RU2147577C1 - Method of preparing n-(2-nitroxyethyl)nicotineamide - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: described is method of preparing N-(2-nitroxyethyl)nicotineamide by nitration of N-(2-hydroxyethyl)nicotineamide. Nitration is carried out with nitrating mixture containing nitric and sulfuric acid and water. EFFECT: cheaper explosion-proof and more technological method. 8 cl, 6 ex

Description

известного также под названием никорандил. N-(2- нитроксиэтил)никотинамид является принципиально новым высокоэффективным антиангинальным лекарственным средством класса органических нитратов. Его различные лекарственные формы находят все более широкое применение в мировой медицинской практике [Am. J. Cardiology, 1989, 63, N 21, 1-85 (15 публикаций по материалам симпозиума "Новое в лечении стенокардии и сердечной недостаточности", Сан-Франциско, 17.10.1987); Машковский М.Д. Лекарственные средства. Тринадцатое издание, новое. Харьков, Олма пресс, т. I, 1998, стр. 396, 429]. N-(2-нитроксиэтил)никотинамид в России не производится.The invention relates to a method for producing N- (2-nitroxyethyl) -nicotinamide of the formula I

also known as nicorandil. N- (2-nitroxyethyl) nicotinamide is a fundamentally new highly effective antianginal drug of the class of organic nitrates. Its various dosage forms are increasingly used in world medical practice [Am. J. Cardiology, 1989, 63, N 21, 1-85 (15 publications on the materials of the symposium "New in the treatment of angina pectoris and heart failure", San Francisco, 10/17/1987); Mashkovsky M.D. Medicines Thirteenth Edition, New. Kharkov, Olma Press, vol. I, 1998, p. 396, 429]. N- (2-nitroxyethyl) nicotinamide is not produced in Russia.

The known processes for the preparation of N- (2-nitroxyethyl) -nicotinamide are based on two different chemical reactions. So, in the Japanese patent [jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983] and subsequent patents obtained by the patent holder [jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983] in Germany [US Pat. Germany N 2714713 dated 2.04.1978, publ. 10.20.1977], Belgium [US Pat. Belgium N 853144 from 01.04.1977, publ. 1.08.1977], USA [US Pat. USA N 4200640 from 09/07/1978, publ. 04/23/1980] and the USSR [US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983], a method for its preparation by the reaction of nicotinic acid derivatives (acid chloride, anhydride, ester, etc.) with 2-nitroxyethylamine (NH ₂ CH ₂ CH ₂ ONO ₂ ) is described. 2-Nitroxyethylamine is introduced into the reaction in the form of a nitrate salt, which is a fairly powerful explosive with detonation characteristics and shock sensitivity superior to TNT [Jahresber. chem. -techn. Reichsanstalt. , 1933-1935, 244].

 This makes the production of N- (2-nitroxyethyl) nicotinamide explosive in this way.

с концентрированной дымящей азотной кислотой с последующим выделением целевого продукта формулы I при подщелачивании безводным карбонатом натрия (или калия) реакционной массы, предварительно разбавленной водой.Other methods for producing N- (2-nitroxyethyl) nicotinamide [lap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983, US Pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983, Japanese application N 2-207072 (A) dated 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982, US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993] based on the interaction of N- (2-hydroxyethyl) -nicotinamide of the formula II (or its hydrochloride, hydronitrate)

with concentrated fuming nitric acid, followed by isolation of the desired product of formula I when alkalinized with anhydrous sodium carbonate (or potassium) carbonate, the reaction mixture previously diluted with water.

 When the concentration of the initial nitric acid is below 90%, the yield of the target product is markedly reduced: at 85% concentration it is below 30%, and at 70% concentration the target product cannot be isolated [Jap. application, N 2-207072 (A) from 02/06/1989, publ. 08.16.1990].

As the closest in technical essence analogue - prototype, we have chosen a Polish patent [US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993], in which, in comparison with other analogues [Jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983, US Pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983, Japanese application N 2-207072 (A) dated 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982], the stage of purification of the target product has been changed. The essence of the method of obtaining N- (2-nitroxyethyl) -nicotinamide is to add 1 weight. including N- (2-hydroxyethyl) -nicotinamide of the formula II to 3 weight. including fuming nitric acid at a temperature of from -10 to -5 ^° C, additionally stirring the reaction mixture at a temperature of 0-5 ^° C for 1 h, pouring the reaction mixture into a mixture of water and ice, alkalizing the resulting solution with crystalline sodium carbonate (or potassium ) and filtering the raw product. Purification of the raw material from impurities was carried out by washing with cold water and subsequent drying at a temperature not exceeding 30 ^o C. The product obtained from this purification has a mp of 92 ^o C and, according to the authors [US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993], does not need additional cleaning. In the Japanese application [jap. application N 2-207072 (A) dated 02/06/1989, publ. 08/16/1990], where organic solvents were used in the purification, the product had mp 92.5-93.5 ^o C.

