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A kind of preparation method of i crystal form atorvastatin calcium

A technology of atorvastatin calcium and atorvastatin, which is applied in organic chemistry methods, organic chemistry and other directions, and can solve the problems of crystal form and purity of atorvastatin calcium.

Active Publication Date: 2020-05-22
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

Method used

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  • A kind of preparation method of i crystal form atorvastatin calcium
  • A kind of preparation method of i crystal form atorvastatin calcium
  • A kind of preparation method of i crystal form atorvastatin calcium

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preparation example Construction

[0035] The present 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 main peak content should not be less than 98%, the single impurities should not be higher than 0.3%, and the total impurities should not be higher than 1.0%. Under acidic conditions, the isopropyl group protection should be removed. 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 of...

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 purified water, 16.4g hydrochloric acid), slowly increase the temperature to 30°C, react for 5 hours, TLC panel monitoring, raw material point The disappearance is the end 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 by TLC dot panel, and the atorvastatin ester point disappears. end.

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

[0066] Add the crude atorvastatin calcium dry product to the ...

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 purified water, 16.4g hydrochloric acid), slowly increase the temperature to 30°C, react for 5 hours, TLC panel monitoring, raw material point The disappearance is the end 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 by TLC dot panel, and the atorvastatin ester point disappears. end.

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

[0080] Add the crude atorvastatin calcium dry product to the ...

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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 simultaneously lower total cholesterol and triglycerides. It belongs to 3-hydroxy-3-methyl-pentane Acyl-CoA (HMG-CoA) reductase inhibitor. By inhibiting the synthesis of HMG-CoA reductase and cholesterol in the liver to reduce the level of cholesterol and lipoprotein in the plasma, and by increasing the liver LDL receptors indicated by cells to enhance the uptake and metabolism of LDL. Because atorvastatin calcium is suitable for simultaneous treatment of increased total cholesterol and triglycerides, the American Heart Association and the Stroke Association recommended in the "Guidelines for Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack" in 2008 The use of statins to...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/34
CPCC07B2200/13C07D207/34
Inventor 刘才义
Owner HUNAN DINUO PHARMA
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