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Preparation method of atorvastatin calcium intermediate

A technology of atorvastatin calcium and body type, which is applied in the field of preparation of atorvastatin calcium intermediates, can solve the problems of slow reaction rate and long reaction time, and achieves the effects of complete reaction, accelerated reaction progress and reduced production cost.

Active Publication Date: 2011-07-20
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above methods have been verified that the reaction time is relatively long, and it takes 22-24 hours to complete the reaction, and the reaction rate is relatively slow.

Method used

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  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 160ml of n-heptane, 19.28g of M4, 19.1g of ATS-9, 2.4g of pivalic acid and 40ml of toluene into the three-necked reaction flask. Stir and heat to reflux (external temperature 110-120°C), and use a water separator to separate the water.

[0032] The progress of the reaction was monitored by TLC method, the developer was ethyl acetate:petroleum ether:triethylamine=1:4:0.2, the spot of the raw material M4 was on the bottom, and the spot on the product was on the top. When the reaction was about 50%, that is, when the product spot and the raw material spot were almost equal in size, 2.47g of pivalic acid was added. When the reaction was about 80% (monitored by TLC method, as above), 80 ml of the reaction solvent was evaporated with a water separator, and 80 ml of a new mixed solvent (toluene:n-heptane=1:4) was added again, and the reaction was complete within 14 hours. The reaction solution was red.

[0033] The end point of the reaction was monitored by TLC. The deve...

Embodiment 2

[0037] Operate in the same way as in Example 1, only change the n-heptane 160ml used in the first step reaction into n-heptane 200ml, the composition of the new mixed solvent added again is toluene: n-heptane=1: 5, and the reflux temperature is 115-120°C, other conditions remain unchanged, and the reaction time is 13h.

[0038] 28.8 g of off-white powdery solid was obtained, melting point: 132.5-134.0° C., purity by gas chromatography normalization detection was 96.8%, and yield was about 92.0%. Nuclear magnetic spectrum data are with embodiment 1.

Embodiment 3

[0040] Operate in the same way as in Example 1, only change the n-heptane 160ml used in the first step reaction into n-heptane 120ml, the composition of the new mixed solvent added again is toluene: n-heptane=1: 3, and the reflux temperature is 115-120°C, other conditions remain unchanged, and the reaction time is 13h.

[0041] 26.5 g of off-white powdery solid was obtained, melting point: 132.5-134.0° C., purity by gas chromatography normalization detection was 96.8%, and yield was about 84.8%. Nuclear magnetic spectrum data are with embodiment 1.

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Abstract

The invention relates to a preparation method of a compound shown as a formula (I) of an atorvastatin calcium intermediate. The structure of the compound is shown in the specifications. In the preparation method of the compound shown as the formula (I), a water-insoluble mixed solvent with an appropriate boiling point and a constant-temperature reflux water diversion mode are adopted, so that the reaction time is greatly shortened, and the yield is high.

Description

technical field [0001] The invention relates to a preparation method of an atorvastatin calcium intermediate, in particular to (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)- 3-Phenyl-4-[(aniline)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester Preparation. Background technique [0002] Atorvastatin calcium is a fully synthetic, highly selective drug that inhibits HMG-CoA reductase. Developed by Pfizer, it is the third generation of statins. It is mainly used for the treatment of hypercholesterolemia, hyperlipidemia and the prevention and treatment of coronary heart disease and cerebral apoplexy. [0003] The structure of the intermediate formula (I) compound of atorvastatin calcium is as follows, [0004] [0005] Related documents report its preparation method: US Patent No. 5,003,080; 5,097,045; 5,103,024; 5,273,995; 5,124,482; Wherein the synthesis of intermediate formula (I) compound can be summarized as follows: M4 an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
Inventor 韦亚锋陈文婕张亚李立标赵辉戴荣欢
Owner BENGBU BBCA MEDICINE SCI DEV
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