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Method for preparing rosuvastatin salts

一种罗苏伐他汀、汀铵盐的技术，应用在制备所述中间体领域，能够解决没有公开等问题

Inactive Publication Date: 2013-08-28
EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENYTARSASAG (EGIS PHARMA PLC)
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0041] There is no disclosure in the prior art about being suitable for directly converting the rosuvastatin amide of the general formula (III) into the rosuvastatin ammonium salt of the general formula (II), the rosuvastatin calcium salt of the formula (IV) respectively. Or the method of the rosuvastatin zinc salt of formula (V)

Method used

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  • Method for preparing rosuvastatin salts

Examples

Experimental program
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Effect test

Embodiment 1

[0082] Preparation of rosuvastatin tert-butylammonium salt starting from rosuvastatin n-butylamide

[0083] Method "A" : to 800cm 3 Add 16.1g (0.03mol) of rosuvastatin n-butylamide in the autoclave, 644cm 3 of water and 43.9g (63.3cm 3 ; 0.60 mol) of tert-butylamine. The reaction mixture was stirred at 120°C for 24 hours. The mixture was cooled to room temperature, diluted with 2-propanol, and evaporated in vacuo. The residue was stirred in a mixture of tert-butylmethyl ether and heptane (2:5, v / v), and the crystals were filtered. In this way, 16.2 g (99%) of rosuvastatin TBA salt were obtained. The crude salt was boiled in acetonitrile / 2-propanol (8.6:1, v / v) mixture followed by further stirring at room temperature, filtered, washed and dried. The product thus obtained was boiled in acetonitrile, 2-propanol was added to the boiled mixture, decolorized with carbon and filtered. Precipitated crystals were filtered, and washed with acetonitrile. 10.9 g (66%) of rosuvast...

Embodiment 2

[0103] Preparation of rosuvastatin tert-butylammonium salt starting from rosuvastatin N,N-dimethylamide

[0104] Method "A": to have 50cm 3 0.89g (1.75mmol) of rosuvastatin N, N-dimethylamide, 35.6cm 3 of water and 2.56g (3.7cm 3 ; 3.5 mmol) of tert-butylamine. The reaction mixture was stirred at 120°C for 16 hours. The mixture was cooled to room temperature, the reaction mixture was diluted in portions with ethanol, and evaporated in vacuo. The evaporation residue was dissolved in tert-butyl methyl ether and heptane (2:5 v / v, 4 cm 3 ), and the crystals were filtered. In this way, 0.87 g (90%) of rosuvastatin TBA were obtained. The crude salt was recrystallized from acetonitrile / 2-propanol. This gave 0.58 g (60%) of rosuvastatin TBA salt with a purity (HPLC) greater than 99.5%.

[0105] Method "B": To have 50cm 3 0.89g (1.75mmol) of rosuvastatin N, N-dimethylamide, 35.6cm 3 Water-ethanol 9:1 (v / v) solvent mixture and 2.56g (3.7cm 3 ; 3.5 mmol) of tert-butylamine. T...

Embodiment 3

[0107] Preparation of rosuvastatin tert-butylammonium salt starting from rosuvastatin pyrrolidinylamide

[0108] To have 50cm 3 Fill the rosuvastatin pyrrolidinyl amide of 0.88g (1.65mmol) in the autoclave of volume, 35.2cm 3 of water and 2.41g (3.5cm 3 ; 3.3 mmol) of tert-butylamine. The mixture was stirred at 120° C. for 16 hours, cooled to room temperature, diluted portionwise with ethanol, and evaporated in vacuo. The residue was stirred in a mixture of ether-hexane (1:1, v / v), and the crystals were filtered. The product thus obtained was recrystallized from acetonitrile / 2-propanol (2:1, v / v). Rosuvastatin TBA was obtained in a yield of 0.55 g (60%) with a purity (as assessed by HPLC) of greater than 99.5%.

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Abstract

The present invention is related to methods for the preparation of pharmaceutically acceptable salts of (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R, 5S, 6E)-dihydroxy-hept-6-enoic acid, intermediates thereof and methods for producing said intermediates.

Description

technical field [0001] The present invention relates to preparation (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl-methyl-amino)-pyrimidin-5-yl]-( Process for pharmaceutically acceptable salts of 3R,5S,6E)-dihydroxy-hept-6-enoic acid, intermediates thereof and processes for the preparation of said intermediates. [0002] (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R ,5S,6E)-dihydroxy-hept-6-enoic acid [0003] [0004] is a pharmaceutically acceptable active ingredient known by the International Nonproprietary Drug Name of Rosuvastatin. Rosuvastatin exerts its pharmacological activity by inhibiting the enzyme 2-hydroxy-2-methyl-glutaryl-CoA reductase in the liver, thereby reducing the rate of cholesterol biosynthesis and cholesterol levels in plasma. Rosuvastatin of formula (I) is used in the treatment of lipid metabolism diseases such as hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Background tech...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCA61P3/06A61P9/10C07D239/42
Inventor M·鲍克斯-玛凯F·L·鲍尔陶G·克劳斯瑙伊B·沃尔克G·鲁日奇L·蓬戈G·卢卡奇T·绍博J·鲍尔科齐J·德布赖采尼A·凯斯特海伊A·潘杜尔E·莫尔纳M·米伦M·托内劳里茨
Owner EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENYTARSASAG (EGIS PHARMA PLC)
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