Patent GB-783139-A (GB)
Title: A process for the manufacture of therapeutically active amines and salts thereof
Filed: 1955-09-06
Abstract: Compounds of the formula: <FORM:0783139/IV (a)/1> and salts thereof (where n is 0 or 1, R represents a hydrogen atom, or an alkyl or acyl radical, R1 represents a tertiary amino group, e.g. dimethylamino-, piperidino-, morpholino- or pyrrolidino-, and "alkylene" represents a divalent saturated aliphatic hydrocarbon radical having a straight or branched chain) are prepared by reacting b -ionone or 4-[21,61,61-trimethyl-cyclohexen - 11 - yl] - 2 - methyl - buten - 2 - al with a diamine of formula H2N-alkylene-R1 in the presence of a reducing agent, and if desired acylating or alkylating the resulting amine and/or converting it into a normal or quaternary salt.  The alkylation is preferably effected with a mixture of formaldehyde and formic acid or by reduction of the N-acylated derivative with lithium aluminium hydride.  Specified salts are those with hydrochloric, hydrobromic, hydriodic, sulphuric, phosphoric, oxalic, acetic, citric, lactic, tartaric and benzene sulphonic acids, and with quaternizing agents, e.g. alkyl halides, dialkyl sulphates and aralkyl halides.  In examples: (1) b -ionone and b -diethylaminoethylamine are hydrogenated in ethanol using Raney nickel giving N2,N2-diethyl-N1-[1-methyl-3[21,61, 61 - trimethyl - cyclohexen - 11 - yl]propyl]ethylenediamine (A), similarly, using the appropriate amine are prepared N1-[1-methyl-3[21,61,61 - trimethyl - cyclohexen - 11 - yl] propyl] - N2,N2 - dimethylpropanediamine-(1,3) (B), the corresponding N2,N2-diethyl and N2,N2 - dibutyl compounds, and 1 - methyl - 3-[21,61,61 - trimethyl - cyclohexen - 11 - yl] propyl 3-morpholinopropyl amine (C), and on replacing b  - ionone by 4 - [21,61,61 - trimethyl - cyclohexen - 11 - yl] - 2 - methyl - buten-2 - al - (1) the following: N1 - [2 - methyl - 4-[21,61,61 - trimethyl - cyclohexen - 11 - yl]butyl]-N2,N2 - diethyl - ethylene diamine (D), the corresponding - N2,N2 - dimethyl - propanediamine - (1,3) (E), - N2,N2 - diethyl - propane diamine - (1,3) (F), and - N2,N2 - dibutylpropanediamine - (1,3); also N1,N1 - diethyl - N2-[2 - methyl - 4 - [21,61,61 - trimethyl - cyclohexen - 11 - yl]butyl] - 4 - methyl - butane diamine - (1,4) (G), and 2 - methyl - 4 - [21,61,61-trimethyl - cyclohexen - 11 - yl]butyl - 3 - morpholino-propylamine (H), and their appropriate dioxalate salts. (2) (A) obtained in (1) above is refluxed with formic acid and formalin, the product concentrated, made alkaline and N2,N2 - diethyl - N1 - methyl - N1 - [1 - methyl 3 [21,61,61 - trimethyl - cyclohexen - 11 - yl] propyl]-ethylenediamine isolated by ether extraction; likewise compounds (B)-(H) are also N1-methylated; (A) is refluxed with diphenylacetyl chloride in benzene to yield N2,N2 - diethyl - N1 - diphenylacetyl - N1 - [1-methyl - 3 - [21,61,61 - trimethylcyclohexen - 11-yl]propyl] - ethylenediamine, which is converted to its hydrobromide (J); similarly (D) with acetyl chloride yields N1-acetyl-N1-[2-methyl - 4 - [21,61,61 - trimethyl - cyclohexen-11 - yl]butyl] - N2,N2 - diethyl - ethylene diamine, which is reduced with lithium aluminium hydride to the corresponding N1-ethyl derivative; (3) N1-methylated (A) in acetone is treated with methyl bromide to give the dimethobromide of N2,N2-diethyl-N1-methyl-N1 - [1 - methyl - 3 - [21,61,61 - trimethyl - cyclohexen - 11 - yl]propyl] - ethylenediamine dihydrate; similarly are prepared the dimethobromides of the N1-methylated (B), (C), (D), (E), (G) and (H), and of N1-diphenylacetylated (A); (J) is treated with aqueous sodium carbonate and after isolation with ether the base is refluxed with p-nitrobenzyl bromide in acetonitrile yielding the p-nitrobenzyl bromide of N2,N2 - diethyl - N1 - diphenylacetyl - N1 - [1-methyl - 3[21,61,61 - trimethyl - cyclohexen - 11-yl]propyl] - ethylenediamine. Specifications 782,820 and 782,821 are referred to.