A kind of preparation method of pitavastatin calcium intermediate

A technology for pitavastatin calcium and intermediates, applied in the field of chemical substance preparation, can solve the problems of expensive atom economy, difficulty in obtaining pure pitavastatin calcium, and poor quality

Active Publication Date: 2022-03-08
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] From the above review, it can be seen that the main difficulty in the synthesis of pitavastatin calcium is the reaction effect with the stereoselectivity of the docking product.
The above-mentioned route is either because of the expensive raw materials and poor atom economy, or because the reaction conditions are relatively harsh and requires column chromatography, or because the post-processing is difficult to obtain pitavastatin calcium with high purity, so that there is a bottleneck in the industrial production of the above-mentioned route. , so the development of raw materials is cheap and easy to get, the reaction conditions are mild, and the synthetic route of pitavastatin calcium intermediate with good atom economy has broad prospects

Method used

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  • A kind of preparation method of pitavastatin calcium intermediate
  • A kind of preparation method of pitavastatin calcium intermediate
  • A kind of preparation method of pitavastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] A preparation method of pitavastatin calcium intermediate, comprising the steps of: (4R-Cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl Ester and p-toluenesulfonyl chloride are sulfonylated under the action of a catalyst to obtain (4R-Cis)-6-p-toluenesulfonyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tertiary Butyl ester; then react with trimercapto-s-triazine under the action of basic catalyst to obtain substance A; then oxidize to obtain substance B through the action of oxidizing agent; finally with 2-cyclopropyl-4-(4-fluorophenyl) quinoline- 3-Formaldehyde reacted under the catalysis of sodium hydride to obtain pitavastatin calcium intermediate.

Embodiment 2

[0061] A preparation method of pitavastatin calcium intermediate, comprising the steps of:

[0062] Mix (4R-Cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, dimethylamine, dichloromethane and cool down to - 5°C, dropwise add the dichloromethane solution of p-toluenesulfonyl chloride, during the dropwise addition, keep the temperature not exceeding 5°C, reflux for 24 hours after the dropwise addition, wash with water, extract the organic phase with dichloromethane, dry, and concentrate to obtain (4R -Cis)-6-p-toluenesulfonyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate, wherein (4R-Cis)-6-hydroxymethyl-2 , The molar ratio of 2-dimethyl-1,3-dioxane-4-tert-butyl acetate to dimethylamine is 1:1.5, (4R-Cis)-6-hydroxymethyl-2,2- The molar ratio of dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester to p-toluenesulfonyl chloride is 1:1.5;

[0063] In a nitrogen atmosphere, trimercapto-s-triazine, sodium hydroxide, 1,4-dioxane, (4R-Cis)-6-p-toluenesulfo...

Embodiment 3

[0067] A preparation method of pitavastatin calcium intermediate, comprising the steps of:

[0068] Mix (4R-Cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, pyridine and dichloromethane, cool to -2°C , dropwise add a dichloromethane solution of p-toluenesulfonyl chloride, keep the temperature not exceeding 5°C during the dropwise addition, reflux for 18h after the dropwise addition, wash with water, extract the organic phase with dichloromethane, dry, and concentrate to obtain (4R-Cis )-6-p-toluenesulfonyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, wherein, (4R-Cis)-6-hydroxymethyl-2,2 -Dimethyl-1,3-dioxane-4-tert-butyl acetate to pyridine in a molar ratio of 1:2, (4R-Cis)-6-hydroxymethyl-2,2-dimethyl- The molar ratio of 1,3-dioxane-4-acetic acid tert-butyl ester to p-toluenesulfonyl chloride is 1:1.3;

[0069] In a nitrogen atmosphere, trimercapto-s-triazine, potassium hydroxide, 1,4-dioxane, (4R-Cis)-6-p-toluenesulfonyl-2,2-dimeth...

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Abstract

The invention discloses a preparation method of pitavastatin calcium intermediate, comprising the following steps: (4R-Cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4 The sulfonylation reaction of tert-butyl acetate and p-toluenesulfonyl chloride under the action of a catalyst gives (4R-Cis)-6-p-toluenesulfonyl-2,2-dimethyl-1,3-dioxane- 4-tert-butyl acetate; then react with trimercapto-s-triazine under the action of a basic catalyst to obtain substance A; then oxidize to obtain substance B through the action of an oxidizing agent; finally react with 2-cyclopropyl-4-(4-fluorophenyl ) quinoline-3-formaldehyde is reacted under the catalysis of sodium hydride to obtain pitavastatin calcium intermediate. The raw material of the present invention is cheap and easy to obtain, good atom economy, green and environmental protection, mild and controllable reaction conditions, simple operation, simple purification treatment, suitable for industrial production, good stereoselectivity, high yield, and the prepared pitavastatin calcium intermediate Good purity.

Description

technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to a preparation method of pitavastatin calcium intermediate. Background technique [0002] The disclosed function of pitavastatin calcium is a blood lipid-lowering drug (HMG-CoA reductase inhibitor), which is the first fully synthetic HMG-CoA reductase inhibitor jointly developed by Nissan Chemical and Kowa Co., Ltd. Belonging to statin drugs, it mainly reduces the ability of the liver to produce cholesterol by inhibiting a liver enzyme called HMG-CoA reductase, so as to improve the elevated blood cholesterol level, and is mainly used for the treatment of hypercholesterolemia and For patients with familial hypercholesterolemia, its lipid-lowering effect is very good, and it is the most powerful lipid-lowering drug so far. Therefore, it is of great significance to study the synthetic route of pitavastatin calcium. [0003] 6-[[(1E)-2-cyclopropyl-4-(4-fluorop...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 黄欢黄庆云李凯张宏远
Owner ANHUI QINGYUN PHARMA & CHEM
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