RU2442770C1 - Way of amine acidylation - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to the field of carboxylic acid N-displaced amids synthesis that may be used in chemical industry, notably to the new way of amine acidylation. The method consists in interaction between the amine and acyl chloride in the inert solvent that is not mixed with water; the reaction is performed within the temperature range from 15 to 25°C by subsequent introduction of amine, lithium hydride, acyl chloride and water into the inert solvent, and extraction of the target product is performed by boiling-down of the spirit separated from the water layer.

EFFECT: increase of purity and yield of the end product and simplification of the extraction stage due to the high purity of the obtained amids.

3 cl, 4 ex

Description

The invention relates to the field of synthesis of N-substituted carboxylic acid amides and determines the conditions for their preparation. The implementation of the present invention leads to the production of N-substituted amides of carboxylic acids - compounds that can be used in the chemical industry.

There are several well-known methods for the acylation of amines, such as: acylation with carboxylic acids, esters of carboxylic acids, halides and carboxylic acid anhydrides.

Thus, a method for acylation of amines with carboxylic acids of amines is known under heating and elevated pressure. Often this results in the oxidation of amines, which requires the introduction of various additives, such as sodium iodide, which is described in US patent No. 3409670. The disadvantages of this method are the process in an autoclave at elevated temperatures and the need for purification of the final product by recrystallization.

A known method of acylation of amines with esters of carboxylic acids in the presence of enzymes (US patent No. 5728876), the disadvantage of this method is the use of an expensive enzyme.

A known method of acylation of amines with 2-benzothiazolylthioesters of carboxylic acids (US patent No. 5359057), the disadvantage of this method is the use of inaccessible reagents.

In the case of acylation with carboxylic acid halides for a more complete reaction, hydrogen halide acceptors, for example, triethylamine, pyridine, aqueous solutions of alkalis or salts of weak acid and strong base (Schotten-Bauman method) are introduced into the reaction medium.

When amines (triethylamine, pyridine, etc.) are used as an acceptor of hydrogen halide, it becomes necessary to purify the final product from the formed amine halide, from unreacted carboxylic acid halide, usually added in a small molar excess, and also from the unreacted amine acceptor and hydrogen halide.

In the case of using the Schotten-Bauman method, the halide is hydrolyzed in an aqueous alkaline medium, as a result of which a significant excess of the carboxylic acid halide is required to completely convert the amine to amide.

Closest to the present invention is a method for the acylation of amines (Canadian patent No. 610182A), in which the reaction between the amine and the carboxylic acid chloride is carried out in the presence of sodium carbonate dissolved in water containing chloride ions to reduce the hydrolysis of the carboxylic acid chloride at a temperature of from 70 up to 75 ° C followed by an additional introduction of carboxylic acid chloride.

The disadvantages of this method are: the process at elevated temperatures, which can lead to side processes for amines containing reactive groups, and the need for additional administration of carboxylic acid chloride to achieve complete amine conversion.

The aim of the invention is to increase the yield and purity of amides, simplifying the stage of separation of target amides.

This is achieved by the sequential introduction of an amine of the general formula into an inert solvent:

,

,

where R is hydrogen, alkyl, aryl;

R 'is alkyl, aryl;

lithium hydride (LiH); carboxylic acid chloride of the general formula:

,

,

where R "is alkyl,

and water at a temperature of from 15 to 25 ° C, followed by separation of the organic and aqueous phases and the allocation of the target amide by evaporation of the organic phase.

Distinctive features of the proposed method are the process at temperatures from 15 to 25 ° C and the sequential introduction of an inert solvent of amine, lithium hydride, carboxylic acid chloride and water.

The general procedure for the acylation of amines with carboxylic acid chlorides is as follows. At a temperature of 15 to 25 ° C in an inert solvent that is not miscible with water, for example, toluene, benzene, xylene, hexane, etc., amine is dissolved, the amine concentration is determined based on its solubility in the selected solvent. Then load lithium hydride in the form of a powder with a particle size of not more than 0.1 mm, with a molar excess in relation to the amine from 1.05 to 2.2 mol and mix until the reaction mass is homogenized, but not less than 20 minutes. After the suspension is formed, the carboxylic acid chloride is charged with a molar excess of at least 1.05 with respect to the amine, with a preferred range of 1.1 to 1.6 mol, and stirred for about 60 minutes. After the specified time, distilled water with an excess of at least 5 mol is charged and stirred until gas evolution ceases, but for at least 30 minutes, the evolved hydrogen is removed from the reactor. After gas evolution ceased, the organic layer was separated, dried with a suitable desiccant and evaporated to dryness to give the desired amide.

In the case of difficultly acylated amines, to separate from the unreacted amine after gas evolution is completed, the aqueous layer is acidified with a suitable acid to ensure protonation of the amine and its dissolution in the aqueous phase, and the organic layer containing the target amide is isolated, which is isolated as described above.

In the case of using a solvent miscible with water, for example acetonitrile, after gas evolution is completed, an additional portion of water and a solvent not miscible with water are added to the reaction mass, and the target amide is extracted, which is then isolated as described above.

The technical result achieved in the claimed invention is to increase the purity and yield of the final product by lowering the temperature in the reaction mass, sequentially introducing amine, lithium hydride, carboxylic acid chloride and water into an inert solvent and simplifying the isolation step due to the high purity of the obtained amides .

The following examples do not limit the scope of the proposed invention.

