CS265750B1 - Process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6r11-dihydrodibenzo / b, e / thiepines and their maleates - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a method for preparing 11-(1-(2-(1-piperazinyl)acetyl)-4-piperidylidene) -6,11-dihydrodibenzo/b,e/thiepines (I) and their maleates. Substances I are both intermediates and, in themselves, exhibit certain local anesthetic, antiarrhythmic and antiulcer effects. The method of their preparation consists of a two-step process in which first 11-(4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine is subjected to the action of chloroacetyl chloride, preferably in boiling benzene in the presence of N,N-dimethylacetamide, the resulting 11-(1-(2-chloroacetyl)-4-piperidylidene)-6,11-dihydrodibenzo/b,e/thiepine is treated by substitution reactions with 1-methylpiperazine, 2-(1-piperazinyl)-ethanol and 3-(1-piperazinyl)-propanol, preferably carried out using a 100 to 110% excess of these amines in boiling chloroform, and the obtained base I is neutralized with maleic acid in ethanol.

Description

(57) The solution falls within the field of synthetic drugs. It is directed to a process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepines (I) and their maleates. Compounds I are on the one hand intermediates, and on the other hand, exhibit certain local anesthetic, antiarrhythmic and antiulcer effects. The process for their preparation consists in a two-step process in which the 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine is first treated with chloroacetyl chloride, preferably in boiling benzene in the presence of Ν, Ν-dimethylacetamide, - (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine was treated by substitution reactions with 1-methylpiperazine, 2- (1-piperazinyl) ethanol and 3- (1-piperazinyl) 1-propanol, preferably using a 100-110% excess of these amines in boiling chloroform and the base I obtained are neutralized with maleic acid in ethanol.

The present invention relates to a process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepines of the formula I

wherein R is methyl, 2-hydroxyethyl or 3-hydroxypropyl, as well as 1 maleate thereof.

The compounds of the formula I according to the invention are, on the one hand, intermediates in the synthesis of medicaments and, on the other hand, have local anesthetic, antiarrhythmic and antiulcer activity on their own.

The process for the preparation of the compounds of the formula I according to the invention consists of a two-stage process starting from 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which is first treated with chloroacetyl chloride, preferably in boiling benzene in the presence of Ν, Ν-dimethylacetamide. There was obtained crystalline 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which was treated in the second step by substitution reactions with 1-methylpiperazinene, 2- (1-piperazinyl) ethanol and 2- (1-piperazinyl) propanol (T. Zawisza et al., Acta Pol. Pharm. 22, 477, 1965). These substitution reactions can be performed under various conditions; preferably, they are carried out using a 100-110% excess of said piperazine derivatives in boiling chloroform. The resulting weights of formula I are generally oily and can be purified by crystallization of salts, preferably maleic acid salts, obtained by neutralizing the crude bases with ethanol in ethanol. The preparation of these salts, which are more advantageous than bases for carrying out pharmacological tests and for preparing dosage forms, is also part of the present invention. The starting 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine has not been described in the literature yet. Its synthesis from the known 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine is described in Example 1. Further details of the process for the preparation of the compounds of formula I according to the invention are given in the Examples. but which are merely illustrative of the possibilities of the invention. The compounds of formula (I) and intermediates described are novel; their identity was assured by analytical and spectral methods.

Example 1

11- (1- (2- (4-methyl-1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (I, R = _CH3)

To a solution of 1.50 g of 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine and 0.62 g of N, N-dimethylacetamide in 20 ml of benzene is added with stirring a solution of 0.81 g of chloroacetyl chloride in 20 ml of benzene and the mixture was refluxed for 1.5 h. After cooling, it is diluted with 60 ml of chloroform, washed thoroughly with water, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The oily residue (1.9 g) slowly crystallized from benzene. Thus, 1.51 g (80%) are obtained.

11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrobenzo (b, e / thiepine, m.p. 145-147 ° C).

