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Preparation method of high-purity milrinone

A milrinone, high-purity technology, applied in the field of medicine, can solve the problems of increasing impurities, reducing purity, and high cost, and achieving the effects of improving product purity, saving production costs, and simplifying process operation steps

Active Publication Date: 2014-08-06
合肥启旸生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The milrinone produced by the prior art has a darker color, and requires repeated refining and decolorization to meet the requirements of the raw material medicine for injection, and the cost is high; forced decolorization will increase impurities and reduce the purity

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Take 200g (1.05mol) of 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone, add 2L of 80vt% ethanol to dissolve, add 97g (1.15mol) of cyanoacetamide, stir to dissolve, add dropwise hydrogen oxidation Sodium 80vt% ethanol solution 630ml (sodium hydroxide content 126g), temperature control below 0°C; after dripping, stir and react at -5~0°C for 16h, add 1.3L of water to the reaction solution, add 50g of activated carbon, stir at room temperature for 20min, filter, Adjust the pH of the filtrate to 7 with hydrochloric acid solution, filter, wash the filter cake with water until the filtrate is colorless, add 200 g of wet dexmilrinone, add 4 L of 50vt% ethanol to reflux to dissolve, filter, stir and crystallize the filtrate at -5~0°C for 6 hours, filter, After drying at 60-70°C for 6 hours, 183 g of white crystalline milrinone was obtained, with a yield of 82.8% and a purity of 99.97% (HPLC method).

Embodiment 2

[0041] Take 2 kg (10.5 mol) of 1-ethoxy-2-(4-pyridyl) vinyl methyl ketone, add 22 L of 70vt% ethanol to dissolve, add 1 kg (11.9 mol) of cyanoacetamide, stir to dissolve, add dropwise hydrogen to oxidize Sodium 80% ethanol solution 6.5L (sodium hydroxide content 1.3kg), temperature control below 0°C; after dropping, stir at -5~0°C for 16h, add 15L of water to the reaction solution, add 500g of activated carbon, stir at room temperature for 20min, filter, Adjust the pH of the filtrate to 7 with dilute hydrochloric acid, filter, wash the filter cake with water until the filtrate is colorless, add 2.2kg of wet dexmilrinone, add 45L of 50vt% ethanol to dissolve under reflux, filter, stir and crystallize the filtrate at -5~0℃ for 6h, filter , and dried at 60-70° C. for 6 hours to obtain 1.86 kg of white crystalline milrinone with a yield of 84.2% and a purity of 99.93% (HPLC method).

Embodiment 3

[0043]Take 2 kg (10.5 mol) of 1-ethoxy-2-(4-pyridyl) vinyl methyl ketone, add 22 L of 60vt% ethanol to dissolve, add 1 kg (11.9 mol) of cyanoacetamide, stir to dissolve, add dropwise hydrogen to oxidize Sodium 80% ethanol solution 6.5L (sodium hydroxide content 1.3kg), temperature control below 0°C; after dropping, stir at -5~0°C for 16h, add 15L of water to the reaction solution, add 500g of activated carbon, stir at room temperature for 20min, filter, Adjust the pH of the filtrate to 7 with dilute hydrochloric acid, filter, wash the filter cake with water until the filtrate is colorless, add 2.1kg of wet dexmilrinone, add 50vt% ethanol 42L to dissolve, filter, stir and crystallize the filtrate at -5~0℃ for 6h, filter , and dried at 60-70° C. for 6 hours to obtain 1.79 kg of white crystalline milrinone with a yield of 81.0% and a purity of 99.96% (HPLC method).

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Abstract

The invention discloses a preparation method of high-purity milrinone. The method comprises the steps of dissolving 1-ethoxyl-2-(4-pyridyl) methyl vinyl ketone, cyanoacetamide and alkali into a monohydric alcohol-water system, reacting for 15-18 hours at -5 DEG C to 10 DEG C, adding water into reaction liquid and diluting to 1.5 times of the original volume after completing reaction, then adding activated carbon, stirring for 15-25 minutes at room temperature, filtering, regulating the pH value of filtrate to be 7 by using a hydrochloric acid solution, filtering, washing a filter cake by using water until the filtrate is colorless, refluxing and dissolving the filter cake by using 50vt% ethanol, filtering, and stirring and crystallizing the filtrate at -5 DEG C to 10 DEG C to obtain white solid milrinone with the purity of more than 99.9%. The method disclosed by the invention is simple and fast in process, high in yield and pure in product, and is more suitable for industrial production.

Description

1. Technical field [0001] The invention relates to a preparation method of known medicines, in particular to a preparation method of high-purity milrinone, which belongs to the technical field of medicine. 2. Background technology [0002] Milrinone (Milirinone, formula (I)), the chemical name is 1,6-dihydro-2-methyl-6-oxo-(3,4'-bipyridine)-5-carbonitrile, first introduced by Sterling in the United States The company successfully developed the product, and it was listed in the United States for the first time in 1987. Milrinone is a cardiac phosphodiesterase inhibitor, which is suitable for short-term treatment of patients with severe congestive heart failure who are ineffective in conventional maintenance therapy. It has stronger curative effect than amrinone and fewer adverse reactions. It has played an increasingly important role in the treatment of congestive heart failure (CHF) and peripheral vasodilation. [0003] There are many synthetic routes of milrinone, and the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 吴标凌林王周红
Owner 合肥启旸生物科技有限公司
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