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Method for synthesizing rosuvastatin intermediate and rosuvastatin

A technology of rosuvastatin calcium and a synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of low reaction temperature and complexity, and achieve the effects of high purity, low equipment requirements, and simple process flow

Inactive Publication Date: 2009-03-04
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the synthesis process of this patent, the reaction temperature is extremely low and the operation of the reaction process is very complicated. Although the yield has been improved compared with other synthetic routes, it remains to further improve the yield of rosuvastatin calcium and the purity of the final product ,cut costs

Method used

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  • Method for synthesizing rosuvastatin intermediate and rosuvastatin
  • Method for synthesizing rosuvastatin intermediate and rosuvastatin
  • Method for synthesizing rosuvastatin intermediate and rosuvastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The synthetic method of compound 1:

[0059] Add 2.5L methanol, 0.8kg (6.45mol) p-fluorobenzaldehyde, 0.85kg (5.90mol) methyl isobutyryl acetate, 1kg (16.67mol) urea, appropriate amount of cuprous chloride, 2.3L1mol / L of sulfuric acid, heated to reflux (internal temperature 65-68°C) for 10 hours, cooled to 0°C in an ice-water bath, continued to stir for 4 hours, then filtered with suction, rinsed the obtained solid with methanol, and dried it in a drying oven at 60°C to obtain off-white Crystal 1.594kg, yield 92.6%. The purity of Compound 1 was determined to be 95% by HPLC.

Embodiment 2

[0061] The synthetic method of compound 1:

[0062] Add 2.5L methanol, 0.8kg (6.45mol) p-fluorobenzaldehyde, 0.85kg (5.90mol) methyl isobutyryl acetate, urea 0.885kg (14.74mol), 2.6L sulfuric acid of 1mol / L in 10L reactor, heat To reflux (internal temperature 65-68°C) for 20 hours, cool in an ice-water bath to 10°C, continue to stir for 5 hours, then filter with suction, rinse the obtained solid with methanol, and dry it at 60°C in a drying oven to obtain 1.574 kg of off-white crystals. The rate is 91.4%. The purity of Compound 1 was determined to be 95.2% by HPLC.

Embodiment 3

[0064] The synthetic method of compound 2:

[0065] Add 5L of 65-68% nitric acid and an appropriate amount of sodium nitrite in a 10L reactor, add 1.5kg (5.14mol) of compound 1 at 20°C when the temperature is controlled, and continue to react at 20-25°C for 1h. TLC detects that the reaction is complete. Add 3L of water to the reaction solution, add 30% sodium hydroxide solution dropwise at a temperature of 20°C to adjust the pH of the reaction solution to 8, cool to 5°C, continue to stir for 1h and then filter with suction, wash the obtained solid with water, and use a drying oven After drying at 80°C, 1.411 kg of a light yellow solid was obtained, with a yield of 94.7%. The purity of compound 2 was determined to be 92.8% by high performance liquid chromatography.

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Abstract

The invention provides a synthetic method of rosuvastatin calcium, which is characterized in that a compound 6 and branched chain react under the action of 2,2,6,6,-tetramethylpiperidine and n-butyl lithium to generate a compound 7, the reaction temperature is increased to minus 30 DEG C and the aspects such as reaction solvent and reaction reagent are improved so that the total reaction route has the advantages of mild condition, low device requirement and suitability for industrial production. Meanwhile, another improved synthetic route of rosuvastatin calcium comprises the following steps: converting esters into acids, synthesizing esters again, and synthesizing the rosuvastatin calcium. The rosuvastatin calcium purity is as high as 99.8%.

Description

technical field [0001] The invention relates to a synthesis method of rosuvastatin and rosuvastatin calcium salt and a preparation method of an intermediate in the synthesis process. Background technique [0002] Rosuvastatin calcium is an aminopyrimidine derivative developed and screened by Shionogi Pharmaceutical Co., Ltd. in Japan in the late 1980s. After that, AstraZeneca developed a new generation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors worldwide except Japan and other East Asian countries. Listed in Canada, the general name is Rosuvastatin calcium, and it is named Rosuvastatin calcium according to the homonym of INN. Chemical name: bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R, 5S)-3,5-dihydroxy-6-heptenoic acid] calcium salt, the molecular formula is (C 22 h 27 FN 3 o 6 S) 2 Ca. [0003] The structural formula is: [0004] [0005] Patent US5260440 and patent WO03 / 097614 respecti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
Inventor 黄仲斌戴连华谌谆韩勇刘毓宏
Owner ENANTIOTECH CORP
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