Patent GB-643012-A (GB)
Title: Improvements in or relating to tri- and tetrasubstituted biguanides and method of preparing same
IPC: C07C279/26
Filed: 1946-11-20
Abstract: Tri- and tetra-substituted biguanides of the general formula <FORM:0643012/IV (b)/1> and acid addition salts thereof (wherein R1, R2, R3 and R4 represent aromatic, aliphatic, alicyclic, araliphatic or heterocyclic radicals, or, in the case of R3 and R4, one but not both of them may represent hydrogen or they may jointly form a heterocyclic ring with the nitrogen atom to which they are attached, but excluding the case in which R1 is halogenophenyl when R2 is alkyl and the case in which R3 is aromatic and R4 hydrogen or alkyl when R1 and R2 are both alkyl) are manufactured by reacting a 1 : 2-disubstituted-3-cyanoguanidine R1-NH-C(: NR2)-NH-CN with a primary or secondary amine R3-NH-R4, which is wholly or in part in the form of an acid addition salt (preformed or formed in situ, preferably from strong mineral acids such as hydrochloric, sulphuric, hydrobromic or phosphoric acid) to form the corresponding salt of the substituted biguanide, and, if desired, neutralizing this to give the free substituted biguanide.  The reaction may be carried out in a solvent or diluent (e.g. water or water-soluble organic solvents or mixtures thereof), or by fusing the reactants together (in which case a preformed amine salt is preferably employed, though some acids, such as acetic, oxalic or benzoic acid, can be added to the fusion mixture).  The substituents R1 and R2 in the 1 : 2 - disubstituted - 3 - cyanoguanidines may be saturated or unsaturated and may themselves carry substituents, examples being g -methoxypropyl, isobutyl, allyl, b -chlorallyl, cinnamyl, phenyl, tolyl, xylyl, p-anisyl, chlorophenyl, bromophenyl, dichlorophenyl, fluorophenyl, chloranisyl, naphthyl, diphenylyl, benzyl, cyclohexyl, pyridyl, piperidyl, chloropyridyl, furfuryl and thenyl, whilst the amines may be aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, examples of each type being given.  Examples describe the preparation of: (1) and (2) 1 : 2-dicyclohexyl-5-p-chlorophenyl-and -5-phenyl-biguanide hydrochloride from 1 : 2 - dicyclohexyl - 3 - cyanoguanidine and p-chloraniline hydrochloride or aniline hydrochloride respectively; (3) 1-n-dodecyl-2-phenyl-5-(21 : 51-disulphophenyl)-biguanide (as disodium salt or internal salt) from 1-n-dodecyl-2-phenyl-3-cyanoguanidine, the monosodium salt of aniline-2 : 5-disulphonic acid and sulphuric acid; (4) 1 : 2 : 5-tri-n-butylbiguanide (as free base, hydrochloride, stearate or picrate) from 1 : 2-di-n - butyl - 3 - cyanoguanidine and n - butylamine hydrochloride; (5) 1-n-dodecyl-2 : 5-diphenylbiguanide from 1-n-dodecyl-2-phenyl-3-cyanoguanidine and aniline hydrochloride. A list of additional amines is given.  1 : 2-Disubstituted-3-cyanoguanidines are obtainable by treating a disubstituted thiourea with cyanamide and lead, mercury or silver oxide, or with the cyanamide salt of lead, mercury or silver, or by reacting cyanamide with a disubstituted carbodiimide.  In examples: (1) symm.-dicyclohexylthiourea is refluxed with basic lead carbonate in benzene and the resulting dicyclohexylcarbodiimide is stirred with cyanamide in methanol containing sodium methoxide; (3) N-n-dodecyl-N1-phenylthiourea is refluxed with lead cyanamide in ethanol; (4) symm.-di-n-butylthiourea is similarly treated.  The Specification as open to inspection under Sect. 91 comprises also the manufacture of the substituted biguanides excluded from the definition above, e.g. 1 : 2-diethyl-5-phenyl- and -5-(11-sulpho-21-naphthyl)-biguanide, 1 : 2-di-n-dodecyl- and 1 : 2-di-n-butyl-5-(21 : 51-disulphophenyl) - biguanide, 1 : 2 - di - isopropyl - 5 - p - chlorophenylbiguanide and 1 : 5 - di - p - chlorophenyl - 2 - isopropylbiguanide.  This subject-matter does not appear in the Specification as accepted.