Patent GB-586135-A (GB)
Title: Manufacture of acylated aliphatic amino carboxylic acid amides
IPC: C07D213/82
Filed: 1943-12-17
Abstract: Acylated aliphatic aminocarboxylic acid amides of the general formula <FORM:0586135/IV/1> wherein R is an alkyl or cycloalkyl group, Ro is an alkyl group which may be linked to R by a carbon or hetero atom, A is an alkylene group, R1 is an acyl radical of a carboxylic acid and R11 is an alkyl or cycloalkyl group, are prepared by acylating aliphatic N-monoalkyl- or N-cycloalkyl-amino carboxylic acid amides of the formula <FORM:0586135/IV/2> with carboxylic acids or their functional derivatives.  In modifications, the compounds may also be prepared by reacting aliphatic N-alkyl- or N-cycloalkyl amino carboxylic acids or their functional derivatives, acylated by carboxylic acids, with secondary aliphatic or cycloaliphatic or heterocylcic amines with endocyclic amino groups; by reacting salts of the acylated aliphatic amino carboxylic acids with carbamic acid halides derived from the above mentioned secondary amines; by reacting monoalkyl or monocycloalkyl amides of carboxylic acids with aliphatic a - or b -halogen carboxylic acid amides of which the amide groups are twice substituted by the groups R and Ro defined above; and by reacting acylated aliphatic amino carboxylic acid amides, which in the amino and/or the amide group still contain replaceable hydrogen atoms, by replacing said hydrogen atoms by an alkali metal atom, for example, by means of sodium metal or sodamide and then reacting with alkylating or cycloalkylating agents.  The compounds are stated to be novel and are suitable for therapeutic use, especially as analeptics, and some may be used as solvent promoters. In examples: (1) ethylamino acetic acid diethyl amide, prepared by reacting chloracetic acid diethyl amide with ethyl amine, is acylated with diethyl acetic acid chloride yielding the ethyl amino acetic acid diethyl amide as its hydrochloride, the base being liberated on treatment with alkali; (2) isobutyl amino acetic acid diethyl amide is acylated with diethyl oxamic acid chloride yielding N-diethyl oxaminoyl-isobutyl amino acetic acid diethyl amide (hydrochloride); (3) cyclohexyl amin acetic acid diethyl amide is acylated with diethyl oxamic acid chloride yielding N-diethyloxaminoyl - cyclohexyl - amino - acetic acid diethyl amide (hydroxhloride), and analogous cyclopentyl compounds such as N-dimethyloxaminoyl-cyclopentyl-amino-acetic acid diethyl amide may be prepared likewise.  Table I gives further examples of compounds of the type <FORM:0586135/IV/3> (4) a -methyl amino propionic acid diethylamide is acylated with dimethyl carbamic acid chloride yielding an acylated amide of the type <FORM:0586135/IV/4> further examples being given in Table 2; (5) a -ethyl amino propionic acid diethyl amide is acylated with isovaleric acid chloride, the product being of the type <FORM:0586135/IV/5> of which further examples appear in Table 3; (6) a -allyl amino propionic acid diethyl amide is acylated with isovaleric acid chloride, analogous products being obtained using b  : b -dimethyl acrylic acid chloride and diethyl oxamic acid chloride; (7) a -n-butyl amino propionic acid diethyl amide is acylated with dimethyl acroyl chloride; similar products of the type <FORM:0586135/IV/6> are given in Table 4; (8)a -sec.-butyl amino propionic acid diethyl amide is acylated with dimethyl acroyl chloride and an analogous compound is obtained using diethyl oxamic acid chloride; (9) b -ethyl amino propionic acid diethylamide is acylated with trimethylacetic acid chloride and further compounds of this type <FORM:0586135/IV/7> are described in Table 5; (10) b -allyl amino propionic acid diethyl amide is acylated with dimethyl acroyl chloride or alternatively with N-diethyl oxamic acid chloride; b -allyl amino propionic acid dimethyl amide is similarly acylated with isovaleric acid; (11)-(16) a -methylamino-, a -ethylamino-, a -allylamino-, a -isopropylamino-, and n-butylaminon-butyric acid diethyl (or dimethyl) amides are acylated with dimethyl acroyl chloride, isovaleric acid