Since the ability of concentrated nitric acid to form explosive solutions with organic combustibles is widely known, we are following the method of [Eremenko LT, Nesterenko DA Proc. 20th Intern. Pyrotechnics Seminar, July 25-29, 1994, pp 265-277], the detonation ability of the homogeneous reaction masses obtained by mixing 1 weight was tested. including N- (2-hydroxyethyl) nicotinamide with 3 weight. including nitric acid in two concentrations: 94 and 100%. Before testing the detonation ability of the nitromass was stirred for 30 minutes at a temperature of about 0 ^o C. Both masses were detonative. A system based on 94% nitric acid has a relative detonation momentum at the level of TNT, a system based on 100% nitric acid is 6% higher. Thus, the nitration process of N- (2-hydroxyethyl) nicotinamide with concentrated nitric acid [Jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983, US Pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983, Japanese application N 2-207072 (A) dated 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982, US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993] is also explosive. A natural consequence of the high chemical activity of concentrated nitric acid is the need for the nitration process at low temperatures (up to -10 ^o C). In addition, the processes of neutralizing the excess of nitric acid and the subsequent conversion of the salt of the target product into its basic form using sodium carbonates (or potassium) are associated with the release of carbon dioxide, foaming of the mass and an increase in the volume of equipment used. These drawbacks are exacerbated by the use of large excesses of concentrated nitric acid: the molar ratio of nitric acid to the substrate is in the range of 8-14 [jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983, US Pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983, Japanese application, N 2-207072 (A) from 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982, US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993].

 The aim of the invention is to develop an explosion-proof, cheaper and more technologically advanced method for producing N- (2-nitroxyethyl) -nicotinamide (I) by nitration of N- (2-hydroxyethyl) nicotinamide (II).

This goal is achieved by the fact that N- (2-hydroxyethyl) nicotinamide is introduced into interaction with a mixture of nitric and sulfuric acids of a certain composition, ensuring the formation of a non-detonating reaction mass, at a temperature of 0-25 ^o C, stirred at this temperature for 0.5-1 h , poured into ice water, neutralized with an aqueous solution of ammonia. The precipitate formed is filtered off, washed from impurities with cold water, dried in a vacuum and N- (2-nitroxyethyl) -nicotinamide is obtained in a yield of 82-88%, etc. 91-92 ^o C. If necessary, N- (2-nitroxyethyl) nicotinamide is recrystallized from distilled water. After drying, a product is obtained with mp. 92.5-93.5 ^o C. The composition of mixtures of nitric and sulfuric acids, which provides non-knockability of the reaction mass under test conditions [Eremenko LT, Nesterenko DA Proc. 20th Intern. Pyrotechnics Seminar, July, 25-29, 1994, pp 265-277] and at the same time allows to obtain a high-quality target product with a high yield, can vary within certain limits. The content of nitric acid in the system of nitric acid-sulfuric acid-water should not exceed 45 weight. %, and the amount of water should be sufficient to obtain a homogeneous and non-detonating reaction mass. The use of such mixtures can significantly reduce the consumption of concentrated fuming nitric acid; they can be prepared, for example, on the basis of much cheaper 65-70% nitric acid. In addition, the use of sulfuric-nitric acid mixtures allows to reduce the molar ratio of nitric acid to the substrate to 3-4 and to carry out nitration at higher temperatures, from 0 ^o C to room temperature, for 0.5-1 hours

 In addition, the goal is achieved by replacing at the stage of neutralization of sodium carbonates (or potassium) with an aqueous solution of ammonia. This allows you to avoid gas evolution and to obtain more water-soluble ammonium salts, as a result of which the volume of the equipment used is reduced and, under salting out conditions, a sufficient completeness of the isolation of the target product is ensured.

A very significant new feature of the invention is the simplification of the purification process of N- (2-nitroxyethyl) nicotinamide by replacing the used fire hazardous and toxic organic solvents [Jap. US Pat. N 58-17463, declared. 04/04/1976, publ. 04/07/1983, US Pat. Germany N 2714713 dated 2.04.1978, publ. 10/20/1977, pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USA N 4200640 from 09/07/1978, publ. 04/23/1980, US Pat. USSR N 999965 dated 1.04.1977, publ. 02/23/1983, Jahresber. chem.-techn. Reichsanstalt., 1933-1935, 244, Japanese. application N 2-207072 (A) dated 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982] on the water. This allows you to get N- (2-nitroxyethyl) -nicotinamide with so pl. 92.5-93.5 ^o C.

 The invention is characterized by the following examples, which only illustrate some of its applications, but do not limit its capabilities. In particular, nitrating mixtures of any given composition containing nitric acid, sulfuric acid and water can be prepared in a variety of ways, taking into account economic and technological feasibility.

Example 1. To 3.48 weight. including nitrating mixture containing 33.5% nitric acid, 52.9% sulfuric acid and 13.6% water, with stirring and a temperature of 8-12 ^o C gradually add 1 weight. including N- (2-hydroxyethyl) - nicotinamide, stirred for another 30 minutes at this temperature. The resulting solution was poured into a mixture of ice water and neutralized with an aqueous solution of ammonia to a slightly alkaline environment. The precipitated crystals are filtered off and washed with cold water. After drying at room temperature, 1.05 wt. including N- (2-nitroxyethyl) nicotinamide (yield 83%) with mp. 91-92 ^o C. After recrystallization from water and drying in vacuum, so pl. 92.5-93.5 ^o C.

