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Preparation technology of atorvastatin

A technology for atorvastatin and preparation process, which is applied in the field of chemical synthesis, can solve the problems of complicated processing, decreased product yield and the like, and achieves the effects of improving reaction yield, improving reaction yield and facilitating separation

Active Publication Date: 2017-02-15
JIANGSU ALPHA PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing method for synthesizing M-4 is as shown in formula (I), with benzoic acid as the starting material, reacts with thionyl chloride to generate phenylacetyl chloride (1), and then carries out Friedel-Crafts acylation reaction with fluorobenzene to generate 4-fluorophenylacetophenone (2), 4-fluorophenylacetophenone (2) reacts with isobutyrylacetanilide after further bromination to generate M-4, wherein phenylacetyl chloride (1) reacts with fluorobenzene The commonly used catalyst for the Friedel-Crafts acylation reaction is AlCl 3 , while AlCl 3 It is easy to complex with the generated product, and the treatment after the reaction is more cumbersome, and leads to a decrease in product yield

Method used

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  • Preparation technology of atorvastatin
  • Preparation technology of atorvastatin

Examples

Experimental program
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Effect test

Embodiment 1

[0019] In the first step, 6.8g of phenylacetic acid was dissolved in 40ml of chloroform, 7.8g of thionyl chloride was added into the reaction flask, and the temperature was raised to reflux for 2-3 hours. 6.31 g of phenylacetyl chloride, the yield is 82%.

[0020] In the second step, add 10.6 g of fluorobenzene into 100 ml of dichloromethane and stir, add 13 g of zeolite molecular sieves under ice bath, then add dropwise 40 ml of dichloromethane containing 15.4 g of phenylacetyl chloride to the above solution under ice bath, drop During the addition process, keep the temperature of the reaction solution not exceeding 10°C, continue the reaction for 2 hours after the dropwise addition, and TLC tracking shows that the reaction is complete. Filter and spin dry to obtain a light yellow solid, which is recrystallized to obtain 17.12 g of 4-fluorophenylacetophenone with a yield of 80%.

[0021] In the third step, dissolve 10.7g of 4-fluorophenylacetophenone in 100ml of glacial acet...

Embodiment 2

[0025] In the first step, 6.8g of phenylacetic acid was dissolved in 40ml of chloroform, 7.8g of thionyl chloride was added into the reaction flask, and the temperature was raised to reflux for 2-3 hours. 6.31 g of phenylacetyl chloride, the yield is 82%.

[0026] In the second step, add 10.6 g of fluorobenzene into 100 ml of dichloromethane and stir, add 13 g of zeolite molecular sieves under ice bath, then add dropwise 40 ml of dichloromethane containing 15.4 g of phenylacetyl chloride to the above solution under ice bath, drop During the addition process, keep the temperature of the reaction solution not exceeding 10°C, continue the reaction for 2 hours after the dropwise addition, and TLC tracking shows that the reaction is complete. Filter and spin dry to obtain a light yellow solid, which is recrystallized to obtain 17.12 g of 4-fluorophenylacetophenone with a yield of 80%.

[0027] In the third step, dissolve 10.7g of 4-fluorophenylacetophenone in 100ml of glacial acet...

Embodiment 3

[0031] In the first step, 6.8g of phenylacetic acid was dissolved in 40ml of chloroform, 7.8g of thionyl chloride was added into the reaction flask, and the temperature was raised to reflux for 2-3 hours. 6.31 g of phenylacetyl chloride, the yield is 82%.

[0032] In the second step, add 10.6 g of fluorobenzene into 100 ml of dichloromethane and stir, add 13 g of zeolite molecular sieves under ice bath, then add dropwise 40 ml of dichloromethane containing 15.4 g of phenylacetyl chloride to the above solution under ice bath, drop During the addition process, keep the temperature of the reaction solution not exceeding 10°C, continue the reaction for 2 hours after the dropwise addition, and TLC tracking shows that the reaction is complete. Filter and spin dry to obtain a light yellow solid, which is recrystallized to obtain 17.12 g of 4-fluorophenylacetophenone with a yield of 80%.

[0033] In the third step, dissolve 10.7g of 4-fluorophenylacetophenone in 100ml of glacial acet...

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Abstract

The invention discloses preparation technology of atorvastatin. The preparation technology comprises the following steps: a first step, the reaction of phenylacetic acid and thionyl chloride is carried out in order to obtain phenylacetyl chloride; a second step, the Friedel-Crafts acylation reaction of phenylacetyl chloride and fluorobenzene is carried out under the action of catalyst, in order to obtain 4-fluorophenyl acetophenone; a third step, 4-fluorophenyl acetophenone is brominated and the brominated 4-fluorophenyl acetophenone is reacted with N-phenyl-isobutyloylacetamide in order to obtain M-4; a fourth step, a reaction is carried out for M-4 and ATS-9 in a cyclohexane, toluene or a mixed solvent of cyclohexane and toluene, pivalic acid is used for catalysis, and a condensation product is obtained. Phenylacetyl chloride and fluorobenzene are reacted in a catalytic action of zeolite molecular sieve, a complexation reaction of the catalyst and products is avoided, reaction yield is improved, and side reactions are few in order to facilitate purification; post-treatment can be carried out for excess M-4 for recycling and reusing, reaction yield is improved, mole proportion of M-4 to ATS-9 and the addition amount of pivalic acid can be adjusted, and final yield of the reaction is improved.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation process of atorvastatin. Background technique [0002] Statins block cholesterol biosynthesis by competitively inhibiting trihydroxytrimethylglutaryl coenzyme A (HMG-CoA) reductase, thereby reducing atherosclerotic low-density lipoprotein-cholesterol (LDL -C) Effect of content. Statins are known as "miracle drugs" in the medical world. Because of its novel mechanism of action, wide range of applications, significant curative effect, less toxic and side effects, and good tolerance, it is considered to be the most classic and effective lipid-regulating drug at present. [0003] Fluvastatin (fluvastatin) is the first fully synthetic HMG-CoA reductase inhibitor, and atorvastatin (atorvastatin) is the second fully synthetic statin drug, containing fluorine benzene ring and nitrogen heterocycle, water soluble Relatively increased sex, relatively decreased ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34C07D405/06
CPCC07D207/34C07D405/06
Inventor 石利平叶银梅漆志文龚仕荣徐春涛杜家龙陈晓佩
Owner JIANGSU ALPHA PHARM CO LTD
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