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Preparation method of atorvastatin calcium intermediate

A technology of atorvastatin calcium and intermediates, which is applied in the field of preparation of atorvastatin, can solve the problems of complicated steps in the intermediate condensate treatment process, large consumption of organic solvents, production safety and the like, and achieves clean production, dangerous The effect of reducing and reducing consumption

Active Publication Date: 2017-07-11
TOPFOND PHARMA CO LTD
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the prior art, the synthesis route of the atorvastatin calcium intermediate condensate is reacted with amine ester and diketone as the starting raw materials. After the reaction, the treatment process of the intermediate condensate has cumbersome steps, complicated operation, long production cycle, The consumption of organic solvent is large, the cost is high, the yield is low, and there are problems of production safety

Method used

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  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Add 16 g of amine ester and 20 g of diketone into a 250 ml reaction flask and dissolve them in a mixed solvent consisting of 34 ml of n-heptane and 68 ml of tetrahydrofuran. The reaction is heated and refluxed for 40 hours. After the reaction is completed, the reaction solution is concentrated to remove the mixed solvent to obtain atorvastatin For the crude calcium intermediate, add 110ml of ethanol to dissolve and clarify the crude intermediate, add 64ml of purified water, cool to 50°C to precipitate the material, and centrifuge to obtain 25.1g of the intermediate. The weight yield relative to the diketone is 125.5%. The HPLC purity is 99.0%.

Embodiment 2

[0024] Add 16g of amine ester and 20g of diketone to a 250ml reaction flask and dissolve them in a mixed solvent consisting of 34ml of n-heptane and 85ml of tetrahydrofuran. The reaction is heated and refluxed for 36 hours. After the reaction is completed, the reaction solution is concentrated to remove the mixed solvent to obtain atorvastatin For the crude calcium intermediate, add 64ml of ethanol to dissolve and clarify the crude intermediate, add 48ml of purified water, cool to 75°C to precipitate the material, and centrifuge to obtain 25.3g of the intermediate condensate, with a weight yield of 126.5% relative to the diketone. , HPLC purity is 99.0%.

Embodiment 3

[0026] Add 16 g of amine ester and 24 g of diketone into a 250 ml reaction flask and dissolve them in a mixed solvent consisting of 34 ml of n-heptane and 85 ml of tetrahydrofuran. The reaction is heated and refluxed for 50 hours. After the reaction is completed, the reaction solution is concentrated to remove the mixed solvent to obtain atorvastatin For the crude calcium intermediate, add 80ml ethanol to make the crude intermediate dissolve and clarify, add 32ml purified water, cool to 70°C to precipitate the material, centrifuge and filter to obtain 25.2g intermediate condensate, relative to the weight yield of diketone 126.0% , HPLC purity is 99.0%.

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Abstract

The invention relates to a preparation method of an atorvastatin calcium intermediate. The preparation method of the atorvastatin calcium intermediate has the advantages of increase of the yield of the atorvastatin calcium intermediate, simple post-treatment process, simplified operating flow, production period shortening, reduction of the consumption of an organic solvent, reduction of the production cost, and reduction of the danger during the production operation. The method comprises the following steps: 1, carrying out a reaction on amine ester and dione used as initial raw materials in a mixed solvent, wherein the mixed solvent comprises n-heptane and tetrahydrofuran according to a volume ratio of 1:(1-3), and 5-8 ml of the mixed solvent is added to every gram of the amine ester; 2, concentrating a reaction solution obtained in step 1 to remove the mixed solvent to obtain a crude atorvastatin calcium intermediate; and 3, adding a crystallization solvent 1 ethanol to the product obtained in step 2, dissolving the product to clarify the obtained solution, adding a crystallization solvent 2 purified water, cooling obtained crystals, and centrifuging and drying the obtained solution to obtain the atorvastatin calcium intermediate.

Description

Technical field [0001] The invention relates to a method for preparing an atorvastatin calcium intermediate, in particular to a method for preparing a high-purity atorvastatin calcium intermediate with simple post-processing steps. Background technique [0002] Atorvastatin calcium, English name: Atorvastatin Calcium, chemical name: [R-(R,R)]-2-(4-fluorophenyl)-β,β-dihydroxy-5-(1-methylethyl) Yl)-3-phenyl-4-[(aniline)carbonyl]-1-hydro-pyrrole-1-heptanoate calcium trihydrate, which is a highly synthetic, highly purified and highly selective drug that inhibits HMG-CoA reductase , Developed by Pfizer, is a third-generation statin drug. It is mainly used for the treatment of hypercholesterolemia, hyperlipidemia and the prevention and treatment of coronary heart disease and stroke. [0003] At present, the synthetic route of atorvastatin calcium is to synthesize intermediate condensate with amine ester and diketone as starting materials, and then further synthesize atorvastatin calciu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 吕伟张忠理吕兰亭徐鹤郭婷婷李青丽张新成陈金春马珍珍王文年蓓蕾刘建国马占坡
Owner TOPFOND PHARMA CO LTD
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