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Preparation method of crystal form I atorvastatin calcium

A technology of atorvastatin calcium and atorvastatin, which is applied in the fields of organic chemistry and organic chemistry, and can solve problems such as the crystal form and purity of atorvastatin calcium

Active Publication Date: 2020-02-11
HUNAN DINUO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The invention provides a preparation method of I crystal form atorvastatin calcium, which aims to solve the crystal form and purity problems of atorvastatin calcium, reduce cost input, and prepare a high-purity I crystal form atorvastatin Statin calcium, the reaction process is safe and environmentally friendly

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  • Preparation method of crystal form I atorvastatin calcium
  • Preparation method of crystal form I atorvastatin calcium

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preparation example Construction

[0035] The invention provides a preparation method of I crystal form atorvastatin calcium, which comprises the following steps:

[0036] S1. Preparation of atorvastatin ester

[0037]Atorvastatin intermediate L1, (4R,6R)-2-[6-[2-[2-(4-fluorophenyl)-5-isopropyl ester-3-phenyl-4-(phenylamine Formyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]tert-butyl acetate (hereinafter referred to as "intermediate L1"), purity testing The content of the main peak shall not be less than 98%, the single impurity shall not be higher than 0.3%, and the total impurity shall not be higher than 1.0%. The protection of the isopropyl group is removed under acidic conditions. The reaction process is as follows:

[0038]

[0039] In some specific embodiments of the present invention, the atorvastatin intermediate L1 is dissolved in alcohol, and the alcohol is selected from one or more of methanol, ethanol, n-propanol, or isopropanol, preferably methanol.

[0040] In some specific embodiments o...

Embodiment 1

[0063] Put 120g of intermediate L1 and 600ml of methanol into a 2000ml reaction kettle, then add the prepared hydrochloric acid solution (142g of purified water, 16.4g of hydrochloric acid), slowly raise the temperature to 30°C, react for 5 hours, TLC spot plate monitoring, raw material point Disappearance is the end point of the reaction.

[0064] After the reaction in the previous step is complete, add 10% NaOH solution (sodium hydroxide 14.2g, water 127.8g) to the reaction solution, react at 30°C for 5 hours, monitor with TLC, and the disappearance of the atorvastatin ester point is the reaction end.

[0065] After the reaction in the previous step is complete, directly add calcium acetate aqueous solution (17.8 g of calcium acetate; 240 g of water), stir and react at 20° C. for 2 hours, and centrifuge to obtain the crude atorvastatin calcium wet product. Dry in a hot air circulation oven at 50°C to obtain the crude atorvastatin calcium dry product.

[0066] Add the crude...

Embodiment 2

[0077] Put 120g of intermediate L1 and 600ml of methanol into a 2000ml reaction kettle, then add the prepared hydrochloric acid solution (142g of purified water, 16.4g of hydrochloric acid), slowly raise the temperature to 30°C, react for 5 hours, TLC spot plate monitoring, raw material point Disappearance is the end point of the reaction.

[0078] After the reaction in the previous step is complete, add 10% NaOH solution (sodium hydroxide 14.2g, water 127.8g) to the reaction solution, react at 30°C for 5 hours, monitor with TLC, and the disappearance of the atorvastatin ester point is the reaction end.

[0079] After the reaction in the previous step is complete, directly add calcium acetate aqueous solution (17.8 g of calcium acetate; 240 g of water), stir and react at 20° C. for 2 hours, and centrifuge to obtain the crude atorvastatin calcium wet product. Dry in a hot air circulation oven at 50°C to obtain the crude atorvastatin calcium dry product.

[0080] Add the crude...

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Abstract

The invention discloses a preparation method of crystal form I atorvastatin calcium. The method includes the steps of: preparation of atorvastatin ester; preparation of an atorvastatin salt; preparation of atorvastatin calcium; refining an atorvastatin calcium crude product; and crystal transformation of the atorvastatin calcium refined product. The method provided by the invention adopts one-potprocess to simplify the synthesis process of the crystal form I atorvastatin calcium, optimizes the reaction conditions, adopts cheap, easily available and environment-friendly materials, directly reduces the industrial cost, and realizes safe and environment-friendly production.

Description

technical field [0001] The invention discloses a production method of I crystal form atorvastatin calcium, which belongs to the technical field of medicine. Background technique [0002] Atorvastatin calcium is a powerful lipid-lowering drug launched by Pfizer in 1997. It is a drug that can lower total cholesterol and triglycerides at the same time. It belongs to 3-hydroxy-3-methyl-pentanedi Acyl-CoA (HMG-CoA) reductase inhibitors. By inhibiting the synthesis of HMG-CoA reductase and cholesterol in the liver, it can reduce the level of cholesterol and lipoprotein in plasma, and by increasing the hepatic LDL receptor expressed by cells to enhance the uptake and metabolism of LDL. Since atorvastatin calcium is suitable for the simultaneous treatment of the increase of total cholesterol and triglycerides, in 2008, the American Heart Association and the Stroke Society recommended in the "Guidelines for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack" ...

Claims

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Application Information

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IPC IPC(8): C07D207/34
CPCC07B2200/13C07D207/34
Inventor 刘才义
Owner HUNAN DINUO PHARMA
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