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Preparation method of high-purity milrinone

A milrinone, high-purity technology, used in the field of medicine, which can solve the problems of harsh operating environment and heavy pollution

Inactive Publication Date: 2015-02-04
ZHENGZHOU SIHUAN MEDICINE ARTICLE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The raw materials used in the above two synthetic routes are easily available in China, but a large amount of acetic anhydride is used in route 2, resulting in relatively harsh operating environment and heavy pollution, so it is not an environmentally friendly synthetic route

Method used

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  • Preparation method of high-purity milrinone
  • Preparation method of high-purity milrinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 2.6 kg of 1-(4-pyridyl)acetone and 10.4 kg of N,N-dimethylformamide dimethyl acetal into a 50L reactor, stir, heat to reflux with steam, and reflux for 2 hours. Concentrate under reduced pressure until almost no distillate is evaporated, stop heating, pass circulating water to cool down, and add n-hexane. After cooling to room temperature, stirring was continued for 1 hour. After centrifugation, the obtained solid was dried at 50°C for 4 hours to obtain 3.2 kg of brown solid with a yield of 88.9%.

Embodiment 2

[0029] Add 2.6 kg of 1-(4-pyridyl)acetone, 10.4 kg of N,N-dimethylformamide dimethyl acetal, and 10 kg of acetonitrile into a 50L reactor, stir, heat to reflux with steam, and reflux for 2 hours. Concentrate under reduced pressure until almost no distillate is evaporated, stop heating, pass circulating water to cool down, and add n-hexane. After cooling to room temperature, stirring was continued for 1 hour. After centrifugation, the obtained solid was dried at 50°C for 4 hours to obtain 3.1 kg of brown solid with a yield of 87.3%.

Embodiment 3

[0031] Add 51.2 kg of methanol, 2.7 kg of sodium methoxide, 3.2 kg of 1-(4-pyridyl)-2-(dimethylamino) vinyl methyl ketone, and 2.8 kg of cyanoacetamide into a 100L reactor, stir and steam Heat to reflux and reflux for 1 hour. Stop heating, lower the temperature to 0-5°C, and continue stirring for 2 hours. Centrifuge, disperse the obtained solid in 10 kg of water, stir, adjust the pH to 2 to 3 with hydrochloric acid, and then adjust the pH to 6 to 7 with about 20% sodium hydroxide solution, and stir at 0 to 5°C for 1 hour. After centrifugation, the obtained solid was dried at 50° C. to obtain 2.1 kg of yellow solid with a yield of 58.1%.

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Abstract

The invention relates to a preparation method of high-purity milrinone as shown in a formula (I) described in the specification. The preparation method comprises the following steps: carrying out reflux reaction on N, N-methyl formamide dimethyl acetal (DMF-DMA) by taking 1-(4-pyridyl) acetone as a starting material, concentrating after the reaction is ended, adding normal hexane into residues to separate out solids to obtain an intermediate 1-(4-pyridyl)-2-(dimethylamino) vinyl methyl ketone; carrying out reflux reaction on the intermediate 1-(4-pyridyl)-2-(dimethylamino) vinyl methyl ketone and cyanoacetamide in the presence of sodium methylate, and regulating the pH value after the reaction is ended to obtain crude milrinone; and refining the crude milrinone by methanol / sodium methylate and alcohol / water to obtain a qualified milrinone product. The preparation method disclosed by the invention is simple in process operation, relatively small in pollution and suitable for industrial production.

Description

【Technical Field】 [0001] The invention relates to a preparation method of milrinone (1,6-dihydro-2-methyl-6-oxy-[3,4-bispyridine]-5-carbonitrile), specifically A preparation method of high-purity milrinone belongs to the field of medical technology. 【Background technique】 [0002] Milrinone (formula I), chemical name is 1,6-dihydro-2-methyl-6-oxy-[3,4-bipyridine]-5-carbonitrile, molecular formula is C12H9N3O, molecular weight is 211.22 , It is white or almost white crystalline powder. [0003] Milrinone is a non-digital cardioside and non-catecholamine positive inotropic drug. It can inhibit the phosphodiesterase of the heart to produce positive contraction and peripheral vasodilation. It is suitable for patients with severe congestive heart failure Treatment. [0004] The synthesis of milrinone reported in the existing literature is all synthesized with 1-(4-pyridyl)acetone as the starting material, and there are mainly the following two synthetic routes: [0005] Synthetic Route ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 阎虎林邓爱相
Owner ZHENGZHOU SIHUAN MEDICINE ARTICLE CO LTD
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