RU2337097C1 - METHOD OF OBTAINING N-(ISO)NICOTINOYL- γ -AMINOBUTYRIC ACID AND ITS SODIUM OR POTASSIUM SALT - Google Patents

Abstract

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to method of obtaining N-(iso) nicotinoyl-γ- aminobutyric acid or its sodium (potassium) salt, which is realized by acidifying γ-aminobutyric acid with mixed anhydride of (iso)nicotinic and aliphatic carboxylic acid or alcoxy-carbonic acid, obtained by interaction of suspension of ammonium salt or alkaline metal salt of (iso)nicotinic acid with chloranhydride of aliphatic carboxylic acid or with chloranhydride of alcoxy-carbonic acid in aprotonic polar solvent medium or in mixture of polar aprotonic and inert solvent, which does not mix with water and forms with it azeotrope. Suspension of sodium (potassium) salt of (iso)nicotinic acid is obtained by interaction of (iso)nicotinic acid with sodium or potassium hydroxide in medium of mixture of polar aprotonic solvent and enert solvent, which does not mix with water and forms azeotrope with it, with further removal of water in form of azeotrope with inert solvent. Sodium (potassium) salt of N-(iso)nicotinoyl-γ-aminobutyric acid is obtained by interaction of N-(iso)nicotinoyl-γ-aminobutyric acid with sodium or potassium hydroxide with its simultaneous or consecutive sedimentation with water-soluble ketone or alcohol, further filtration and drying or by interaction of N-(iso)nicotinoyl-γ-aminobutyric acid with sodium or potassium hydroxide in mixture of polar aprotonic solvent and inert solvent, which does not mix with water and which forms azeotrope with it or, in medium of at least one inert solvent, which does not mix with water and forms azeotrope with it, with further removal of water from reaction mixture in form of azeotrope with inert solvent and product isolation by known methods. Method allows to obtain N-(iso)nicotinoyl-γ-aminobutyric acid and its sodium or potassium salt with 87-94% output in terms of (iso)nicotinic acid.

EFFECT: increase of product output, eliminating organic amins application and simplification of technology of target product obtaining.

9 cl, 9 ex

Description

The invention relates to a technology for producing organic compounds, and in particular to a method for producing N- (iso) nicotinoyl-γ-aminobutyric acid and its sodium (potassium) salt using mixed pyridinecarboxylic and aliphatic fatty acids or carbonic esters as acylating reagents. N-acyl derivatives of γ-aminobutyric acid are used in the manufacture of pesticides and pharmaceuticals. Derivatives of nicotinic and isonicotinic acids are of particular interest. So, for example, the sodium salt of N-nicotinoyl-γ-aminobutyric acid is used as a substance of the well-known pharmaceutical preparation picamilon. Picamilon has a nootropic effect that improves cerebral circulation, it is also a part of drugs effective for stopping the symptoms of acute alcohol intoxication and for the treatment of alcohol and drug addiction

Known methods for producing N-acyl derivatives of γ-aminobutyric acid by the interaction of nicotinic acid azide [A.S. USSR 325232, MKI C07d 31/34, published on January 7, 1972] or isonicotinic acid azide [A.S. USSR 789517, MKI C07d 213/81, published December 30, 80] with the sodium salt of γ-aminobutyric acid. However, these methods are only of preparative interest, since the starting azide of (iso) nicotinic acid is difficult to access, thermally unstable and explosive.

A known method of producing a N-nicotinoyl-γ-aminobutyric acid ester by acylation of γ-aminobutyric acid ethyl ester hydrochloride hydrochloride of nicotinic acid chloride using pyridine as an acceptor of hydrogen chloride [A.S. USSR 325232, MKI C07d 31/34, published on January 7, 1972]. The same publication describes a method for producing N-nicotinoyl-γ-aminobutyric acid by acylation of γ-aminobutyric acid with mixed nicotinic anhydride and ethyl carbonate. Mixed anhydride is prepared by reacting nicotinic acid with carbonic ethyl ester acid chloride in a solvent medium using triethylamine as an acceptor of hydrogen chloride. The main disadvantages of these methods are the multi-stage technology, low yield and low product quality, the need for purification of the target product, the relatively laborious technology for the preparation of the initial nicotinic acid hydrochloride, the use of expensive hydrogen chloride acceptors such as triethylamine and pyridine, as well as the difficulty of recovering solvents and chloride acceptors hydrogen.

