GB1008263A - Dibenzocycloheptene derivatives and their preparation - Google Patents

Abstract

Compounds of the general formula <FORM:1008263/C4-C5/1> (wherein each of X and X1 represents a hydrogen atom or a C1- 6 alkyl radical and the dotted line indicates that the compounds may be saturated or unsaturated at the 10, 11-positions) are produced by dehydrating compounds of the general formula <FORM:1008263/C4-C5/2> by means of a chemical dehydrating agent. Specification 858,188 is referred to.ALSO:The invention comprises aminopropylidene dibenzocycloheptenes and their 10,11-dihydro derivatives, of the general formula <FORM:1008263/C2/1> and the corresponding aminopropyl compounds of the general formula <FORM:1008263/C2/2> (in which formulae the dotted lines indicate that the compounds may be saturated or unsaturated at the 10,11-positions, R represents a hydrogen atom or a C1-6 alkyl radical, and each of X and X1 represents a hydrogen or halogen atom or a trifluoromethyl, C1-6 alkyl, C1-4 alkoxy, mercapto, C1-4 alkylmercapto, C1-4 alkylsulphonyl, sulphamoyl, C1- 4 alkylsulphamoyl or C2- 6 dialkylsulphamoyl radical, but excluding, in formula (I), compounds in which X and X1 are both hydrogen or one is hydrogen and the other a halogen, when R = C1-6 alkyl, and their acid addition salts, and the preparation of these compounds by processes illustrated by the following reaction schemes:-(A) (for primary amines I, R = H): <FORM:1008263/C2/3> (the first step being effected in an inert solvent with subsequent hydrolysis, the second step by the action of a chemical dehydrating agent, the third step in a low-boiling solvent, the fourth step with any cyanide salt and the fifth step with a metal hydride in the presence of a solvent); (B) (for secondary amines, R = C2-6 alkyl): <FORM:1008263/C2/4> (or analogously for the aminopropyl compounds, R here representing a C1-5 alkyl radical, the first step alternatively employing an acyl halide and the second step being effected with a metal hydride in a solvent): (C) (for primary amines II, R-H): <FORM:1008263/C2/5> (R here representing a C1-6 alkyl radical and Hal a halogen atom); (D) (for secondary amines R = C1-6 alkyl): <FORM:1008263/C2/6> (or analogously for the aminopropylidene compounds, R1 and R11 representing hydrogen atoms or alkyl radicals and together containing at most 5 carbon atoms, the initial reaction with an aldehyde or ketone R1.CO.R11 being effected in a solvent and the reduction step with a metal hydride in a solvent); (E) (for secondary amines I, R = C1-6 alkyl): <FORM:1008263/C2/7> (the hydrolysis step being alternatively performed in an alkaline medium); (F) (for secondary amines II, R = C1-6 alkyl): <FORM:1008263/C2/8> (the hydrolysis being performed in an acid or alkaline medium); (G) (for primary amines II, R = H): <FORM:1008263/C2/9> (R here representing a C1-6 alkyl radical and Hal a halogen atom); (H) (for secondary amines II, R = C1-6 alkyl): <FORM:1008263/C2/10> 5 - (3 - Dimethylaminopropyl) - 5H - dibenzo [a,d] cycloheptene and its 10,11-dihydro derivative and their 3-chloro derivatives are prepared by treating 5 - chloro - 5H - dibenzo[a,d] cycloheptene or the corresponding 10,11-dihydro compound or their 3-chloro derivatives with a solution of 3-dimethylaminopropyl magnesium chloride in tetrahydrofuran. The first compound is isolated in the form of its hydrochloride. 3 - Dimethylsulphamoyl - 5 - (3 - dimethylaminopropyl) - 5H - dibenzo[a,d]cycloheptene is prepared similarly from 5-chloro-3-dimethylsulphamoyl - 5H - dibenzo[a,d]cycloheptene, obtained by treating 3-bromo-10,11-dihydro-5H-dibenzo [a,d]cycloheptene-5-one with fluorosulphonic acid to form its 7-fluorosulphonyl derivative, reacting this with dimethylamine to form the corresponding 7-dimethylsulphamoyl compound, removing the bromine atom by catalytic hydrogenation, dehydrogenating the product at the 10,11-positions by the action of N-bromosuccinimide followed by triethylamine, reducing the 5-one to the 5-ol with potassium borohydride, and treating the product with dry hydrogen chloride in dry dioxane and absolute ether. 5 - (3 - Dimethylaminopropylidene) - 3 - methylsulphonyl - 5H - dibenzo[a,d]cycloheptene is prepared by reacting 3-bromo-5H-dibenzo[a,d] cyclohepten-5-one with cuprous methylmercaptide (prepared from cuprous chloride and methyl mercaptan in aqueous alcoholic ammonia solution) to replace the bromine atom by -SCH3, reacting the product with 3-dimethyl-aminopropyl magnesium chloride to form 5 - (3 - dimethylaminopropyl) - 5 - hydroxy - 3-methylmercapto - 5H - dibenzo[a,d]cycloheptene, oxidizing the -SCH3 group to -SO2CH3 with hydrogen peroxide in acetic acid and dehydrating the product with trifluoroacetic anhydride in trifluoroacetic acid. The final product is separated into two isomers, isolated as hydrochloride and free base respectively. These isomers may be hydrogenated in the presence of Raney nickel to give their 10,11-dihydro derivatives. 5 - (3 - Dimethylaminopropyl) - 3 - methylsulphonyl - 5H - dibenzo[a,d]cycloheptene is prepared by reducing 3-methylmercapto5H-dibenzo[a,d] cyclohepten-5-one to the 5-ol, treating the product with dry hydrogen chloride in dry dioxane to form 5-chloro-3-methylmercapto-5H-dibenzo [a,d]cycloheptene, treating this with dimethylaminopropyl magnesium chloride and finally oxidizing the -SCH3 group to -SO2CH3. Grignard compounds.-3 - Ethoxypropylmagnesium bromide is prepared by reacting 3-ethoxypropyl bromide with magnesium in ether. 3-Dimethylaminopropylmagnesium chloride is prepared from 3-dimethylaminopropyl chloride and magnesium turnings in dry tetrahydrofuran in the presence of iodine and under an atmosphere of dry nitrogen, the reaction being initiated by the addition of a small amount of previously prepared 3-dimethylaminopropyl-magnesium chloride or of ethyl bromide. Pharmaceutical preparations.-The compounds of the invention, especially the acid addition salts, may be administered as antidepressants, mood elevators and psychic energizers. Specification 858,188 is referred to.