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Process for the manufacture of nicorandil

A nicorandil and molar ratio technology, applied in the field of preparing nicorandil, can solve the problems of large processing volume, unfavorable economic and industrial safety, safety hazards and the like

Active Publication Date: 2015-03-18
PROCOS SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The industrial synthesis of 2-aminoethyl nitrates is extremely dangerous in terms of safety, since low molecular weight nitroesters are known to involve high hazards associated with their explosive potential, as evidenced by the strict restrictions governing the transport of these substances
[0037] Safe industrial application of these methods therefore requires plants, properly dimensioned in terms of isothermal performance, fitted with adequately controlled or rapid quenching systems (although quenching systems are usually based on immediate dilution of runaway reactive species, they require very large process volume, requires the use of small industrial batches and is detrimental to the productivity of the method in practice)
[0038] Therefore, the synthesis method of nicorandil described in the literature is disadvantageous in terms of economy and industrial safety; therefore, there is a need for a method that is economically efficient and at the same time has a safety profile

Method used

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  • Process for the manufacture of nicorandil
  • Process for the manufacture of nicorandil
  • Process for the manufacture of nicorandil

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Synthesis of Nicorandil

[0058] 6.00 g of glacial acetic acid was charged into a 100 mL three-necked reaction flask equipped with an anchor-shaped magnetic stirrer, a temperature probe, and a dropping funnel, and then 1.35 g of 68% nitric acid was added. The system was kept constant at a temperature of 22°C, and 4.00 g of acetic anhydride was added in about 15 minutes. Stir the system for about 15 minutes; then add 1.00 g of N-(2-hydroxyethyl)nicotinamide in ≈15 minutes at a temperature not exceeding 22°C. The system was stirred at 22°C for 30 minutes, and then the progress of the reaction was checked by HPLC. N-(2-hydroxyethyl)nicotinamide content <1%. Pour the contents of the flask slowly into 24% ammonia water (14.0g), being careful not to exceed 35°C. Reduce the temperature to 5°C and keep it for about 30 minutes. The solid was separated by filtration and washed with 1 mL of water.

[0059] The solid was dried at 40°C for 48 hours to obtain 1.13 g of crude nicorand...

Embodiment 2

[0061] Initial zoom

[0062] 300 g of glacial acetic acid was charged into a 1000 mL three-necked reaction flask equipped with an anchor-shaped magnetic stirrer, a temperature probe, and a dropping funnel, and then 67.5 g of 68% nitric acid was added. Keep the system at a constant temperature of 18°C, and add 200g of acetic anhydride within about 45 minutes, being careful not to exceed 25°C, and stop adding if it exceeds the threshold. The reaction is very fast, so the reaction can be controlled by adding reagents. Stir the system for about 30 minutes; then cool to 15°C, and add 50.0g of N-(2-hydroxyethyl)nicotinic acid amide in five portions of the same 10.0g each at 15-minute intervals. Take care to restore the temperature to 15°C before. The system was stirred at 22°C for 90 minutes, and then the progress of the reaction was checked by HPLC. N-(2-hydroxyethyl)nicotinamide content <1%. Pour the contents of the flask slowly into 24% ammonia (700g), being careful not to excee...

Embodiment 3

[0065] Synthesis from sulfuric acid / nitric acid mixture (reaction time 90 minutes; temperature 10℃)

[0066] 18.4 g of concentrated sulfuric acid was charged into a 100 mL three-necked reaction flask filled with nitrogen and equipped with an anchor-shaped magnetic stirrer, a temperature probe, and a dropping funnel. The mixture was cooled to 0°C, and then 16.9 g of 68% nitric acid was added dropwise thereto. In view of the strong exothermic reaction, proceed with care. The system was kept at a constant temperature of 10°C, and 10.0 g of N-(2-hydroxyethyl)nicotinamide was added in about 5 minutes to maintain the temperature. The system was stirred for 30 minutes, and then the conversion was checked by HPLC. The residual N-(2-hydroxyethyl)nicotinamide content is 33.5%. The reaction mixture is colorless. The mixture was left at 10°C with stirring for another 1 hour, and then the conversion was checked again. The residual N-(2-hydroxyethyl)nicotinamide content is 25.3%. The reac...

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Abstract

Disclosed is a process for the synthesis of Nicorandil (1), 2-(nicotinamide)ethyl nitrate, starting from N-(2-hydroxyethyl)nicotinamide (15), using nitration with nitric acid in the presence of acetic anhydride Said synthesis method is particularly advantageous because it solves the safety problems involved in the use of nitric acid as nitrating agent, and allows a product with excellent yields and quality to be isolated.

Description

Summary of the invention [0001] The present invention relates to a method for synthesizing nicorandil (1) 2-(nicotinamide) ethyl nitrate by nitration with nitric acid in the presence of acetic anhydride starting from N-(2-hydroxyethyl)nicotinamide (15) . Background of the invention [0002] Nicorandil is a vasodilator used to treat angina pectoris. Many synthetic methods are known. [0003] DE2714713 discloses the preparation of nicorandil (1) starting from nicotinic chloride hydrochloride (2) and the nitrate of 2-aminoethyl nitrate (3). [0004] [0005] A slightly modified version of the procedure proposed in DE2714713 has been used in various references. US4200640 discloses the preparation of nicorandil starting from nicotinic chloride hydrochloride (2) and 2-aminoethyl nitrate in the presence of pyridine. [0006] [0007] In "Journal of Pharmaceutical Sciences (1999), 61(5), 304-305", the reaction is initiated from nicotinic acid chloride (5), which is used in the presence of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C201/02
CPCC07C201/02
Inventor A·巴罗扎M·科隆博J·罗来多P·派索尼
Owner PROCOS SPA
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