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Preparation method of nicorandil

A technology of nicorandil and dilute nitric acid, applied in the direction of organic chemistry, etc., can solve the problems of expensive starting materials, unsatisfactory yields, unstable nitrates, etc.

Inactive Publication Date: 2020-02-28
BEIJING VOBAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this synthesis process, nitrates with low carbon chains are used as intermediates. The intermediates have no ultraviolet absorption and are not easy to react and monitor, and the nitrates with low carbon chains are unstable, and improper handling is prone to safety accidents such as explosions.
The yield reported in the process patent is not very ideal, and there are many by-products, and the synthesis process needs to be further optimized
[0016] Among the three synthetic reaction routes, the starting materials used in method two are expensive and difficult to obtain, and the low-carbon chain nitrates used in method three are all very dangerous as intermediates. The starting materials used in method one The price is low and can be supplied in large quantities, but the reaction selectivity is not high and the yield is low, so there is a lot of room for improvement

Method used

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  • Preparation method of nicorandil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: the preparation of nicorandil

[0057] Pour 6.97g (75.22mmol) of 68% dilute nitric acid into a 100ml three-necked reaction flask, cool down in an ice bath to 0-10°C, weigh 17.50g of propionic acid and 12.50g of propionic anhydride into two constant-pressure dropping funnels, Slowly add them dropwise into the reaction system respectively. If the system is exothermic, control the temperature of the reaction system at 0-10°C. The dropwise addition is completed in about 10 minutes, and then keep stirring for 1 hour. Weigh 5.00g (30.088mmol) of N-(2-hydroxyethyl) nicotinic acid amine and add it to the reaction system, remove the ice bath, warm up to 20-25°C, stir and react for 3 hours, and the liquid phase monitors that the remaining raw materials are less than 1.0 %. Stop the reaction, pour the reaction solution into 50ml of 10% dilute ammonia water to disperse and stir, a large amount of white solids precipitated, lower the temperature to 0-10°C, stir and cr...

Embodiment 2

[0058] Embodiment 2. Preparation of Nicorandil

[0059] Take a 100ml three-necked reaction flask and add 8.36g (90.264mmol) of 68% dilute nitric acid, cool down in an ice bath to 0-10°C, weigh 20.00g of propionic acid and 15.00g of propionic anhydride into two constant pressure dropping funnels, respectively Slowly add dropwise to the reaction system, the system will generate heat, control the temperature of the reaction system at 0-5°C, complete the dropwise addition in about 15 minutes, keep stirring for 1.5 hours. Weigh 5.00g (30.088mmol) of N-(2-hydroxyethyl) nicotinic acid amine and add it to the reaction system, remove the ice bath, warm up to 20-30°C, stir and react for 3.5 hours, and the liquid phase monitors that the remaining raw materials are less than 0.5 %. Stop the reaction, pour the reaction solution into 50ml of 12% dilute ammonia water to disperse and stir, a large amount of white solids precipitated, lower the temperature to 0-5°C, stir and crystallize, filt...

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Abstract

The invention discloses a preparation method of nicorandil. According to the method, N-(2-hydroxyethyl)niacinamide is used as a raw material and is subjected to nitrifying under the actions of dilutenitric acid, propionic acid and propionic anhydride to obtain nicorandil. The method has the advantages of mild conditions, simple operation, stable process, cheap and easily available raw materials,high product yield, easy treatment of three wastes, small environmental pollution, and suitability for industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a medicinal compound, in particular to a preparation method of nicorandil, a drug for treating coronary heart disease and angina pectoris. Background technique [0002] Nicorandil has the following chemical structure: [0003] [0004] Nicorandil is a vasodilator drug developed by Chugi Corporation of Japan. Its chemical name is ethoxynicotinamide nitrate. It belongs to nitrate compounds and is a partial structure of N-(2-hydroxyethyl) nicotinamide vitamins and organic nitrates. It is also an ATP-sensitive potassium channel opener. Nicorandil was launched in Japan in 1984. With the further clinical application of Nicorandil, its clinical efficacy in coronary heart disease and angina pectoris has been more and more affirmed. The nicorandil dosage form listed in Japan has tablet and injection at present, and the injection dosage form was listed in Japan in 1993. After years of clinical application ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 张卫锋王磊
Owner BEIJING VOBAN PHARMA TECH CO LTD
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