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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 long reaction steps, post-treatment of toxic and harmful chemical reagents, cumbersome problems, etc., and achieve the effects of mild chemical reaction conditions, three wastes treatment, and three wastes easy

Active Publication Date: 2017-05-31
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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  • Preparation method of novel rosuvastatin calcium intermediate
  • Preparation method of novel rosuvastatin calcium intermediate
  • 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-butyldimethylsilyloxy)-5-(1H-imidazol-1-yl)-5-oxopentanoic acid methyl ester (compound II)

[0047]

[0048] Put 30.0g 108.5mmol of compound III and 150ml of dichloromethane into a three-necked reaction flask, stir to dissolve. 18.5 g 114.1 mmol of carbonyldiimidazole was added in batches at a controlled temperature of 20-30°C. Stir the reaction for 2-3 hours, take a sample and control it until the residual amount of compound III in the reaction liquid is ≤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. Concentrate under reduced pressure to remove the solvent to obtain 31.9 g of a yellow oil. Yield 90.0%, GC purity 95.0%.

Embodiment 2

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

[0051]

[0052] Put 30.0g 108.5mmol of compound III and 150ml of dichloromethane into a three-necked reaction flask, stir to dissolve. 35.2 g 217.1 mmol of carbonyldiimidazole was added in batches at a controlled temperature of 20-30°C. Stir the reaction for 2-3 hours, take a sample and control it until the residual amount of compound III in the reaction liquid is ≤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. Concentrate under reduced pressure to remove the solvent to obtain 34.0 g of a yellow oil. The pure yield is 84.0%, and the GC purity is 88.0%.

Embodiment 3

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

[0055]Put 30.0g 108.5mmol of compound III and 150ml of dichloromethane into a three-necked reaction flask, stir to dissolve. 40.5g 249.6mmol of carbonyldiimidazole was added in batches under temperature control at 20-30°C. Stir the reaction for 2-3 hours, take a sample and control it until the residual amount of compound III in the reaction liquid is ≤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. Concentrate under reduced pressure to remove the solvent to obtain 34.5 g of a yellow oil. The pure yield is 80.0%, and the GC purity is 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, first launched in the United States in 2003, is a selective HMG-COA reductase inhibitor. It is clinically used 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-calcium heptenoate, the structural formula is as follows: [0003] [0004] (3R)-tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphine hexanoic acid methyl ester (compound I) described in the present invention is the key intermediate for the preparation of rosuvastatin calcium body. [0005] [0006] The patent document JP 06135975 of Shionogi Pharmaceutical Co., Ltd. first reported the synthesis method of compound ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64C07F9/535
CPCC07D233/64C07F9/5352Y02P20/55
Inventor 向科张杰廖明飞
Owner ZHEJIANG YONGTAI PHARMA
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