Example 2. In the conditions of example 1 to 4.31 weight. including a mixture containing 34.5% nitric acid, 54.5% sulfuric acid and 11% water, at a temperature of 15-18 ^o C add 1 weight. including N- (2-hydroxyethyl) nicotinamide, stirred for another 1 h at this temperature and secrete 1.07 weight. including N- (2-nitroxyethyl) nicotinamide (yield 84%), mp 91-92 ^o C. After purification in the conditions of example 1 so pl. 92.5-93.5 ^o C.

Example 3. In the conditions of example 2, the reaction mass was obtained at a temperature of 20-25 ^o C, stirred for another 30 minutes at this temperature and secrete 1.06 weight. including N- (2-hydroxyethyl) nicotinamide (yield 83%), mp 91-92 ^o C. After purification in the conditions of example 1 so pl. 92.5-93.5 ^o C.

Example 4. In the conditions of example 1 to 4.83 weight. including a mixture containing 24.2% nitric acid, 65.5% sulfuric acid and 10.4% water, 1 weight is added. including N- (2-hydroxyethyl) nicotinamide and secrete 1.12 weight. including N- (2-nitroxyethyl) -nicotinamide (88% yield), mp 91-92 ^o C. After purification in the conditions of example 1 so pl. 92.5-93.5 ^o C.

Example 5. In the conditions of example 1 to 5.02 weight. h of a mixture containing 23.1% nitric acid, 62.9% sulfuric acid and 14% water, add 1 weight. h N- (2-hydroxyethyl) nicotinamide and secrete 1.05 weight. including N- (2-nitroxyethyl) nicotinamide (83% yield), mp 91-92 ^o C. After purification in the conditions of example 1 so pl. 92.5-93.5 ^o C.

Example 6. In the conditions of example 1 to 4.46 weight. including a mixture containing 44.4% of nitric acid, 42.2% of sulfuric acid and 13.4% of water, at a temperature of 0-5 ^o C add 1 weight. including N- (2-hydroxyethyl) nicotinamide, stirred for another 1 h at this temperature and allocate 1.05 weight. including N- (2-nitroxyethyl) nicotinamide (yield 84%), mp 91-92 ^o C. After purification in the conditions of example 1 so pl. 92.5-93.5 ^o C.

 Thus, the use of the proposed technical solution allows you to achieve your goal and get 2-nitroxyethyl nicotinamide of the formula I explosive and fireproof, more technological and cheap way. So, ceteris paribus, N- (2-nitroxyethyl) nicotinamide obtained by the proposed method, only at the cost of the initial chemical raw materials is 1.5 times cheaper than when obtained by the prototype method [US Pat. Poland N 162496 from 01/31/1990, publ. 12/31/1993] and significantly cheaper compared to other analogues [US Pat. Belgium N 853144 from 01.04.1977, publ. 08/08/1977, US Pat. USSR N 999965 dated 1.04.1977, publ. 11/23/1983, Japanese application N 2-207072 (A) dated 02/06/1989, publ. 08.16.1990, US Pat. USSR N 942593 from 07.28.1978, publ. 07/10/1982]. In the preparation of mixtures of nitric acid-sulfuric acid-water, nitric acid of various concentrations is used (including relatively cheap nitric acid with a concentration of 65-70%), and the total consumption of nitric acid is significantly reduced. Such mixtures are more stable and generally cheaper than fuming nitric acid. In addition, any of the selected compositions can be prepared in various ways, taking into account economic and technical aspects. The use of ammonia at the stage of neutralization eliminates undesirable processes of gas formation and foaming and allows the production of ammonia salts, the utilization of which creates fundamental opportunities for further cheapening the target product and organizing the entire process of its production as a whole without generating harmful production waste. And finally, a simple, fireproof and cheaper way to purify the target product by recrystallization from water is proposed.

Claims (8)

1. The method of obtaining N- (2-nitroxyethyl) nicotinamide of the formula I

nitration of N- (2-hydroxyethyl) nicotinamide of the formula II

characterized in that the compound of formula II is reacted with a nitration mixture containing nitric and sulfuric acids and water.  2. The method according to claim 1, characterized in that the use of nitric acid of various concentrations, including 65 - 70%.  3. The method according to claims 1 and 2, characterized in that the molar ratio of nitric acid to the compound of formula II is at least three.  4. The method according to claims 1 to 3, characterized in that the nitrating mixture contains not more than 45 wt.% Nitric acid. 5. The method according to PP.1 to 4, characterized in that the nitration process is carried out at a temperature of from 0 ^o C to room temperature for 0.5 to 1 hour  6. The method according to claims 1 to 5, characterized in that the compound of formula I is isolated by diluting the reaction mass with water, followed by neutralization with ammonia.  7. The method according to claims 1 to 6, characterized in that the compound of formula I is washed with water and dried.  8. The method according to PP. 1 to 6, characterized in that the target product is purified by recrystallization from water, followed by drying in a known manner.