The closest in technical essence and the achieved result to the proposed is a method for producing N-nicotinoyl-γ-aminobutyric acid, described in [RF Patent No. 2190604, IPC C07D 213/82, publ. 10/10/2002]. In this method, the synthesis of the target product is carried out by acylation of γ-aminobutyric acid or its water-soluble salt with mixed nicotinic anhydride and pivalic acid. Mixed anhydride is prepared by reacting pivaloyl chloride and nicotinic acid in acetonitrile using triethylamine as an acceptor of hydrogen chloride. The selection of the target product is carried out by crystallization from the reaction mixture at a pH of the medium in the range of pH 3.0-5.5.

The disadvantages of the method of producing N-nicotinoyl-γ-aminobutyric acid of the prototype are:

- relatively low product yield;

- the duration of the crystallization process of the target product at the stage of selection;

- the difficulty of regeneration of acetonitrile, triethylamine and pivalic acid, the need for their thorough drying from traces of moisture;

- the use of relatively expensive triethylamine and acetonitrile.

The aim of the proposed method for producing N-nicotinoyl-γ-aminobutyric acid is:

- increase the yield of the target product and equipment performance;

- the exception from the process of expensive organic amine and simplification of the regeneration of the solvent.

The goal is also to increase the yield, quality and simplification of the technology for producing the sodium or potassium salt of N-nicotinoyl-γ-aminobutyric acid.

This goal is achieved in that the acylation of γ-aminobutyric acid is carried out with mixed pyridinecarboxylic anhydride and aliphatic carboxylic or alkoxycarbonic acid obtained by the interaction of an ammonium salt or alkali metal salt of pyridinecarboxylic acid with an aliphatic carboxylic acid chloride or alkoxychloride. The reaction is carried out in an aprotic polar solvent or in a mixture of two solvents. One of the solvents is aprotic, polar, for example, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and the second is inert, forming a heterogeneous azeotrope with water, for example benzene, toluene, xylene, ethylbenzene, etc.

The resulting reaction mixture, directly or after separation of ammonium chloride or alkali metal chloride, is reacted with γ-aminobutyric acid or a suspension of γ-aminobutyric acid in an aprotic polar solvent. From the resulting reaction mixture, the product is isolated by filtration, washing with an organic solvent, then with water and drying. Rinsing is best carried out with a low-boiling water-soluble solvent (for example, alcohol, acetone, acetonitrile, etc.), then with water and preferably again with the same solvent.

Drying of the product is usually carried out at a temperature of 35-90 ° C in a dryer of any type, preferably in a suspended layer.

At the stage of obtaining mixed anhydride and at the stage of acylation of γ-aminobutyric acid with it, the presence of moisture leads to a sharp decrease in yield due to side reactions of hydrolysis of acid chlorides and mixed anhydride. In order to avoid hydrolysis, the preparation of a suspension of a salt of (iso) nicotinic acid is carried out from its aqueous solution or a salt containing moisture in a mixture of at least one polar aprotic solvent and at least one inert solvent immiscible with water and forming an azeotrope with it, followed by removal of water in the form of an azeotrope with an inert solvent.

The regeneration of the solvents used is carried out by simple distillation, while their clear separation is not required. After distillation and composition adjustment, the solvents are used in further operations.

Extraction of by-products - alcohol or aliphatic fatty acid - is also carried out by distillation depending on the nature of the mixed (iso) nicotinic acid anhydride and aliphatic fatty acid or alkoxycarbonyl chloride used.

