Process for the manufacture of nicorandil

A technology of nicorandil and nitric acid, applied in the field of preparing nicorandil, can solve problems such as safety hazards, unfavorable economic and industrial safety, large processing volume and the like

Active Publication Date: 2013-10-23
PROCOS
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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 (althou

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
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis of Nicorandil

[0058] A 100 mL three-neck reaction flask purged with nitrogen and equipped with an anchor magnetic stirrer, temperature probe and dropping funnel was charged with 6.00 g of glacial acetic acid, followed by the addition of 1.35 g of 68% nitric acid. The system was thermostated at a temperature of 22°C, and 4.00 g of acetic anhydride was added within about 15 minutes. Stir the system for about 15 minutes; then add 1.00 g of N-(2-hydroxyethyl)nicotinamide in batches within ≈15 minutes, and the temperature does not exceed 22°C. The system was stirred at 22°C for 30 minutes, then the progress of the reaction was checked by HPLC. N-(2-hydroxyethyl)nicotinamide content <1%. The contents of the flask were slowly poured into 24% aqueous ammonia (14.0 g), taking care that the temperature did not exceed 35 °C. The temperature was lowered to 5°C and held for about 30 minutes. The solid was isolated by filtration and washed with 1 mL of water.

[0059...

Embodiment 2

[0061] initial magnification

[0062] 300 g of glacial acetic acid was charged to a 1000 mL three-neck reaction flask purged with nitrogen and equipped with an anchor magnetic stirrer, temperature probe and dropping funnel, followed by the addition of 67.5 g of 68% nitric acid. The system was kept at a temperature of 18°C, and 200 g of acetic anhydride was added within about 45 minutes, being careful not to exceed 25°C and stopping the addition if it exceeded this threshold. The reaction is very rapid, so the reaction can be controlled by reagent addition. The system was stirred for about 30 minutes; then cooled to 15°C, and 50.0 g of N-(2-hydroxyethyl)nicotinamide was added in five identical 10.0 g portions at 15 minute intervals, after each addition Take care to return the temperature to 15°C before. The system was stirred at 22°C for 90 minutes, then the progress of the reaction was checked by HPLC. N-(2-hydroxyethyl)nicotinamide content <1%. The contents of the flask w...

Embodiment 3

[0065] Synthesized by sulfuric acid / nitric acid mixture (reaction time 90 minutes; temperature 10°C)

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

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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 the method for the synthesis of nicorandil (1) 2-(nicotinamide) ethyl nitrate starting from N-(2-hydroxyethyl) nicotinamide (15) and using nitric acid nitration in the presence of acetic anhydride . Background of the invention [0002] Nicorandil is a vasodilator used in the treatment of angina. Many synthetic methods are known. [0003] DE2714713 discloses the preparation of nicorandil (1) starting from nicotinoyl chloride hydrochloride (2) and 2-aminoethyl nitrate nitrate (3). [0004] [0005] A slightly modified version of the protocol proposed in DE2714713 was used in various references. US4200640 discloses the preparation of nicorandil starting from nicotinoyl 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 by nicotinyl chloride (5), which is treated with 2...

Claims

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Application Information

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IPC IPC(8): C07C201/02
CPCC07C201/02C07C203/04
Inventor A·巴罗扎M·科隆博J·罗来多P·派索尼
Owner PROCOS
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