CS247594B1 - Process for the preparation of (E) -2-cyano-11 '(3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine and its salts - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is a new method for the preparation of (E)-2-cyano-ll-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo(b,e) thiepine (I) and its salts with pharmaceutically acceptable inorganic or organic acids. The substance I according to the invention and its salts have the properties of selective inhibitors of serotonin reuptake in some brain structures and are useful in the therapy of mental depressions. The essence of the process according to the invention is the selective reaction of 2-cyanodibenzo(b,e)thiepin-11(6H)-one with 1 mol of 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran, subsequent gentle dehydration of the obtained 2-cyano-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo(b,e)thiepin-11-ol by heating with thionyl chloride in pyridine, purification of the obtained crude base by crystallization of hydrochlorides and conversion of the pure base I by neutralization with acids to the desired salts.

Description

The present invention relates to a process for the preparation of (E) -2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of the formula I

CN (I)

CH, HI ² ch ₂ n (ch ₃ ) ₂ and its salts with pharmaceutically acceptable inorganic or organic acids.

Z Evr. Fri. No. 101,234, it is known that 2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine has the properties of a selective serotonin reuptake inhibitor in some brain structures, which is the basis for its therapeutic use in mental depression. However, this application does not address the question of geometric isomerism of the product (due to the presence of the double bond and the asymmetric structure of the tricyclic skeleton it was possible to assume the existence of the (E) (trans) - and (Z) (cis) isomer. discloses only a method of preparing a substance which is apparently a mixture of both isomers by reacting 2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (also a mixture of isomers) with cuprous cyanide in boiling dimethylformamide. Described in the descriptive section are several other options for the preparation of the desired cyano compound, but neither of these options gives experimental details or properties of the intermediates, so it should be understood that these options have not been experimentally realized at all.

It has now been found that 2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepin in the form of the pure (E) -isometer of formula I is permissible in a preparative manner not included in the subject matter. is not mentioned in the descriptive part of this application. This novel process is an object of the present invention and consists in the selective reaction of 2-cyandibenzo (b, e) thiepin-11 (6H) -one of formula II

O with 1 mole of 3-dimethylaminopropylmagnesium chloride and in the subsequent gentle acid catalyzed dehydration of the resulting 2-cyano-11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepin-11-ol of formula III

HO (CH ₂ ) ₃ N (CH ₃ ) ₂

In the ketone molecule of formula II, the keto group is preferably reacted with the Grignard reagent, and using insufficient 3-dimethylaminopropylmagnesium chloride and working in tetrahydrofuran yields the desired amino alcohol of formula III in 60% yield and about 40% of the starting ketone II is tegenerated; calculated on the conversion, therefore, the yield of this reaction is theoretical. The amino alcohol of formula III is a crystalline substance which results directly in a virtually pure state by reaction. The dehydration thereof can be advantageously carried out by heating with thionyl chloride in pyridine, and in a yield of over 90% a nearly homogeneous base of the formula I is obtained. Crystallization from this base-prepared oxalate then leads in high yield to a completely homogeneous (E) -isomer. to give a pure and crystalline base of formula I which, by acid neutralization, provides additional salts (hydrochloride, hydrobromide, hydrogen oxalate in two crystal modifications).

The starting material, i.e. the ketone of formula II, was given only by the formula in the descriptive part cited by Evr. U.S. Pat. No. 101,234, but neither its preparation nor its properties have been described. Its preparation is therefore described in the example. It is obtained in good yield by the reaction of the known 2-bromodibenzo (b, e) thiepin-11 (6H) -one (Protiva M. et al., Experientia 18, 326, 1962; Rajsner M. et al., Czech Farm. 11 , 451, 1962) with copper (I) cyanide in hexamethylphosphoric triamide at 150 ° C. It is a great advantage of the process of the present invention that this complex reaction with cuprous cyanide is shifted from a relatively sensitive olefinic base such as 2-bromo-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine to the very stable ketone of formula II.

The details of the preparation process according to the invention are given in an example which illustrates the possibilities of the invention, but it is not intended to fully describe these possibilities. The identity of all the novel compounds described in the example was ensured by both analyzes and conventional spectral methods. The configuration of the final product of formula I was determined based on the 1 H NMR spectrum using the Eu (FOD) ₃ ά ₂ γ shift reagent, ie tris (1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane) -4,6-dione europia-d ₂₇ .

