CS213292B1 - Method of preparation of new derivatives of 2-chlor-1%-piperazino-1%,11-dihydrodibenzo/b,f/thiepine with oxygenous function in the position 6 and the salts thereof - Google Patents

Abstract

The invention relates to a process for preparing new ones 2-chloro-6-methoxy (and hydroxy) -10- (4- -hydroxyethyl) piperazine-10,11-dihydradibenzo (b.f) thiepines and their salts. Those substances are intermediates for the preparation of drugs with neurotransmitters and psychiatric activity and themselves and have properties of noncataleptic tranquilizers. Their way of preparation lies in the substitution reaction of 2,10-dichloro- -6-methoxy-10,11-dihydrodibenza (b, f) thiepine with 1- (2-hydroxyethyl) piperazine, as follows demethylation with boron tribromide v chlorobenzene and finally in the preparation of the salt by neutralization the bases obtained in the previous two stages.

Description

(54) A process for the preparation of 2-chloro-10-piperazine-10,11-dihydradibenza (b, f) thiepine derivatives having a function in pelose 6 and salts thereof.

The invention relates to a process for preparing new ones

2-chloro-6-methoxy (and hydroxy) -10- [4- (2-hydroxyethyl) piperazine-10,11-dihydradibenzo (bf) thiepines and their salts. These substances are intermediates for the preparation of drugs with neuratrepic and psychatrapic activity and possess in themselves the properties of non-cataleptic tranquillizers. ^J heir preparation method consists in the substitution reaction of 2,10-dichlar-6-methoxy-10,11-dihydro-dibenzo (b, f) thiepin with l- (2-hydroxyethyl) piperazine in subsequent demethylation with boron tribromide in chlorobenzene and finally prepare salts by neutralizing the bases obtained in the previous two steps.

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The present invention relates to a process for the preparation of novel 2-chloro-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine derivatives having an oxygen function at position 6 of general formula I,

in which R represents a hydrogen atom or a methyl group, and whose salts with inorganic and organic acids.

The compounds of the present invention are intermediates for the preparation of pharmacodynamically active substances with neurotrophic and psychotropic activity. Some of them, in themselves, already have some neurotrophic and psychotropic activity. 2-chloro-6-methoxy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydro-dibenzo (b, f) thiepine (1, R = CILj) was tested on animals in the form of bis (methanesulfenate) in oral administration. It showed acute toxicity in mice, LD _g0 = 440 mg / kg. In the rotating rod test it has an intense incoordinating action; median effective dose ED _go = 3.1 mg / kg. In contrast, at a dose of 100 mg / kg, the compound does not act cataleptically in rats and does not inhibit apomorphine-induced oral stereotypes in rats; it only somewhat suppresses apomorphine-induced agitation. Thus, the substance may be referred to as a non-cataleptic tranquilizer.

The process for the preparation of the compounds of the formula I according to the invention consists of a two-step process starting from 2,10-dichloro-6-methoxy-10,11-dihydrodibenzo (b, f) thiepine of the formula II

The substance of formula II in the first step is subjected to a substitution reaction with 1- (2-Hýdrexyethyl) piperazine, which resulted in a compound of formula I, R = CH ₃ · This substitution reaction may be conducted under various conditions ^ hair is preferred to operate with an excess of L- ( 2-hydroxyethyl) piperazine, which then serves simultaneously as a condensing agent; the excess used must be at least 100%. The reaction can be carried out either at ambient temperature of about 100 ° C or in a suitable inert solvent, e.g., boiling chloroform. The substitution reaction may also be carried out using an equivalent of 1- (2-hydroxyethyl) piperazine; then it is necessary to work in the presence of a condensing agent, e.g. anhydrous alkali carbonate, again either without the environment or in a suitable solvent (acetone, methyl ethyl ketone, dimethylformamide, etc.).

In the second step, 2-chloro-6-methoxy-10- [4- (2-hydroxyethyl) -piperazine] -10,11-dihydrodibenzo (b.f) thiepine (1, R = CH 3) is subjected to demethylation. For this purpose, it is preferred to use boron tribromide and chlorobenzene as the medium; the reaction proceeds under mild conditions, preferably at room temperature. The resulting primary product (bromoboronate ester of undefined composition) is subjected to hydrolysis with dilute boiling ethanolic sodium hydroxide solution and the desired phenolic base is isolated by virtue of its amphoteric character.