To a solution of 2.50 g of the preceding chloroacetyl derivative in 40 ml of chloroform was added 1.5 g of 1-methylpiperazine and the mixture was heated under reflux for 2.5 h. Dilute with 60 ml of chloroform, wash with water, dry over anhydrous potassium carbonate and evaporated under reduced pressure. The residue crystallizes from benzene to give 2.42 g of the desired base, m.p. Neutralization with maleic acid in ethanol gives a crystalline bis (hydrogen maleate) which crystallizes from aqueous ethanol and melts at 161-164 ° C.

The starting 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which is a novel substance, is prepared by a two-step process from the known 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo (b, e) thiepine (Adlerova E. et al., Cesk. Farm. 12, 122, 1963) as follows:

To a solution of 5.00 q of 11- (1-methyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (lit.

<it <> v.í »1.1 ί v '*» ml]>' - 117. (- 1111 · i, m / min) gives a solution of 53 g of ethyl acetate in ethyl acetate 35 ml of benzene and refluxed for 2.5 h, cooled, washed with dilute hydrochloric acid and water, dried over anhydrous potassium carbonate and evaporated under reduced pressure to give 6.04 g of crude oil which was dissolved. in 25 ml of benzene and the solution was filtered through a column of 15 g of silica gel, the column was washed with 400 ml of benzene and the filtrate was evaporated to give 5.05 g (85%) of an almost homogeneous, oily 11- (1-ethoxycarbonyl-4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, whose analytical and spectral characterization confirms its identity.

A mixture of 4.47 g of the above ethoxycarbonyl derivative, 3.43 g of potassium hydroxide and 30 ml of ethanol is stirred and refluxed for 2 hours. After partial cooling, the mixture was diluted with 50 ml of water and extracted with benzene. Work-up of the extract gave 2.58 g (72%) of 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine, which crystallized from a mixture of benzene and ether and melted at 91-94 ° C.

Example 2

11- (1- (2- (4- ( 2- hydroxyethyl) -1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (I, _R-CH? CH ₂ OH )

Similar to Example 1, 2.50 g of 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (see Example 1) is reacted with 1.94 g 2 - (1-piperazinyl) ethanol in 40 ml of chloroform at reflux (3 h). Similar work-up gave 3.10 g of crude, oily base which was converted to crystalline bis (hydrogen maleate) (4.20 g, 89%) by neutralization with maleic acid in ethanol (m.p. Mp 151-154 ° C. Decomposition of a sample of this salt with aqueous ammonia, extraction with ether and evaporation of the extract yields a homogeneous, oily base which can be characterized by analytical and spectral methods.

Example 3

1.1 - (. 1- (2- (4- (3-hydroxypropyl) -1-piperazinyl) acetyl) -4-piperidylidene) -6,11-dihydro-dibenzo / b, e / thiepin (1 R - CH ₂ CH ₂ CH ₂ OH)

Similar to Example 1, the reaction of 2.40 g of 11- (1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine (see Example 1) with 2.06 g of 3 is carried out. - (1-piperazinyl) propanol (lit. quoted) in 40 ml boiling chloroform. Similar work-up gave 3.1 g of crude, oily base which was converted by neutralization with maleic acid in ethanol to give crystalline bis (hydrogen maleate), m.p. 110 DEG-113 DEG C. (ethanol). As in the previous cases, a homogeneous, oily base suitable for characterization by both analytical and spectral methods is released from this salt.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 11- (1- (2- (1-piperazinyl) acetyl, -4-piperidylidene) -6,11-dihydrodibenzo [b] el thiepines of formula I wherein R is methyl, 2-hydroxyethyl or 3-hydroxypropyl, and the maleate thereof, characterized in that 11- (4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine is treated with chloroacetyl chloride, preferably in boiling benzene in the presence of the-, Ν-dimethylacetamide formed by 11- ( 1- (2-chloroacetyl) -4-piperidylidene) -6,11-dihydrodibenzo [b, e] thiepine was treated by substitution reactions with piperazine derivatives of formula II. (R) (ii), wherein R is the same as in Formula I, preferably using a 100-110% excess of the amine of formula II in boiling chloroform, and then the bases of formula I obtained are neutralized with maleic acid in ethanol to the corresponding salts, generally bis (hydrogen maleate).