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Preparation method of high-purity pitavastatin calcium

A kind of pitavastatin calcium, high-purity technology, applied in the field of medicine, can solve the problem that the lactone content is not easy to control and the like

Active Publication Date: 2015-12-30
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the problem that the content of lactone (II) in pitavastatin calcium is not easy to control, it provides a method of reducing lactone (II) in pitavastatin calcium content technical solution

Method used

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Experimental program
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Effect test

Embodiment 1

[0030] Weigh 51.7g (0.1mol) of material IV, add 300ml ethanol, 50ml water and 15.2ml (0.15mol) of 36% hydrochloric acid, stir at room temperature for 5 hours, TLC detects that there is no raw material IV, then add 12g (0.3mol) sodium hydroxide The solution (dissolved with 100ml of water) continued to react for 6 hours, and no intermediate state V was detected by TLC. The reaction liquid ethanol was concentrated under reduced pressure, 100 ml of water was added, and extracted twice with dichloromethane. Take the water layer, adjust the pH to 10 with hydrochloric acid, and slowly add 6.6g (0.06mol) of calcium chloride aqueous solution (dissolved in 60ml of water) dropwise under nitrogen protection. After the dropwise addition is complete, continue stirring for 2 hours. Filter, water first, and dry below 45°C to obtain 83.5 g of crude pitavastatin calcium (with crystal water), with a yield of 86.0%. HPLC detection (area normalization method), purity 99.72%, lactone (II) 0.042%...

Embodiment 2

[0033] Weigh 51.7g (0.1mol) of material IV, add 300ml ethanol, 50ml water and 15.2ml (0.15mol) of 36% hydrochloric acid, stir at room temperature for 5 hours, TLC detects that there is no raw material IV, then add 12g (0.3mol) sodium hydroxide The solution (dissolved with 100ml of water) continued to react for 6 hours, and no intermediate state V was detected by TLC. The reaction liquid ethanol was concentrated under reduced pressure, 100 ml of water was added, and extracted twice with dichloromethane. Take the water layer, adjust the pH to 8 with hydrochloric acid, and slowly add 10.6g (0.06mol) of calcium acetate (monohydrate) aqueous solution (dissolved in 90ml of water) dropwise under nitrogen protection. After the dropwise addition is complete, continue stirring for 2 hours. Filter, water first, and dry below 45°C to obtain 86.0 g of crude pitavastatin calcium (with crystal water), with a yield of 88.6%. HPLC detection (area normalization method), purity 99.81%, lacton...

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Abstract

The invention relates to a preparation method of high-purity pitavastatin calcium. The technical scheme adopted by the invention is characterized by comprising the following steps of step one, preparing a crude product: dissolving a material IV by using a mixed solvent of ethanol water, adding concentrated hydrochloric acid, adding excessive sodium hydroxide solution after the reaction is ended, hydrolyzing at the room temperature, reducing pressure and distilling out ethanol in a system after the reaction is ended, adding dichloromethane, extracting, retaining a water layer, adjusting the PH value of the water layer to be 8-10 by using hydrochloric acid, carrying out nitrogen protection, dropwise adding a calcium acetate aqueous solution, filtering, washing and drying to obtain the crude product of pitavastatin calcium; and step two, refining: dissolving the crude product by using the 90%-95% mixed solvent of ethanol water, filtering, slowly adding a low-polarity solvent into the filtrate under the nitrogen protection, stirring, filtering and drying to obtain a fine product of pitavastatin calcium. Through the implementation of the technical scheme, the pitavastatin calcium product, in which the content of inner ester which is expressed as the formula II is smaller than 0.02%, can be obtained; the high-quality raw medicine can be provided for clinic application.

Description

technical field [0001] The invention relates to a preparation method of high-purity pitavastatin calcium, belonging to the technical field of medicine. Background technique [0002] Pitavastatin Calcium is a HMG-CoA reductase inhibitor with a trade name of Livalo, developed by Nissan Chemical Industry Co., Ltd. of Japan. This product has been launched in Japan in October 2003. It is used to treat primary hypercholesterolemia and familial hypercholesterolemia. The drug has obvious lipid-lowering effect, less interaction with other drugs, and has good safety sex and effectiveness. [0003] At present, the common method for preparing pitavastatin calcium is to add an aqueous calcium chloride solution to the sodium salt solution of pitavastatin to prepare the crude product of pitavastatin calcium. Due to the extremely low solubility of pitavastatin calcium in aqueous solution, the step of preparing the calcium salt is extremely rapid, and impurities are entrained. [0004] Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 吴荣贵徐可岭王兆杰安冬华
Owner 迪嘉药业集团股份有限公司
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