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It is 2-chloro-6-hydroxy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydredibension (b, f) thiepine (I, R = H).

The starting 2,10-dichloro-6-methoxy-10,11-dihydredibenzene (b, f) thiepine of formula II is a novel compound, the preparation of which from known intermediates is described in the exemplary embodiment.

The final compounds of the invention of general formula (I) are basic in nature and, by neutralization with inorganic or organic acids, give crystalline pigments, the preparation of which is included in the scope of the invention.

The identity of all the critical substances described in the invention, i.e. especially the end products and the intermediates, was assured by analyzes and spectra (UF, IR, 1 H-NMR, MS), examples of the conversion:

I. 2-Chloro-6-methoxy-10- / 4- (2-hydroxyethyl) piperazine / -10, ll-dihydro-dibenzo (b, f) thiepin (I, R = CH _3).

A solution of 2,10-dichloro-6-methoxy-10,11-dihydrodibension (b, f) thiepine (11.4 g) and 9.5 g of 1- (2-hydroxyethyl) piperazine in 35 ml of chloroform was boiled for 6 h under reflux condenser. The chloroform was evaporated under reduced pressure, the residue was diluted with water and extracted with benzene. The extract was washed with water, and the base was converted to the aqueous phase by shaking with excess 1 M SM-H 2 SO 4. The scientific layer of the sulfate solution was separated, basified with concentrated aqueous ammonia and the base extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. In yield

II g (74%) gave the desired oily base which crystallized from a mixture of benzene and petroleum ether and melted at 136-138 ° C. Neutralization methansulfonevou acid in ethanol and addition of ether to give crystalline bis (methanesulfonate), which in the pure form melts at 192 to 194 C ^e (ethanel-ether).

The starting 2,10-dichloro-6-methexy-10,11-dihydrodibension- (b, f) thiepine used is a novel substance not previously described in the literature. It is accessible as follows from known starting materials:

A mixture of 44 g of 2,5-dichloroacetephenone (M. Rajsner et al., Cellect.Czech.Chem.Cemmun. 43.

1276, 1978). 34 g of 2-methoxythiophenol (F. Mauthner, Ber.Deut.Chem. Ges. 39, 1348, 1906). 38 g of anhydrous potassium carbonate and 1 g of powdered copper (freshly prepared) are stirred and heated at 140 ° C for 1 hour. After cooling to 80 ° C, the thick mixture is diluted with 10 ml of ethanol and refluxed for 3 hours. After standing overnight, dilute with 200 ml of water and extract with benzene. The extract was dried (MgSO4) and evaporated. Crystallization of the residue from methanol gave 19.3 g (28%) of 5-chloro-2- (2-methexyphenylthia) acetophenene, m.p. 81-82 ° C (methanol).

A mixture of 28.5 g of the preceding product, 4.7 g of sulfur and 17 g of morphine is stirred and refluxed for 4.5 hours in a 145 ^e C bath. After cooling, the mixture is diluted with 150 ml of chloroform and the solution is filtered with active uhlím. The filtrate was washed with water and dilute hydrochloric acid, dried over magnesium sulfate and evaporated. The residue was crystallized from a mixture of benzene and petroleum ether. 23 g (60%) of crude (5-chloro-2- (2-methoxyphenylthia) phenyl) acetic acid thiemorpholide melting at 153-156 ° C are obtained. The pure material was obtained by crystallization from benzene, mp162-163 ® C.

To a solution of 18 g of potassium hydroxide in 45 ml of ethanol was added 25.5 g of the previous thiemorpholide, and the mixture was heated under reflux (bath 120 ° C) with stirring for 2 h. After cooling, the mixture is diluted with 250 ml of water, the solution is filtered and the filtrate is acidified with dilute hydrochloric acid.

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The precipitated solid product is filtered off with suction, washed with water and recrystallized from aqueous ethanol. 18.0 g (91%) of (5-chloro-2- (2-methexyphenylthia / phenyl) acetic acid melting at 127-132 ° C is obtained.

the pure material was obtained by further crystallization from 70% ethanol, m.p. 137-138 ° C.

