CS235613B1 - Method of 4-methyl piperazide 2-arylthiobenzoic acids preparation and of their maleates - Google Patents

Abstract

The invention is within the scope of drug synthesis. It relates to a process for preparing 4-methylpiperazides 2-arylthiobenzoic acids formula I, /IN wherein R is hydrogen, methyl, atom chlorine or hydroxymethyl in the o- or p-position nuclei, and their maleates. Substances by of the invention are intermediates for the preparation of others pharmacodynamically active piperazine derivatives and their maleates themselves pharmacodynamic effects, such as centrally stimulating, antitussive, hypotensive and adrenolytic. The process for preparing the compounds I according to the invention is based on the invention in 4-methylpiperazide acid reactions 2-iodobenzoic acid with the corresponding thiophenols in the presence of dimethylformamide, carbonate potassium and small amounts of copper and iodide copper catalyst. Bases I obtained by neutralization with maleic acid to crystalline maleates.

Description

The invention relates to a process for the preparation of 4-methylpiperazines of 2-arylthiobenzoic acids of the general formula I,

(1) in which R represents a hydrogen atom, a methyl, a chlorine atom or a hydroxymethyl in the o- or β-position of the core, and the maleate thereof.

The compounds of the invention are primarily intermediates for the synthesis of other piperazine derivatives having therapeutically useful pharmacodynamic or generally biological properties. Some of the substances according to the invention also exhibit in themselves certain effects which indicate a practical application. For example, 2- (2-tolylthio) benzoic acid 4-methylpiperazide has been tested in the form of hydrogen maleate. For intravenous administration, mice show acute toxicity, the median lethal dose LD <j ₀ = 50 mg / kg. At 10 mg / kg sc, it has stimulatory efficacy as it significantly increases the spontaneous motility of mice. At an oral dose of 25 mg / kg, it has an antitussive effect in guinea pigs using a citric acid aerosol aerosol cough model of guinea pig respiratory tract irritation. At this dose, coughing attacks were reduced to approximately 50 8 (1 hour after administration) compared to control; this corresponds approximately to an effect of 10 mg / kg after codeine.

Furthermore, 2- (2-hydroxymethylphenylthio) benzoic acid 4-methylpiperazide, which has also been tested in the hydrogen maleate form, can be mentioned. Its acute toxicity by intravenous administration, LDjq = 175 mg / kg (in mice). At a dose of 35 mg / kg i.v. it induces a significant decrease in blood pressure in normotensive rats. At the same dose, it reduces the pressor response by 40% to the standard dose of adrenaline in rats. Thus, the substance has hypotensive and adrenolytic activity.

The process for the preparation of the compounds of the formula I according to the invention consists in the reaction of the known 2-iodobenzoic acid 4-methylpiperazide [Example A. et al., Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1976, 450; Chem. Abstr. 85, 155, 678, 1976 (with thiophenols of formula II) (11)

SH in which R denotes the same as in formula I.

This reaction is preferably carried out in the presence of dimethylformamide as the diluent, potassium carbonate as the condensing agent which binds the released hydrogen iodide, and finally in the presence of small amounts of copper and copper iodide as catalysts.

The reactions were carried out under reflux in a bath at 150-160 ° C. The isolation procedure described in detail below yields oily or crystalline bases of the formula I which are converted by neutralization with maleic acid into well-crystallizing hydrogen maleate. The starting thiophenols are mostly commercially available and are generally known. If necessary, reference is made to the literature in the examples. The identity of the novel compounds according to the invention was determined analytically and by spectral methods. The following examples are illustrative of the possibilities of the invention, but are not intended to fully describe them.

Example 1

1-methyl-4- (2-phenylthio) benzoyl / piperazine

A mixture of 4.0 g of thiophenol, 10 ml of dimethylformamide, 9.9 g of 2-iodobenzoic acid 4-methylpiperazide, 6.4 g of potassium carbonate, 0.2 g of copper and 0.2 g of cuprous iodide is stirred and refluxed. h in a bath heated to 150-160 ° C. After cooling, the mixture was partitioned by shaking between water and benzene, the benzene layer was filtered, washed with water, dried over potassium carbonate and evaporated under reduced pressure. 9.4 g of crude oily base are obtained, which is neutralized with 3.5 g of maleic acid in 13 ml of boiling ethanol. 10.7 g (83%) of the desired hydrogen maleate crystallize on standing, which crystallizes from ethanol and melts at 178-180 ° C.

