SU464115A3 - Method for preparing 5thiazolcarboxylic acid derivatives - Google Patents

Description

lots include, according to the invention, esters of this acid with alcohols, where alkyl contains I-6 carbon atoms.

The reaction of 5-thiazolecarboxylic acid II with feiylpiperazia III is carried out under heating in the presence of a water removal agent, for example, dicyclohexylcarbodiimide.

The reaction of the acid chloride or anhydride of 5thiazolecarboxylic acid II with feiylpiperazine III is carried out in inert solvents such as benzene, toluene, xylene, chloroform, ether.

The reaction of the mixed 5-thiazolecarboxylic anhydrides And with phenylpiperazium III is preferably carried out in a solvent, for example acetone.

Target products can be converted by conventional methods into salts of pharmacologically active acids, such as hydrochloric, sulfuric, phosphoric, hydrobromic, acetic, benzoic, tartaric, fumaric, maleic, methanesulfonic acid, and toluene sulfonic acid.

Example 1. N-p - 4- (o-methoxyphenyl) -Gpnepazinyl-ethyl-2-n - propylthiazole-5-carboxamide and its hydrochloride

N - ((o - methoxyphenyl (-G-piperazinyl) ethyl-2n-propylthiazole-5-carboxamide

A solution of 7.2 g of triethylamine in 30 ml of acetone is added to a suspension of 11.1 g of 2-n-propyl-5-carboxythiazole in 80 ml of acetone and cooled to 6 ° C; then, with stirring and a temperature of 6 ° -8 ° C, a solution of 8.7 g of ethyl chlorofluate in 30 ml of acetone is added; bring to room temperature, stir for an additional 30 minutes, and separate the triethylamine hydrochloride by filtration. The filtrate is cooled to 8 ° C, a solution of 11.4 g of 4- (o-methoxyphenyl) -1- (raminoethyl) piperazine in 30 ml of acetone is added, and left for 48 hours; acetone is evaporated, the oily residue is taken up in 300 ml of ethyl ether and 20 ml of water, the ether layer is washed with a 20% aqueous solution of potassium carbonate and then with water until neutral wash water and dried over magnesium sulfate; evaporated to dryness and the residue is crystallized from isopropyl ether; 8.4 g of M- | 3- 4- (o-methoxyphenyl) -G-piperazinyl ethyl-2-n-propylthiazole-5-carboxamide are obtained in the form of colorless crystals; m.p. 113 ° C.

Found,%: N 14,32; S 8.16,

C2H28N402S 388.53.

Calculated,%: N 14.42; S 8.23.

(O-methoxyphenyl) -G-piperazinyl-ethyl 2-n-propylthiazol-5-carboxamide hydrochloride.

8.4 g of (o-methoxyphenyl) H-piperazinyl) -ethyl-2-n-propylthiazole-5 carboxamide is dissolved in 43 ml of ethanol, 5 ml of 4.29 n are added. ethanolic hydrogen chloride solution, filtered, and the precipitate is crystallized from ethanol; 7.4 g of (o-methoxyphenyl) -H-piperazinyl-ethyl-2n-propylthiazole-5-carboxamide hydrochloride are obtained as colorless crystals, soluble in water, ethanol and methanol, insoluble in ethyl ether and benzene; m.p. 180 ° C.

-Found,%: C 56.3; H 6.7; C1 8.4; N 13.1; S 7.4.

C2H28N402S-HCl 424.98.

Calculated,%: C 56.52; H 6.88; C1 8.34; N 13.18; S 7.55.

Example 2. N- | p- (4-o-methoxy; phenyl) -G-piperazinyl-ethyl-2-ethylthiazole-5-carboxamide and its hydrochloride.

(o-methoxyphenyl) -G-piperazinyl ethyl-2-ethylthiazole-5-carboxamide.

A solution of 3.2 g of triethylamine in 10 ml of acetone is added to 4.5 g of a suspension of 2-ethyl-5-carboxythiazole in 30 ml of acetone and cooled to 6 ° C; while stirring at a temperature of 6-8 ° C, a solution of 3.3 g of ethyl chlorotic acid ester in 15 ml of acetone is added; is brought to room temperature, stirred for 30 minutes, and the resulting precipitate is separated by filtration.

Cool the filtrate to 8 ° C, add a solution of 5.9 g of 4-o-methoxyphenyl -1 (, p-amino) ethylpiperazine in 15 ml of acetone and leave for 16 h; acetone is evaporated, the oily residue is taken up in 100 ml of methylene chloride and 10 ml of water, the organic layer is washed with a 10% aqueous solution of potassium carbonate and then with water until the washing water is neutral and dried over magnesium sulfate; evaporated to dryness, the residue is taken up in 20 cm of isopropyl ether, filtered and the precipitate is crystallized from cyclohexane; 4.4 g of H -. (o-methoxyphenyl) -G-piperazinyl -2-ethylthiazole-5-carboxamide are obtained in the form of colorless crystals, soluble in methanol, ethanol, acetone and chloroform, insoluble in water; m.p. 110 ° C.

