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Preparation method of cis-rosuvastatin calcium impurity

A technology of rosuvastatin calcium and cis, which is applied in the field of drug synthesis, can solve the problems such as difficulty in obtaining cis products, and achieve the effects of convenient post-processing, high product purity and high yield

Active Publication Date: 2015-11-04
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method reported in this literature requires the use of column chromatography, and the cis product is very difficult to obtain (about 5%, separated by column chromatography)

Method used

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  • Preparation method of cis-rosuvastatin calcium impurity
  • Preparation method of cis-rosuvastatin calcium impurity
  • Preparation method of cis-rosuvastatin calcium impurity

Examples

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Embodiment 1

[0033] The compound of the present invention bis-[Z-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R, The preparation method of 5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1) adopts the following steps:

[0034] (1) Compound (IV) 6-[(1Z)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine] Vinyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and compound (V) 6-[(1E)-2-[4-(4-fluorophenyl) )-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert Preparation of butyl ester:

[0035] Add DMSO 250ml and 19g D7((4R-cis)-6-carbaldehyde-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate) into a 1000mL four-necked flask, add Z8.2([4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonamido)-5-pyrimidinyl]triphenylphosphonium bromide) 45g , Add 20.8g of potassium carbonate, increase the temperature, keep at 75°C for 2h, after the Z8.2 reaction is complete, lower the ...

Embodiment 2

[0041] The compound of the present invention bis-[Z-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R, The preparation method of 5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (2:1) adopts the following steps:

[0042] (1) Compound (IV) 6-[(1Z)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine] Vinyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and compound (V) 6-[(1E)-2-[4-(4-fluorophenyl) )-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid tert Preparation of butyl ester:

[0043] Add 250ml of DMF and 20g of D7 to a 1000mL four-necked flask, add Z8.245g, add 20.8g potassium carbonate, increase the temperature, keep it at 80°C for 2h, after the Z8.2 reaction is complete, reduce the temperature to 20°C, add 200ml of toluene, stir and filter. Add 200 ml of water to the organic layer and stir for 10 min. Separate the liquids, extract the aqueous layer with 100m...

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Abstract

The invention discloses a preparation method of a cis-rosuvastatin calcium impurity. According to the preparation method, (4R-cis)-6-carbaldehyde-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinyl]triphenylphosphonium bromide are used as the raw materials for preparing a target compound by virtue of Witting reaction, isomer separation, deprotection, hydrolysis and salt forming reaction. The method has the characteristics of originality, simplicity in operation, convenience in after-treatment, high product purity and yield and the like. The preparation method has the beneficial effect that certain help is provided for the registration, the declaration, the production and the center control of cis-rosuvastatin calcium as well as the quality improvement of cis-rosuvastatin calcium.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a cis-rosuvastatin calcium impurity bis-[Z-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (Methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt (2:1). Background technique [0002] Rosuvastatin calcium, chemical name: Bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2(N-methyl-N-methanesulfonamido)pyrimidine-5 -Yl]-(3R,5S)-3,5-dihydroxyhept-6-(E)-enoic acid] calcium salt (2:1), the structure is as follows: [0003] [0004] Rosuvastatin calcium is a cardiovascular drug, developed by AstraZeneca and first approved for marketing in the Netherlands in November 2002. It was approved by the U.S. FDA in August 2003 and has been listed in more than 60 countries. Clinical trials have been completed in my country under the trade name Crestor. The drug has strong HMG-COA reductase inhibitory activity, and its effect of lowering LDL-C and raising HDL-C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 龚杰谢永居刘霞张桂菊徐军辉周忠波余翔涂俊
Owner JIANGXI FUSHINE PHARMA CO LTD
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