Method for preparing milrinone

A technology of milrinone and compounds, which is applied in the field of preparation of milrinone, can solve the problems of unremovable refining, long reaction time, strict water requirements, etc., so as to save labor costs and raw material costs, facilitate industrial production, and reduce raw material costs Effect

Inactive Publication Date: 2016-12-21
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of method is such as reaction scheme 1, and its first step can be realized by 2 paths, and the 1st path is the phenyllithium that uses, but it is strict to water, and reaction condition is harsh, and production cost is high, and in the reaction process There is a risk of producing highly toxic benzene, so it is not suitable for industrial production
The second path reacts with acetyl chloride at room temperature for 16 hours. Although the reaction conditions are relatively mild, the reaction time is too long
This method requires 3 steps of reaction to prepare milrinone, and the yield of the last step reaction is only 34%, which has no competitive advantage compared with the yield of 70% of other routes, and the milrinone produced Reddish with color, refining can not be removed

Method used

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  • Method for preparing milrinone
  • Method for preparing milrinone
  • Method for preparing milrinone

Examples

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Embodiment 1

[0032] In the present embodiment, the preparation method of milrinone comprises the following steps:

[0033] 1) Under the protection of nitrogen, add 120ml of tetrahydrofuran and 24ml of diisopropylamine into the reaction flask, cool down to below 20°C, add 74g of 2.0M n-butyllithium solution, and stir at 0-5°C for 20min after the addition is complete. Add 17ml of 4-picoline dropwise, and then add 2ml of hexamethylphosphoric triamide. After the addition is complete, stir at 0-5°C for 1 hour. Then add 25ml of ethyl acetate, heat up to 25°C and stir for 1.5h, cool down to 0°C, add 32ml of hydrochloric acid dropwise, after the drop is complete, concentrate under reduced pressure at 40°C to remove the solvent, add appropriate amount of water and dichloromethane, extract the organic phase, and extract three times , combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to remove the organic solvent to obtain a brown liquid, distilled, collected fracti...

Embodiment 2

[0038] In the present embodiment, the preparation method of milrinone comprises the following steps:

[0039] 1) preparing 1-(4-pyridyl)-2-propanone, comprising the following steps:

[0040] Under the protection of nitrogen, add 120ml of ether and 24ml of diisopropylamine into the reaction flask, lower the temperature to below 20°C, add 74g of 2.0M n-butyl lithium solution, after the addition is complete, stir at 0-5°C for 20min. Add 17ml of 4-picoline dropwise, and then add 2ml of hexamethylphosphoric triamide. After the addition is complete, stir at 0-5°C for 1 hour. Then add 25ml of ethyl acetate, heat up to 20°C and stir for 2.5h, cool down to 0°C, add 32ml of hydrochloric acid dropwise, after the drop is complete, concentrate under reduced pressure at 40°C to remove the solvent, add appropriate amount of water and ethyl acetate, extract the organic phase, and extract three times , combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated to...

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Abstract

The invention provides a method for preparing milrinone, wherein the method comprises the following steps: with 4-methyl pyridine (SM) as a raw material, in ethyl acetate, generating 1-(4-pyridyl)-2-acetone (represented by the formula I); then under action of triethyl orthoformate, acetic acid and acetic anhydride, generating 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone (represented by the formula II); and finally, under an alkaline condition, carrying out a reaction of 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone with cyanoacetamide to generate milrinone. The method has the advantages of simple and efficient operation, mild reaction conditions, strong safety, easy control and relatively high yield, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method and application of milrinone. Background technique [0002] Milrinone is the general name of 2-methyl-6-oxo-1,6-dihydro-3,4'bipyridine-5carbonitrile, and its structure is as follows: [0003] [0004] Milrinone was first successfully developed by Sterling Company of the United States. It was first approved by the FDA in the United States in 1987. It was officially launched in the United States in 1992, and was subsequently marketed in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries. [0005] This product is a phosphodiesterase inhibitor, the homologous drug of amrinone, and its mechanism of action is the same as that of amrinone. Oral and intravenous injection are effective, both positive inotropic effect and vasodilator effect. But its effect is 10 to 30 times stronger than amrinone. Well ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 王伟牛明玉张沛王庆辉鹿贵花朱圣红马立金
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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