Found,%: C 61.1; H 6.9; N 14.6; S 8,2.

Ci9H26N402S 374.49.

Calculated,%: C 60.93; H 7.00; N 14.96; S 8.56.

Hydrochloride (o-methoxyphenyl) - G-piperazinyl -2-ethylthiazole - 5 - carboxamide

3.6 g of (o-methoxyphenyl) H-piperazinyl-ethyl-2-ethylthiazole-5-carboxamide was dissolved in 20 ml of ethanol, and 3.05 ml of 3.15 n were added. ethanolic hydrogen chloride solution and the precipitate crystallized from ethanol; 2.95 g of (o-methoxyphenyl) -G-piperazinyl-ethyl-2-ethylthiazole-5-carboxamide hydrochloride are obtained in the form of colorless crystals, soluble in water, ethanol, methanol and chloroform; m.p. 190 ° C.

Found,%: C 55.6; H 6.7; C1 8.6; N 13.4; S 7.7.

C, 9H26N4O2S, HCl 410.96.

Calculated,%: C 55.53; H 6.62; C1 8.63; N 13.63; S 7.80.

Example 3. (o-methoxyphenyl) - Gpiperazinyl-ethyl-2-phenylthiazole - 5-carboxamide, and its hydrochloride.

(o-methoxyphenyl) -G-piperazinyl ethyl-2-phenylthiazole-5-carboxamide. A solution of 3.65 g of triethylamine in 15 ml of acetone is added to a suspension of 6.8 g of 2-phenyl-5-carboxythiazole in 35 ml of acetone and cooled to 3 ° C; a solution of 3.8 g of chloroic acid ethyl ester in 20 ml of acetone is added, left for 30 minutes, allowed to reach room temperature, and then the precipitate is filtered off. The filtrate is cooled to 6 ° C and a solution of 6.8 g of 4- (o-methoxyphenyl) -1- (| p-amino) ethylpiperazine in 35 ml of acetone is added at a temperature; warmed to room temperature and left overnight; filter, wash the precipitate with acetone and get 4 g of colorless crystals with so pl. 152 ° C. The filtrate is evaporated, the residue is dissolved in 100 cm of methylene chloride, the solution is washed with water and then with a 10% aqueous solution of potassium carbonate and again with water; dried over magnesium sulphate and the solvent evaporated in vacuo; the residue is washed with ether, filtered and crystallized from ethanol; 3 g of crude product are obtained with mp. 151 - 152 ° С; 4 g of the product obtained above were added to this product and recrystallized from ethanol; 6.2 g of N-ip-4- (omethoxyphenyl) -H-piperazinyl) ethyl-2-phenylthiazole-5-carboxamide are obtained in the form of colorless crystals, soluble in chloroform, poorly soluble in ethanol, and 1N. a solution of hydrochloric acid, insoluble in water and ether with m. pl. 152 ° C. Found,%: C 65.3; H 6.1; N 13.2; S 7,8. С2зН2бН4О25 422.54. Calculated,%: C 65.37; H 6.20; N 13.26; S 7.59. (O-methoxyphenyl) -G-piperazinyl-ethyl 2-phenylthiazole-5-carbosamide hydrochloride. 5.9 g of (o-methoxyphenyl) -G-piperazinyl-ethyl-2-phenylthiazole-5-carboxamide is dissolved in 750 ml of ethyl acetate, 4.8 ml of 3.15 n are added. ethanolic hydrogen chloride solution, filtered, the precipitate is washed with ethyl acetate and crystallized from ethanol containing 5% water; 3.45 g of (o-methoxyphenyl) -H-piperazinyl-ethyl-2-phenyl-thiazole-5-carboxamide hydrochloride are obtained in the form of colorless crystals, soluble in chloroform, slightly soluble in water and insoluble in ether and acetone, m.p. 244 ° C. Found,%: C 60.2; H 5.7; C1 7.9; N 12.1; S 6,8. C23H27C1N4O2S 459. Calculated,%: C 60.18; H 5.93; C1 7.72; N 12.21; S 6.98. Example 4. M-methyl-M-: p- 4- (o-methoxyphenyl) -G-piperazinyl-etnl-2-n-propylthiazol5-carboxamide and its hydrochloride. N-methyl N-; p-4- (o-methoxyphenyl) -1 -piperazinyl-ethyl-2-n-propylthiazole-5-carboxamide. To a suspension of 1.60 g of 2-n-propyl-5-carboxythiazole in 10 ml of acetone, a solution of 1.01 g of triethylamine in 5 ml of acetone is added; The mixture is cooled to 4 ° C and a solution of 1.04 g of ethyl chlorotic acid ester in 5 ml of acetone is added, and then the precipitate formed is filtered off. The filtrate is cooled, a