Patent GB-774858-A (GB)
Title: Tropane and -Î-tropane derivatives and process for preparation thereof
Filed: 1955-10-14
Abstract: The invention comprises acid amide derivatives of the tropane and q -tropane series, of the general formula: <FORM:0774858/IV(b)/1> (wherein R1 represents hydrogen or an alkoxy group, and wherein n is 1 and R2 represents a nicotinoyl, salicyloyl, benzoyl, p-nitrobenzoyl, benziloyl, Alkyl-O-CO-or (Alkyl)2N-CO-group, or n is 2 and R2 represents a malonyl, diphenylmalonyl or -CO- group, and the preparation thereof by reducing tropinone oxime or a 6-alkoxy derivative thereof (e.g. by catalytic hydrogenation or by means of sodium and an aliphatic alcohol) and reacting the resulting 3-amino-tropane or -q -tropane with the chloride or azide of a mono- or di-carboxylic acid R2(OH)n.  Reference is also made to compounds containing a diphenylmalonyl group substituted in either or both of the phenyl groups by chlorine or bromine.  The products are useful as pharmacodynamic agents for regulating the heart rhythm, or as intermediates in the manufacture of medicaments.  In examples: (1)-(5) and (19) tropinone oxime is reduced with hydrogen at room temperature and 60 atmospheres pressure in the presence of Raney nickel in alcohol and acetic acid, and the resulting crude 3-aminotropane (containing 20-30 per cent of 3-amino-q -tropane) is reacted with (1) an ethereal solution of benzilic acid azide (prepared by adding an aqueous solution of sodium nitrite to a solution of benzilic acid hydrazide in dilute hydrochloric acid); (2) nicotinic acid azide (analogously prepared) in ether and ethyl acetate; (3) salicylic acid azide (analogously prepared) in ethyl acetate; (4) ethyl chlorocarbonate in benzene in the presence of triethylamine; (5) phosgene in benzene; and (19) diphenylmalonyl dichloride in chloroform in the presence of triethylamine; (6)-(12) and (20) 3-amino-q -tropane is reacted with (6) nicotinic acid chloride in benzene; (7a) salicylic acid chloride in benzene; (7b) salicylic acid azide in ethyl acetate; (8) benzilic acid azide in ether; (9) malonyl dichloride in benzene; (10) ethyl chlorocarbonate in benzene in the presence of triethylamine; (11) phosgene in benzene; (12) dimethylcarbamyl chloride in benzene in the presence of triethylamine; and (20) diphenylmalonyl dichloride similarly; (13)-(16) 6-ethoxytropinone is reacted with hydroxylamine hydrochloride in the presence of caustic potash, the oxime is reduced with sodium and amyl alcohol, and the resulting 6-ethoxy - 3 - amino - q  - tropane is reacted with (13) nicotinic acid chloride in benzene; (14) salicylic acid azide in ethyl acetate; (15) benzilic acid azide in ethyl acetate; and (16) ethyl chlorocarbonate in benzene in the presence of triethylamine; (17) and (22) 6-methoxy-3-amino-q -tropane (prepared analogously to the ethoxy compound and characterized by reaction with phenyl isothiocyanate to form N-(6-methoxy - q  - tropyl - 3) - N1 - phenylthiourea) is reacted with (17) malonyl dichloride in chloroform in the presence of triethylamine; and (22) diphenylmalonyl dichloride similarly; (18), (21) and (23) 6-methoxytropinone oxime hydrochloride is reduced with hydrogen at room temperature and 50 atmospheres pressure in the presence of Raney nickel in methanol, and the resulting 6-methoxy-3-aminotropane is reacted with (18) benzoyl chloride in chloroform in the presence of triethylamine; (21) diphenylmalonyl dichloride similarly; and (23) p-nitrobenzoyl chloride similarly. The hydrochlorides of the products of (1)-(16) are described.