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A kind of preparation method of pitavastatin calcium

A technology of pitavastatin calcium and calcium chloride, applied in the direction of organic chemistry, can solve the problems of flammability and explosion of tetrahydrofuran, long reaction time, cumbersome steps, etc., save separation and purification steps, improve process safety, and reduce side effects The effect of product increase

Active Publication Date: 2015-09-02
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This invention has the following disadvantages: first, the obtained intermediate product (pitavastatin tert-butyl ester) needs post-treatment processes such as neutralization, extraction, and drying, and the steps are cumbersome and time-consuming
Second, using tetrahydrofuran as the reaction solvent, the reaction speed is slow, requiring more than 2 hours of reaction time, and the efficiency is low
Third, column chromatography operation is difficult to achieve industrial scale-up production, which affects product marketization
Fourth, the two-step reaction uses tetrahydrofuran and methanol as solvents respectively, requiring the use of two different solvents, and tetrahydrofuran is flammable and explosive, and there are high requirements for workshops and solvent recovery during production
Fifth, the proportion of water in the hydrolysis reaction process is too low, which is not conducive to the occurrence of hydrolysis reaction, and the reaction time is too long
[0014] Therefore, the prior art lacks a simpler, safer and energy-efficient preparation method for pitavastatin calcium from compound II as a starting material

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1. Weigh 30.0g of compound II into the reaction flask, start stirring, add 300ml of methanol, dropwise add 58ml of 2mol / L hydrochloric acid, and finish adding in 20 minutes. After the dropwise addition, react at 10-40°C for 1 hour; 0-50 Add 150ml of 0.5mol / L sodium hydroxide solution dropwise at ℃, finish adding in 20-30 minutes, react for 2 hours, add dropwise 1mol / L hydrochloric acid to adjust the pH value to 7-8; concentrate the reaction solution under reduced pressure, add 700ml of purified water and Extract with 400ml of ethyl acetate, separate the water layer; add 115ml of 0.4mol / L calcium chloride aqueous solution dropwise to the obtained water layer solution at 20-30°C, a large amount of white solid precipitates, stir for 30 minutes, filter, wash with water, and dry in vacuo to obtain White Pitavastatin Calcium Solid 23.0g. Overall yield: 90.2%. 99.67% purity.

Embodiment 2

[0035] Example 2. Weigh 30.0g of compound II into the reaction flask, start stirring, add 300ml of methanol, dropwise add 58ml of 2mol / L hydrochloric acid, finish adding in 20 minutes, and react at 10-40°C for 1 hour after the addition; 0-50 Add 70ml of 1mol / L sodium hydroxide solution dropwise at ℃, finish adding in 20-30 minutes, add 80ml of purified water, react for 2 hours, add 1mol / L hydrochloric acid dropwise to adjust the pH value to 7-8; the reaction solution is concentrated under reduced pressure, added Extract with 700ml of purified water and 400ml of ethyl acetate, and separate the water layer; add 115ml of 0.4mol / L calcium chloride aqueous solution dropwise to the obtained water layer solution at 20-30°C, a large amount of white solid precipitates, stir for 30 minutes, filter, and wash with water , and vacuum-dried to obtain 23.1 grams of white pitavastatin calcium solid. Overall yield: 90.6%. 99.72% pure.

Embodiment 3

[0036] Example 3. Weigh 30.0g of compound II into the reaction flask, start stirring, add 400ml of absolute ethanol, add 58ml of 2mol / L hydrochloric acid dropwise, finish adding in 20 minutes, and react at 10-40°C for 1.5 hours after the dropwise addition; Add 70ml of 1mol / L sodium hydroxide solution dropwise at ~50°C, finish adding in 20-30 minutes, add 130ml of purified water, react for 1 hour, add dropwise 1mol / L hydrochloric acid to adjust the pH value to 7-8; the reaction solution is concentrated under reduced pressure , add 700ml of purified water and 400ml of ethyl acetate for extraction, and separate the water layer; add 115ml of 0.4mol / L calcium chloride aqueous solution dropwise to the obtained water layer solution at 20-30°C, and a large amount of white solid is precipitated; stir for 30 minutes, filter , washed with water, and dried in vacuum to obtain 23.3 grams of white pitavastatin calcium solid. Overall yield: 91.4%. 99.65% pure.

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Abstract

The invention relates to a method for preparing pitavastatin calcium, comprising the following steps of: (a) adopting C1-C4 lower alcohol to dissolve a compound II, and adding an acid catalyst to carry out deprotection reaction so as to obtain a compound III; (b) adding water liquor of alkali to the compound III liquor obtained in the step (a), carrying out hydrolysis reaction, adjusting pH value to 7-8 with acid, concentrating, extracting with water and fat soluble liquor, and separating a water layer to obtain pitavastatin calcium liquor; and (c) adding calcium chloride liquor to the liquor obtained in the step (b), stirring, filtering the separated solid, washing, and drying to obtain the pitavastatin calcium. The method disclosed by the invention saves the middle steps of separation and purification, so that the production process is simplified, the working time is reduced, the production efficiency is improved, and the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of statin blood lipid-lowering drugs, in particular to a one-pot method for preparing pitavastatin calcium. Background technique [0002] Statins are a class of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors that competitively inhibit the rate-limiting enzyme of endogenous cholesterol synthesis (HMG-CoA) Reductase, blocking intracellular valonate metabolism pathway, thereby reducing blood lipids. Since the first statin drug, lovastatin, was launched in 1987, simvastatin, fluvastatin, atorvastatin calcium, rosuvastatin calcium and pitavastatin calcium have been launched successively, and have gained clinical and market recognition. Great success. [0003] Pitavastatin calcium (I) was launched in Japan in July 2003 for the treatment of hypercholesterolemia and familial hypercholesterolemia, the trade name is The drug was first developed by Nissan Chemical Industry Co., Ltd., and joi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/14
Inventor 郑利刚梁敏王世霞张明何元宋倩男刘勋涛邢松松刘亚英
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD