CS268628B1 - Process for the preparation of N- [2- (2-chloro-10,11-dihydrodibenzo [b] f] thiepin-10-ylthio (ethyl) piperazines) salts thereof - Google Patents

Abstract

The invention relates to the field of drug synthesis. Its subject is a method for the preparation of N-/2- -/2-chloro-10,11-dihydrodibenzo|b,f|thiepin-10-ylthio/ethyl/piperazines and their salts, which show antimicrobial activity in in vitro tests and are therefore potential chemotherapeutics. The method for the preparation of these drugs according to the invention consists in the reaction of crude Z2-/2-chloro-10,11- -dihydrodibenzo)b,f|thiepin-10-ylthio/ethyl/-4-toluenesulfonate with anion-substituted piperazine, namely 1-acetylpiperazine, 2-Z1-piperazinyl-ethynyl, 3-/1-piperazinyl/propanol and 3-71-piperazinyl/propionyl. The resulting oily bases, which are neutralized with pharmaceutically acceptable inorganic or organic acids, are converted into crystalline salts and their crystallization is purified.

Description

The invention relates to a process for the preparation of N- [2- / 2-chloro-10,11-dihydrodigenzo [b] thiothiepin-10-ylthio] ethyl] piperazine of general formula I

^(I) z wherein n is 1 or 2 and R is hydrogen, OH, CH 2 OH or CONH 2, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I in the form of a salt show considerable antiaicrobial activity in in vitro tests, so that they can be considered as potential chemotherapeutics. The minimum inhibitory concentrations (in .mu.g / ml) of several substances according to the invention against several microorganisms are given below. exemplified substances are designated as follows: ZAZ n 1, R H ZdihydroehloridZ

Z8Z n «2, R OH Zuccinate monohydrate Z / CZ n« 2, R »CHOH OH Zishydrogen maleateZ.

ZAZ Streptococcus / ^ -haemolyticus 25, Streptococcus faecalis 25, Staphylococcus pyogenes aureus 25, Proteus vulgaris 100, Trichophyton mentagrophytes 50

ZBZ Streptococcus / 3 -haemolyticus 16, Streptococcus faecalis 8, Staphylococcus pyogenes aureus 8, Pseudomonas aeruginosa 64, Proteus vulgaris 64, Saccharomyces pasterianus 25, Trichophyton mentagrophytes'6,2, Aspergillus niger 50

ZCZ streptococcus / ^ -haeaolyticus 16, Streptococcus faecalis 8, Staphylococcus pyogenes aureus 128, Escherichia coll 4, Saccharomyces pasterianus 50, Trichophyton mentagrophytes 12,5, Aspergillus niger 50.

The process for the preparation of the compounds of the formula I according to the invention consists in the substitution reaction of Z2-Z2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthiozethylZ-4-toluenesulfonate of the formula XI

(II) with monosubstituted piperazines of formula III

(III), in which η and R denote the same as in formula I. The starting material of formula II is new and its preparation is described in Example 1. It is used in the crude state and is obtained by reaction

4-toluenesulfonyl chloride and 2- [2-chloro-10,11-dihydrodibenzo [b] phthiepin-10-ylthiozethanolea, the preparation of which is also included in Example 1 * The piperazines of formula III are generally commercially available; if it is necessary to prepare them according to the literature, it is from

CS 268 628 B1 cited these examples in the accompanying example. Said substitution reactions can be performed in various ways. The process described in the examples, which consists in reacting the components of the formulas II and III in boiling dioxane in the presence of anhydrous sodium carbonate, has proved particularly useful. The bases of the formula I obtained are generally oily. They are converted into crystalline salts by neutralization with pharmaceutically acceptable inorganic or organic acids and purified in the form of these by crystallization. Homogeneous bass released from pure salts can be used to measure spectra. All substances according to the invention and the described intermediates are new. Their identity was ensured by analytical and spectral methods. Further details on the preparation of the compounds of the formula I according to the invention follow from the examples, which, however, illustrate the possibilities of the invention.

Example 1

2- [4- [2- (2-Chloro-10,11-dihydrobenzobenzo [b, f] thiepin-10-ylthio) ethyl] -1-piperazinyl / ethanol

A mixture of 7.5 g of crude (2- (2-chloro-10,11-dihydrodibenzene), t-piperidin-10-ylthio) ethyl) -4-toluenesulfonate, 3.0 g of 2- (1-piperazinyl) ethanol. , 3. g of anhydrous sodium carbonate and 10 .mu.l of dioxane are stirred and refluxed for 4 hours. After cooling, it is diluted with 50 .mu.l of chloroform, the solution is washed with water, 10% strength sodium bicarbonate solution and again with water, filtered off with activated charcoal and evaporated under reduced pressure. 6.0 g (88%) of crude oily product are obtained. Neutralization with succinic acid in 95X ethanol gives crystalline succinate monohydrate which melts in pure form at 134.5-137 ° C.

The starting crude toluenesulfonate is prepared with the known 2,10-dichloro-10,11-dihydro-dibenzo [b, f] Ithiepine [Pelz K. et al., Collect.Czech.Chea.Conaun. 33, 1852) 1968) / further described in a four-step process; .

A mixture of 4.2 g of 2,10-dichloro-10,11-dihydrobenzo Ib, f11hepine, 1.3 g of thiourea and 10 .mu.l of dimethylformamide was stirred at 80 DEG C. for 3.5 hours and the solvent was evaporated in vacuo. The residue is crystallized from a mixture of ethanol and acetone and purified by crystallization from 2-propanol. Yield 5.0 g (94%) of form N- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) isothluronium chloride melting at 137-140 ° C. Crystallization from ethanol / ether gave Form B, melting at 183.5-184 ° C.

4.4 g of the preceding substance (form A or B, or a mixture of both) and 6 ml of 6K-HaOH are stirred and refluxed for 2 hours under a nitrogen atmosphere. Dilute with 15 al of water, acidified with 5 H H ₂ S0 ^ pH 2 and the product isolated by extraction with benzene. Work-up of the extract gave 3.3 g (99%) of crude 2-chloro-10,11-dihydrodibenzo [b, f] thiopine-10-thiol melting at 90-110 ° C. Crystallization from cyclohexane prints the pure material, mp 100-102 ° C.

A solution of sodium ethoxide was prepared by dissolving 0.7 g of sodium in 20 ml of ethanol, to which 8.37 g of the previous thiol was added. After stirring for 10 minutes, 5.0 g of 2-bromoethanol are added and the mixture is refluxed for 1.5 h. After cooling, the precipitated sodium bromide is filtered off, the filtrate is evaporated under reduced pressure and the residue is chromatographed on a column of 100 g of silica gel. Benzene elutes first with 2.0 g of less polar substances and then with 7.2 g (74%) of waxy 2- (2-chloro-10,11-dihydro-dibenzoyl) -thiepin-10-ylthio] -ethanol, which gives a satisfactory analysis. for C ₁₆ H ₁₅ ClOS ₂ and II and the NMR spectra confirm its identity.

To a stirred solution of 7.3 g of the previous alcohol in 5.4 g of pyridine was slowly added 4.5 g of 4-toluenesulfonyl chloride at 3-5 ° C. The mixture is dried for 1 hour at 0 DEG C., decomposed for 2 hours at room temperature and slowly added dropwise with 35 ml of water at -5 DEG C.. It is extracted with chloroform, the extract is washed with water, then 100 ml of 0.2M tartaric acid and again with water, dried over magnesium sulphate and evaporated in vacuo. 10.8 g (theoretical yield) of crude tosylate are obtained, which is used for longer work in this state.

CS 268 628 B1

Example 2

3- [4- [2- [2-Chloro-10,11-dihydrodibenzo] benzyl] thiepin-10-ylthio] ethyl-1-piperazinyl] propanol]

A similar reaction was 13.5 g of crude [2- (2-chloro-10,11-dihydrohydrobenzb]], thiepin-10-ylthio] ethyl] -4-toluenesulfonate, 4.9 g of 3- (1-piperazinyl) propanol / Zawisza T et al., Acta Pol. Phara. 22.477 119651 (and 5.4 g of sodium carbonate in 20 l of boiling dioxane) 10.2 g of crude oily base are prepared, which is converted to crystalline bis (hydrogen aleate) by neutralization and purified in this form by crystallization from a mixture of acetone and ethanol, m.p. 149-150 ° C.

Example 3

3- [4- (2-Chloro-10,11-dihydrodibenzo] b, f-thiepin-10-yl) ethyl (1-piperazinyl) propionamide

In a similar reaction 13.3 g of crude [2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethyl] -4-toluenesulfonate, 6.2 g of 3- (1-piperazinyl) propionate «Idu / Protiva M. et al., Collect.Czech.Chea.Coaaun. 51, 2598 119861) and 5.5 g of sodium carbonate in 25 .mu.l of boiling dioxane give 9.2 g (77%) of crude oily product, which is converted into crystalline succinet and in this form is purified by crystallization from acetone, m.p. 132-135.5 ° C. Example 4 '

1- [2- (2-Chloro-10,11-dihydro-benzo [b, f] thiopin-10-ylthio] ethyl] -4-ethylpiperazine

In a similar reaction, 13.5 g of crude [2- (2-chloro-10,11-dihydrodibenzo [b] phthiepin-10-ylthio) ethyl] -4-toluenesulfonate, 5.0 g of 1-ethylpiperazine and 5.5 g of sodium carbonate in 20 .mu.l of boiling dioxane is obtained in 80X yield of a crude oily base, which is converted into the dihydrochloride by neutralization of hydrogen chloride in aqueous ethanol and purified in this solution by crystallization from aqueous ethanol, m.p. 221-223 ° C.

Claims (1)

BACKGROUND OF THE INVENTION Process for the preparation of N-Z2-chloro-10,11-dihydrodibenzolb, 1H-thiepin-10-ylthio [ethyl] pi] perazine of the general formula I in which n represents 1 or 2 and R 1 of their salts, characterized by thia, denotes a hydrogen atom, an OH, CH 2 OH or ONH 2 group, and which is crude (2-) 2-chloro-10,11-. f | thíe «> CS 268 628 B1 pnn-10-ylthio [ethyl] -4-toluenesulfonate of formula II (ID reacts and monosubstituted «1 plperazines of formula III +14 _(III) X / KJ JX-Y in which · R on the same meaning as in formula 1 _t then the base obtained formula I into a pharmaceutically neutralised nezévadnými inorganic or organic acids into salts přisluiné.