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A kind of preparation method of rosuvastatin calcium intermediate

A technology for rosuvastatin calcium and intermediates, which is applied in the field of compound synthesis technology, can solve problems such as a large amount of waste water, waste gas, poor selectivity, unfriendly environment, etc., and achieve the effects of simple raw materials, mild reaction conditions and environmental friendliness.

Inactive Publication Date: 2015-11-18
ZHEJIANG UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods have poor selectivity, produce a large amount of waste water, waste gas, and waste residue, and are not environmentally friendly.

Method used

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  • A kind of preparation method of rosuvastatin calcium intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0010] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 50ml of tetrahydrofuran to the reaction flask, then add 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-methanol 35.3 gram, cool down to 10°C, add (R)-3-[(tert-butyldimethylsilyl)oxyl group]-5-oxo-6-triphenylphosphonohexanoic acid tert-butyl ester 50.8 grams, add 7.06 Gram 60-100nm NiNPs, reacted at 50°C for 24 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel column, eluted with chloroform, and concentrated under reduced pressure to obtain a yellow oily liquid 7-[4-(4- Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyl)- 43.9 grams of tert-butyl 5-oxo-6-heptanoate, yield 69.1%.

[0011] 1 H-NMR (CDCl 3 )δ:0.05(3H,s,SiCH 3 ),0.061(3H,s,SiCH 3 ,0.80(9H,s,Si(CH 3 )...

Embodiment 2

[0013] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 50ml of 2-methyltetrahydrofuran into the reaction flask, then add 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine- 35.3 grams of 5-methanol, cooled to -5°C, added (R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphonohexanoic acid tert-butyl 48.4 grams, 3.53 grams of 30-60nm NiNPs were added, reacted at 80 ° C for 15 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel column, eluted with chloroform, and concentrated under reduced pressure to obtain a yellow oily liquid 7-[ 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethyl Silyl)-5-oxo-6-heptanoic acid tert-butyl ester 45.6 grams, yield 71.8%.

Embodiment 3

[0015] In a 250ml three-necked flask, a thermometer, a pH meter, a constant pressure dropping funnel and a magnetic stirrer were installed. At room temperature, add 100ml of tetrahydrofuran to the reaction flask, then add 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-methanol 35.3 gram, cool down to 0°C, add (R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphonohexanoic acid tert-butyl ester 50.0 grams, add 5.29 Gram 30-60nm NiNPs, reacted at 60°C for 20 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was applied to a silica gel column, eluted with chloroform, and concentrated under reduced pressure to obtain a yellow oily liquid 7-[4-(4- Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyl)- 49.8 grams of tert-butyl 5-oxo-6-heptanoate, yield 77.6%.

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Abstract

The invention discloses a preparation method of a rosuvastatin calcium intermediate. The preparation method comprises the following steps: adding 4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino) pyrimidine-5-methanol into a solvent, cooling to (-5) to 10 DEG C, adding (R)-3-[(tertiary butyl dimethyl silane) oxy]-5-oxo-triphenylphosphine caproic acid tert-butyl ester, adding NiNPs, reacting for 15-24 hours at 50-80 DEG C, filtering, carrying out vacuum concentration on a filtrate, feeding a residue on a silica gel column, eluting with trichloromethane, carrying out vacuum concentration, thus obtaining a yellow oil packed solution. In the preparation method, the raw materials are feasible, and the reaction condition is moderate; and in addition, the preparation method is environment-friendly and can be used for industrialized mass production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyl Dimethylsilyl)-5-oxo-6-heptanoic acid tert-butyl ester is a key intermediate for the synthesis of rosuvastatin (Current Organic Chemistry, 2010, 14, 816-845). Cai Wei et al. (Jiangsu Pharmaceutical and Clinical Research, 2005, 13 (4) 8-10) reported a 6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl- The synthetic method of 2-[methyl (methylsulfonyl) amino]-5-pyrimidine] vinyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid methyl ester, with 4- (4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-carbaldehyde is the starting material, and (R)-3-[(tert-butyl dimethylsilyl)oxy]-5-oxo-6-triphenylphosphonohexanoic acid methyl ester is prepared by condensation reaction. CN102617481 Sy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
Inventor 蒋成君
Owner ZHEJIANG UNIVERSITY OF SCIENCE AND TECHNOLOGY