CS245900B1 - Preparation method of new benzylpiperazine derivatives of dibenzo(b,f)thiepine series - Google Patents

Description

(54) A process for preparing novel benzylpiperazine derivatives of the dibenzo (b, i) thiepine series

2

The solution falls within the field of synthetic drugs. It relates to a process for the preparation of novel benzylpiperazine derivatives of dibenzo (b, f, mepine series of formula I,

O) wherein R represents a chlorine atom at the 6 or 7 position of the skeleton. This preparation process involves the substitution reaction of 2,6,10-trichloro-2,7,10-trichloro-10,11-dihydrodibe, nzo (b, f) thiepine with 1-benzylpiperazine. The substitution reactions are performed using a 100- to 300% excess of 1-benzylplperazine at temperatures of 60 to 120 ° C. The resulting compounds of formula I are intermediates in the preparation of psychotropically active drugs.

The present invention relates to a process for the preparation of novel benzylpiperazine derivatives of the dibenzo (b, f) thiepine series of formula I,

wherein R represents a chlorine atom at position 6 or 7 of the skeleton. The compounds of this formula are intermediates in the preparation of psychotropic substances, in particular neuroleptically active substances, and as such are technically valuable.

Preparation of compounds of formula I according to this invention consists in a substitution reaction the chloro derivatives of formula ¹ II

(n) wherein R is the same as in Formula I, with excess 1-benzylpiperazine (Cymerman Craig J., Yonng RJ: Org. Syn., Coll. Vol. 5, 88, 1973 J. For this substitution reaction, 1- benzylpiperazine is used in a 100-300% excess, the reaction is carried out at elevated temperature at 60-120 ° C and operated either without the environment (in this case excess 1-benzylpiperazine serves as the reaction medium) or in the presence of suitable inert solvents. Treatment of the reaction mixtures yields inhomogeneous products containing, on the one hand, the desired bases of the formula I and, on the other hand, the starting excess 1-benzylpiperazine. Since the base of formula (I) is oily, it is first necessary to separate from the mixture by crystallization 1-benzylpiperazine in the form of a methanesulfonic acid salt. lye after this salt is then isolated the methanesulfonate of the desired base of formula I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE PREFERRED EMBODIMENTS OF THE INVENTION The compounds of formula I of the present invention are described in the following examples, which are intended only to illustrate the possibilities of the invention, but in more detail. The starting chloro derivatives of formula II are novel and their preparation is also described in the examples. This preparation is based on 2,5-diehloiracetophenone (Rajsner M. et al., Collect. Czech. Chem. Commun. 43, 1276, 1978), 2-chlorothiophenol (Godt HC Jr., Wann RE, J. Org. Chem. 26, 4047 (1961) and 3-chlorothiophenol (Daccomo G., Jahresber. Fortscbr. Chem. 1891, 1 375) as known starting materials. The end products described, as well as all intermediates, are novel and have not been described in the literature. Their identity was assured by usual analyzes and all common spectral methods.

Example 1

10- (4-Benzylplperazino) -2,6-dichloro-10,11-dihydrodibenzo (b, f Jthiepine (I, R = 6-C1))

To a stirred mixture of 31.7 g of 2-chlorothiopheinol and 37.8 g of 2,5-dichloroacetophenone was added 1.0 g of freshly reduced copper and 55 g of anhydrous potassium carbonate. Addition of 10 ml of ethanol allows stirring to continue and the mixture is refluxed for 6 h (bath temperature 120 ° C). 100 ml of water and 100 ml of benzene are added to the still warm mixture, the mixture is stirred and shaken, then filtered and the aqueous layer of the filtrate is extracted with benzene. The benzene solutions were combined, dried over magnesium sulfate, filtered with charcoal, and the filtrate was evaporated under reduced pressure. The residue crystallized on standing slowly and recrystallized from 35 ml of boiling ethanol. 41.2 g (69%) of almost pure 5-chloro-2- (2-chlorophenylthio) acetophenone are obtained, which melts at 86-87 ° C. An analytically pure sample was obtained by further crystallization from ethanol, mp 87-88.5 ° C. In larger batches where the mother liquors are processed, the product is obtained in a yield of up to 78%.

A mixture of 140 g of the preceding product, 22.5 g of sulfur (sulfur blossom and 81 g of morpholine) was stirred and refluxed for 4.5 h at a bath temperature of 145-150 [deg.] C. After standing overnight the mixture was diluted with 500 ml of chloroform. The filtrate was washed with water, 1: 9 dilute hydrochloric acid and water again, dried over magnesium sulfate, filtered and evaporated under reduced pressure. let it crystallize.

