CS199212B2 - Method of producing amides of pyridine-carboxylic acid - Google Patents

Abstract

Piperazides, having the general formula I <IMAGE> and their acid addition salts, wherein R<1> is a methyl or a benzyl group are prepared by reacting a compound of the general formula IV <IMAGE> wherein R is alkyl of 1 to 3 carbon atoms with a substituted piperazine of the general formula V <IMAGE> The compound of general formula IV may be made by reaction of a salt of pyridinecarboxylic acid with an alkyl chloroformate and can be used without isolation.

Description

The present invention relates to a novel process for the preparation of known pyridine carboxylic amides. The compounds obtainable according to the invention have valuable cardiovascular activity and antidepressant activity.

The piridinecarboxylic acid amides obtainable according to the invention correspond to the general formula I,

Axis-O · »· (0 in which denotes

R ^{1 is} methyl or benzyl.

The compounds of formula I are known from the following literature: Pharmacy (Bucharest) 10, 35, 81 (1962); Hungarian Patent Specification No. 162,396

a) pyridinecarboxylic acid and the corresponding piperazine derivative of formula V ^H o ^{_r <(V)} are reacted in the melt at from 140 to 250 ^{C, and} about 20 to 25 hours to obtain a yield of about 40-60%, or

(b) an ester or amide is prepared from pyridinecarboxylic acid and reacted under the conditions of (a) with a piperazine derivative of the general formula V, the yield being the same as in (a); or

c) acid chloride is prepared from pyridinecarboxylic acid and reacted with a piperazine derivative of formula V at 0-100 ° C in a yield of about 68%.

In the actual reproduction experiments, the reaction according to process variant a) was monitored thermogravimetrically in order to find an explanation for a relatively low yield. It has been found that when melting pyridine-2-carboxylic acid or when melting pyridine-2-carboxylic acid and N-benzylpiperazine together, the reaction proceeds with considerable weight losses already at 120 DEG C., i.e. significant side reactions (decarboxylation).

The reaction of (b) appears to be more favorable, but taking into account that the production of the starting material takes place in a further chemical process, the overall yield is preferably the same as or even weaker as in variant a). For reasons of air protection, the production of the starting material and the binding of a considerable amount of ammonia produced during the reaction cause difficulties in the reaction of pyridine carboxylic acid amides. The same difficulties are encountered in process variant c) by removing the resulting hydrochloric acid.

In all three production variants, the compound of formula I produced must be purified by fractional vacuum distillation.

It is an object of the present invention to provide a process which does not have the above-mentioned disadvantages (e.g. low and medium yield, long reaction time, high reaction temperature, necessity of purification by fractional vacuum distillation, formation of environmentally harmful by-products).

Surprisingly, it has now been found that virtually all the disadvantages of the described processes can be overcome and an unpolluted, extremely pure product can be obtained by reacting the pyridine carboxylic acid salt of formula ¹¹ (Q ^ COOH (II) with an organic or inorganic base first with an ester chloroformic acid of formula III,

Cl-CO 2 -R (III) wherein

R represents a C 1 -C 3 alkyl group, and the product is then reacted, expediently without isolation, with a piperazine derivative of the formula V, and the resulting compound of the formula I is optionally converted into a salt by an inorganic or organic acid.

With respect to the reaction, any solvent which does not react under the reaction conditions and does not affect the course of the reaction can be considered inert. For example, the following solvents are suitable: tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate.

The pyridine carboxylic acid salt can be formed with a tertiary amine, particularly preferably with triethylamine or N-methylmorpholine. Of the salts formed with inorganic bases, the potassium salt is particularly preferred, but other alkali metal salts can also be used successfully.

. The temperature can be varied over a wide range without appreciably affecting the yield. In general, the reaction is carried out at temperatures between -20 and +40 ° C, preferably between -5 and +20 ° C.

Purification of the end product by fractional vacuum distillation is not necessary for 1-benzyl-4- (2 4--picolinoyl) piperazine when the reaction mixture is treated with water, since in this case the product precipitates in crystalline form as a dihydrate.

The advantages of the method according to the invention over the method known from the literature can be summarized as follows:

a) a long reaction time is not required to carry out the reaction,

(b) the reaction temperature is low;

c) no special apparatus is required,

d) the resulting by-products do not cause any environmental protection problems,

(e) The compounds of formula (I) are produced in virtually quantitative yield and highly pure.