Although the starting 4-methylpiperazide of 2-iodobenzoic acid used has been described (cited) in the literature, the description of its preparation is very imperfect and also the characterization is insufficient. Therefore, the method used to prepare this starting material is also given:

To a stirred mixture of 1-methylpiperazine (75 ml) and chloroform (25 ml) was added slowly a mixture of 2-iodobenzoyl chloride (133 g) / Raiford L.C., Lankelma H.P., J. Amer. Chem. Soc. 47, 1,121,

The mixture was stirred at room temperature for 1 h. The mixture was then refluxed for another 1 h in a bath heated to 120 ° C. After standing overnight, the precipitated hydrochloride of the desired 2-iodobenzoic acid 4-methylpiperazide is filtered off with suction and recrystallized from ethanol. It is obtained in a yield of 143 g (78%) and melts at 245-250 ° C. After further crystallization from ethanol, the substance is analytically pure and melts at 248-252 ° C. The cited literature reports a melting point of 163-165 ° C for hydrochloride, which is not consistent with the finding now made. Decomposition of the hydrochloride with aqueous ammonia liberates the 2-iodobenzoic acid 4-methylpiperazide base, which is isolated by extraction with benzene. After evaporation, it is obtained as a crystalline substance melting at 104 DEG-106 DEG C. (benzene-petroleum ether).

Example 2

1-methyl-4- (2- (2-methylphenylthio) benzoyl) piperazine

The preparation was carried out similarly to the previous case using 2.6 g of 2-methylthiophenol / Leuckart R., J. Prakt. Chem. / 2 / 41,188,1908? Bourgeois E. Rec. Trav. Chim. Pays-Bas 18,426,1998; Chem. Zentralbl. 1900, 1, 252) and 5.75 g of 4-methylpiperazide acid

2-iodobenzoic acid in the presence of 5 ml of dimethylformamide, 3.7 g of potassium carbonate, 0.1 g of copper and 0.1 g of cuprous iodide. 5.7 g of a crude oily base are obtained which, by neutralization with 2.3 g of maleic acid in 13 ml of ethanol, yields 6.3 g (82%) of crystalline hydrogen maleate melting at 179-181 [deg.] C. (ethanol).

Example 3 1-methyl-4- (2- (4-methylphenylthio) benzoyl) piperazine

By a similar reaction as in the previous cases, 2.24 g of 4-methylthiophenol and 4.95 g of 2-iodobenzoic acid 4-methylpiperazide were prepared in the presence of 5 ml of dimethylformamide, 3.2 g of potassium carbonate, 0.1 g of copper and 0.1 g. g of cuprous iodide 4.8 g of crude oily base which is neutralized with 1.75 g of maleic acid in 35 ml of ethanol. On standing, 5.3 g (80%) of hydrogen maleate crystallized, melting at 146-149 [deg.] C. (ethanol-ether). Decomposition of the pure maleate with 10% sodium hydroxide solution and extraction with ether / benzene gives a pure base which crystallizes from a mixture of benzene and petroleum ether and melts at 87-89 ° C.

Example4

1- (2- (4-chlorophenylthio) benzoyl) -4-methylpiperazine

Similar reaction of 2.6 g of 4-halothiophenol with 4.95 g of 2-iodobenzoic acid 4-methylpiperazide in the presence of 6 ml of dimethylformamide, 3.2 g of potassium carbonate, 0.1 g of copper and 0.1 g of copper iodide at 140-150 5.2 g of crude oily base are obtained, which are purified by crystalline maleate in a similar manner to the previous case. The crystalline base melting at 87-89 ° C (hexane) is then obtained. Hydrogen maleate crystallizes from ethanol and melts at 145-149 ° C.

Example 5 1- (2- (2-hydroxymethylphenylthio) benzoyl) -4-methylpiperazine

A mixture of 11.2 g of 2-hydroxymethylthiophenol / Grice R., Owen L. N., J. Chem. Soc. 1963, 1947; Pelz, K. et al., Collect., Collect. Czech. Chem. Commun. 33, 1895 (1968), 19.8 g of 2-iodobenzoic acid 4-methylpiperazide, 12 ml of dimethylformamide, 12.8 g of potassium carbonate,

0.1 g of copper and 0.1 g of copper iodide are stirred and refluxed for 8 hours. After cooling, the mixture was diluted with 200 ml of benzene, the solid was removed by filtration, the filtrate was washed with water, dried and evaporated under reduced pressure. 20.5 g of a crude oily base are obtained, which is neutralized with 6.8 g of maleic acid in 400 ml of boiling ethanol. By cooling the solution and adding ether, crystalline hydrogen maleate precipitates, which is filtered off with suction, washed with ether and dried. It is obtained in a yield of 23.3 g (85%) and melts at 147-150 ° C (ethanol-ether) in the pure state.

Claims (1)

A process for the preparation of 4-methylpiperazides of 2-arylthiobenzoic acids of the general formula I, in which R is hydrogen, methyl, chlorine or hydroxymethyl in the o- or β-position of the nucleus, and their maleate, characterized in that 4- 2-iodo-benzoic acid methylpiperazide is reacted with thiophenols of formula II in which R is the same as in formula I in the presence of dimethylformamide, potassium carbonate and small amounts of copper and copper iodide as catalyst at 150 to 160 ° C and the base of formula I are converted to maleate by neutralization with maleic acid.