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Preparation method of Nicodil

A nicorandil and molar ratio technology, applied in the field of preparation of nicorandil, can solve the problems of large consumption of reagents, low production efficiency, many reaction steps, etc., and achieve the effects of good product quality, low cost and easy operation

Inactive Publication Date: 2021-10-15
HAIKOU TIANXINGJIAN PHARMA RES CO LTD
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  • Abstract
  • Description
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Problems solved by technology

But the reaction temperature is as high as 180°C, and the reaction yield is only 69.6%.
[0010] In order to solve the technical problems of many reaction steps in the existing preparation process, large consumption of reagents, low production efficiency, large environmental pollution, poor product quality and low yield, it is necessary to carry out the synthesis process route of nicorandil. Re-optimize the design

Method used

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  • Preparation method of Nicodil
  • Preparation method of Nicodil
  • Preparation method of Nicodil

Examples

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preparation example Construction

[0040] For ease of understanding, see Figure 1~2 , a preparation method of nicorandil, comprising the following steps:

[0041] Step (1): Add nicotinamide, ethanolamine and catalyst into the reaction kettle, heat to 120-180°C, preferably to 150-160°C, stir for 4-10 hours, and the molar ratio of ethanolamine to nicotinamide is 1.0-2.0 : 1, preferably the molar ratio of ethanolamine to nicotinamide is 1.4-1.6. Catalysts include boric acid, borate salts or borate esters, preferably boric acid, to make the reaction milder. The molar ratio of catalyst to nicotinamide is 0.01-0.3:1. The specific chemical reaction formula is as follows:

[0042]

[0043] After the reaction is over, distill under reduced pressure at 120-180°C, and control the vacuum degree ≤ -0.08Mpa until no obvious liquid is distilled out, then stop the distillation; cool the concentrate to 60-80°C, add glacial acetic acid to dissolve under stirring, and cool to room temperature. The obtained N-(2-hydroxyethyl...

Embodiment 1

[0051] One embodiment of the preparation method of a kind of nicorandil provided by the invention, comprises the following steps:

[0052] Step (1): Take 122g of nicotinamide, the catalyst boric acid and ethanolamine, and add them to the reaction kettle respectively. The molar ratio of boric acid and nicotinamide is 0.1:1, and the molar ratio of ethanolamine and nicotinamide is 1.6:1. The temperature was 140°C, and the reaction was stirred for 10h. After the reaction, carry out vacuum distillation to remove excess ethanolamine, the temperature is 140°C, turn on the vacuum, control the vacuum degree ≤ -0.08Mpa, and stop the distillation when almost no liquid flows out again. The product distilled under reduced pressure was cooled to 60°C, 122 g of glacial acetic acid was added with stirring to dissolve, and cooled to room temperature to obtain N-(2-hydroxyethyl)nicotinamide solution. The N-(2-hydroxyethyl)nicotinamide content in the N-(2-hydroxyethyl)nicotinamide solution was ...

Embodiment 2

[0058] The present embodiment provides a kind of preparation method of nicorandil, comprises the following steps:

[0059] Step (1): Take 122g of nicotinamide, the catalyst boric acid and ethanolamine, and add them to the reaction kettle respectively. The molar ratio of boric acid and nicotinamide is 0.1:1, and the molar ratio of ethanolamine and nicotinamide is 1.6:1. At 155°C, the reaction was stirred for 8h. After the reaction is over, excess ethanolamine is distilled off under reduced pressure. The temperature is 155° C., the vacuum is turned on, and the vacuum degree is controlled to be ≤ -0.08 Mpa. When almost no liquid flows out again, the distillation is stopped. The concentrated product distilled under reduced pressure was cooled to 65°C, 122 g of glacial acetic acid was added under stirring to dissolve, and cooled to room temperature to obtain N-(2-hydroxyethyl)nicotinamide solution. The N-(2-hydroxyethyl)nicotinamide content in the N-(2-hydroxyethyl)nicotinamide so...

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Abstract

The invention discloses a preparation method of Nicorandil, the preparation method comprises the following steps: directly synthesizing N-(2-ethoxyl) nicotinamide by taking nicotinamide as an initial raw material through a transamidation method, and nitrifying by using a mixture of non-fuming nitric acid, acetic anhydride and concentrated sulfuric acid to obtain Nicorandil. The method simplifies the existing synthesis process, is easy and convenient to operate and is more suitable for large-scale production; meanwhile, the yield of products obtained in each step of reaction is increased, the types and the dosage of reaction reagents are greatly reduced, and the production cost is lower. The technical problems of more reaction steps, high reagent consumption, low production efficiency, serious environmental pollution, poor quality of the prepared product and low yield of the existing preparation process are solved.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of nicorandil. Background technique [0002] Nicorandil, formerly known as Nitrazine Ester, Ethoxynicotinamide Nitrate and Nicotinamide, and its chemical name is N-(2-hydroxyethyl) Nicotinamide Nitrate, is a nitrate antianginal drug with Dilate large coronary arteries, dilate blood vessels, and reduce preload. At the same time, Nicorandil, as a highly selective potassium ATP channel opener, can relax vascular smooth muscle, dilate small coronary arteries, increase coronary blood flow, simulate ischemic preconditioning, and protect the myocardium. [0003] Nicorandil was first developed by Chugai Pharmaceutical Co., Ltd. In 1976, Chugai Pharmaceutical Company of Japan applied for patent DT2714713, and at the same time applied for US patent US4200640, which first disclosed the preparation method, pharmacology and toxicology of Nicorandil and...

Claims

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Application Information

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IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 李庆明陈恳邱安毅凌秀才尹朝亮黄敢行
Owner HAIKOU TIANXINGJIAN PHARMA RES CO LTD
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