Patent GB-612980-A (GB)
Title: Improvements in the manufacture of amidines
Filed: 1946-06-12
Abstract: Amidines of the general formula RC( : NH) NH2 (wherein R represents an alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alicyclic or heterocyclic radical) are manufactured (in the form of their salts, from which the bases may be liberated by treatment with an alkali) by treating a mono-, di- or tri-N-substituted amidine of the general formula RC( :NR1)NR2R3 (wherein R is as above and R1, R2 and R3 may be hydrogen atoms or alkyl, aralkyl, aryl, substituted aryl, alicyclic or heterocyclic radicals, or R2R3 may form a polymethylene chain, but R1, R2 and R3 may not all be hydrogen atoms) with ammonia (which may be in excess) in the presence of an acid in quantity sufficient to form the salt of the amidine, which acid may be introduced as its ammonium salt or its substituted amidine salt or its salt with a base employed as diluent or solvent or may be added as such to a mixture of ammonia and substituted amidine. The acid is preferably a sulphonic acid, though other acids which form amidine salts stable at the reaction temperature, e.g. hydrochloric, nitric, acetic or picric acid, may be employed.  The reaction may be carried out at temperatures up to about 160 DEG  C., and may be effected by bringing together gaseous ammonia and the molten salt salt of the substituted amidine, or preferably by bringing the reactants together in a solvent or diluent, e.g. a tertiary base of a base substantially weaker than ammonia, such as aniline, toluidine, 2-aminopyridine, pyridine, quinoline, methylaniline or dimethylaniline, or an inert liquid such as nitrobenzene or acetamide, or ethylene glycol (though most other hydroxylic solvents are unsuitable).  Salts of the amidines other than those initially formed may be made by treating the free base with the requisite acid, or, in some cases, by double decomposition from the first salt.  In examples: (1) ammonia gas is passed into molten N-phenylbenzamidine benzenesulphonate at 140 DEG C. to produce benzamidine benzenesulphonate; (2) ammonia gas is passed into a solution of N-phenylbenzamidine hydrochloride in aniline at 140 DEG  C. to yield benzamidine hydrochloride; (3) ammonia gas is passed into a solution of N - phenylbenzamidine benzenesulphonate in nitrobenzene, and (4) into a molten mixture of N - methyl - N1 - phenylbenzamidine benzenesulphonate and a trace of aniline, both at 140 DEG  C.; (5) N-phenyl-2 : 4-dichlorobenzamidine benzenesulphonate is treated as in (2) to give 2 : 4-dichlorobenzamidine benzenesulphonate; (6) a  : b -bis-(p-N-phenylamidinophenoxy)-ethane dibenzenesulphonate similarly yields a  : b -bis-(p-amidinophenoxy)-ethane dibenzenesulphonate; (7) ammonia gas is passed into a solution of N-phenylbenzamidine benzenesulphonate in aniline at 100 DEG  C., and (8) in nitrobenzene at 56 DEG  C.; (9) ammonia is passed into a mixture of N-phenylbenzamidine and glacial acetic acid at 100 DEG  C. to form benzamidine acetate; (10) ammonia is passed into a solution of N-phenylbenzamidine benzenesulphonate in acetamide (or nitrobenzene or ethylene glycol) at 140 DEG  C.; (11) a mixture of N-phenylbenzamidine, ammonium benzenesulphonate and pyridine is left to stand for two weeks at room temperature; (12) N - phenyl - N1 : N1 - pentamethylenebenzamidine benzenesulphonate is treated as in (2); (13) ammonia is passed into a solution of N-phenyl-N-methylbenzamidine and ammonium toluene-p-sulphonate in nitrobenzene at 140 DEG  C., producing benzamidine toluene-p-sulphonate; (14) N-phenyl-N-methylbenzamidine picrate is