Method for preparing atorvastatin calcium intermediate

A technology of atorvastatin calcium and intermediates, which is applied in the field of pharmaceutical organic synthesis, can solve the problems of reduced condensation reaction yield, poor solubility, heterogeneous system, etc. rate increase effect

Inactive Publication Date: 2012-11-07
ZHEJIANG HONGYUAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The present inventor finds after researching the above-mentioned condensation reaction, while the reaction catalyst is converted into compound C along with compound A and compound B, the molar ratio of trimethylacetic acid and compound A will become larger and larger, especially reacting to In the later stage, the molar weight of trimethylacetic acid is much higher than that of compound A, which will bring a certain inhibitory effect on the condensation reaction and is not conducive to the reaction, eventually leading to a reduction in the yield of the condensation reaction
[0008] In addition, in the existing synthetic reaction, the reaction solvent also limits the yield, and this is because the solubility of compound B in toluene and hexane or n-heptane is not good, causing the reaction to be in a heterogeneous system

Method used

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  • Method for preparing atorvastatin calcium intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Under the protection of nitrogen, put 10g of compound A and 18g of compound B into a four-necked flask, add 80g of tetrahydrofuran and 80g of n-butyl ether, stir at room temperature for 15 minutes, add 2g of trimethylacetic acid, and slowly raise the temperature to reflux, After stirring and reflux reaction at 95°C for 6 hours, the purity of Compound C was detected to be 50%, and 0.65g of triethylamine or 1.2g of tert-butylamine was added to continue stirring and reflux reaction for 6 hours, and then the purity of Compound C was detected, and the purity of Compound C was detected to be 78%. , then add 0.65g or 1.2g tert-butylamine triethylamine, and continue the reflux reaction for 6 hours. At this time, the detection purity is greater than 98%, and the reaction is terminated.

[0034] Control the temperature at 60~90℃ and -0.08~-0.096Mpa and concentrate under reduced pressure until no dripping, add 120ml of ethyl acetate and 40ml of water, stir and dissolve, let it stan...

Embodiment 2

[0036] Under the protection of nitrogen, put 10g of compound A and 15g of compound B into a four-necked flask, add 60g of tetrahydrofuran and 60g of n-butyl ether, stir at room temperature for 10 minutes, add 1.5g of trimethylacetic acid, and slowly raise the temperature to reflux , after stirring and reflux reaction at 94°C for 8 hours, the purity of compound C was detected to be 60%, adding 0.35g triethylamine or 0.64g tert-butylamine to continue stirring and reflux reaction for 4 hours, and then continuing to detect the purity of compound C, the purity of compound C was detected to be 80% %, then add 0.35g triethylamine or 0.64g tert-butylamine, and continue the reflux reaction for 4 hours. At this time, the detection purity is greater than 98%, and the reaction is terminated.

[0037] Control the temperature at 60~90℃ and -0.08~-0.096Mpa and concentrate under reduced pressure until no dripping, add 120ml of ethyl acetate and 40ml of water, stir and dissolve, let it stand fo...

Embodiment 3

[0039] Under the protection of nitrogen, put 10g of compound A and 20g of compound B into a four-necked flask, add 100g of tetrahydrofuran and 100g of n-butyl ether, stir at room temperature for 20 minutes, add 2.5g of trimethylacetic acid, and slowly raise the temperature to reflux , after stirring and reflux reaction at 96°C for 4 hours, the purity of compound C was detected to be 55%, adding 0.5g triethylamine or 0.75g tert-butylamine to continue stirring and reflux reaction for 6 hours, and then continuing to detect the purity of compound C, the purity of compound C was detected to be 76% %, then add 0.5g triethylamine or 0.75g tert-butylamine, and continue the reflux reaction for 6 hours. At this time, the detection purity is greater than 98%, and the reaction is terminated.

[0040]Control the temperature at 60~90℃ and -0.08~-0.096Mpa and concentrate under reduced pressure until no dripping, add 120ml of ethyl acetate and 40ml of water, stir and dissolve, let it stand for...

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Abstract

The invention provides a method for preparing atorvastatin calcium intermediate and belongs to the technical field of drug organic synthesis. The method includes the following steps: 1) a compound A and a compound B are mixed according to weight ratio of 1:1.5-2.0; 2) tetrahydrofuran and n-butyl ether are added in the material obtained in the step 1) according to weight ratio of the compound A, the tetrahydrofuran and the n-butyl ether as 1:6-10:6-10 and stirred evenly; 3) trimethylacetic acid occupying 15-25% of the weight of the compound A is added in the material obtained in the step 2), and backflow reaction is performed at the temperature of 94-96 DEG C to obtain a compound C; 4) concentration of the compound C is detected in a reaction process, triethylamine or tert-butylamine is added equivalently in two batches, total addition of the triethylamine is 7-13% of the weight of the compound A, and total addition of the tert-butylamine is 12.8-24% of the weight of the compound A. The method for preparing the atorvastatin calcium intermediate can improve conversion rate of products and reduce pollutant generated in reaction remarkably.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical organic synthesis, and in particular relates to a method for preparing an atorvastatin calcium intermediate. Background technique [0002] Atorvastatin Calcium is a drug originally developed by the pharmaceutical giant Pfizer. This drug is a new type of HMG-CoA reductase inhibitor, which can effectively reduce blood lipids. Favored by people, so the prospect of the drug is extremely broad. [0003] The synthetic route of the key intermediate compound C of atorvastatin calcium in the prior art is as follows: [0004] [0005] Wherein the chemical name of compound A is: (4R, Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-tert-butyl acetate; the chemical name of compound B is: 4 -Fluoro-a-(2-methyl-1-oxypropyl)-γ-oxygen-N,β-diphenyl-benzenebutyramide; Compound C chemical name: (4R-cis)-6-[2 -[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl]-1H-pyrrol-1-yl]ethyl]-2, tert-b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
Inventor 张智岳梅光耀方真荣孟校威武进国
Owner ZHEJIANG HONGYUAN PHARMA
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