Refining method of pitavastatin tert-butyl ester

A technology of pitavastatin tert-butyl ester and refining method, which is applied in the direction of organic chemistry, organic chemistry, etc., can solve the problems of inability to remove and affect, and achieve the effect of low uncontrollability, good refining effect and high yield

Active Publication Date: 2018-12-14
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] It can be seen from this route that the 3 isomer impurities in pitavastatin tert-butyl ester are introduced by side chain ylides, and general refining methods can remove process impurities in the pitavastatin route such as: pitavastatin propylidene tert-butyl ester, pitavastatin Aldehydes and side chain ylides, etc., but the three optical isomers (whose structural formula is shown below) cannot be removed by conventional refining methods due to their structure is very similar to pitavastatin tert-butyl ester, so find an effective method to remove the isomers directly affects the product purity of pitavastatin calcium

Method used

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  • Refining method of pitavastatin tert-butyl ester
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  • Refining method of pitavastatin tert-butyl ester

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Experimental program
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Effect test

Embodiment 1

[0033] Mix 40g of pitavastatin tert-butyl ester and 120mL of methyl tert-butyl ether, raise the temperature to reflux temperature, stir for 30min, dissolve and clear, add dropwise 360mL of n-heptane, the solution is clear, cool down to 25°C for crystallization for 2h, and filter with suction. The filter cake was vacuum-dried at 50°C for 5 hours to obtain 33.7 g of pitavastatin tert-butyl ester. See Table 2 for the HPLC purity and yield.

Embodiment 2

[0035] Mix 40g of pitavastatin tert-butyl ester, 120mL of methyl tert-butyl ether and 480mL of n-heptane, raise the temperature to reflux temperature, stir for 30min, the solution is clear, cool down to 25°C for crystallization for 2h, suction filter, and vacuum the filter cake at 50°C After drying for 5 hours, 36.5 g of pitavastatin tert-butyl ester was obtained. See Table 2 for HPLC purity and yield.

Embodiment 3

[0037] Mix 40g of pitavastatin tert-butyl ester and 120mL of methyl tert-butyl ether, raise the temperature to reflux temperature, stir for 30min, dissolve, add 600mL of n-heptane dropwise, the solution is clarified, add 0.8g of activated carbon, reflux for 45min to decolorize, while hot After suction filtration, the filtrate was cooled to 25°C to crystallize for 2 hours, then suction filtered, and the filter cake was vacuum-dried at 50°C for 5 hours to obtain 37.1 g of pitavastatin tert-butyl ester. See Table 2 for HPLC purity and yield.

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Abstract

The invention discloses a refining method of a pitavastatin tert-butyl ester. The refining method comprises the following steps: cooling and crystalizing a mixed solvent dissolved with a pitavastatintert-butyl ester material, filtering, and drying, wherein the mixed solvent is a mixture of methyl tertiary butyl ether and a nonpolar organic solvent; and the nonpolar organic solvent is n-hexane, n-heptane, cyclohexane, n-pentane, cyclopentane, octane and isooctane. According to the refining method, the content of isomer in the obtained pitavastatin tert-butyl ester is low, the refining effect is good, and the contents of an epimer impurity 1, an epimer impurity 2 and an enantiomer impurity is lower than 0.05%. In addition, the yield of the refining method is high, the uncontrollability is low, the operation is simple, the refining method is suitable for industrial product, and the high-purity pitavastatin calcium is prepared.

Description

technical field [0001] The invention relates to a refining method of pitavastatin tert-butyl ester. Background technique [0002] Coronary heart disease is a common and frequently-occurring disease that threatens human health and life. Hypercholesterolemia characterized by elevated low-density lipoprotein (LDL) is one of the main risk factors for coronary heart disease. Commonly used blood lipid-lowering drugs such as niacin, resins or fibrates have unsatisfactory curative effects, and the drugs with the best lipid-lowering effect are known as statins (statins). The common mechanism of action of statins is that they all belong to 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors. At present, there are mainly six kinds widely used in the world: lovastatin (lovastatin) ), pravastatin, simvastatin, cerivastatin, fluvastatin and atorvastatin. Pitavastatin Calcium, developed by Kowa Company, is called "Superstatin" because of its good cholesterol-lowering ef...

Claims

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Application Information

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IPC IPC(8): C07D215/14
CPCC07B2200/07C07D215/14
Inventor 朱建荣彭春勇任小娟林庆梁洪江
Owner ZHEJIANG JINGXIN PHARMA
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