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A kind of preparation method of novel rosuvastatin calcium intermediate

A technology of rosuvastatin calcium and intermediates, applied in the field of medicinal chemistry, can solve the problems of post-processing of toxic and harmful chemical reagents, long and cumbersome reaction steps, etc., and achieve the effects of three wastes treatment, mild chemical reaction conditions, and easy three wastes

Active Publication Date: 2019-07-16
ZHEJIANG YONGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In summary, there are problems such as long reaction steps, toxic and harmful chemical reagents involved in the process, and cumbersome post-processing in the above-mentioned methods.

Method used

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  • A kind of preparation method of novel rosuvastatin calcium intermediate
  • A kind of preparation method of novel rosuvastatin calcium intermediate
  • A kind of preparation method of novel rosuvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of (R)-methyl 3-(tert-butyldimethylsiloxane)-5-(1H-imidazol-1-yl)-5-oxopentanoic acid methyl ester (compound II)

[0047]

[0048] 30.0 g of compound III, 108.5 mmol, and 150 ml of dichloromethane were put into a three-necked reaction flask, and the mixture was stirred to dissolve. 18.5 g 114.1 mmol of carbonyldiimidazole was added in batches at a temperature of 20-30 °C. The reaction is stirred for 2 to 3 hours, and the sampling is controlled until the residual amount of compound III in the reaction solution is less than or equal to 0.5%, and the reaction is completed.

[0049] The above reaction solution was added to a flash silica gel column for column purification, and the eluate was collected. The solvent was removed by concentration under reduced pressure to obtain 31.9 g of a yellow oil. The yield was 90.0%, and the GC purity was 95.0%.

Embodiment 2

[0050] Example 2: Preparation of (R)-methyl 3-(tert-butyldimethylsiloxane)-5-(1H-imidazol-1-yl)-5-oxopentanoic acid methyl ester (compound II)

[0051]

[0052] 30.0 g of compound III, 108.5 mmol, and 150 ml of dichloromethane were put into a three-necked reaction flask, and the mixture was stirred to dissolve. 35.2 g 217.1 mmol of carbonyldiimidazole was added in batches at a temperature of 20-30 °C. The reaction is stirred for 2 to 3 hours, and the sampling is controlled until the residual amount of compound III in the reaction solution is less than or equal to 0.5%, and the reaction is completed.

[0053] The above reaction solution was added to a flash silica gel column for column purification, and the eluate was collected. The solvent was removed by concentration under reduced pressure to obtain 34.0 g of a yellow oil. The pure yield was 84.0%, and the GC purity was 88.0%.

Embodiment 3

[0054] Example 3: Preparation of (R)-methyl 3-(tert-butyldimethylsiloxane)-5-(1H-imidazol-1-yl)-5-oxopentanoic acid methyl ester (compound II)

[0055]30.0 g of compound III, 108.5 mmol, and 150 ml of dichloromethane were put into a three-necked reaction flask, and the mixture was stirred to dissolve. 40.5 g 249.6 mmol of carbonyldiimidazole was added in batches at a temperature of 20-30 °C. The reaction is stirred for 2 to 3 hours, and the sampling is controlled until the residual amount of compound III in the reaction solution is less than or equal to 0.5%, and the reaction is completed.

[0056] The above reaction solution was added to a flash silica gel column for column purification, and the eluate was collected. The solvent was removed by concentration under reduced pressure to obtain 34.5 g of a yellow oil. The pure yield was 80.0%, and the GC purity was 83.0%.

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Abstract

The invention provides a preparation method of a novel rosuavastatin calcium intermediate I which is suitable for industrial large-scale production. The preparation method comprises the step of enabling triphenyl methyl phosphorus bromide to react with a compound II, thus obtaining an intermediate I. The preparation method provided by the invention is safe and simple and is strong in operability, and a final finished product which is high in efficiency and purity can be obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new preparation method of a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin calcium was first marketed in the United States in 2003 and is a selective HMG-COA reductase inhibitor. Clinical application in hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. Rosuvastatin calcium (or CRESTOR), the chemical name is (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N -methanesulfonamido)-5-pyrimidine]-3,5-dihydroxy-6-heptenoic acid calcium, the structural formula is as follows: [0003] [0004] The (3R)-tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphonic acid methyl ester (compound I) described in the present invention is the key intermediate for preparing rosuvastatin calcium body. [0005] [0006] The patent document JP 06135975 of Shionogi Pharmaceutical Co., Ltd. first reported the synthesis method of compound I. I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/64C07F9/535
CPCY02P20/55
Inventor 向科张杰廖明飞
Owner ZHEJIANG YONGTAI PHARMA
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