Patent GB-837747-A (GB)
Title: Phenylcyclohexane compounds
Filed: 1958-02-27
Abstract: The invention comprises compounds of the formula <FORM:0837747/IV (b)/1> (wherein R1 and R2 are the same or different alkyl or alkenyl radicals, together containing at most 5 carbon atoms) and their acid-addition salts.  They may be prepared by reacting a 1-cyano-1-NR1R2-cyclohexane with a phenyl alkali metal compound in the presence of a Lewis acid such as a magnesium halide, BF3, AlCl3, FeCl3 or ZnCl2, or with a phenyl magnesium halide in an inert organic solvent and hydrolysing the reaction product; by introducing the group R2 into a 1-phenyl-1-NHR1-cyclohexane, directly by alkylation with, for example, an alkyl halide or a dialkyl sulphate in a solvent or in a stepwise fashion by treatment with an aldehyde or ketone and subsequent reduction, preferably with hydrogen and a hydrogenation catalyst or by acylation with an acyl halide or anhydride with subsequent reduction, preferably with lithium aluminium hydride in an inert solvent; by reacting an acid-addition salt of a 1-NR1R2-cyclohex-1-ene with a phenyl magnesium halide or a phenyl alkali metal compound and hydrolysing the reaction product; or by reacting an N-R1R2-benzamide with a compound Me-(CH2)5-Me wherein Me is an alkali metal or a magnesium halide and hydrolysing the reaction product.  In examples: (1) cyclohexanone and aqueous sodium metabisulphite are stirred together, potassium cyanide and diethylamine are added and the mixture is allowed to stand at a low temperature to give, on working up, 1-diethylamino-cyclohexanecarbonitrile which on reaction with phenyl magnesium bromide and subsequent hydrolysis yields 1-phenyl-1-diethylaminocyclohexane; (2) the corresponding dimethylamino compound is similarly prepared via 1-dimethylamino-cyclohexanecarbonitrile, a mixture of magnesium bromide and phenyl lithium replacing the phenyl magnesium bromide of (1); (3) cyclohexanone cyanohydrin and ethyl - n - propylamine are allowed to stand in benzene over potassium carbonate to give 1-(ethyl-n-propylamino)-cyclohexanecarbonitrile from which 1-phenyl-1-(ethyl-n-propylamino)-cyclohexane is obtained by the method of (1); (4) the product of (2) is prepared by heating pentamethylene-bis-magnesium bromide with N-benzoyl-dimethylamine in ether and hydrolysing the reaction product; (5) 1-phenyl-1-ethylamino-cyclohexane is refluxed with formic acid in toluene to give a solution of crude N - (1 - phenylcyclohexyl) - N - ethyl formamide which on reduction with lithium aluminium hydride yields 1-phenyl-1-(ethylmethylamino) - cyclohexane; (6) 1 - phenyl - 1-ethylamino-cyclohexane is refluxed with acetic anhydride in benzene to give N-(1-phenylcyclohexyl) - N - ethyl - acetamide, which on reduction with LiAlH4 yields the product of (1); (7) 1-phenyl-1-n-butylaminocyclohexane is refluxed with formic acid in toluene and the product is reduced with LiAlH4 to give 1-phenyl-1-(n-butyl-methyl-amino)-cyclohexane; (8) the product of (5) is prepared by heating 1-phenyl-1-ethylaminocyclohexane with formic acid and formaldehyde; (9) a mixture of 1-phenyl-1-methylamino-cyclohexane with n-butyraldehyde in ethanol is hydrogenated at 70 DEG  C. and 1500 pounds pressure in presence of Raney nickel to give the product of (7); (10) cyclohexanone and allylamine give N-cyclohexylideneallylamine, this with phenyl-lithium yields 1-phenyl-1-allylamino-cyclohexane and this with formic acid and formaldehyde gives 1-phenyl-1-(allyl-methylamino)-cyclohexane; (11) the product of (2) is obtained by exhaustive methylation of 1-phenyl-1-aminocyclohexane with formaldehyde and formic acid; (12) 1-phenyl-1-amino-cyclohexane is formylated and the product reduced to 1-phenyl-1-methylamino-cyclohexane and this is refluxed with methyl p-toluenesulphonate in toluene to give the product of (2); (13) 1-phenyl-1-ethylaminocyclohexane is reacted with allyl bromide in benzene at 60 DEG  C. to give 1-phenyl-1-(allylethylamino)-cyclohexane; (14) cyclohexanone is refluxed with ethyl-n-propylamine in benzene to give N-(1-cyclohexenyl)-ethyl-n-propylamine which on reaction with phenyl magnesium bromide in ether in presence of p-toluenesulphonic acid yields the product of (3); and (15) ethylamine and cyclohexanone give N-cyclohexylidene-ethylamine, this is warmed with iodomethane in ether and then the mixture is refluxed with phenyl lithium and hydrolysed to give the product of (5).  Hydrochlorides, hydrobromides, sulphates, p-toluenesulphonates, benzenesulphonates and acetates of some of the products are described and a list of further saltforming acids is given.ALSO:Pharmaceutical and veterinary compositions comprise compounds of the formula <FORM:0837747/VI/1> (wherein R1 and R2 are the same or different alkyl or alkenyl radicals, together containing at most 5 carbon atoms) or, preferably, acid-addition salts thereof made up as tablets, dragees, capsules, syrups, suppositories or parenteral solutions. Suitable acid salts are the hydrobromide, sulphate, phosphate, succinate, benzoate, acetate, sulphamate and p-toluene sulphamate.