treated as in (2) to yield benzamidine picrate; (15) N-p-anicylbenzamidine is treated as in (11), but for only 6 days; (16) ammonia is passed into a suspension of ammonium nitrate in a solution of N-p-chlorophenylbenzamidine in pyridine at 100 DEG  C., giving benzamidine nitrate; (17) ammonia is passed into a suspension of N - p - nitrophenylbenzamidine benzenesulphonate in nitrobenzene at 140 DEG  C.; (18) ammonia is passed into a solution of N-2-pyridylbenzamidine and ammonium toluene-p-sulphonate in 2-aminopyridine at 140 DEG  C.; (19) N-phenylveratramidine benzenesulphonate is treated as in (3) to produce veratramidine benzenesulphonate; (20) ammonia is passed into a solution of N-ethyl-p-methylsulphonylbenzamidine toluene-p-sulphonate in aniline at 140 DEG  C. to form p-methylsulphonylbenzamidine toluene-p-sulphonate; (21) ammonia is passed into a solution of N : N-diethyl-p-methylsulphonylamidine toluene-p-sulphonate in quinoline at 100 DEG  C., yielding the product of (20), from which the free amidine is formed by the action of sodium hydroxide solution; (22) N-p-tolylanisamidine toluene-p-sulphonate is treated as in (2) to produce anisamidine toluene-p-sulphonate, from which the free amidine is obtained as in (21); (23) N-phenyl-a -naphthamidine benzenesulphonate similarly yields a -naphthamidine benzenesulphonate and the free amidine, from which the picrate may be made by the action of an alcoholic solution of picric acid; (24) N-o-tolyl-b -naphthamidine benzenesulphonate is treated as in (3) to give b -naphthamidine benzenesulphonate, and the free amidine as in (21); (25) 2-N-phenylamidinopyridine benzenesulphonate is treated as in (2) to form 2-amidinopyridine benzenesulphonate; (26) a solution of N-p-tolylphenylacetamidine toluene-p-sulphonate in liquid ammonia is kept at - 33 DEG  C. for 5 days, producing phenylacetamidine toluene-p-sulphonate; (27) N-phenyl-p-nitrophenylacetamidine benzenesulphonate is treated as in (2), yielding p-nitrophenylacetamidine benzenesulphonate; (28) ammonia is passed into a melt of N-p-tolylvaleramidine toluene-p-sulphonate at 140 DEG C. to give valeramidine toluene-p-sulphonate; (29) ammonia is passed into a solution of N-p-tolyl-p-toluamidine and ammonium benzenesulphonate in dimethylaniline at 140 DEG  C., forming p-toluamidine benzenesulphonate; (30) ammonia is passed into a solution of N-p-chlorophenyl-p-toluamidine and ammonium toluene-p-sulphonate in methylaniline at 140 DEG  C. to produce p-toluamidine toluene-p-sulphonate; (31) ammonia is passed into a solution of a  : g -bis-(p-N-phenylamidinophenoxy) - propane dibenzene - sulphonate in aniline at 100 DEG  C. to yield 4 : 41-diamidino - a  : g  -diphenoxypropane dibenzenesulphonate; (32) ammonia is passed into a solution of N - phenyl - N1 - benzylbenzamidine picrate in aniline at 140 DEG  C.; (33) ammonia is passed into a molten mixture of N-phenylamidinocyclohexane and methylaniline benzenesulphonate, and the product is dissolved in aqueous alcohol and treated with a saturated aqueous solution of lithium picrate to precipitate amidinocyclohexane picrate.  N - Substituted amidines.-The starting materials of examples (15), (19), (22), (23), (26), (27), (29), (30) and (31) are obtainable by the process of Specification 573,266, that of (12) by refluxing diphenylketoxime benzenesulphonate with piperidine in benzene and treating the resulting amidine with benzenesulphonic acid in acetone, whilst those of (25) and (28) are prepared in situ by heating respectively 2-cyanopyridine with aniline benzenesulphonate and n-butyl cyanide with p-toluidine toluene p-sulphonate.