solution of 1.83 g of 4- (o-methoxyphenyl) -1- (rmethylaminoethyl) piperazine in 5 ml of acetone is added and left overnight; acetone is evaporated, the residue is taken up in 30 ml of methylene chloride and 5 ml of water, the organic layer is washed with a 0% aqueous solution of potassium carbonate and then with water, dried over magnesium sulfate and the solvent is evaporated; the residue is chromatographed on silica gel, eluting with acetone-cyclohexane (6: 4) and 1.04 g of H-methyl-M-p-4- (o-methoxyphenyl) -H-piperazinyl-ethyl-2-n-propylthiazole-5-carboxamide is obtained in the form of colorless crystals, with t. pl. 65 ° C. N-Methyl-M- | p-4- (o-methoxyphenyl) -H-piperazinyl-ethyl-2-n-propylthiazol-5-carboxamide hydrochloride. 1.54 g of N-methyl-Mr-4- (o-methoxyphenyl) -H-piperazinyl-ethyl-2-n-propylthiazole-5-carboxamide is dissolved in 7 cm of ethanol, 1.3 ml 3 are added, 15 n. ethanolic hydrogen chloride solution and the precipitate formed is separated by filtration. After crystallization from isopropanol, 1.25 g of N-methyl N -. (Omethoxyphenyl) -1-piperazinyl-ethyl-2-n-propylthiazole-5-carboxamnda hydrochloride are obtained in the form of colorless crystals, soluble in chloroform and in water, poorly soluble in ethanol , insoluble in ether, so pl. 185 ° C. Found,%: C 57.1; H 7.1; N 12.6; C1 8.1; S 7 5 C2, H3iClN402S- 439.02. Calculated,%; C, 57.45; H 7.12; N 12.76; C1 8.07; S 7.30. Example 5. (o-methoxyphenyl) -Hpiperazinyl-butyl-2-n-propylthiazole-5-carboxamide. 8.6 g of 2-n-propyl-5-carboxythiazole is dissolved in 50 ml of toluene and 5.1 g of triethylamine are added. Then, a solution of 5.5 g of chlorogolic acid ethyl ester in 20 ml of toluene is added at -20 ° C, and then a solution of 15 g of 4- (o-methoxyphenyl) -G - (b - aminobutyl) piperazine in 50 ml of toluene. Move for 15 hours at room temperature, wash the solution with water, dry and evaporate to dryness. The residue is crystallized from a mixture of isopropyl ether and isopropanol, 7.5 g (o-methoxyphenyl) -H-piperazinyl-butyl-2-n-propylthiazole-5-carboxamide are obtained; m.p. 100 ° C. Found,%: C 63.4; H 7.9; N 13.7; S 7.6. C22H32N4O2S 416.6. Calculated,%: C 63.43; H 7.74; N 13.45; S 7.70. Example 6. (o-methoxyphenyl) -Hpiperazinyl ethyl-2-n-propylthiazole - 5-carboxamide. At 40 ° C, 7 g of 4- (o-methoxyphenyl) -1- (p-amino) ethylpiperazne are melted. 6 g of 2-n-propylthiazole 5carboxylic acid ethyl ester are added and the mixture B is heated for 3.5 hours at 125 ° C in nitrogen atmosphere; is brought to room temperature, 20 ml of ethyl ether is added, triturated and left overnight; the precipitate is separated by filtration, washed with ether and crystallized from isopropyl ether; 5.5 g are obtained (o-labels: siphenyl) -G-piperazinyl-ethyl-2-npropylthiazole-5-carboxamide, similar to the product obtained in Example 1. The subject matter of the invention is d. The method of producing 5-thiazolecarboxylic acid derivatives of general formula I (cf. where RI is alkyl with 1-6 carbon atoms, phenyl; R2 is hydrogen, alkyl with 1-4 carbon atoms; Xi and X2 are hydrogen, halogen, alkyl, alkoxy , alktio, where alkyl with 1-4 carbon atoms, trifluoromethyl; or their salts, characterized in that 5thiazole-carboxylic acid of general formula II j X -cooH where RI has the indicated values, or its functional derivative is reacted with phenylpiperazine of general formula III R.-BN-ICH);, -. where Ra, p, Xj, and X have the indicated meanings with the release of the target products in free form or being converted into salts by known methods. 2. A method according to claim 1, characterized in that anhydride, mixed anhydride, acid chloride or ester with lower alcohols are used as the functional derivative of 5-thiazolecarboxylic acid.