Distinctive features of the proposed method for producing N- (iso) nicotinoyl-γ-aminobutyric acid and its sodium or potassium salt are:

- the use of anhydrous ammonium salt or alkali metal salt of pyridinecarboxylic acid for the synthesis of mixed pyridinecarboxylic anhydride and aliphatic carboxylic or carbonic ester;

- carrying out the stages of obtaining the ammonium salt or alkali metal salt of pyridine carboxylic acid, mixed anhydride and N-nicotinoyl-γ-aminobutyric acid in the medium of at least one aprotic polar solvent, preferably in a mixture of two inert solvents, one of which is relatively high boiling polar an aprotic solvent, and the second is a low-boiling inert solvent, forming a heterogeneous azeotrope with water;

- the use of dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a mixture thereof as a high boiling polar aprotic solvent;

- use as a low boiling solvent forming a heterogeneous azeotrope with water, benzene, toluene, xylene, ethylbenzene or a mixture thereof;

- obtaining a suspension of the sodium or potassium salt of pyridinecarboxylic acid by reacting (iso) nicotinic acid with anhydrous sodium hydroxide or potassium hydroxide or with aqueous solutions of sodium hydroxide or potassium hydroxide in a polar aprotic solvent and an inert solvent immiscible with water and forming an azeotrope with it, or in an environment of at least one inert solvent which is not miscible with water and forms an azeotrope with it, followed by removal of water from the reaction mixture in the form of aze path with an inert solvent;

- obtaining a suspension of the ammonium salt of pyridinecarboxylic acid by reacting (iso) nicotinic acid with ammonia in a polar aprotic solvent and an inert solvent immiscible with water and forming an azeotrope with it, or in the medium of at least one inert solvent not miscible with water and forming an azeotrope with it;

- obtaining the sodium or potassium salt of N- (iso) nicotinic acid by reacting N- (iso) nicotinic acid with aqueous solutions of sodium hydroxide or potassium hydroxide with simultaneous or sequential precipitation of it with water-soluble ketone or alcohol, filtering and drying;

- obtaining the sodium or potassium salt of N- (iso) nicotinoyl-γ-aminobutyric acid by reacting N- (iso) nicotinoyl-γ-aminobutyric acid with anhydrous sodium hydroxide or potassium hydroxide or with aqueous solutions of sodium hydroxide or potassium hydroxide in polar aprotic a solvent and an inert solvent immiscible with water and forming an azeotrope with it, or in the medium of at least one inert solvent immiscible with water and forming an azeotrope with it, followed by removal of water from the reaction a mixture in the form of an azeotrope with an inert solvent and product isolation by filtration, washing and drying;

- obtaining the sodium or potassium salt of N- (iso) nicotinoyl-γ-aminobutyric acid by reacting N- (iso) nicotinoyl-γ-aminobutyric acid with aqueous solutions of sodium hydroxide or potassium hydroxide with simultaneous or sequential precipitation of it with water-soluble ketone or alcohol, filtering and drying.

The combination of the above features allows you to get the following positive technical result:

- increase the yield of the target product - N- (iso) nicotinoyl-γ-aminobutyric acid to 87-94% due to the elimination of the possibility of side reactions of hydrolysis of the starting acid chloride of aliphatic carboxylic acid or carbonic ester, as well as intermediate mixed anhydride;

- reduce the time of selection of the target product;

- to exclude the use of expensive organic amine as an acceptor of hydrogen chloride and, accordingly, to exclude the stage of its regeneration from the process;

- simplify the regeneration of solvents;

- to isolate related products - aliphatic acids or alcohols, depending on the acid chlorides used.

The following are examples that demonstrate the essence of the proposed method for producing N- (iso) nicotinoyl-γ-aminobutyric acid and its sodium or potassium salt, which in no way limit the scope of the claims of the description and claims.

Example 1. Obtaining sodium salt of nicotinic acid

In a reactor equipped with a stirrer, a thermometer, a Dean-Stark nozzle and a reflux condenser, 500 dm ^{3 of} toluene, 250 dm ^{3 of} dimethylformamide and 123 g of nicotinic acid are charged. The resulting suspension with stirring is heated to a temperature of 70-75 ° C, then 95 g of an aqueous 42.1% sodium hydroxide solution (40.0 g of 100%) are loaded into the reactor. The reaction mass is heated to a temperature of 95-115 ° C and at this temperature water is distilled off in the form of an azeotrope with toluene. Azeotrope vapors condense in the reflux condenser and are collected in a Dean-Stark trap, where they are divided into the lower water layer and the upper toluene layer. The toluene layer is returned to the reactor. Water is distilled off until the level of the water layer in the Dean-Stark nozzle stops increasing. After distilling off the water, the suspension of the nicotinic acid Na-salt is cooled to a temperature of 10-15 ° C, held for 1 hour and filtered. The filter cake was washed with toluene and dried at a temperature of 60-80 ° C to constant weight. Obtain 144.2 g of Na-salt of nicotinic acid with a basic substance content of 99.7%. The yield based on nicotinic acid is 98.5%.

