Process for producing important synthesis midbody of high purity atorvastatin

Abstract

The invention relates to a method for preparing high-purity (4R, 6R)-6-{2-[5-isopropyl-3-phenyl-2(4-fluorophenyl)-4-(phenylcarbamoyl)-yrrol-1-yl]- ethyl}-2, 2-dimethyl-[1, 3]-dioxane-4-yl-tert-butyl acetate, which comprises the following steps: step one, [5-methyl-4-isopropyl-2-phenyl-1(4-fluorophenyl)-3-(phenylcarbamoy1)-1,4-hexanedione](II) and [(4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxane-4-yl-tert-butyl acetate](III) with a mol ratio of between 0.71 and 1.12 to 1 are weighed, an acid catalyst which is 1.05 to 1.15 times of mol number of the formula (II) is weighed, the mixture is dissolved in a non-hydroxy solvent which is 3.0 to 4.2 times of the weight of the formula (II) under the protection of nitrogen and the stirring, and heating reflux and azeotropic water entrainment are performed until an HPLC shows that the reaction is finished; and second two, the solvent is removed under vacuum, then a water-isopropanol mixed solvent with a volume ratio of 2 to 5 is used to recrystallize the mixture, and a key intermediate of synthetic atorvastatin calcium which has an HPLC purity not less than 99.0 percent and is expressed by the formula (I) is obtained after the pump filtration and drying. The method has the advantages of simple process, low equipment requirement, low cost, convenient and quick recovery of the solvent, less environmental pollution, and high product purity.

Description

technical field [0001] The present invention relates to a method for preparing high-purity (4R, 6R)-6-{2-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(phenylcarbamoyl) -pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]-dioxan-4-yl-tert-butyl acetate, the compound is the preparation of atorvastatin calcium key intermediates. The invention belongs to the technical field of pharmaceutical synthesis technology. Background technique [0002] (4R,6R)-6-{2-[5-isopropyl-3-phenyl-2-(4-fluorophenyl)-4-(phenylcarbamoyl)- Pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]-dioxan-4-yl-tert-butyl acetate, is synthetic atorvastatin calcium (Lipitor, Atorvatatin) key intermediates. The chemical name of atorvastatin calcium is (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl 4-(phenylcarbamoyl)pyrrole-1- Base]-3,5-dihydroxyheptanoic acid calcium salt trihydrate is a statin blood lipid regulating drug developed by Burke-Davis Company (Warner-Lambert Branch) and jointly sold with Pfizer. Atorvastatin calcium b...

AI Technical Summary

Problems solved by technology

In EP1,659,110, the 7-step synthetic route of atorvastatin calcium disclosed in A1 includes the preparation process of the key intermediate represented by formula (I), and the preparation process of this key intermediate uses n-heptane, tetrahydrofuran, toluene As a reaction solvent, expensive pivalic acid is used as a catalyst, heated to reflux, and the post-treatment includes cumbersome processes such as alkali washing-acid washing-salt washing-activated carbon treatment, complicated operations, serious losses, and more process waste. The yield of the method is low, and the HPLC purity of ≥99% is obtained only after 2 recrystallizations, and the recovery of the solvent is difficult

IE2006 / 0197 discloses the process of catalytically synthesizing key intermediates represented by the formula (I) with organic acid salts. The conditions are mild, but it has the disadvantages of relatively long reaction time, expensive catalysts and difficult removal.

The post-treatment steps of the preparation method disclosed in US5,298,627 are relatively cumbersome and use environmentally unfriendly toluene

All in all, the main problem that existing technology exists is: the key intermediate that the formula (I) that prepares atorvastatin calcium is used has reaction velocity too slow, conversion rate is low, and energy consumption is big; And need drop into excessive expensive formula [(4R,6R)-2,2-dimethyl-6-(2-aminoethyl)-[1,3]-dioxan-4-yl-tert-butyl acetate] raw material represented by (III) , thereby greatly increasing the cost, the residue of excessive raw material (III) affects the purification of the intermediate represented by formula (I), resulting in the preparation of the key intermediate represented by high-purity formula (I) requiring very cumbersome post-treatment procedures

[0007]Due to the high production cost of the existing process route, the large-scale preparation of atorvastatin calcium still faces difficulties, and it is difficult to become a popular drug

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