Patent GB-853775-A (GB)
Title: Pharmaceutical compositions and methods for producing phenylcyclohexane compounds
Filed: 1958-02-27
Abstract: 1-Phenylcyclohexylamine is prepared (1) by treating 1-phenylcyclohexane carboxylic acid with hydrazoic acid in a strong mineral acid; (2) by treating 1-phenylcyclohexane carboxamide with an alkali metal hypohalite and subjecting the resulting isocyanate to acid hydrolysis; (3) by reacting an alkyl 1-phenylcyclohexane carboxylate with hydrazine, reacting the hydrazide so produced with nitrous acid, treating the azide so obtained with an aliphatic alcohol containing 1 to 4 carbon atoms and treating the resulting N-(1-phenylcyclohexyl)-carbamic acid alkyl ester with a strong mineral acid; (4) by reacting a 1-phenylcyclohexane alkali metal compound or magnesium halide with a haloamine or alkoxyamine under anhydrous conditions, advantageously in an inert organic solvent; (5) by hydrolysing a 1-phenylcyclohexane isocyanate or isothiocyanate or acylamino, urea or N-carboalkoxyamino compound, preferably with a mineral acid; (6) by reducing 1-phenylcyclohexyl hydrazine which may be further substituted on the nitrogen atoms, advantageously by catalytic hydrogenation; (7) by reducing a 1-phenyl-(halo-substituted)-cyclohexylamine, itself prepared by halogenating e.g. with thionyl chloride, a corresponding hydroxy-substituted compound the reduction being performed, for example, with lithium aluminium hydride or catalytically; (8) by reducing a 1-phenyl-(keto-substituted)-cyclohexylamine e.g. with hydrazine hydrate and alkali, or with lithium aluminium hydride to the hydroxy substituted compound, the keto compound itself being prepared for example by boiling with aqueous alkali a 1-phenyl-(keto-substituted)- cyclohexylamine containing as a substituent adjacent to the keto group a cyano, carboxyl or ester group; (9) by reacting a compound of the formula Me-(CH2)5-Me, wherein Me is an alkali metal or magnesium halide, with benzonitrile under anhydrous conditions and decomposing the resulting product with water; and (10) by catalytically hydrogenating N-benzyl-1-phenyl-cyclohexylamine. Examples illustrate each of the above processes.  Salts of the product with organic and inorganic acids are described.  1-Phenyl-cyclohexane carboxamide is prepared from the acid chloride (itself prepared from the acid and thionyl chloride) and ammonium hydroxide.  Methyl 1-phenyl cyclohexane carboxylate is prepared from the acid chloride and methanol. 1-Phenyl cyclohexyl isothiocyanate is prepared by warming 1-phenylcyclohexene with sodium thiocyanate and sulphuric acid. 1-Phenyl-1-methyl-2-(1-phenylcyclohexyl) - hydrazine is prepared by refluxing 1-methyl-1-phenyl-hydrazine with cyclohexanone in benzene, concentrating, refluxing with phenyl lithium in ether and decomposing with water.  2-Amino-2-phenyl-cyclohexanone is prepared by reacting 2-phenyl-cyclohexanone with ethyl nitrite in presence of sodium ethoxide to give 2-phenyl-2-nitroso-cyclohexanone and reducing this with stannous chloride.  1-Phenyl-4-chloro-cyclohexylamine hydrochloride is prepared by reacting acrylonitrile with a -nitro-toluene in presence of benzyl-trimethylammonium hydroxide to give bis-[a -(2-cyanoethyl)]-a -nitro-toluene, cyclizing this with lithium diethylamide to give 4-phenyl-4-nitro-2-cyanocyclohexanone, catalytically reducing this to 4-phenyl-4-amino-2-cyano-cyclohexanone, refluxing this with hydrochloric acid to give 4-amino-4-phenyl-cyclohexanone, reducing this with Li-A1H4 to 4-amino-4-phenyl-cyclohexanol and reacting this with thionyl chloride.  N-Benzyl-l-phenyl-cyclohexylamine is prepared by refluxing benzylamine with cyclohexanone in toluene and then reacting with phenyl lithium and decomposing with water.ALSO:Pharmaceutical compositions comprise 1-phenylcyclohexylamine, hereinafter denoted as (X), or a non-toxic acid-addition salt thereof e.g. the hydrochloride +p-toluene-sulphonate and one of more conventional solid or liquid diluents or carriers, in the form of tablets, liquid or dry-filled capsules, aqueous or non-aqueous solutions-for oral or parenteral administration, dragees suppositories, inhalents, jellies or sprays, and the compositions may also contain preservatives or flavouring agents.  Specific examples relate to aqueous liquid preparations, tablets, hard and soft gelatine capsules, ampoules (aqueous and oil solutions), suppositories.