Reaction of 4.8 g of 3-dimethylaminopropyl chloride with 1.0 g of magnesium in 30 ml of tetrahydrofuran (starting the reaction with an iodine bead and a few drops of 1,2-dibromoethane) prepared a Grignard reagent solution (boiling the mixture for 1 hour until the reaction of magnesium). After cooling to 10 ° C, a solution of 6.2 g of 2-cyandibenzo (b, e) thiepin-11 (6H) -one in 50 ml of tetrahydrofuran is added and the mixture is stirred at 10-20 ° C for 2 h. It is then quenched by the addition of 30 ml of 20% ammonium chloride solution, diluted with a mixture of ether, benzene and ethyl acetate and the basic product is taken up in 100 ml of 10% hydrochloric acid. The organic phase was washed with water, the wash water was combined with an acidic aqueous solution which was immediately basified with aqueous ammonia and the base extracted with chloroform. The extract was dried over potassium carbonate and evaporated. 5.0 g (60%) of crude 2-cyano-11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepine-11-ol are obtained, which crystallizes from a mixture of benzene and petroleum ether and melts at 162 DEG. to 163 ° C. 2.5 g of the starting ketone II are recovered by evaporation of the organic phase (after the base is extracted with hydrochloric acid).

To a mixture of 4.15 g of the preceding cyanoamino alcohol in 20 ml of pyridine was added 1.3 ml of thionyl chloride and the mixture was heated under reflux for 5 hours. It is then partitioned between ether and dilute aqueous ammonia, the organic phase is dried over potassium carbonate and evaporated. 3.8 g (97%) of an almost homogeneous oily base (E) -2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine (I) are obtained, which is dissolved in ether. and the solution was neutralized with a solution of 1.5 g of oxalic acid in acetone. Crystallization gave 4.5 g of hydrogen oxalate which crystallized from aqueous ethanol and melted at 229.5-230.5 ° C. This oxalate crystallizes from a mixture of ethanol and ether as a second crystal modification melting at 210-213 ° C. Decomposition of both modifications and extraction with ether gives a crystalline and homogeneous (E) -base I melting at 87.5 to 88.5 ° C (cyclohexanepetrol ether). Neutralization of this base with hydrogen chloride can produce either anhydrous hydrochloride, mp 256-258.5 ° C (ethanol) or hydrochloride hemihydrate, mp 250-255 ° C with decomposition (95% ethanol). Neutralization of the base with hydrogen bromide in ethanol gives the hydrobromide melting at 255-256 ° C (ethanol-ether). Citovaná Evr. U.S. Pat. No. 101,234 discloses for hydrobromide m.p. 213 DEG-215 DEG C., indicating that it was a mixture of geometric isomers.

The starting 2-cyandibenzo (b, e) thiepin-11 (6H) -one is obtained as follows: A mixture of 30.0 g of 2-bromo dibenzo (b, e) thiepin-11 (6H) -one (literature cited), 15 g of cyanide of copper (I) and 60 ml of hexamethylphosphoric triamide were heated at 150 ° C for 5.5 h. After cooling, it is partitioned by shaking between chloroform and dilute aqueous ammonia, the mixture is filtered off with suction, the organic phase is separated, washed with water, dried over potassium carbonate and evaporated. From the semi-crystalline residue, 16.15 g (65%) of the desired 2-cyandibenzo (b, e) thiepin-11 (6H) -one, which melts in pure form at crystallization from ethanol / benzene, including mother liquor treatment, is obtained. Mp 165-166.5 ° C.

Claims (3)

Preparation method (E) - 2-cyano-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of formula I ch ₂ n (ch ₃ ) ₂ and its salts with pharmaceutically acceptable inorganic * or organic acids, characterized in that: 2-cyandibenzo (b, e) thiepine-11 (6H) -one is reacted with an equivalent amount 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran, the obtained 2-cyano-11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo (b, e) thiepin-11-ol is dehydrated by treatment with thionyl chloride in pyridine, the crude base 1 obtained crystallizes in the form of hydrogen oxalate to remove the (Z) -isomer admixture, release the base from the pure (E) -oxalate and convert the acid neutralization to the desired salts.