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A kind of preparation method of nicorandil dimer

A technology of nicorandil dimer and condensation reaction, which is applied in the field of pharmacy and can solve the problems that it cannot be used as a reference substance for nicorandil medicines.

Active Publication Date: 2020-07-28
YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the content of nicorandil dimer impurities available in the market is less than 70%, which cannot be used as a reference substance for nicorandil medicines

Method used

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  • A kind of preparation method of nicorandil dimer
  • A kind of preparation method of nicorandil dimer
  • A kind of preparation method of nicorandil dimer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Preparation of 1-(2-(nicotinamide) ethyl)-3-((2-(nitrooxy) ethyl)carbamoyl)pyridinium-1-ium iodide

[0024] Put 50 grams of Nicorandil in 250 ml of DMF at room temperature, dissolve until clear, add 16 ml of DMF solution of methyl bromide, adjust the pH value to 7.0-9.0 with triethylamine, and stir in the dark for about 10 days under this condition , the reaction solution gradually became turbid and gradually produced LC-MS with yellow oil droplets, 315.01 (M-NO 2 ).

Embodiment 2

[0025] Example 2: Preparation of 1-(2-(nicotinamide) ethyl)-3-((2-(nitrooxy) ethyl)carbamoyl)pyridinium-1-ium iodide

[0026] At room temperature, about 1 liter of acetone was added and stirred, the oil droplets slowly disappeared and a flocculent precipitate was formed, filtered under nitrogen protection, washed with acetone to obtain a yellow solid (2.3 g, 1.99%) (purity 95.2%).

Embodiment 3

[0027] Example 3: Preparation of 1-(2-(nicotinamide) ethyl)-3-((2-(nitrooxy) ethyl)carbamoyl)pyridinium-1-ium iodide

[0028] Put 10 g of Nicorandil in 100 ml of DMF at room temperature, dissolve until clear, add 2 ml of methyl iodide, adjust the pH value to 7.0-9.0 with triethylamine, and stir in the dark under this condition for about 9 days, The reaction solution gradually became turbid and gradually produced yellow oil droplets. Add about 200 milliliters of butanone and stir, the oil droplets slowly disappeared and produced flocculent precipitates, filtered under nitrogen protection, washed with butanone to obtain a light yellow solid (0.13g, 0.56% ) (purity 97.1%).

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Abstract

The invention discloses a preparation method of high-purity nicorandil dimer. The preparation method comprises the following steps: a, in a dark environment, carrying out molecular condensation reaction on nicorandil and halogenated methane CH3X, taken as raw materials, in a neutral or weakly-alkaline environment in a polar organic solvent, so as to obtain crude nicorandil dimer; and b, adding thecrude nicorandil dimer obtained in the step a to a crystallization solvent, and precipitating and filtering to obtain high-purity nicorandil dimer, wherein X in halogenated methane CH3X is chlorine,iodine or bromine. In the preparation method, the content of dimer impurities is increased to 60% or above by a synthesis method, and then the impurities are separated and purified with crystallization process technology till the purity is up to 95% or above.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of nicorandil dimer impurities. Background technique [0002] Patent WO2012089769A1 describes the synthesis method of Nicorandil. The required raw materials include nicotinic acid, ethanolamine, absolute ethanol, sodium bicarbonate, fuming nitric acid, ether, thionyl chloride, chloroform, potassium carbonate, anhydrous magnesium sulfate, Ethanol, etc., undergoes three steps of nitration reaction, acylation reaction and refining in sequence. [0003] [0004] Nicorandil is left for a long time to undergo a degradation reaction, producing a certain by-product, Nicorandil dimer impurities. At present, the contents of dimer impurities of nicorandil available in the market are all lower than 70%, and cannot be used as reference substances for nicorandil medicines. Contents of the invention [0005] The following is an overview of the topics described in de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 桑建德康兴凯陈东王建耀韩桂芳孔维娜
Owner YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA