Synthesis method of milirinone

A synthesis method and condensation reaction technology, applied in organic chemistry and other directions, can solve the problems of expensive raw materials, complex synthesis routes, and high equipment requirements, and achieve the effects of simplifying operations, simplifying technological processes, and reducing production environment.

Inactive Publication Date: 2014-05-21
SICHUAN XINSIDUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are generally disadvantages such as complex synthetic rout

Method used

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  • Synthesis method of milirinone
  • Synthesis method of milirinone

Examples

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example 1

[0016] Take 192g of 4-picoline, 662g of acetic anhydride, and 1.5ml of concentrated sulfuric acid in a three-necked flask, place a thermometer, stir, heat up to 75°C for 4 hours, cool down and add 850ml of absolute ethanol, reflux for 2 hours, and depressurize concentrate. Then add 163g of triethyl orthoformate, 184g of acetic anhydride, and 150ml of glacial acetic acid in sequence, keep the temperature in the bottle at 50°C, react for 2.5 hours, concentrate under reduced pressure, then add 1000ml of absolute ethanol, 54.2g of malononitrile, and heat to reflux. Dissolve with alkaline solution at room temperature, decolorize activated carbon, filter, and soak twice with purified water, adjust pH to 6.5-7.0 with glacial acetic acid, filter and dry, and dry to obtain 288 g of crude product, then recrystallize with DMF, collect milrinone Refined product 254g, the yield is 58.3%.

example 2

[0018] Take 145g of 4-picoline, 500g of acetic anhydride, and 1.2ml of concentrated sulfuric acid in a three-necked flask, place a thermometer, stir, heat up to 75°C for 4 hours, cool down and add 650ml of absolute ethanol, reflux for 2 hours, and depressurize concentrate. Then add 115g of triethyl orthoformate, 140g of acetic anhydride, and 115ml of glacial acetic acid in sequence, keep the temperature in the bottle at 50°C, react for 2.5 hours, concentrate under reduced pressure, then add 800ml of absolute ethanol, 40.9g of malononitrile, and heat to reflux. Dissolve with alkaline solution at room temperature, decolorize with activated carbon, filter, and soak twice with purified water, adjust pH to 6.5-7.0 with glacial acetic acid, dry by suction, dry to obtain 216g of crude product, recrystallize with DMF, and collect milrinone Refined product 188g, the yield is 57.2%.

example 3

[0020] Take 950g of 4-picoline, 3350g of acetic anhydride, and 8ml of concentrated sulfuric acid in a reaction flask, place a thermometer, stir, heat up to 75°C for 4 hours, cool down and add 4250ml of absolute ethanol, reflux for 2 hours, and concentrate under reduced pressure. Then add 815g of triethyl orthoformate, 920g of acetic anhydride, and 750ml of glacial acetic acid in sequence, keep the temperature in the bottle at 50°C, react for 2.5 hours, concentrate under reduced pressure, then add 5000ml of absolute ethanol, 270g of malononitrile, and heat to reflux. Dissolve with alkaline solution at room temperature, decolorize with activated carbon, filter, and soak twice with purified water, adjust pH to 6.5-7.0 with glacial acetic acid, filter to dryness, and dry to obtain 1418g of crude product, then recrystallize with DMF, collect milrinone Refined product 1241g, the yield is 57.6%.

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Abstract

Belonging to the fields of chemical industry and chemical medicine, the invention discloses a synthesis method of milirinone. The method includes: adopting 4-methylpyridine as a raw material to undergo acetylation reaction with acetic anhydride, subjecting the acetylate to condensation with triethyl orthoformate directly without purification, and subjecting the condensation product and malononitrile to cyclization reaction in ethanol absolute, thus obtaining milirinone. The method is characterized by starting with relatively simple and easily available raw materials to directly obtain a complicated structure molecule without separation and purification of the intermediates. The milirinone synthesized by the method provided by the invention has the advantages of high yield and high sample purity. Milirinone is an important chemical product, and can be used as a cardiotonic drug and the like.

Description

technical field [0001] The invention relates to a preparation method of the compound milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile), which belongs to the chemical industry and chemical medicine industry . Background technique [0002] Milrinone (Milirinone) is the general name of -1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile, and its structural formula is [0003] [0004] Milrinone is a phosphodiesterase III (PDEIII) inhibitor, a drug of the same class as 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 tolerated. Therefore, since the drug was launched in the United States in 1987, many companies have completed the preparation of milrinone through multiple routes. However, there are generally disadvantages such as complex synthetic routes, expen...

Claims

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Application Information

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IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 袁仕云庄慧祥舒勇蔡孙均
Owner SICHUAN XINSIDUN PHARMA
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