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Method for preparing intermediate of synthesizing rosuvastatin calcium

A technology of rosuvastatin calcium and intermediates, which is applied in the field of intermediate preparation, can solve the problems of long reaction time, high temperature, increased process cost and the like, and achieves the effects of mild reaction conditions, short time and improved yield

Active Publication Date: 2007-05-09
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] 3. The reaction time of aldehyde and chiral ylide condensation is long, the temperature is high (reaction at 80°C for 14 hours), and the reaction is incomplete as detected by TLC, column chromatography purification is required
[0008] Therefore, the above three points have greatly increased the process cost of the technology disclosed in U.S. Patent No. 5,260,440, which cannot meet the requirements of industrial production.

Method used

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  • Method for preparing intermediate of synthesizing rosuvastatin calcium
  • Method for preparing intermediate of synthesizing rosuvastatin calcium
  • Method for preparing intermediate of synthesizing rosuvastatin calcium

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol (III)

[0051] Potassium borohydride (2.8g, 53.8mmol) was added to 1,4-dioxane (50ml), then dried anhydrous zinc chloride (3.6g, 26.5mmol), and stirred at 10°C for 2 hours. A solution of the starting ester (II) (5.0 g, 12.7 mmol) dissolved in 1,4-dioxane (30 ml) was added dropwise. Heat to 90°C for 2 hours, filter, concentrate the filtrate and dilute with ethyl acetate (50ml), adjust the pH value to 3 with 1N hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate (20ml×2), combine the organic layer, washed with 10% sodium bicarbonate solution until neutral, washed with water, and concentrated to obtain 4.1 g of off-white solid III, with a yield of 91.8%.

Embodiment 2

[0053] Preparation of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol (III)

[0054] Lithium borohydride (1.2g, 54.5mmol) was added to 1,4-dioxane (50ml), and anhydrous aluminum chloride (3.5g, 26.2mmol) was added, and stirred at 35°C for 1.5 hours. A solution of the starting ester (II) (5.0 g, 12.7 mmol) dissolved in 1,4-dioxane (30 ml) was added dropwise. Heat to 80°C to react for 2 hours, filter, concentrate the filtrate and dilute with ethyl acetate, adjust the pH value to 3 with dilute hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate, combine the organic layers, and wash with 10% sodium bicarbonate solution Wash until neutral, wash with water, and concentrate to obtain 3.7 g of off-white solid III, with a yield of 82.8%.

Embodiment 3

[0056] Preparation of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol (III)

[0057] Potassium borohydride (2.8g, 53.8mmol) was added to diethylene glycol diethyl ether (50ml), then dried anhydrous zinc chloride (3.6g, 26.5mmol), and stirred at 25°C for 3 hours. A solution of starting ester (II) (5.0 g, 12.7 mmol) dissolved in diethyl ether (30 ml) was added dropwise. Heat to 150°C to react for 1 hour, filter, concentrate the filtrate and dilute with ethyl acetate, adjust the pH value to 3 with dilute hydrochloric acid, separate the layers, extract the aqueous layer with ethyl acetate, combine the organic layers, and wash with 10% sodium bicarbonate solution Wash until neutral, wash with water, concentrate and purify by column chromatography to obtain 2.4 g of a white solid III with a yield of 53.7%.

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Abstract

This invention discloses a method for preparing methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate as the intermediate for synthesizing rosuvastatin calcium. The method comprises: reducing pyrimidine carbonate (II) by borohydride / chloride to obtain pyrimidine methanol (III), oxidizing by potassium dichromate to obtain pyrimidine formaldehyde, and condensing in the presence of chiral phosphonate to obtain methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate (VI). The method has such advantages as abundant raw materials, low cost, mild reaction conditions, short time and high yield. The byproduct is water-soluble.

Description

technical field [0001] The present invention relates to a kind of preparation method for the intermediate of synthetic rosuvastatin calcium, specifically, relate to (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2- Preparation of (N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3-(tert-butyldimethylsilyl)oxy-5-carbonyl-6(E)-heptenoic acid methyl ester method. technical background [0002] Rosuvastatin calcium, chemical name bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl ](3R,5S)-3,5-dihydroxy-6-heptenoic acid]calcium salt is a new generation of statins with a fully synthesized single enantiomer, which belongs to HMG-CoA reductase inhibitors and can reduce Elevated concentrations of low-density cholesterol, total cholesterol, triglycerides, and apoprotein B, along with elevated concentrations of high-density cholesterol. It can be used for comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hyp...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07F9/28C07D239/42
Inventor 袁哲东杨玉雷
Owner SHANGHAI INST OF PHARMA IND
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