Patent GB-608935-A (GB)
Title: Manufacture of n-substituted imino-di-fatty acid amides
IPC: C07C233/00
Filed: 1944-05-12
Abstract: Alkyl-, cycloalkyl-, or aralkyl-imino-di-fatty acid amides, in which at least one amido group is disubstituted and stated to be useful for therapeutic purposes, e.g. as analeptics, are prepared by reacting an a -alkyl-, a -cycloalkyl-, or a -aralkyl-amino-fatty acid amide with a halogen fatty acid amide, or by reacting an alkyl-, cycloalkyl-, or aralkyl-amino-fatty acid amide with an a -halogen fatty acid amide, the amido group in at least one of the starting compounds in each case being disubstituted.  When the products have a symmetrical structure they may also be obtained by reacting a -halogen fatty acid amides, in which the amido nitrogen is disubstituted with primary amines in the molar proportion of 2 to 1.  N-Substituted imino-di-fatty acid amides whose amido groups still have a replaceable hydrogen atom can be treated with an alkylating agent to produce the corresponding compounds disubstituted in both amido groups and imino-difatty acid amides unsubstituted in the imino group can be substituted at the imino-nitrogen by treatment with alkylating, cycloalkylating or aralkylating agents, e.g. methyl iodide, diethyl-sulphate, benzyl chloride, phenylethyl bromide or cyclohexyl bromide or methylation can be effected by treatment with formaldehyde and formic acid.  A further method of production consists in amidating N-substituted imino-di-fatty acids in which at the most one carboxyl group is already amidated, or their esters, halides or anhydrides, by reaction with secondary amines, or by reacting the salts of these imino-di-fatty acids or of their monoamides with carbamic acid halides which are derived from secondary amines.  The N-substituted-a -amino fatty acid amides may be obtained by conversion of a -halogen fatty acid amides with primary amines, the a -halogen fatty acid amides being produced by known methods from the corresponding acids or their esters, halides or anhydrides and primary or secondary amines, e.g. methyl amine, ethylamine, dimethylamine, diethylamine, diallylamine, methyl - ethyl - amine, methyl - propylamine, methyl aniline, methyl benzyl amine, piperidine or morpholine.  In examples: (1) a -ethylamino butyric acid diethylamide (produced from a -bromo-butyric acid diethylamide and ethylamine) is heated to boiling in anisole solution, chloroacetic acid diethylamide added and the mixture refluxed, the anisole solution is made acid with hydrochloric acid, the anisole removed and the hydrochloride saturated with potassium hydroxide to form the N-ethylimino - butyric acid - acetic - acid - bis - diethylamide; (2) a -ethylamino propionic acid dimethylamide (prepared from a -bromopropionic acid dimethylamide and ethylamine) is refluxed with a -bromo-propionic acid diethylamide in anisole solution and the N-ethylimino-dipropionic acid diethyl-dimethylamide separated as in (1); (3) a -ethylamino butyric acid diethylamide (prepared from a -bromobutyric acid diethylamide and ethylamine) is reacted with a -bromo-propionic acid diethylamide in tetrahydronaphthalene and the N-ethylimino butyric acid propionic acid bis-diethyl-amide obtained is separated as in (1); (4) chloroacetic acid diethylamide dissolved in benzene is heated with ethylamine in an autoclave, the benzene solution is washed with caustic potash and distilled and the first runnings consist of ethylamino acetic acid diethylamide after which the N-ethylimino diacetic acid bis-diethylamide passes over; (5) N-ethylimino butyric acid monoethylamide-acetic acid diethylamide are dissolved in xylene and then heated with sodamide to form the sodium compound which is then heated in an autoclave with potassium ethyl sulphate, the potassium sodium sulphate is separated, the solvent distilled off, N-ethylimino-butyric acid acetic acid bis-diethylamide being obtained; (6) iminodipropionic acid bisdiethylamide is heated with formic acid and formaldehyde, concentrated hydrochloric acid added and formic acid and excess formaldehyde are distilled off.  The residue is mixed with water and saturated with potassium hydroxide to form N-methyliminodipropionic acid bisdiethylamide; the same compound can be obtained by methylation with dimethyl sulphate or methyl iodide; (7) N-ethylimino-di-n-butyric acid diethyl ester (produced from a -bromo butyric acid ethyl ester and ethylamine) is boiled under reflux with concentrated hydrochloric acid, the solution is then evaporated to dryness and heated with phosphorus pentachloride, freed from the phosphorus oxychloride formed and the hydrochloride of N-ethyliminodi-n-butyric acid dichloride obtained is treated with excess diethylamine solution, the diethylamino hydrochloride is filtered off and distillation under reduced pressure yields N-ethylimino-di-n-butyric acid bis-diethyl-amide; the same compound is obtained by heating the disodium salt of N-ethylimino-di-n-butyric acid with diethyl carbamic acid chloride.  Several additional starting materials are specified and tables are also given which indicate the method, production and properties of a large number of compounds obtainable by the processes of examples (1), (2) and (3).