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Method for preparing atorvastatin calcium

A technology of atorvastatin calcium and calcium salt, which is applied in the direction of organic chemistry, etc., can solve the problems of low product purity, difficult separation, turbidity, etc., and achieves the effects of easy reaction process, simple reaction steps and stable quality.

Active Publication Date: 2009-07-29
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are certain disadvantages in this approach. The preparation of atorvastatin calcium from lactone is equivalent to increasing the reaction steps and increasing the production cost.
[0010] In addition, in Chinese patent CN1561341, calcium hydroxide is used to directly hydrolyze atorvastatin ester to obtain calcium salt. The disadvantage of this reaction is that there is no purification step in the reaction mixture, and product precipitation is directly obtained during hydrolysis, and the purity of the product is not high. Calcium aqueous solution is very easy to react with carbon dioxide in the air to form calcium carbonate and become turbid, and the resulting calcium carbonate will be difficult to separate from the final product when filtered

Method used

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  • Method for preparing atorvastatin calcium
  • Method for preparing atorvastatin calcium
  • Method for preparing atorvastatin calcium

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Embodiment 1: Preparation of atorvastatin calcium

[0025] Add (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl] to the reaction flask -1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate 4g, methanol 30ml, stir to dissolve the solid, add hydrochloric acid 2.4ml , stirred and reacted for 70 minutes; added 0.25g of sodium hydroxide, and reacted for 50 minutes; then added 20ml of methyl tert-butyl ether and 80ml of water, stirred for 10 minutes, separated the phases, and extracted the water phase once with 15ml of methyl tert-butyl ether , the aqueous solution is atorvastatin sodium salt aqueous solution; 12ml aqueous solution of 1.6g of calcium acetate was added to the aqueous solution, reacted for 4 hours, filtered, the filter cake was washed with water, and the obtained solid was vacuum-dried to obtain 3.0g of the final product. Yield 81.3%, HPLC purity 99.1%, [M-Ca+2H] + : 559.6.

Embodiment 2

[0026] Embodiment 2: Preparation of atorvastatin calcium

[0027] Add (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl] to the reaction flask -1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate 4g, methanol 25ml, stir to dissolve the solid, add hydrochloric acid 1.5ml , stirred and reacted for 40 minutes; added 0.5 g of sodium hydroxide, and reacted for 10 minutes; added 20 ml of methyl tert-butyl ether and 60 ml of water, stirred for 10 minutes, separated the phases, and extracted the water phase once with 15 ml of methyl tert-butyl ether, The aqueous solution was the aqueous solution of atorvastatin sodium salt; 1.6 g of calcium acetate in 12 ml of aqueous solution was added to the aqueous solution, reacted for 4 hours, filtered, the filter cake was washed with water, and the obtained solid was vacuum-dried to obtain 3.0 g of the final product. Yield 81.3%, HPLC purity 98.9%, [M-Ca+2H] + : 559.6.

Embodiment 3

[0028] Embodiment 3: Preparation of atorvastatin calcium

[0029] Add (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl] to the reaction flask -1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate 4g, ethanol 30ml, stir to dissolve the solid, add hydrochloric acid 2.4ml , stirred and reacted for 20 minutes; added potassium hydroxide 1.7g, reacted for 5 minutes; added 20ml methyl tert-butyl ether and 210ml water, stirred for 10 minutes, separated the phases, and extracted the water phase once with 15ml methyl tert-butyl ether, The aqueous solution was atorvastatin sodium salt aqueous solution; 1.6 g of calcium acetate in 12 ml aqueous solution was added to the aqueous solution, reacted for 4 hours, filtered, the filter cake was washed with water, and the obtained solid was vacuum-dried to obtain 2.8 g of the final product. Yield 75.9%, HPLC purity 99.1%, [M-Ca+2H] + : 559.6.

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Abstract

The invention relates to a method for preparing Atorvastatin calcium. In the method, (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl]-1H-pyrrole-1-group] ethyl]-2, 2-dimethyl-1, 3-dioxolane-4-tert-butyl acetate is used as an initial raw material for preparing the Atorvastatin calcium by a one-pot method.

Description

technical field [0001] The invention relates to a preparation method of atorvastatin calcium. Background technique [0002] Atorvastatin is [R-(R,R)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[ (Phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, listed product is its hemicalcium salt trihydrate, is listed and sold by U.S. Warner Company (Warner-Lambert), trade name is LIPITOR, and the structural formula is as follows: [0003] [0004] Atorvastatin is a member of a class of drugs known as statins, which are currently the most effective drugs available to reduce the concentration of low-density lipoprotein (LDL) particles in the bloodstream of patients at risk of cardiovascular disease. High levels of LDL in the bloodstream are associated with coronary injury, they impede blood flow, may rupture and promote thrombus formation; Goodman Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Lowering plasma LDL levels has been shown to re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34
Inventor 郑利刚马玉秀吴立红张明陈玉洁杨汉煜
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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