111 g (60%) of crude [5-chloro-2- (2-chloro-phenylthio) -phenyl] -acetothiomorpholide, m.p. 134-137 [deg.] C. were obtained, an analytically pure sample was obtained by further crystallization from benzene, m.p. 142-143 [deg.] C.

To a solution of 28 g of potassium hydroxide in 100 ml of ethanol is added 40.0 g of the previous thiomorpholide and the mixture is refluxed for 3 hours. While still warm, dilute with 1 L of water, filter with charcoal and acidify the filtrate with hydrochloric acid.

The precipitated oily product crystallizes slowly. Filter, wash with water and dry in vacuo. 24.0 g (76%) of [5-chloro-2- (2-chlorophenylthi-o) phenyl] acetic acid, melting at 135-138 ° C, are obtained. An analytical sample is obtained by recrystallization from 70% aqueous ethanol. mp 139-141 ° C.

The stirred mixture of 50 g of the previous acid and 500 g of polyphosphoric acid is heated at 150 ^DEG C. for 4 hours and then poured into > 2.5 kg of ice-water mixture. The precipitated solid product is filtered off with suction and the oily layer of the filtrate is extracted twice with 500 ml of benzene. The filtered solid product is dissolved in the extract with heating, filtered and washed at 40 ° C with water, 5% sodium hydroxide solution and again with water, dried over magnesium sulfate and evaporated.

42.5 g (89%) of almost pure 2,6-dichlorodibenzo (b, f) thlepin-10 (11H) -one are obtained, melting at 159 DEG-162 DEG C. The analytically pure product is obtained by recrystallization from benzene; Mp 164-165 ° C.

To a stirred suspension of 42.5 g of the preceding ketone in 900 ml of ethanol at 65-70 ° C was added a solution of 27.2 g of sodium borohydride in 270 ml of water containing 1 ml of 20% sodium hydroxide solution over 15 minutes. The mixture was refluxed for 6 hours, the ethanol was evaporated under reduced pressure and the residue was partitioned by shaking between 600 ml of benzene and 250 ml of water. The organic layer was washed with 250 ml of 2% sodium hydroxide solution and 250 ml of water, dried over magnesium sulfate, filtered. with activated carbon and evaporate. The crystalline residue was recrystallized from 90 ml of benzene. 33.6 g (79%) are obtained.

2,6-Dichloro-10,11-dihydrodibenzyl (b, phthiepin-10-ol, melting at 132-134 ° C. Analytical sample was obtained by crystallization from ethanol, m.p. 134-135 ° C.

To a solution of 36.5 g of the preceding alcohol in 1 L of benzene was added 50 g of powdered anhydrous calcium chloride and the stirred suspension was saturated with hydrogen chloride gas at 20 ° C for 7.5 h. The calcium chloride is then removed by filtration, washed with 50 ml of benzene and the filtrate is evaporated under reduced pressure. 38.6 g (100%) of almost pure 2,6,10-trichloro-10,11-dihydrodibenzo [b, phthiepine (II, R = 6-Cl3), mp 115-116 [deg.] C. are obtained. recrystallization from a mixture of benzene and petroleum ether, mp 115.5-116 degrees Celsius.

A mixture of 11.3 g of the preceding chloro derivative, 30 ml of chloroform and 18.9 g of 1-benzylpiperazine is stirred and refluxed for 8 hours. The chloroform is evaporated, the residue is diluted with 60 ml of benzene and the solution is washed three times with 3% sodium hydroxide solution. The base is then extracted into excess 1 "25M-H ₂ SO _4, the aqueous sulfate solution basified with aqueous ammonia and the base extracted with benzene. Drying and evaporation of the extract yielded 21.2 g of a base mixture (desired product and starting 1-benzylpiperazine). Part of the 1-benzylpiperazine was removed by extracting twice with 30 ml of boiling water each time, the undissolved bases were dissolved in 20 ml of ethanol. Crystallization was induced by addition of 30 g of methanesulfonic acid and 30 ml of ether, and the precipitated methanesulfonate was filtered off with suction and crystallized from 50 ml of ethanol to give 7.2 g of pure 1-benzylpiperazine dimethanesulfonate (mp 204-206 ° C). The residue is dissolved in water, the solution is filtered with charcoal, evaporated under reduced pressure and the residue is made alkaline with aqueous ammonia and 5.3 g of oily are isolated by extraction of benzene 2.6-dichloro-10- (4-benzylpiperazinoj-10). 1,11-dihydrodibenz-o (b, phthiepine (I, R = 6-Cl);

Dissolve in 12 roles of ethanol, add 2.24 g of methanesulfonic acid and then 20 ml of ether. The salt precipitates first as an oil, but crystallizes completely within 12 hours. It is 5.1 g (21%) of the dimethanesulfonate monohydrate of said base I (R = 6-Cl), mp 148-151 ° C.

