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Method for preparing amorphous atorvastatin calcium

An atorvastatin calcium and amorphous technology is applied in the field of chemistry, which can solve the problems of long time for releasing tert-butyl group, difficult separation of the final product, low product purity, etc., and achieves shortened preparation period, good product quality and synthetic yield. high effect

Active Publication Date: 2012-02-08
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage of this reaction is that there is no purification step in the reaction mixture, and the product is precipitated directly during hydrolysis, and the purity of the product is not high. Difficult to separate from the final product when filtered
The inventors of the present invention found that when studying the synthesis method: the first step condensation reaction, the reaction yield is low, and it is difficult to crystallize; Requires more complex work-up to achieve desired purity

Method used

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  • Method for preparing amorphous atorvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Compound III (4R-CIS)-6-[2-2[-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-(anilinecarbonyl) - Preparation of tert-butyl 1H-pyrrol-1-ylbutylethyl]-2,2-dimethyl-1,3-dioxolane-4-acetate.

[0018] Put 72.0g of compound I and 50g of compound II into a flask, add 250ml of n-heptane, 90ml of tetrahydrofuran, and 4.2g of pivalic acid, heat up and reflux at 80-100°C to separate water for about 28h, after the reaction is complete, recover the solvent to dryness under reduced pressure, add 200ml of methanol was heated to reflux to dissolve, cooled to 0-5°C, crystallized for 1.0h, centrifuged and dried to obtain 78.0g of compound III. HPLC≥99%, molar yield 0.92.

Embodiment 2

[0019] Example 2: Preparation of amorphous atorvastatin calcium.

[0020] Add 20.0g of compound III to the reaction bottle, use 100ml of methanol and 20ml of THF as solvents, heat up to 30°C to dissolve, add 17.0g of 1.5N hydrochloric acid, keep it at 25-30°C for 2.0-3.0h, HPLC traces the completion of the reaction of the material, and cools down to At about 10°C, add 15.0g of 15% NaOH, keep it at 20-25°C for 2.0-3.0h, and track it by HPLC until the reaction is complete. Add 80ml of n-hexane and 120ml of water, stir for 10min, separate the phases, extract the water phase with 80ml of n-hexane again, add 9.0g of calcium acetate and 20ml of purified water to the water phase, stir for 1.0h, then add 100ml of ethyl acetate Extract, concentrate the organic phase to dryness under reduced pressure, add 100ml of acetone and stir to dissolve, distill under reduced pressure at an internal temperature ≦50°C, concentrate to 40ml, pour into a watch glass, and dry under reduced pressure at ...

Embodiment 3

[0021] Example 3: Preparation of amorphous atorvastatin calcium.

[0022] The ethyl acetate in the step of embodiment 2 is replaced with propyl acetate, and others are the same as embodiment 2.

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Abstract

The invention provides a method for preparing amorphous atorvastatin calcium. The amorphous atorvastatin calcium is prepared by undergoing a four-step reaction. The method comprises the following steps of: continually performing acidolysis deprotection and an alkali hydrolysis reaction in the same boiler under the condition that methanol and tetrahydrofuran are taken as solvents; particularly extracting a generated calcium salt with propyl acetate or butyl acetate or ethyl acetate; adding acetone for dissolving; concentrating a part; and directly drying under reduced pressure to obtain amorphous atorvastatin calcium, wherein the total yield is more than or equal to 75 percent. Due to the adoption of the method, the reaction period is greatly shortened, the preparing period can be shortened by more than 30 hours, the production cost is lowered, environmental pollution is reduced, the product quality is improved, the process operating steps are simplified, industrial production is easy, operation is convenient, the synthesis yield is high, the raw material cost is low, the product quality is good, and the obtained atorvastatin calcium is amorphous.

Description

technical field [0001] The invention relates to a preparation method of amorphous atorvastatin calcium, which belongs to the technical field of chemistry. Background technique [0002] Atorvastatin is [R-(R,R)]-2-(4-fluorophenyl)-β,γ-dihydroxy-5-(1-methylethyl-3-phenyl)-4- [(anilino)carbonyl]-1H-pyrrole-1-heptanoic acid, the marketed product is its hemicalcium salt trihydrate, i.e. atorvastatin calcium, which is a fully synthetic, highly purified, highly selective inhibitor of HMG-COA reduction Ester drugs, developed by Warner-Lambert (now incorporated into Pfizer) in the United States, were first launched in the United Kingdom and the United States in 1997. They are the third-generation statin drugs, mainly used for the treatment of high cholesterol, hyperlipidemia and mixed hyperlipidemia Hyperemia, also used for the prevention and treatment of coronary heart disease and stroke. [0003] When synthesizing atorvastatin calcium with U.S. Patent No. 5,510,448 and 5,470,981,...

Claims

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Application Information

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IPC IPC(8): C07D207/34
Inventor 刘雨林陈祥强周强陶义唐松青
Owner JIANGXI FUSHINE PHARMA CO LTD
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