CS268629B1 - Process for the preparation of (2-chloro-10,11-dihydrodibenzoyl) flepepin-10-ylthio / alkene acids and their amides - Google Patents

Abstract

The solution falls into the field of synthesis of substances. Its subject is a method for preparing /2-chloro-10,11-dihydrodibenzoIb,f1th1ep1n-10-ylthiol/alkanoic acids with 2 or 4 carbons in the acid chain and their amides. The named acids have a moderate anti-inflammatory and analgesic activity, the amides are potential antiepileptics. The method for preparing substances according to the solution consists in the reaction of 2-chloro-10,11-dihydrodibenzoIbzfIth1ep1n-10-thiol with ethyl esters of chloroalkanoic acids with 2 or 4 carbon atoms in the chain, in the subsequent alkaline hydrolysis of the ethyl esters to acids according to the solution and, optionally, in the subsequent reaction of these acids with th1 onyl chloride and in the reaction of the crude acid chlorides with ammonia to form the corresponding amides.

Description

The invention relates to a process for the preparation of (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) alkenoic acids and their amides of the general formula I

(I) in which R represents OH or NH 2 from R ¹ is a hydrogen atom or methyl and represents 0 or 2.

The acids of formula I (R OH) have mild anti-inflammatory activity in two models of inflammation in rats and mild analgesic activity in mice using stimulation by intraperitoneal injection of 0.7X acetic acid. The amides of formula (I) are potentially anticonvulsants.

The acids of formula I, the biological activity of which is given by way of example, are designated as follows for simplicity:

/ A /, I, R · OH, R ¹ »Η, n = 0/8 /, I, R OH, R ¹ “ CHj _Z n «0 / C /, I, R» OH, R ^ «H, n “2 ''

In the test, the acids (A), (B) and (O) were administered at oral doses of 100 mg / kg, and the efficacy was evaluated for two types of inflammation and is expressed in X Inhibition of inflammation ( ⁺ sign indicates statistical significance); analgesic efficacy was evaluated in the following test and is expressed in X pain inhibition:

Carrageenan inflammation: / A / 23 ⁺ , / 8/11, / € / 23 ⁺

Kaolinitis: / B / 7, / 0/21

Analgesic effect: / A / 16 at 200 mg / kg _z / B / 30, / 0/26.

The compounds of formula I according to the invention are prepared by chain synthesis, the first step of which is the reaction of the sodium salt of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol with ethyl esters of chloroalkanoic acids of formula II.

CICH / CH. / COOC, H c n č j / 11 /.

The resulting esters can be isolated in the pure state, but can also be treated in the crude state by hydrolysis with alkali hydroxides in boiling aqueous ethanol to the acids of formula I, where R <OH. These acids are further converted by treatment with boiling thionyl chloride to the crude chlorides, which upon reaction with ammonia, preferably in chloroform, give the desired amides of formula I wherein R> NH ₂ . The starting 2-chloro-10,11-dihydrodibenzo [b, f] thiophene-10-thiol is a novel substance, the preparation of which is described in Example 1. All the substances described in the invention are novel and their identity has been ensured by analytical and spectral methods;

Example 1

2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) acetic acid

To a solution of sodium ethoxide (prepared from 1.25 g of sodium · 50. g of ethyl chloroacetate in 10 ml of ethanol and the mixture is boiled with stirring for 6 h

CS 268 629 B1 under reflux condenser. The ethanol was evaporated under reduced pressure, the residue was diluted with water and extracted with benzene. Work-up of the extract gives 18/2 g (99%) of crude ethyl ester of the desired acid. Most of the product (17.8 g) was dissolved in 50 .mu.l of ethanol. A solution of 7 .mu.g of sodium hydroxide in 30 ml of water was added and the mixture was dried and refluxed for 2 hours. After evaporating the ethanol, the residue was dissolved in 175 bL of water, the solution was filtered with charcoal, and the filtrate was acidified to pH 1 with hydrochloric acid at 50 ° C. The product was isolated by extraction with chloroform. Work-up of the extract gave 10.7 g (64%) of the desired acid, m.p. 120-125 ° C. Crystallization from benzene / hexane gave pure material melting at 128-129 ° C.

The starting 2-chloro-10,11-dihydrodibenzene, f, thiepine-10-thiol, which has not yet been described in the literature, is prepared from the known 2,10-dichloro-10,11-dihydrodibenzo [b] thiopine / Pelz K et al., Collect.Czech.Chem.Commun. 33, 1852 I1968 I as follows:

4.2 g of 2,10-dichloro-10,11-dihydrohydrobenzylbenzylbenzene, 1.3 g of thiourea and 10 ml of dimethylformamide are stirred at 80 DEG C. for 3.5 hours and the solvent is evaporated off under vacuum. The residue is crystallized from a mixture of ethanol and acetone and purified by crystallization from 2-propanol. In a yield of 5.0 g (94%), Form A S- (2-chloro-10,11-dihydrodibenzo [b, f] pyridin-10-yl) sothiuronyl chloride secretion is obtained at 137-140 ° C. Crystallization from ethanol / ether gave the form melting at 183.5-184 ° C.

4.4 g of the preceding substance (form A or 8) and 6 ml of 5M-NaOH are stirred and refluxed for 2 h under a nitrogen atmosphere. The mixture was diluted with 15 ml of water, acidified to pH 2 with SM-H 2 SO 4 and the product was isolated by extraction with benzene. Work-up of the extract gave 3.3 g (99%) of crude thiol melting at 90-110 ° C. Crystallization from cyclohexene gives the pure substance, m.p. 100-102 ° C.