Example 2. Obtaining a suspension of ammonium salts of isonicotinic acid

In a reactor equipped with a stirrer, thermometer, bubbler and reflux condenser, 500 dm ^{3 of} toluene, 250 dm ^{3 of} dimethylformamide and 123.0 g of nicotinic acid are charged. The resulting suspension with stirring is heated to a temperature of 30-35 ° C, then 17.0 g of ammonia are passed through a bubbler into the reactor. The resulting suspension contains 140.0 g of the ammonium salt of isonicotinic acid. The yield of ammonium salt of isonicotinic acid is quantitative.

Example 3. Obtaining a suspension of potassium salts of nicotinic acid

The synthesis is carried out analogously to example 1, except that instead of an aqueous solution of caustic soda, an aqueous solution of potassium hydroxide (140 g of a solution containing 56 g of potassium hydroxide) is used and after separation of the water the product is not isolated, but used directly in the form of the resulting suspension. The yield of potassium salt of nicotinic acid is quantitative.

Example 4. Obtaining potassium salt of nicotinic acid

In a reactor equipped with a stirrer, a thermometer and a reflux condenser, 120 dm ^{3 of} water and 56 g of solid potassium hydroxide are charged. The mixture is stirred until complete dissolution of potassium hydroxide, then 123 g of nicotinic acid are sprinkled, the mixture spontaneously warms up to 65-75 ° C and at this temperature it is kept for 15-20 minutes, then cooled to 25-30 ° C and poured with 500 dm ^{3 of} isopropyl alcohol . The resulting suspension of the potassium salt of nicotinic acid in a water-alcohol mixture is cooled to a temperature of 10-15 ° C, then the resulting salt is separated by filtration and dried. After drying, 141.6 g of the expected (99.1%) product are obtained. The yield is 97.65%.

Example 5. Obtaining N-nicotinoyl-γ-aminobutyric acid

350 dm ^{3 of} dimethylformamide, 100 dm ^{3 of} toluene and 145 g of nicotinic acid Na-salt are charged into a reactor equipped with a stirrer, a thermometer and a reflux condenser, then 128.9 g of 95% isopropyl chloroformate are dosed at a temperature of 5-7 ° C. Dosage is carried out at such a rate that the temperature in the reaction mass does not exceed 10 ° C. After dosing at a temperature of 10-12 ° C, the reaction mass is maintained for one hour and the chloride formed as a result of the reaction is separated by filtration. A suspension of 103 g of γ-aminobutyric acid in 150 dm ^{3 of} dimethylformamide is poured to a filtrate, which is a solution of a mixed nicotinic anhydride of isopropyl carbonic acid in a mixture of dimethylformamide and toluene, at a temperature of 10-15 ° C and kept at this temperature for one hour. After exposure, the resulting N-nicotinoyl-γ-aminobutyric acid was separated by filtration, washed successively with toluene, acetone, water and then dried to constant weight. After drying, 155.2 g of the expected product are obtained. The yield is 85%. The mother liquor is left at a temperature of 0-10 ° C for 24 hours and an additional 21.6 g of the target product is isolated. The total yield is 96.8%.

