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Advanced intermediate of rosuvastatin calcium and preparation method of advanced intermediate

A technology for rosuvastatin calcium and advanced intermediates, which is applied in the field of synthesis of drugs and drug intermediates, and can solve problems such as unfavorable industrial application and promotion, difficulty in balancing production cost and product quality, and high cost

Pending Publication Date: 2021-04-02
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Synthesize the above-mentioned chiral side chain containing phenyl sulfone structure, except 2-mercaptobenzimidazole ( ), other precursors are often very costly (such as ), and even requires special customization (such as ), it is difficult to balance production cost and product quality, which is not conducive to industrial application and promotion

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Feed 120g of D4 (95~105g after discount), 100g of sodium carbonate, 60g of 2-mercapto-5-ethyl-1,3,4-thiadiazole and 250g of DMAC, start stirring and heat up to 100~110°C, and keep it warm for 8 hours. Cool down to below 100°C, and concentrate under reduced pressure until there is no distillate. Cool down, add 550g of dichloromethane, 400g of drinking water, stir evenly and let stand for stratification. The organic layer is D4-1 solution.

[0058] The D4-1 solution was transferred to the reactor, and 150g of drinking water, 5g of sodium carbonate and 3g of tetrabutylammonium chloride were fed in, stirred and dissolved, and the temperature was controlled at 10-15°C. Add a mixture of 450g 50% hydrogen peroxide and 6g ammonium tungstate dropwise, and control the temperature at 15-20°C. Insulated and stirred for 20 hours. After the reaction was completed, the reaction solution was allowed to stand for stratification, and the organic layer was washed once with 300g of 5% s...

Embodiment 2

[0060] Feed 110g D4 (87~97g after discount), 110g sodium bicarbonate, 50g 2-mercapto-5-methyl-1,3,4-thiadiazole and 225g DMF, start stirring and heat up to 110~120°C, keep warm for 7 Hour. Cool down to below 100°C, and concentrate under reduced pressure until there is no distillate. Cool down, add 500g of dichloromethane, 425g of drinking water, stir evenly and let stand to separate layers. The organic layer is D4-1 solution.

[0061] The D4-1 solution was transferred to the reactor, and 130g of drinking water, 8g of sodium bicarbonate and 2.2g of tetrabutylammonium bromide were fed in, stirred and dissolved, and the temperature was controlled at 15-20°C. Add dropwise a mixture of 500g 30% hydrogen peroxide and 5g ammonium molybdate, and control the temperature at 20-25°C. Keep stirring for 16 hours. After completion of the reaction, the reaction solution was allowed to stand for layering, and the organic layer was washed once with 225g of 5% sodium sulfite solution and 22...

Embodiment 3

[0063] Feed 130g D4 (100~110g after discount), 90g potassium carbonate, 70g 2-mercapto-5-phenyl-1,3,4-thiadiazole and 260g tert-butanol, start stirring and heat up to 90~100°C, Keep warm for 10 hours. Cool down to below 85°C, and concentrate under reduced pressure until there is no distillate. Cool down, add 615g of dichloromethane, 400g of drinking water, stir evenly and let stand to separate layers. The organic layer is D4-1 solution.

[0064] The D4-1 solution was transferred to the reactor, fed with 160g of drinking water, 6.5g of potassium bicarbonate and 4g of dodecyltrimethylammonium chloride, stirred and dissolved, and the temperature was controlled at 20-25°C. Add dropwise a mixture of 835g 30% hydrogen peroxide and 6g ammonium phosphomolybdate, and control the temperature at 25-30°C. Keep stirring for 22 hours. After completion of the reaction, the reaction solution was allowed to stand for layering, and the organic layer was washed once with 400g of 5% sodium su...

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PUM

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Abstract

The invention discloses an advanced intermediate of rosuvastatin calcium and a preparation method of the advanced intermediate. An intermediate R1 is prepared from a chiral side chain D42 containing athiadiazole sulfone structure and a parent nucleus Z8.1 containing a pyrimidinecarboxaldehyde structure through Julia enylation reaction. The invention discloses a novel preparation method of R1. Theproduct provided by the invention has the advantages of low preparation cost, high total yield and good quality, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of drugs and drug intermediates, in particular to an advanced intermediate of rosuvastatin calcium and a preparation method thereof. Background technique [0002] Rosuvastatin calcium was first successfully developed by Shionogi Company (US5260440A) in Japan, and later the company transferred the technology to Zeneca (now AstraZeneca) (WO0049014A1) in the UK, and was approved by the US FDA in August 2003 The drug was launched in my country in 2006, and its global sales exceeded US$6.9 billion in 2009. Rosuvastatin Calcium, known as "Super Statin", will add a valuable new option for the treatment of dyslipidemia. [0003] R1(6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidine]vinyl]-2 ,2-Dimethyl-1,3-dioxane-4-tert-butyl acetate) is an advanced intermediate for the preparation of rosuvastatin calcium. [0004] The structural formula is [0005] . [0006] The synthe...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06C07B2200/07
Inventor 李望孙海涛谢兰伟潘启娇许华富胡钊侠龚道新
Owner 安徽美诺华药物化学有限公司
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