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A kind of method for preparing rosuvastatin intermediate

A technology for rosuvastatin and intermediates, applied in the field of pharmaceutical intermediates, can solve the problems of long reaction time, expensive catalyst, low yield, etc., reduce the generation of by-products, have a good prospect for industrial production, and reduce production costs Effect

Active Publication Date: 2018-05-22
SHANGHAI INST OF TECH
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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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  • A kind of method for preparing rosuvastatin intermediate
  • A kind of method for preparing rosuvastatin intermediate
  • A kind of method for preparing rosuvastatin intermediate

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) respectively in a three-necked flask equipped with a thermometer and a condenser, and solvent 20mL of 1,4-dioxane, stirred and heated to 90°C, reacted for 12h, the reaction solution was washed with cooling water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and then subjected to column chromatography (EA / PE=1:4) isolated and obtained rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydropyrimidine-5-acetic acid methyl ester.

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

[0045]

[0046]

[0047]

Embodiment 2

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

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

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

Embodiment 3

[0056] In this example, aromatic aldehyde, 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 substrates.

[0057] Add aromatic aldehyde (5.0mmol), isobutyryl acetate (6.0mmol), thiourea (7.5mmol) and magnesium chloride (0.5mmol) respectively into a three-necked flask equipped with a thermometer and a condenser, solvent 1,4-diox Hexacyclic 20mL, stirred and heated up to 90°C, tracked by TLC until the reaction was complete, 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) to obtain rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1,4-dihydropyrimidine-5-acetic acid methyl ester.

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

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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, in particular to a pharmaceutical intermediate, specifically a preparation of rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-thiocarbonyl-1 , 4-dihydropyrimidine-5-carbonate method. Background technique [0002] Cardiovascular disease is a major disease that seriously endangers human health. The etiology of cardiovascular and cerebrovascular diseases mainly comes from atherosclerosis, which is mostly manifested as hyperlipidemia, leading to coronary heart disease and hypertension. Statins have become the representative varieties of cardiovascular and cerebrovascular drugs because of their high efficiency and low toxicity. Among them, rosuvastatin calcium was developed by AstraZeneca and was the latest statin drug approved for marketing in Europe in 2002. The results of clinical trials show that its effect on treating cardiovascular drugs is better than that of other statins (such as...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/22
CPCC07D239/22
Inventor 余焓杭智军韩生祝俊蒋继波
Owner SHANGHAI INST OF TECH
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