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Method for preparing atorvastatin calcium intermediate

A technology of atorvastatin calcium and system, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of long synthesis route, complicated operation, expensive raw materials and the like, and achieves the effects of less pollution, simple operation and cheap raw materials

Active Publication Date: 2018-08-24
SHANXI DATONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention aims at the problems of long synthetic route, complicated operation and expensive raw materials in the existing synthesis method of atorvastatin calcium intermediate, and provides a method for preparing atorvastatin calcium intermediate

Method used

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  • Method for preparing atorvastatin calcium intermediate
  • Method for preparing atorvastatin calcium intermediate
  • Method for preparing atorvastatin calcium intermediate

Examples

Experimental program
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Embodiment 1

[0029] Under the protection of nitrogen, 1.73g isobutyraldehyde, (4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane Alk-4-yl] tert-butyl acetate 5.46g, tetrahydrofuran 15ml, add 5g 3Å molecular sieve 100ml two-necked flask (with stirring magnet), stir at room temperature for 12-24h; under the protection of nitrogen, use a syringe to 2.34g of p-fluorobenzoyl chloride was slowly added dropwise to the reaction solution with constant stirring. After the addition, after reacting for 1h at room temperature, 1.66g of tert-butyl isonitrile was added dropwise to the reaction solution with a syringe and continuously stirred. After completion, after reacting at room temperature for 1 hour, 3.17g of potassium carbonate was added to the above reaction solution, and 4.42g of 3-phenylpropioanilide was added dropwise to the reaction solution with a syringe, and stirring was continued. After the addition, React at room temperature for 24 hours. After the reaction is complete, extract with ethyl ...

Embodiment 2

[0031] Under the protection of nitrogen, 1.73g isobutyraldehyde, (4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane Alk-4-yl] tert-butyl acetate 5.46g, tetrahydrofuran 15ml, put into a 100ml two-necked flask with 3Å molecular sieve 5g, magnet, stirred at room temperature for 12-24h; then the molecular sieve in the above reaction solution was filtered out, Under the protection of nitrogen, use a syringe to slowly add the filtrate dropwise to a 100ml two-necked flask (with stirring magnet) containing 3.17g of p-fluorobenzoyl chloride, 3.31g of potassium carbonate, and 10ml of tetrahydrofuran, and continue to stir. Then, after reacting for 1 hour at room temperature, 1.66 g of tert-butyl isonitrile was added dropwise to the reaction solution with a syringe and stirring continuously. After the addition, after reacting for 1 hour at room temperature, 3.31 g of potassium carbonate was added, and the 3- 4.42g of phenylpropionylanilide was added dropwise to the reaction solution and sti...

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Abstract

The invention discloses a method for preparing an atorvastatin calcium intermediate, and belongs to the technical field of synthesis of medicinal intermediates. The problems that an existing synthesismethod of the atorvastatin calcium intermediate is long in synthesis line and complicated in operation and raw materials are expensive can be solved. By adoption of a 'one-pot' method, firstly, isobutyraldehyde and ATS-9 are condensed to generate imine, and the imine and fluorobenzoyl chloride generate N-acylation reaction and then react with tertiary butyl isonitrile; and finally, the product and 3-phenyl propylene aniline generate 1,3-dipolar cycloaddition-removal reaction to generate a target (4R-cis)-6-[2-[2-(4-fluorinated phenyl)-5-(1-isopropyl)-3-phenyl-4-[( anilino) carboxyl]-1H-pyrrole-1-radical]-ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate. The yield of the final product obtained by the synthesis method disclosed by the invention is as high as 72 to 75 percent.

Description

Technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and specifically relates to a method for preparing an atorvastatin calcium intermediate. Background technique [0002] The chemical name of atorvastatin calcium is [R,(R*,R*)]-2-(4-fluorophenyl)- β , δ -Dihydroxy-5-(1-methylethyl)-3-phenyl-[(anilino)-hydroxy]-1 H -Pyrrole-1-heptanoate calcium salt (2:1), the drug is a selective inhibitor of HMG-CoA reductase, used to treat hypercholesterolemia, mixed hyperlipidemia and other diseases. It is an imported drug Lipp The active ingredient of the Chinese medicine Ale. (4R-cis)-6-[2-[2-(4-Fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(anilino)carboxy]-1 H -Pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate is one of the key intermediates for the preparation of atorvastatin calcium. [0003] So far, reports on the synthesis route of this intermediate are as follows: US Patent: 7,250,444 discloses that p-fluorophenyla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 刘慧君王科伟马琦卢珍解海刘建红冯锋郭永
Owner SHANXI DATONG UNIV
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