Example 1

In a reactor equipped with a stirrer and thermometer, 10 ml of toluene and 0.5 g (5.7 mmol) of N-methylbutylamine are charged. Then, at a temperature of 15 to 25 ° C., 0.1 g (12.5 mmol) of lithium hydride was charged and stirred for 20 minutes. After homogenizing the reaction medium, 0.85 g (9.2 mmol) of propionic acid chloride are charged and stirred for 60 minutes, while gas is released. Then, 10 ml of distilled water is charged into the reactor and stirred for 30 minutes, while gas evolution is also observed. After the specified time, the organic layer is separated, dried with anhydrous sodium sulfate, the desiccant is filtered off, washed with toluene, the filtrate is analyzed (according to gas chromatographic analysis, the ratio of the peak area of the final amide to the peak area of the starting amine is 100%) and evaporated to dryness. Obtain 0.8 g of N-methyl-N-butylpropanamide. Yield 97.4%.

Example 2

In a reactor equipped with a stirrer and thermometer, 10 ml of toluene and 1 g (5.9 mmol) of N, N-diphenylamine are charged. Then, at a temperature of 15 to 25 ° C., 0.1 g (12.5 mmol) of lithium hydride was charged and stirred for 20 minutes. After homogenizing the reaction medium, 0.85 g (9.2 mmol) of propionic acid chloride are charged and stirred for 60 minutes. Then, 10 ml of distilled water is charged into the reactor and stirred for 30 minutes, while gas evolution occurs. After the specified time, the organic layer is separated and analyzed (according to gas chromatographic analysis, the ratio of the peak area of the final amide to the peak area of the starting amine is 74.5%), it is washed with 18% of the mass. hydrochloric acid, dried with anhydrous sodium sulfate, the desiccant is filtered off, washed with toluene and the filtrate is evaporated to dryness. 0.98 g of N, N-diphenylpropanamide is obtained. Yield 73.6%.

Example 3

In a reactor equipped with a stirrer and thermometer, 10 ml of acetonitrile and 1 g (5.9 mmol) of N, N-diphenylamine are charged. Then, at a temperature of 15 to 25 ° C., 0.1 g (12.5 mmol) of lithium hydride was charged and stirred for 20 minutes. After homogenizing the reaction medium, 8.5 g (92 mmol) of propionic acid chloride are charged and stirred for 60 minutes. Then, 10 ml of distilled water is charged into the reactor and stirred for 30 minutes, while gas evolution occurs. After the specified time to the reaction mass add 20 ml of 50% of the mass. potassium hydroxide solution and extracted three times with 20 ml of diethyl ether. The organic layer is analyzed (according to gas chromatographic analysis, the ratio of the peak area of the final amide to the peak area of the starting amine is 90.1%), washed with 18% of the mass. hydrochloric acid, dried with anhydrous sodium sulfate, the desiccant is filtered off, washed with ether and the filtrate is evaporated to dryness. 1.18 g of N, N-diphenylpropanamide are obtained. Yield 88.7%.

Example 4

0.1 g (12.5 mmol) of lithium hydride are charged to a reactor equipped with a stirrer and a thermometer, 15 to 25 ° C, and stirred for 20 minutes. After homogenizing the reaction medium, 0.85 g (9.2 mmol) of propionic acid chloride are charged and stirred for 60 minutes. Then, 10 ml of distilled water is charged into the reactor and stirred for 30 minutes, while gas evolution occurs. After this time, the organic layer is separated, dried with anhydrous sodium sulfate, the desiccant is filtered off, washed with toluene, the filtrate is analyzed (according to gas chromatographic analysis, the ratio of the peak area of the final amide to the peak area of the starting amine is 100%) and evaporated to dryness. 0.675 g of N-phenylpropanamide is obtained. The yield is 76.6%.

Thus, when carrying out the acylation of amines by the proposed method, the purity and yield of the final products are increased and the isolation step is simplified due to the high purity of the resulting amides.

Literature

1. US patent 3409670. Acylation of aromatic amines / Earl A. Nielsen, Applicant and Patent Holder, Universal Oil Products Company - No. 530358; declared 02/28/1966; publ. 11/05/1968. - 2 p.

2. US patent 5359057, IPC ⁵ C07D 501/06, C07D 499/12. Acylation of amines / Andre Furlenmeier, Urs Weiss, Applicant and Patent Holder Hoffmann-La Roche Inc. - No. 822173; declared 01/16/1992; publ. 10/25/1994. - 9 p.

3. US patent 5728876, IPC ⁶ C07C 231/02; C07C 231/16. Resolution of the racemates of primary and secondary amines by enzyme-catalyzed acylation / Friedhelm Balkenhohl, Bemhard Hauer, Uwe Pressler, Christoph Nubling, applicant and patent holder BASF Aktiengesellschaft. - No. 596238; declared 09/16/1994; publ. 03/17/1998. - 6 p.

4. Patent 610182A Canada. Acylation of amines / Kinstler Robert, applicant and patent holder of American Cyanamid Co. - No. 610182D; publ. 12/6/1960. - 5 sec.

Claims (3)

1. The method of acylation of amines by the interaction of an amine with a carboxylic acid chloride in an inert solvent not miscible with water, characterized in that the reaction is carried out in the temperature range from 15 to 25 ° C, with the sequential introduction of an amine, lithium hydride, carboxylic acid chloride into an inert solvent and water, the selection is carried out by evaporation of an organic solvent separated from the aqueous layer. 2. The method according to claim 1, characterized in that a solvent miscible with water is used as an inert solvent, the isolation is carried out after additional introduction of water and a solvent not miscible with water, by evaporation of the latter after separation from the aqueous layer. 3. The method according to claims 1 and 2, characterized in that when the initial amine is not completely consumed, the organic solvent containing the product with the starting amine is purified from the amine by washing with water at a pH that ensures dissolution of the starting amine in an aqueous medium.