution to an organic solution of crude ATS-9; performing heating to achieve dissolving in order to obtain a dissolved clear solution, adding medical activated carbon, performing filtration, cooling and crystallizing the obtained filtrate under stirring, and carrying out suction filtration; dissolving the obtained salt in water, and adding an alkali to adjust the pH value to be more than 7; and performing extraction by using an organic solvent, drying the obtained extract, andevaporating away the organic solvent to obtain the ATS-9 having a purity of above 99.5%. The crude product ATS-9 reacts with the acid to form the salt, and the purity of the finally obtained ATS-9 reaches 99.5% or above, so the method is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of preparation of high-purity atorvastatin calcium intermediate ATS-9, and specifically relates to a purification method of atorvastatin calcium intermediate ATS-9. Background technique [0002] Atherosclerosis can cause coronary heart disease, angina pectoris, myocardial infarction and many other cardiovascular diseases. Statins are a new type of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors that are effective It reduces serum total cholesterol, low-density lipoprotein cholesterol and triglycerides, thereby slowing down the progression of coronary artery disease and significantly reducing the mortality of cardiovascular events or coronary heart disease. [0003] [0004] The structure of atorvastatin calcium is a multi-substituted pyrrole ring. In the synthesis, side chain fragment ATS-9 and fragment M4 are usually used for cyclization through Paal-Knorr reaction. At present, the synthesis m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D319/06C07D207/34
CPCC07D207/34C07D319/06
Inventor 姜玉钦刘玮樊振陈杰王俊臣张玮玮王辉张向飞李伟
Owner HENAN NORMAL UNIV
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