Example 6. Obtaining N-isonicotinoyl-γ-aminobutyric acid

In a reactor equipped with a stirrer, a thermometer, a reflux condenser, the suspension of the isonicotinic acid ammonium salt obtained in Example 2 is loaded, then it is cooled to 0-5 ° C with stirring and 126.8 g of 95% pivaloyl chloride are dosed. Dosage is carried out at such a rate that the temperature in the reaction mass does not exceed 10 ° C. After dosing at a temperature of 10-12 ° C, the reaction mass is kept for one hour and the chloride formed as a result of the reaction is separated by filtration. A suspension of 103 g of γ-aminobutyric acid in 150 dm ^{3 of} dimethylformamide is added to a filtrate, which is a solution of a mixed isonicotinic and pivalic acid anhydride in a mixture of dimethylformamide and toluene, at a temperature of 10-15 ° C and maintained at this temperature for one hour. After exposure, the resulting N-isonicotinoyl-γ-aminobutyric acid is filtered off, washed successively with toluene, acetone, water and then dried to constant weight. After drying, 176.8 g of the expected product are obtained. The yield is 85.0%. The mother liquor is left at a temperature of 0-10 ° C for 24 hours and an additional 24.5 g of the target product is isolated. The total yield is 96.8%.

Example 7. Obtaining N-isonicotinoyl-γ-aminobutyric acid

In a reactor equipped with a stirrer, a thermometer, a reflux condenser, a suspension of the potassium salt of isonicotinic acid obtained in Example 3 is loaded, then it is cooled with stirring to 0-5 ° C and 100.5 g of 94% methyl chloroformate are metered. Dosage is carried out at such a rate that the temperature in the reaction mass does not exceed 5 ° C. After dosing at a temperature of 5-10 ° C, the reaction mass is maintained for one hour and potassium chloride formed as a result of the reaction is separated by filtration. To the filtrate, which is a solution of mixed isonicotinic and methyl carbonic anhydride in a mixture of dimethylformamide and toluene, at a temperature of 10-15 ° C, 103 g of γ-aminobutyric acid are metered and kept at this temperature for one hour. After extracting from the resulting suspension, N-isonicotinoyl-γ-aminobutyric acid is separated by filtration, washed successively with toluene, acetone, water and then dried to constant weight. After drying, 185.1 g of the expected product are obtained. The yield is 89%. The mother liquor is left at a temperature of 0-10 ° C for 24 hours and an additional 16.2 g of the target product are isolated. The total yield is 96.8%.

Example 8. Obtaining the sodium salt of N-isonicotinoyl-γ-aminobutyric acid

370 dm ³ desalted water, 40.0 g sodium hydroxide and 208 g N-isonicotinoyl-γ-aminobutyric acid are charged into a reactor equipped with a stirrer, a thermometer, a Dean-Stark nozzle and a reflux condenser. After dissolving the contents, 2 g of activated carbon are loaded into the reactor and kept under stirring for 2 hours, then the activated carbon is separated by filtration. The mother liquor is returned to the reactor and 340 dm ^{3 of} dimethylformamide and 1050 dm ^{3 of} toluene are charged. The reaction mass is heated to a temperature of 100-120 ° C and water is distilled off in the form of an azeotrope with toluene. The azeotrope condenses in the reflux condenser and enters the Dean-Stark nozzle, where separation occurs into the lower water and upper toluene layers, while the toluene layer returns to the reactor. Water is distilled off until the level in the nozzle is constant. After distillation of water, the contents of the reactor are cooled to a temperature of 20-25 ° C and the precipitate of the product is filtered off, washed with toluene, then with acetone and dried. After drying, 226.5 g of product is obtained that meets all the indicators of pharmacopeia article OS 42-2862-98. The yield based on the starting acid is 98.5%.

Example 9. Obtaining a potassium salt of N-nicotinoyl-γ-aminobutyric acid

In a reactor equipped with a stirrer, a thermometer and a reflux condenser, 120 dm ^{3 of} water and 56 g of solid potassium hydroxide are charged. The mixture is stirred until complete dissolution of potassium hydroxide, then loaded with 123 g of nicotinic acid, the mixture spontaneously warms up to 65-75 ° C and at this temperature it is kept for 15-20 minutes, then cooled to 25-30 ° C and poured into 500 dm ^{3 of} acetone. The resulting suspension of the potassium salt of nicotinic acid in a water-acetone mixture is cooled to a temperature of 10-15 ° C, then filtered and dried. After drying, 141.6 g of the expected product are obtained. The yield is 97.65%.

From the above examples it follows that the proposed method allows to obtain N- (iso) nicotinoyl-γ-aminobutyric acid and its sodium or potassium salt with a yield of 87-94% in terms of (iso) nicotinic acid, eliminate the use of organic amines and simplify the production technology target product.