Example 2 ’

2- [2-Chloro-10,11-dihydrohydrobenzo [b, f] thien-10-ylthio] propionic acid;

Similarly to the previous example, 14.0 g of 2-chloro-10,11-dihydrodibenzene, 1, thiepine-10-thiol were converted into a sodium salt solution by dissolving in a solution of sodium ethoxide (1.25 g of sodium in 50 ml of ethanol). and treated with 8.2 g of ethyl 2-chloropropionate in 10 ml of ethanol (var. 4 h). Similar work-up gave 18.7 g (99%) of crude, oily ethyl ester of the desired acid. A portion of this ester (3.5 g) was hydrolyzed for 2 hours by boiling with 1/4 g of sodium hydroxide in a mixture of 10 ml of ethanol and 5 ml of water. 3.2 g (theoretical yield) of an oily mixture of two racemic, named acids are obtained. One crystallization from a mixture of 2 ml of benzene and 10 ml of hexane gave 2.6 g (81%) of the crystalline mixture, which was blurred at 128-165 ° C. Triple crystallization from a 1: 1 mixture of benzene and hexane gave a homogeneous, minor racemate A, m.p. 162-165 ° C. Treatment of the mother liquors gives the predominant racemate 8, m.p. 128 DEG-130 DEG C. (benzene petroleum ether).

Example 3

4- (2-Chloro-10,11-dihydro-benzo [b, f] piperidin-10-ylthio) butyric acid

2-Chloro-10,11-dihydrodibenzo [b, e] thiepine-10-thiol (14.0%) is added to a solution of sodium ethoxide (1.25 g of sodium and 50 ml of ethanol), after stirring for a while. a solution of 9.04 g of ethyl 4-chlorobutyrate in 10 ml of ethanol and the mixture is refluxed for 6 hours. The ethanol was evaporated, the residue was diluted with water and extracted with benzene. Work-up of the extract gave 19.5 g (99%) of crude ethyl ester of the desired acid, which was distilled off; t.v. 230-235 ° C / 47 Pa. a portion of this ester (7.1 g) was dissolved in 10 ml of ethanol, a solution of 3.0 g of sodium hydroxide in 10 ml of water was added and the mixture was refluxed for 2 h. The ethanol was evaporated, the residue was diluted with water, the solution was acidified with 25 ml of 2,5H-HCl product and extracted with chloroform. Workup of the extract gave 6.6 g of an oily yellow product which, after trituration with 2 ml of petroleum ether, gave 5.9 g (90%) of petroleum ether, m.p. 107-10 ° C.

CS 268 629 B1

Example 4

2- [2-Chloro-10,11-dihydro-dibenzo [b, f] thion-10-ylthio] -acetamide

A mixture of 4.1 g of 2- (2-chloro-10,11-dihydrohydrin 1 benzo Ib, 11-epin-10-ylhio) acetic acid, 10 .mu.l of benzene and 5 _of 0 g of thionyl chloride was stirred and refluxed for 5 hours. . Evaporation in vacuo gave 4.5 g of crude acid chloride. It is dissolved in 50 .mu.l of chloroform and the solution is saturated with ammonia for 5 hours with stirring at room temperature. It is then diluted with 50 .mu.l of chloroform (washed with 10X sodium bicarbonate solution and water), dried over magnesium sulphate and evaporated. / crude amide, mp 98-110 ° C. Crystallization from a mixture of benzene and hexane gave the pure amide, mp 110-112 ° C.

Example 5

2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) propionamide

As in the previous example, 1.7 g of a racemic mixture of 2- (2-chloro-10,11-dihydro-benzo [b, f] heppin-10-yl-thio] -propionic acid are reacted with 2.0 g of thionyl chloride in 5 ml of benzene. The obtained crude acid chloride (1.9 g) was dissolved in 45 .mu.l of chloroform and the solution was saturated with ammonia. Work-up of the reaction mixture gave 1.6 g (91%) of a mixture of two racemic amides. Recrystallization from a mixture of benzene and ethanol gives 0.6 g / 35 XZ of homogeneous racemate 1, m.p. 203-204 ° C. Treatment of the aqueous liquor gives 1.0 g / 56%! of crude racemate 8 / m.p. 130 DEG-135 DEG C., which is purified by triple crystallization from benzene, m.p. 135-136.5 ° C.

Example 6

4- [2-Chloro-10,11-dihydrobenzo [b, f] thiepin-10-ylthio] butyride

As in the previous examples, 4- [2-chloro-10,11-dihydrodibenzoic acid], butothien-10-yl] thiobutyric acid was converted to the crude acid chloride, which was treated with ammonolysis in chloroform. Thus the desired amide is obtained in 85X yield, which crystallizes from toluene and melts in pure state at 118-119.5 ° C.

Claims (1)

PRIORITY OF THE INVENTION Process for the preparation of Z2-chloro-10,11-dihydrodibenzo [b, f] epiopin-10-ylthio] acolic acids and their amides of general formula I ^(I) in which R is OH or NH 2, R ¹ is hydrogen or methyl and n is 0 or 2, characterized in that 2-chloro-10,11-dihydrodigenzoyl, phthiepine-10-thiol in the form of the sodium salt is reacted with ethyl esters of chlorine of tissue tissues of formula II C l Z _n CHZCH ₂ COOC ₂ H _5/11 / in which · R ^{1 and} n have the same meaning as in formula I, to give ethyl hydrolysujl on ky EN 268 629 Bl Selina formula I where R = 0H _from boiling »aqueous ethanolic sodium hydroxide solution and acid is optionally converted to the chloride by treatment with thionyl onylchtoridu and these chlorides are converted to amides of formula I, wherein R" NH-reaction with ammonia .