A mixture of 15.8 g of 5-chloro-2- (2-methexyphenylthia) phenyl / acetic acid, 80 ml of toluene and 100 g of polyphosphoric acid is stirred and refluxed for 11 hours. After cooling, the mixture is poured into 250 ml of ice cold water and the product is extracted with benzene. The extract was washed with water and 3% sodium hydroxide, dried over magnesium sulfate and evaporated. 12.9 g (87%) of crystalline 2-chloro-6-methoxy-dibenz (b, f) thiepin-10 (11H) -one, mp 134-137 ⁰ C, are obtained. The pure material is obtained by crystallization from benzene, m.p. 137-139 * C.

A solution of 7.2 g of sodium borohydride in 70 ml of water containing 1 ml of 20% sodium hydroxide solution is added dropwise at 75 ° C over 15 minutes to a stirred suspension of 11.0 g of the preceding ketone in 160 ml of ethanol. The mixture was heated at reflux for 6 h to give a clear solution. The ethanol is evaporated off under reduced pressure, the residue is diluted with 150 ml of water and the product is extracted with warm benzene. The extract was washed with 2% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. 2-chloro-6-methoxy-10,11-dihydrodibenz- (b, f) thiepin-10-ol is obtained in a theoretical yield of 11.0 g, mp 133-135 ^° C. Crystallization from a mixture of benzene and petroleum ether gives: sample of pure substance, mp 137-138 ⁰ C.

To a solution of 14.7 g of the preceding alcohol in 250 ml of benzene was added 20 g of anhydrous calcium chloride powder and the suspension was saturated with anhydrous hydrogen chloride at 20 ^° C for 4 h. The calcium chloride was filtered off, washed with benzene and the filtrate evaporated under reduced pressure. The residue crystallized upon addition of hexane: 13.9 g (88%) of the desired 2,1-10-dichloro-6-methoxy-10,11-dihydro-dibenz (bf) thiepine melting at 83-85 ° C. Crystallization from a mixture of benzene and petroleum ether gave the pure product with mp 85-87 ° C.

2. 2-Chloro-6-hydroxy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I,

R = H).

To a stirred solution of 3.1 g of 2-chloro-6-methoxy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (Example 1) in 50 ml of chlorobenzene is added dropwise at 15 ml. ^A solution of 5.76 g of boron tribromide in 30 ml of chlorobenzene was added over 15 minutes. The mixture was stirred at room temperature for 7 h and allowed to stand overnight. It is decomposed by the addition of a solution of 1.5 g of methanesulfonic acid in 30 ml of water, the mixture is stirred and cooled for 5 minutes and the precipitated solid is filtered off with suction, controlled on the aqueous phase of the filtrate, basified with 10% sodium hydroxide solution. 8.0), 80 ml of ethanol are added and the solution is refluxed for 5.5 hours. The ethanol is distilled off, the residue is diluted with 60 ml of water and the mixture is neutralized with 2.0 ml of acetic acid. 0.45 g (15%) of the crude desired base is obtained, which is filtered off with suction and washed with a little water. It is then extracted with a boiling mixture of 15 ml of ethanol and 2 ml of water and the insoluble fraction is repeatedly crystallized from a mixture of ethanol and benzene. Thus a pure product is obtained which melts at 197.5-200 ° C.

Claims (3)

SUBJECT OF THE INVENTION Process for the preparation of novel 2-chloro-10-piperazino-10,11-dihydrodibenzene (b, f) thiepine derivatives having an oxygen function at the 6-position of the general formula I 213 292 wherein R represents a hydrogen atom or a methyl group, and their salts with both inorganic and organic acids, characterized in that 2,10-dichloro-6-methoxy-10, H-dihydrodibenzo (b, f) thiepine of the formula II (II) undergoes a substitution reaction with 1- (2-hydroxyethyl) piperazine, obtained by 2-chloro-6-methoxy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b, phthiepine optionally); demethylated and the base of the formula I obtained is converted into a salt by neutralization with inorganic or organic acids. 2. A process according to claim 1 wherein R = CHg, wherein the substitution reaction of the compound of formula II with 1- (2-hydroxyethyl) piperazine is carried out with a 100-300% excess of this amine in boiling chloroform. . 3. The process of claim 1 wherein R = H, wherein the demethylation of 2-chloro-6-methexy-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo (b) f) tbiepine is carried out with boron tribromide in chlorobenzene at room temperature, the undefined primary product is subjected to hydrolysis with a boiling soda-alcoholic dilute sodium hydroxide solution and the product is isolated on the basis of its amphoteric character.