Claims (9)

1. The method of producing N- (iso) nicotinoyl-γ-aminobutyric acid by acylation of γ-aminobutyric acid with mixed (iso) nicotinic acid anhydride and aliphatic carboxylic acid or alkoxycarbonic acid, characterized in that the anhydride obtained by reacting the salt suspension an alkali metal or ammonium salt of (iso) nicotinic acid and an aliphatic carboxylic acid chloride or an alkoxycarbonyl chloride in at least one polar aprotic acid solvent or a mixture of at least one polar aprotic solvent and at least one inert solvent immiscible with water and forming an azeotrope with it, and the γ-aminobutyric acid acylation reaction is carried out by reacting the resulting mixed anhydride solution, possibly, but not necessarily after separation by filtration of ammonium chloride or alkali metal chloride, with γ-aminobutyric acid or a suspension of γ-aminobutyric acid in an inert solvent, preferably in polar apro Onn solvent, followed by isolation of the product by known methods. 2. The method according to claim 1, characterized in that the polar aprotic solvent is predominantly a solvent selected from the group consisting of: dimethylformamide, dimethylacetamide, dimethyl sulfoxide or mixtures thereof. 3. The method according to claim 1, characterized in that as an inert solvent immiscible with water and forming an azeotrope with it, a solvent selected from the group consisting of benzene, toluene, xylene, ethylbenzene or mixtures thereof is predominantly used. 4. The method according to claim 1, characterized in that as a suspension of an alkali metal salt of (iso) nicotinic acid, a suspension is obtained obtained by reacting (iso) nicotinic acid with anhydrous sodium or potassium hydroxide or with an aqueous solution of sodium or potassium hydroxide in a medium mixtures of a polar aprotic solvent and an inert solvent immiscible with water and forming an azeotrope with it, followed by removal of water in the form of an azeotrope with an inert solvent. 5. The method according to claim 1, characterized in that as a suspension of the ammonium salt of (iso) nicotinic acid, a suspension obtained by reacting ammonia and a solution of (iso) nicotinic acid in an aprotic polar solvent or in a mixture of an aprotic polar solvent and an inert solvent is used. 6. The method according to claim 1, characterized in that the sodium or potassium salt of (iso) nicotinic acid obtained by reacting (iso) nicotinic acid with an aqueous solution of sodium hydroxide or potassium hydroxide is used as the alkali metal salt of (iso) nicotinic acid with simultaneous or sequential precipitation of the salt with a water-soluble ketone or alcohol, followed by filtration and drying of the product. 7. A method for producing the sodium or potassium salt of N- (iso) nicotinoyl-γ-aminobutyric acid by reacting N- (iso) nicotinoyl-γ-aminobutyric acid with anhydrous sodium hydroxide or potassium hydroxide or with an aqueous solution of sodium hydroxide or potassium hydroxide followed by crystallization, filtration and drying, characterized in that the interaction of sodium hydroxide or potassium hydroxide with N- (iso) nicotinoyl-γ-aminobutyric acid is carried out in a mixture of a polar aprotic solvent and an inert solvent immiscible with water and forming an azeotrope with it or, in the medium, at least one inert solvent that is not miscible with water and forming an azeotrope with it, followed by removal of water from the reaction mixture as an azeotrope with an inert solvent and isolating the product by known methods. 8. The method according to claim 7, characterized in that as N- (iso) nicotinoyl-γ-aminobutyric acid using an acid in the reaction mixture obtained by the reaction of a mixed anhydride of (iso) nicotinic acid and an aliphatic carboxylic acid or alkoxycarbonic acid with γ-aminobutyric acid in at least one polar aprotic solvent and at least one inert solvent immiscible with water and forming an azeotrope with it. 9. The method according to claim 7 or 8, characterized in that the interaction of sodium hydroxide or potassium hydroxide with N- (iso) nicotinoyl-γ-aminobutyric acid is carried out with simultaneous or sequential precipitation of the sodium or potassium salt of N- (iso) nicotinoyl-γ -aminobutyric acid with a water-soluble ketone or alcohol, followed by isolation of the product by known methods.