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Method for preparing rosuvastatin midbody

A technology for rosuvastatin and intermediates, applied in the field of pharmaceutical intermediates, can solve the problems of expensive catalysts, low yields, long reaction times, etc., achieve good industrial production prospects, reduce production costs, and reduce the generation of by-products Effect

Active Publication Date: 2015-12-23
SHANGHAI INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a method for preparing rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydro The method of pyrimidine-5-carbonate, the preparation method described in the prior art solves the technical problems of long reaction time, low yield and expensive catalyst in the preparation method in the prior art

Method used

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  • Method for preparing rosuvastatin midbody
  • Method for preparing rosuvastatin midbody
  • Method for preparing rosuvastatin midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] In this example, 4-fluorobenzaldehyde, methyl isobutyryl acetate and thiourea were used as substrates to confirm the activity of related catalysts in catalyzing the bigienlli reaction.

[0043] Add 4-fluorobenzaldehyde (5.0mmol), methyl isobutyryl acetate (6.0mmol), thiourea (7.5mmol) and the corresponding catalyst (0.5mmol) into a three-necked flask equipped with a thermometer and a condenser. Solvent 20 mL of 1,4-dioxane was stirred and heated to 90°C. After 12 hours of reaction, the reaction solution was washed with cooling water, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and then subjected to column chromatography (EA / PE=1:4) The rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydropyrimidine-5-acetic acid methyl ester was isolated.

[0044] Table 1 shows the effect of different catalysts on the reaction

[0045]

[0046]

[0047]

Embodiment 2

[0049] In this example, 4-fluorobenzaldehyde, methyl isobutyryl acetate and thiourea were used as substrates, and magnesium chloride was used as a catalyst. The effect of solvent and temperature on the reaction activity was investigated.

[0050] Add 4-fluorobenzaldehyde (5.0mmol), methyl isobutyryl acetate (6.0mmol), thiourea (7.5mmol) and magnesium chloride (0.5mmol) into a three-necked flask equipped with a thermometer and a condenser, and add the corresponding Solvent (20mL), stirred and warmed to the specified temperature, after 12h reaction, the reaction solution was washed with cold water, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and then subjected to column chromatography (EA / PE=1 :4) The rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydropyrimidine-5-methyl acetate was isolated and obtained.

[0051] Table 2 shows the influence of solvent and reaction temperature on the...

Embodiment 3

[0056] In this example, aromatic aldehydes, isobutyryl acetate and thiourea were used as substrates, magnesium chloride was used as a catalyst, and the stability of the reaction conditions was investigated by changing the R group of the substrate.

[0057] Add aromatic aldehyde (5.0mmol), isobutyryl acetate (6.0mmol), thiourea (7.5mmol) and magnesium chloride (0.5mmol) into a three-necked flask equipped with a thermometer and a condenser. The solvent 1,4-diox 20 mL of six rings, stirred and heated to 90°C, followed by TLC until the reaction was complete, the reaction solution was washed with cold water, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and then subjected to column chromatography (EA / PE= 1:4) The rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydropyrimidine-5-methyl acetate was isolated and obtained.

[0058] Table 3 shows the stability of the reaction conditions to diffe...

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Abstract

The invention discloses a method for preparing a rosuvastatin midbody. The method comprises the steps of weighing lewis acid MgCl<2>, aromatic aldehyde, isobutyryl acetate and thiourea, wherein the mole ratio of aromatic aldehyde to isobutyryl acetate to thiourea is 1:1-1.5:1-2.0, and the mole number of a lewis acid catalyst accounts for 5-20% of the total mole number of aromatic aldehyde, isobutyryl acetate and thiourea; adding aromatic aldehyde, isobutyryl acetate, thiourea and the lewis acid catalyst MgCl<2> into a reaction vessel, adopting 1, 4-dioxane as solvent, stirring the mixture and raising the temperature, after the reaction is conducted sufficiently, getting a reaction solution to be subjected to cooling, washing, extraction, drying, filtration and reduced pressure distillation, then conducting column chromatography isolation, and obtaining the rosuvastatin midbody, namely 4-(4-fluoro-phenyl)-6-isopropyl-2-thiocarbonyl-1, 4-dihydropyrimidine-5-acetate. By means of the method, the rosuvastatin midbody high in purity can be obtained, the catalyst is low in price and easy to obtain, reutilization can be conducted, and the production cost is lowered.

Description

Technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a pharmaceutical intermediate, specifically a preparation of 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1, an intermediate of rosuvastatin , 4-Dihydropyrimidine-5-carbonate method. Background technique [0002] Cardiovascular disease is a major disease that seriously endangers human health. The cause of cardiovascular and cerebrovascular diseases mainly stems from atherosclerosis, which is mostly manifested as high blood lipids, leading to coronary heart disease and hypertension. Statins have become a representative variety of cardio-cerebrovascular drugs due to their high efficiency and low side effects. Among them, rosuvastatin calcium is the latest statin drug developed by AstraZeneca and approved for marketing in Europe in 2002. The results of clinical trials show that its effect of treating cardiovascular drugs is better than other statins that have been marketed...

Claims

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Application Information

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IPC IPC(8): C07D239/22
CPCC07D239/22
Inventor 余焓杭智军韩生祝俊蒋继波
Owner SHANGHAI INSTITUTE OF TECHNOLOGY
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