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Process for producing important synthesis midbody of high purity atorvastatin

A high-purity, isopropyl technology is applied in the field of key intermediates for preparing atorvastatin calcium, and achieves the effects of convenient solvent recovery and utilization, reduced water content and low price

Active Publication Date: 2010-12-15
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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  • Process for producing important synthesis midbody of high purity atorvastatin
  • Process for producing important synthesis midbody of high purity atorvastatin
  • Process for producing important synthesis midbody of high purity atorvastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Under nitrogen protection, the raw material represented by formula (II) (12.51 g, 0.03 mol), the raw material represented by formula (III) (10.65 g, 0.039 mol) and n-butyric acid (3.02 g, 0.03425 mol) were dissolved under uniform stirring in n-pentane (27.5ml) and isopropyl ether (32.5ml). Heating at 80°C to reflux, constant boiling with water. Until HPLC showed the reaction was complete. The solvent was removed in vacuo, recrystallized with a mixed solvent of water (100 ml)-isopropanol (250 ml); suction filtration, and vacuum drying at 30° C.; 14.8 g of the key intermediate represented by formula (I) was obtained, with HPLC purity ≥99.0%.

Embodiment 2

[0036] Under nitrogen protection, formula (II) (12.51 g, 0.03 mol), formula (III) (9.83 g, 0.036 mol) and polyphosphoric acid (3.26 g) were dissolved in n-pentane (27.5 ml) and Methyl tert-butyl ether (32.5 ml). Heating at 70 ℃ reflux, constant boiling with water. Until HPLC showed the reaction was complete. The solvent was removed in vacuo, recrystallized with a mixed solvent of water (100 ml)-isopropanol (250 ml); suction filtered, and dried under vacuum at 30° C. to obtain 14.4 g of the key intermediate represented by formula (I), with HPLC purity ≥99.0%.

Embodiment 3

[0038] Under nitrogen protection, formula (II) (12.51 g, 0.03 mol), formula (III) (10.65 g, 0.039 mol) and acetic acid (2.05 g, 0.03425 mol) were dissolved in n-hexane (27.5 ml) and 2 under uniform stirring. - methyltetrahydrofuran (32.5ml). Heating at 90 ° C reflux, constant boiling with water. Until HPLC showed the reaction was complete. The solvent was removed in vacuo, and recrystallized with a mixed solvent of water (100 ml)-isopropanol (250 ml); suction filtration, and vacuum drying at 30° C.; 14.6 g of the key intermediate represented by formula (I) was obtained, with HPLC purity ≥99.0%.

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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 areperformed 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
Inventor 胡文浩周俊季竟竟杨琍苹
Owner 安徽美诺华药物化学有限公司