Example 2

2,7-Dichloro-10- (4-benzylpiperazino) -10,11-dihydrodibenzo (b, phthiepin (I, R = 7-C1J)

To a stirred mixture of 31.7 g of 3-chlorothiophenol and 37.8 g of 2,5-dichloroacetophenone was added 1.0 g of copper, 55 g of anhydrous potassium carbonate and 10 ml of ethanol, and the mixture was heated under reflux for 6 h (120 degree bath). Celsius). Work-up in a similar manner to that described in Example I gave 38.0 g (64%) of 5-chloro-2- (3-chlorophenylthio) acetophenone, which melted at 57-58 ^° C (ethanol) in pure form.

A mixture of 99 g of the preceding ketone, 16.0 g of sulfur and 58 g of morpholine was treated similarly to the corresponding step in Example 1,

The crude product obtained is crystallized from a mixture of 150 ml of benzene and 200 ml of petroleum ether. The product was 75 g (56%) of [5-chloro-2- (3-chloro-phenylthio) -phenyl] -acetonitrile-o-olfolide, which melted at 110-111 ° C (benzene) in pure form.

Hydrolysis of the previous thiomorpholide (40 g) with potassium hydroxide (28 g) in ethanol (80 ml) was carried out similarly to the corresponding step in Example 1. 27 g (86%) of [5-chloro-2- (3-chlorophenylthio) phenyl] were obtained. i-acetic acid, which melts in the pure state at 115-116 ° C (70% ethanol).

Cyclization of 53 g of the previous acid with 530 g of polyphosphoric acid was carried out similarly as described in the corresponding step in Example 1. 45.7 g (91%) of the title compound were obtained.

2.7-dichlorodibenzo (b, phthiazin-10 (11H) -one, which melts at 157-158 ° C (benzene) in pure state.

Reduction of 45.7 g of the previous ketone with 29.1 g of sodium borohydride in the mixture

1 L of ethanol and 290 ml of water were carried out in a similar manner as described in the corresponding step of 24SIB8 in Example 1. 36.9 g (80%) of 2,7-dichloro-10,11-dihydrodiibe were obtained. nzo (b, phthalene-10-oil) melts in the pure state at 125-126 ° C (ethanol).

To a solution of 39.5 g of the preceding alcohol in 1.3 L of benzene was added 50 g of anhydrous calcium chloride and the suspension was saturated with hydrogen chloride for 16 h at room temperature. Work up similarly as described in the appropriate step of Example 1. The crude product obtained is recrystallized from 130 ml of benzene. 35.8 g (85%) of pure 2,7,10-trichloir-10,11-dihydrochloride benzo (b, phthepime) melting at 157-158 ° C is obtained.

A mixture of 12.0 g of the preceding chioperative, 30 ml of chloroform and 20.1 g of 1-benzylpiperazine was refluxed for 8 hours. After standing overnight, the chloroform was evaporated under reduced pressure and the oil dissolved in 60 ml of benzene. The solution was washed three times with 3% sodium hydroxides solution and the base was extracted into potoim excess of 1.25M H _{2 SO-fourth} The aqueous sulfate solution was basified with aqueous ammonia and the bases were isolated by extraction with benzene. The extract was dried over sodium sulfate, filtered with charcoal and evaporated. 22.5 g of an oily base mixture are obtained, from which 14.5 g of the crude desired product crystallized in 24 h. The crystals were isolated after addition of a little ice-cold benzene and filtration. This afforded 11.7 g (67%) of the desired 2,7-dSchfor-10- {4-benzyl] -l ^Q ,, ll-dihydro-dibenzo (b, fjthiepiuu fl, R = 7-C1), which melts 134 to 136 ^Q C (Bonzo n). Neutralization with methanesulfonic acid gives a crystalline dimethanesulfonate melting at 158-159 ° C (ethanol).

Claims (1)

SUBJECT A process for the preparation of novel benzylpiperazine azine dibenzo (b, f) thiepinc derivatives of the general formula I, Or a skeleton, characterized in that the chloro-chlorates of the general formula II, in which R is the same as in the formula I, are reacted with a substitution reaction with 1-benzylpiperazine used in a 100- to 300% excess at 60 to 120 ° C.