Preparation method of rosuvastatin

A technology of rosuvastatin and fluorophenyl, which is applied in the field of preparation of pharmaceutical compounds, can solve problems such as high equipment requirements, large pollution, and high cost, and achieve the effects of shortening reaction steps, reducing production costs, and increasing production efficiency

Active Publication Date: 2012-01-11
苏州莱克施德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the early patents reported on the synthesis process of rosuvastatin include EP0521471, JP1993178841, and US5260440, and later the original process has been greatly improved, and the reported patents include WO2006 / 067456, WO2009 / 024323, and WO2010 / 086438, but There are steps in the process route, low yield, and high cost. The synthesis of the mother nucleus requires nine-step reactions, including two oxidations (DDQ and mCPBA) and one reduction reaction (Dibal-H), and the atomic efficiency (atomefficiency) is poor.
mCPBA is a peroxide, and there are serious safety hazards in production; Dibal-H reduction requires ultra-low temperature reaction, high equipment requirements, and large pollution

Method used

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  • Preparation method of rosuvastatin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation method of rosuvastatin is made up of following five steps:

[0043] Step 1: Preparation of 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione

[0044] Under nitrogen protection, add 153.0g (1.0 mol) of 4-fluoropropiophenone and 1,500ml of 1,4-dioxane into a 5000ml three-neck flask respectively, add 80g of sodium hydride (60% NaH, 2.0 mol) under stirring, and stir After uniformity, 139.2g (1.2mol) of ethyl isobutyrate was slowly added dropwise, and gas was generated during the dropwise addition; after the dropwise addition, the temperature was raised to 75-80°C, and the reaction was carried out for 5 hours. The reaction liquid was cooled to 0°C, and kept at 0 ~5°C, 2000ml of 2M hydrochloric acid solution was added dropwise, the reaction solution was extracted with ethyl acetate (3×500ml), the organic layer was washed once with 500ml of saturated brine, concentrated under reduced pressure to obtain the oily substance 1-(4-fluorophenyl)- 2,4-dimethylpentane-...

Embodiment 2

[0054] Embodiment 2 is basically the same as Embodiment 1, the only difference is that step 1 is different. Step 1 of this embodiment is specifically as follows:

[0055] Preparation of 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione

[0056] Under the protection of nitrogen, add 91.8g (0.6mol) of 4-fluoropropiophenone and 700ml of absolute ethanol to a 2000ml three-necked bottle respectively, and add 87.0g (1.2mol) of sodium ethylate under stirring, after stirring evenly, slowly add isobutyl Ethyl acetate 83.9g (0.7mol), after the dropwise addition, heat up to reflux, react for 7h, cool the reaction solution to 0°C, keep 0-5°C, add 2M hydrochloric acid solution dropwise, adjust the pH value to 5-6, The reaction solution was extracted with ethyl acetate (3×0.5L), the organic layer was washed once with 500ml of saturated brine, and concentrated under reduced pressure to obtain the oily substance 1-(4-fluorophenyl)-2,4-dimethylpentane-1 , 3-diketone 128.6g. Yield 96%, HPLC p...

Embodiment 3

[0058] Embodiment 3 is basically the same as Embodiment 1, the only difference is that step 4 is different. Step 4 of this embodiment is specifically as follows:

[0059] Preparation of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

[0060] Under the protection of nitrogen, add N-(5-methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonate to a 50ml three-necked flask Amide 3.4g (10mmol) and N-bromosuccinimide 2.3g (13mmol), acetonitrile 20ml, the reaction solution with a λ=310nm light source, light for 5h, 25ml of water was added to the reaction solution, and the mixture was extracted with dichloromethane ( 3×10ml), the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4.0g of the crude product, which was recrystallized with petroleum ether: methyl tert-butyl ether = 1:1 to obtain a white solid N-(5 -(Bromomethyl)-4-(4-fluoropheny...

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Abstract

The invention discloses a preparation method of rosuvastatin, comprising the following steps of: using 4-fluoropropiophenone as a raw material, followed by a condensation reaction with ethyl isobutyrate to obtain 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione, performing a cyclization reaction with 1-methylguanidine to obtain 4-(4-fluorophenyl)-6-isopropyl-N,5-dimethyl pyrimidine-2-amine, followed by mesyl substituent and bromination to obtain N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropyl pyrimidine-2-yl)-N-methyl methanesulfonamide, and reacting with triphenyl phosphine to form a wittig reagent so as to prepare rosuvastatin provided by the invention. By the adoption of the preparation method provided by the invention, reaction steps are shortened from nine step reactions in original technology to fine step reactions; in addition, two oxidation reactions and an ultralow temperature reduction reaction are avoided, the production efficiency is effectively increased, the product quality is raised, the environmental pollution is minimized, and the production cost is reduced.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of rosuvastatin. Background technique [0002] Vascular disease is one of the diseases that seriously endanger human health. In recent years, the morbidity and mortality of such diseases have shown a significant upward trend. According to the statistics of the World Health Organization, about 15 million people die of cardiovascular and cerebrovascular diseases in the world every year. Diseases, in my country, the incidence of cardiovascular and cerebrovascular diseases is as high as 8%, and the mortality rate is close to 50% of the total mortality rate; on average, one person dies of cardiovascular and cerebrovascular diseases every 20 minutes. Cardiovascular and cerebrovascular diseases are mainly rooted in atherosclerosis, and more than 80% of atherosclerosis is caused by hyperlipidemia. According to the survey, 40% of the people aged 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/54
Inventor 俞菊荣孙光明顾志锋蔡杰关众
Owner 苏州莱克施德药业有限公司
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