chloride or diethyl oxamic acid chloride and analogous compounds are described in Tables 6-9, of the types <FORM:0586135/IV/8> and <FORM:0586135/IV/9> ; (17) ethylamino isobutyric acid diethyl amide, from ethyl amine and a -bromisobutyric acid diethylamide, is acylated with isobutyric acid chloride, other examples of products of the type <FORM:0586135/IV/100> being given in Table 10; (18) a -ethylamino- or a -methylamino-isovaleric acid diethyl amide is acylated with diethyl oxamic acid chloride; (19) a -ethylamino-n-valeric acid diethyl amide is acylated with acetyl chloride; similar compounds of the type <FORM:0586135/IV/111> are described in Table 11; (20) a -ethylamino-n-caproic acid dimethyl amide is acylated with isovaleric acid chloride; (Table 12 describes similar compounds of the type <FORM:0586135/IV/122> (21) ethylamino-n-butyric acid ethyl ester, from ethyl amine and a -bromo-n-butyric ethyl ester, is reacted with isovaleric acid chloride, and the resulting N-isovaleroyl-a -ethylamino-n-butyric acid ester hydrolysed, converted into the acid chloride by means of phosphorus pentachloride and then treated with diethylamine; the same acylated disubstituted amide may also be formed from a -ethylamino butyric acid diethyl amide and isovaleric acid chloride; (22) N-n-butyroyl-a -aminobutyric acid diethylamide, from a -aminobutyric acid diethyl amide and n-butyryl chloride, is heated with sodamide and then alkylated by means of ethyl iodide; the same product may be obtained by triethylating n - butyroyl - a  - aminobutyric acid amide or by the method of (1) above.  In addition to the already mentioned staring materials, there are specified for the acylation, inter alia, crotonic acid, sorbinic acid, phenyl acetic acid, 3 : 4-dimethoxy-benzoic acid, picolinic acid, nicotinic acid, 3 : 5-dimethyl-isoxazol-4-carboxylic acid, furan carboxylic acid, pyrazine carboxylic acid, acetyl salicylic acid and 4 : 6-dimethyl cumalinic acid (prepared from ethyl aceto-acetate by means of sulphuric acid).  The N-alkyl or N-cycloalkylated aliphatic amino carboxy amides may be prepared by reaction of aliphatic a - or b -halogen carboxyamides with primary aliphatic or cycloaliphatic amines such as methylamine, ethylamine propyl amine, isopropyl amine, allyl amine and cyclohexylamine; the halogen carboxy amides themselves may be prepared by reacting the corresponding acids or their functional derivatives with secondary aliphatic, cycloaliphatic or heterocylic amines with endocyclic amino groups such as dimethylamine, diethylamine, diallyl amine, methyl-propyl amine, methylcyclohexyl amine, piperidine and morpholine.  Samples have been furnished under Sect. 2 (5) of the following compounds: (1) N-(3 : 4-dimethoxybenzoyl) - ethylamino acetic acid-diethyl amide; (2) b -[N-(o-acetoxybenzoyl)-ethylamino] propionic acid diethylamide; (3) b - [N - (3 : 4 - dimethoxy - benzoyl) ethylamino] propionic acid diethylamide; (4) a -[N-(3 : 5-dimethyl-isoxazol-carboxylic acid) ethylamino]-butyric acid diethylamide; (5) a -[N-(2 : 4-dimethyl-coumalinic acid) diethylamino] isobutyric acid diethylamide; (6) a -[N-(nicotinic acid)-isopropylamino] butyric acid diethylamide; (7) a -[N-(2-furan-carboxylic acid)-ethylamino] propionic acid diethylamide; (8) a -[N-(b 1-chloro-b 1-methyl-acroyl) -ethylamino]-propionic acid diethylamide; (9) a  - [N - (b  - chloro - b  - methyl - acroyl) - propylamino] - pro - pionic acid dimethylamide; (10) a -[N-(b -chloro-b  - methyl - acroyl) - methylamino] butyric acid diethylamide; all these products were prepared according to example (1) above; (11) a -[N-(b -chloro-b -methyl-acroyl) ethylamino] - propionic acid dimethylamide, prepared by acylating a -ethylamino propionic acid ethyl ester with b -chloro-b -methyl acroyl chloride, saponifying with caustic soda and reacting the resulting salt with dimethyl carbamic acid chloride; (12) a  - [N - (b  : b  - dimethyl - acroyl) - ethylamino] - butyric acid morpholide, from a -ethylamino butyric acid morpholide (obtained by reacting a -bromo-butyric acid morpholide with ethylamine) and b : b -dimethyl-acroyl chloride.