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Preparation method of nikkodil

A technology of nicorandil and hydroxyethyl, applied in the field of preparation of nicorandil, can solve problems such as prolonged reaction time, degradation of target substances, consumption of alkali, etc., to solve safety problems, mild reaction process, and reduce environmental protection. effect of stress

Active Publication Date: 2020-06-12
ZHANGJIAGANG JIULI NEW MATERIAL TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation of 2-aminoethyl nitrate has high risk, low melting point, poor stability, and is not conducive to amplification, storage or handling
[0010] A method for determining nitrification conditions with sulfuric acid / nitric acid mixtures in the presence of water is further discussed in "Russian Journal of Applied Chemistry (2009), 82(10), 1776-1779", but this method is not practical and requires strict control Dangers posed by proportionality and exothermic effects
[0011] Disclosed in the patent CN103370301B is the method for preparing Nicorandil, adopts acetic acid as diluent, consumes the moisture in the concentrated nitric acid with a larger amount of acetic anhydride, this needs to release a large amount of heat in the dehydration process, prolongs the reaction time time, and creates a risk of exothermic
At the same time, there is a large amount of acetic acid. On the one hand, it is inevitable to consume a large amount of alkali for neutralization. If it is distilled, it needs to be heated, which will lead to the degradation of the target.
On the other hand, there will be a large proportion of by-products of acetate, the published data is <2%, but in practice, it is not easy to control
[0012] Therefore, the synthetic method of nicorandil described in existing literature has some adverse effects on cost and safety and environmental protection. Therefore, it is necessary to find a safe and economical method

Method used

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  • Preparation method of nikkodil
  • Preparation method of nikkodil
  • Preparation method of nikkodil

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Add 10 mL of acetonitrile into a 100 mL three-necked reaction flask, and add 2 mL of concentrated nitric acid at one time. The temperature of the system does not rise above 5°C, add 1.8mL of acetic anhydride, and control the temperature not to exceed 40°C. Then, below 25°C, 1.66g (10mmol) of N-(2-hydroxyethyl)nicotinamide was added at one time, and the temperature rise did not exceed 5°C. The reaction was monitored by TLC for 10 minutes and monitored by HPLC for 1 hour to ensure that the content of N-(2-hydroxyethyl)nicotinamide was <1%. If it was still greater than 1%, concentrated nitric acid could be added appropriately. After the reaction is complete, 5 mL of water is added to concentrate the acetonitrile, and the remaining liquid is adjusted to pH=7-8 with concentrated ammonia water, about 25-30 mL is needed. Control the temperature not to exceed 35°C. After the addition, cool to 7±2°C in ice water, stir for 1.5±0.5h, filter, wash with 2mL water to obtain a white...

Embodiment 2-9

[0042] The preparation methods of Examples 2-9 are the same as those of Example 1, except that the reaction raw materials are different. The raw materials of Examples 2-9 are shown in Table 1 below.

[0043] Table 1 embodiment 2-9 raw material and reaction result

[0044]

Embodiment 10

[0046] Add 500mL of acetonitrile, 55mL of fuming nitric acid and 80mL of acetic anhydride into a 1L three-neck flask equipped with a thermometer and a mechanical stirring device, and mix the three. The temperature does not exceed 35°C, and there is no significant exothermic feature. Then add 83g of compound N-(2-hydroxyethyl)nicotinamide at one time, and control the temperature not to exceed 42°C, usually 25±5°C is better. React for 1.5±0.5h, add 100mL of water, concentrate under reduced pressure to remove acetonitrile, adjust the pH of the residue to 7-8 with concentrated ammonia water (about 75-80ml, ie 68-73g), and precipitate a large amount of solids, forming white or slightly yellow Mushy. After filtering, the filter cake was washed with 150 ml of water for 3 times and dried to obtain 92 g of the product with a yield of 81% and a crude product purity of 99.5%. The main impurity is acetate, less than 0.2%, which can be removed by recrystallization.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of nikkodil. The preparation method includes: performing a reaction on nitric acidwith N-(2-hydroxyethyl) nicotinamide under the action of a dehydrating agent and a diluent to prepare N-(2-hydroxyethyl) nicotinamide nitrate, wherein the molar ratio of the N-(2-hydroxyethyl) nicotinamide to the nitric acid to the dehydrating agent is 1 : (2-3) : (1-2), and the volume-weight ratio of the diluent to the N-(2-hydroxyethyl) nicotinamide is (5-20) : 1. According to the preparation method of the nikkodil, the reaction process is mild and controllable, the preparation risk is low, the heat release is not obvious, a large amount of acid water is not generated, the safety problem issolved, and the environmental protection pressure is reduced; and the prepared product is high in purity and excellent in quality.

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 is a new class of anti-angina pectoris drug developed in Japan, which has dual anti-angina pectoris mechanism: the effect of nitrates is to dilate veins and epicardial coronary arteries, and to open K+-ATP channels to cause peripheral arterial and coronary artery resistance vasodilation . Its pharmacological effect is to reduce the preload and postload of the heart, increase coronary blood flow, improve coronary circulation, and prevent coronary artery spasm. Expand systemic resistance and capacity blood vessels, reduce cardiac preload and myocardial oxygen consumption; in addition, it can also relieve coronary artery spasm, increase collateral circulation and subendocardial blood supply. Therefore, Nicorandil reduces myocardial oxygen consumption while increasing myocardial oxygen s...

Claims

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Application Information

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IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 苏旭吴茂江戴霞
Owner ZHANGJIAGANG JIULI NEW MATERIAL TECH CO LTD
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