Method for preparing atorvastatin calcium intermediate

A technology for atorvastatin calcium and intermediates, which is applied in the field of preparation of atorvastatin calcium intermediates, and can solve the problems of long reaction steps, foul smell, and difficulty in obtaining catalysts, etc.

Active Publication Date: 2012-10-03
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this route is that the steps are relatively simple and suitable for large-scale industrial production. The main disadvantages are: 1) the key intermediate p-fluorobenzaldehyde is relatively expensive; Thiazole-like carbene catalysts, such catalysts are not easy to obtain, the cost is high, and there is a foul smell, which is not environmentally friendly
But there are still some disadvantages, mainly: 1) The reaction steps are longer; 2) The reaction needs to be brominated at the α-position of the carbonyl first, and then the bromine is removed in the last step of substitution, and the atom economy is poor; 3) Although the reaction avoids Expensive catalysts are used, but the liquid bromine used is still irritating and corrosive, and improvement in waste pollution treatment and environmental protection is still needed

Method used

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  • Method for preparing atorvastatin calcium intermediate
  • Method for preparing atorvastatin calcium intermediate
  • Method for preparing atorvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Dissolve Compound A (2.3g) and Compound B (2.7g) in 50ml of dry toluene solvent, heat to 45°C, stir for 30min, slowly add 3.5g of concentrated sulfuric acid dropwise, continue stirring for 30min, heat up to 90 ℃, the water separator separates the water. React for 24 hours. After the reaction, wash with water until neutral, and wash the organic phase with saturated sodium bicarbonate solution. Dry over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, dissolve it with 50ml ethyl acetate and stir it mechanically. Heat to 30°C, slowly add 150ml of petroleum ether dropwise to obtain the product. Repeat the above recrystallization steps twice to obtain 3.2g of the product.

Embodiment 2

[0024] Dissolve compound A (30g) and compound B (35g) in 300ml of dry toluene solvent, heat to 45°C, stir for 30min, slowly add 50g of concentrated phosphoric acid dropwise, continue stirring for 30min, raise the temperature to 90°C, separate the water The device divides the water. React for 26 hours. After the reaction, wash with water until neutral, and wash the organic phase with saturated sodium bicarbonate solution. Dry over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, dissolve it with 200ml of ethyl acetate and stir it mechanically. Heat to 30°C, slowly add 600ml of petroleum ether dropwise to obtain the product. Repeat the above recrystallization steps twice to obtain 44.8g of the product .

Embodiment 3

[0026] Dissolve compound A (100g) and compound B (115g) in 1000ml of dry toluene solvent, heat to 45°C, stir for 30min, slowly add 160g of concentrated phosphoric acid dropwise, continue stirring for 30min, heat up to 90°C, separate water Separate the water. React for 26 hours. After the reaction was completed, it was washed with water until neutral, and the organic phase was washed with saturated sodium bicarbonate solution. Dry over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, it was dissolved in 1000ml ethyl acetate and stirred mechanically. Heat to 30°C, slowly add 3000ml of petroleum ether dropwise to obtain the product. Repeat the above recrystallization steps twice to obtain 151.0g of the product.

[0027]

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Abstract

The invention provides a method for preparing atorvastatin calcium intermediate. The method comprises the steps of dissolving compound A and compound B into a solvent with a molar ratio of A to B of 1:(1.0-1.5), heating to 30-60 DEG C, stirring to dissolve, slowly dripping concentrated acid with a mole number of 2-8 times of that of compound A for a reaction for 16-36 hours at 80-110 DEG C, removing water formed during the reaction by using a water separator after the reaction, removing the solvent through rotary dying, dissolving with ethyl acetate, adding petroleum ether dropwise for recrystallization and treating for several times to obtain the final product. The two raw materials A and B used in the method are cheap and available, the catalyst of the reaction is common acid, and the product of the side reaction is only water. The obtained product has a purity of over 98% and a yield of about 80% and accords with the requirements of friendly environment and green chemistry.

Description

technical field [0001] The invention relates to a preparation method of an atorvastatin calcium intermediate, belonging to the technical field of pharmaceutical production. Background technique [0002] Atorvastatin (Lipitor) is currently the most prescribed cholesterol-lowering drug in the world. Since 2002, it has become the world's best-selling prescription drug, with annual sales of tens of billions of dollars. The five patents on Lipitor will all expire in the near future. Among them, the Lipitor calcium salt patent (US 5273995) involved in this subject will expire in June 2011. At present, by the end of 2010, Ruihui's Lipitor accounted for 69.18% of the annual sales volume in the Chinese market, with annual sales reaching hundreds of millions of yuan. In addition, domestic preparations on the market mainly include atorvastatin calcium tablets (trade name: Ale) registered by Beijing Jialin Pharmaceutical Co., Ltd. and atorvastatin calcium capsules (trade name: Youjia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/80C07C231/14
Inventor 胡玉玺路显峰冯建鹏程瑞玲张薇居斌胡丽娜陆良喆
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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