The process according to the invention is explained in more detail in the examples below, without being limited thereto.

Example 1 1-Benzyl-4- (2'-picolinoyl) -piperazine

246.2 g (2.0 mol) of pyridine-2-carboxylic acid are treated with 202.4 g (2.0 mol) of triethylamine in ethyl acetate at room temperature. 217.1 g (2.0 mol) of ethyl chloroformate are added to the reaction mixture at -5 to 0 ° C, then the mixture is stirred at the indicated temperature for 30 minutes. A solution of 352.5 g (2.0 mol) of N-benzylpiperazine in 400 ml of ethyl acetate was then added to the mixture over half an hour. After the addition was complete, the mixture was stirred at 10 ° C for 2 hours. The solution was evaporated in vacuo, the residue was dissolved in methanol and precipitated with water. 615 g (97%) of 1-benzyl-4- (2'-picolinoyl) -piperazine dihydrate melting at 81-82 ° C is obtained. ,

For C17H23N30.2H2O calculated:

% C, 64.33;% H, 7.30;% N, 13.24 ^. 7рпп ·

H, 7.42; N, 13.15.

The hydrogen fumarate melts at 165-166 ° C (melting point 164 ° C).

139212

EXAMPLE 2 1-Methyl-4- (3'-nicotinoyl) piperazine,

16.1 g (0.1 mol) of potassium nicotinic acid are treated with 10.8 g (0.1 mol) of ethyl chloroformate in a mixture of dimethylformamide and tetrahydrofuran at -5 to 0 ° C. A solution of 10.0 g (0.1 mol) of methylpiperazine in ethyl acetate was added to the mixture at the same temperature. After the addition was complete, the reaction mixture was stirred at + 10 ° C for 2 hours and then evaporated in vacuo. The residue was dissolved in dichloroethane, the solution was washed with water, then evaporated and the residue fractionated in vacuo. 18.25 g (89.0%) of the product is obtained. Boiling point 146-149 ° C / 13.3 Pa.

For C 11 H 15 N 3 O calculated:

% C, 64.36;% H, 7.34;% N, 20.47%.

H, 7.43; N, 20.56.

The melting point of the dihydrochloride was 130 ° C.

Example 3 1-Methyl-4- (4 (-isonicotinoyl) -piperazine

Isonicotinic acid (12.3 g, 0.1 mol) was converted into N-methylmorpholine (10.1 g, 0.1 mol) in ethyl acetate at room temperature. 9.40 g (0.1 mol) of methyl chloroformate are initially introduced into the reaction mixture at -5 to 0 ° C, then a solution of 10.0 g (0.1 mol) of N-methylpiperazine is added at the same temperature. in ethyl acetate. After the addition was complete, the mixture was stirred at + 10 ° C for two hours. The N-methylmorpholine hydrochloride is then filtered off, the filtrate is evaporated and the residue is fractionated in vacuo.

Yield 17.2 g (84%), b.p. 147-149 ° C / 1 mm Hg.

For C 11 H 15 N 3 O calculated:

% C, 64.36;% H, 7.37;% N, 20.47.

H, 7.48; N, 20.31.

Melting point of the dihydrochloride 271 ° C.

Claims (3)

A process for the preparation of piridinecarboxylic acid amides of the general formula I, wherein: R ¹ represents methyl or benzyl, and addition salts thereof with acids, wherein the acid salt of pyridine of formula II 0 ° ^C ( ^H ) with an organic or inorganic base is reacted in a homogeneous or heterogeneous system in the presence of an inert solvent with a chloroformic acid ester of formula III, Cl — CO2 — R. (III) where R represents a C 1 -C 3 alkyl group and the pyridinecarboxylic acid derivative of the formula IV obtained, CO-COyR ⁰ (IV) wherein R is as previously described, conveniently without isolation, reacted with a piperazine derivative of the general formula V, R ^{1, as} previously defined, and the base of the formula I obtained, optionally converted with an acid into a salt. 2. Process according to claim 1, characterized in that the salt of pyridine carboxylic acid is a salt with a tertiary amine, preferably triethylamine or N-methylmorpholine. 3. A process according to claim 1, wherein the salt of the pyridine carboxylic acid is an alkali metal salt, preferably potassium hydroxide.