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Method for preparing pitavastatin calcium

A technology of pitavastatin calcium and its compounds, which is applied in the field of preparation of pitavastatin calcium, can solve the problems of Mitsunobu reaction being difficult to scale up, low yield, sulfide environmental hazards, etc.

Inactive Publication Date: 2014-01-15
ASYMCHEM LAB TIANJIN +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses sulfides, which is harmful to the environment, and the Mitsunobu reaction is difficult to amplify and the yield is low

Method used

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  • Method for preparing pitavastatin calcium
  • Method for preparing pitavastatin calcium
  • Method for preparing pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: A method for preparing pitavastatin calcium, characterized in that the specific preparation steps are as follows:

[0049] (1) Synthesis of methyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate (compound 3)

[0050] Add 215g (1mol) of (2-aminophenyl)(4-fluorophenyl)methanone (compound 2), 2.1L (10mL / g) of acetic acid, and 3-cyclopropyl-3 to a 5L four-necked flask. -170g (1.2mol) of methyl oxopropionate and 4.8g (0.05mol) of concentrated sulfuric acid, heated to 90-100°C. After the TLC reaction is over, the temperature is lowered to 0-10°C. The system was added to 2.1L (10mL / g) of 30% ammonia water to quench the reaction, and 2.1L (10mL / g) of dichloromethane was added to extract the product. The organic phase was washed with 2.1L saturated sodium chloride aqueous solution and concentrated to dryness to obtain the crude product. 1.05L of petroleum ether (5mL / g) was added to recrystallize to obtain the solid product 2-cyclopropyl-4-(4-fluorophenyl)quine. ...

Embodiment 2

[0063] Example 2: A method for preparing pitavastatin calcium, characterized in that the specific preparation steps are as follows:

[0064] (1) Synthesis of ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate (compound 3)

[0065] Add 215g (1mol) of (2-aminophenyl)(4-fluorophenyl)methanone (compound 2) and 2.1L (10mL / g) of N,N-dimethylformamide to a 5L four-necked flask. , 156 g (1.0 mol) of ethyl 3-cyclopropyl-3-oxopropionate and 9.8 g (0.10 mol) of concentrated sulfuric acid, the temperature is increased from 90 to 100°C. After the TLC reaction is over, the temperature is lowered to 0-10°C. The system was added to 2.1L (10mL / g) of 30% sodium hydroxide, and 2.1L (10mL / g) of dichloromethane was added to extract the product. The organic phase was washed with 2.1 L saturated aqueous sodium chloride solution and concentrated to dryness. The obtained crude product was recrystallized by adding 1.05L of cyclohexane (5mL / g) to obtain solid ethyl 2-cyclopropyl-4-(4-fluorophen...

Embodiment 3

[0078] Embodiment 3: A method for preparing pitavastatin calcium, characterized in that the specific preparation steps are as follows:

[0079] (1) Synthesis of methyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate (compound 3)

[0080] Add 215g (1mol) of (2-aminophenyl)(4-fluorophenyl)methanone (compound 2), 1.05L (5mL / g) of propionic acid, and 3-cyclopropyl- 340g (2.0mol) of methyl 3-oxopropionate and 9.6g (0.1mol) of concentrated sulfuric acid were heated to 100°C. After the TLC reaction is over, the temperature is reduced to 0-10°C. The system was added to 2.1L (10mL / g) of 15% sodium hydroxide aqueous solution, and 1.05L (5mL / g) of dichloromethane was added to extract the product. The organic phase was washed with 2.1 L saturated aqueous sodium chloride solution and concentrated to dryness. The obtained crude product was recrystallized by adding 1.05 L of petroleum ether (5 mL / g) to obtain methyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate with a yield o...

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Abstract

The invention discloses a method for preparing pitavastatin calcium. The method comprises the following step: performing seven-step synthesis on 3-cyclopropyl-oxopropionate (comprising methyl ester and ethyl ester), (2-aminophenyl)(4-fluorophenyl) ketone and (4R-cis)-6-[(acetoxy)methyl]2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate which are used as initial raw materials so as to obtain the product. The reaction in each step is a conventional reaction and is suitable for large-scale production. The process is stable, the reaction conditions are mild, the after-treatment operation is simple, the intermediate is easy to separate, and the technical bottleneck in the existing pitavastatin calcium synthesis is solved.

Description

(1) Technical field: [0001] The invention relates to the technical field of medical synthesis, in particular to a method for preparing pitavastatin calcium. (2) Background technology: [0002] Pitavastatin calcium, chemical name: (+)-monocalcium bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(fluorophenyl)quinoline-3-phenyl] -3,5-Dihydroxy-6-heptenoic acid ethyl ester} salt (Compound I), is the first fully synthetic HMG-CoA reductase inhibitor developed by Nissan Chemical Company and Kowa Co., Ltd., in 1999 It was registered in Japan in November 2015, and was approved for listing in Japan for the first time on July 17, 2003. Pitavastatin calcium has an antagonistic inhibitory effect on the rate-limiting enzyme HMG-CoA reductase for cholesterol synthesis, thereby inhibiting liver cholesterol synthesis. Tests in the Japanese population have shown that Pitavastatin Calcium Salt (NK-104) has a significant effect on lowering low-density lipoprotein cholesterol (LDL-C). Its effect is similar to t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 洪浩马建国李九远黄俊
Owner ASYMCHEM LAB TIANJIN
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