Patent GB-603069-A (GB)
Title: Manufacture of biguanide derivatives
IPC: C07C279/26
Filed: 1946-01-07
Abstract: Biguanide derivatives, useful as chemotherapeutic agents or as intermediates therefor, and of the general formula <FORM:0603069/IV(b)/1> wherein R represents a hydrocarbon radical, R\sv, R" and R\sv" represent hydrogen or hydrocarbon radicals, and of X and Y one represents hydrogen and the other hydrogen or a hydrocarbon radical, provided that at least one but not more than two of R, R\sv, R", R\sv", X and Y represent aryl groups and that any or all of the hydrocarbon radicals may bear one or more non-acidic substituents, are manufactured by the interaction of an amino compound R"NHR\sv" with an S - substituted guanylisothiourea RXN - C(=NY) - NH - C(=NR") -S-Alk (where Alk represents an alkyl or substituted alkyl group, e.g. methyl, ethyl or benzyl), or, in the presence of a desulphurizing agent, with a guanylthiourea RXN-C(=NY)-NH-CS-NHR\sv.  The reaction is advantageously effected in the presence of a solvent or diluent, e.g. methanol, ethanol or b -ethoxyethanol, or an excess of the p  amino compound if liquid.  The guanyl-thiourea or -isothiourea may be used as such, or in the form of a salt, in which case the base may be liberated in situ by the addition of a basifying agent, e.g. sodium ethoxide or methoxide or excess of the amino compound. Suitable desulphurizing agents (the use of which is essential with the guanylthioureas and optional but sometimes advantageous with the S-alkylguanylisothioureas) are the oxides and salts of the heavy metals, particularly of lead, copper, silver and mercury. The products may be converted into salts with organic or inorganic acids, e.g. acetic, lactic, methanesulphonic, methylenedisalicylic, methylene - bis - 2 : 3 - hydroxynaphthoic or hydrochloric acids, by dissolving the biguanides in aqueous solutions of the acids and evaporating off the water, or more conveniently by mixing the components in an organic solvent such as acetone, or an alcohol in which the salts are sparingly soluble.  In examples: (1) N1-p-chlorophenylguanyl-N2-methylthiourea hydrochloride is stirred with sodium methoxide in methanol, and the resulting mixture is stirred with isopropylamine and mercuric oxide to produce N1-p-chlorophenyl-N4 - isopropyl - N5 - methylbiguanide, which is isolated in the form of its monohydrochloride; (2) N1 - p - chlorophenylguanyl - N2 - isopropyl - thiourea hydrochloride is stirred and warmed with litharge and a solution of ammonia in ethanol to form N1-p-chlorophenyl-N5-isopropylbiguanide (isolated as the acetate); (3) to (28), there may similarly be obtained the hydrochlorides of N1 - 4 - chloro - 3 - methyl-, -3-chloro-4-methyl-, -p-fluoro-, 3 : 4- and -3 : 5-dichloro-, -p-iodo-, -3 : 4 : 5-trichloro-, -3-chloro-4-bromo- and -iodo-, -3 : 5-dichloro-4-bromo-, -3-iodo-, -4-chloro- and -iodo-3-bromo-, -3 : 4-dibromo-, -3-bromo-, -4-bromo-3-iodo-, -3 : 4-diiodo-, -4-chloro-3-iodo- and -p-bromo-phenyl-N5 - isopropylbiguanides, N1 - p - bromo- and -chloro - phenyl - N5 - ethyl-, - n - propyl- and -n-butyl - biguanides, and N1 - p - bromophenyl - N5-sec.-butylbiguanide; (29) N1 - p - chlorophenylguanyl-N2-isopropylthiourea is stirred with isopropylamine and mercuric oxide in methanol to give N1 - p - chlorophenyl - N4 : N5 - diisopropylbiguanide (as hydrochloride); (30) N1-p-chlorophenylguanyl - N2 - n - propylthiourea is stirred with methylamine hydrochloride, sodium methoxide and mercuric oxide in methanol to produce N1-p-chlorophenyl-N4-methyl-N5-n-pro pylbiguanide (as hydrochloride); (31) N1-p-chlorophenylguanyl - N2 - n - propylthiourea is similarly treated; (32) the starting material of (31) is stirred with n-butylamine and mercuric oxide in methanol to form N1-p-chlorophenyl-N4 - n - propyl - N5 - n - butylbiguanide (as hydrochloride); (33) N1 - (N :\sv - di - p - chlorophenylguanyl) - N2 - isopropylthiourea is stirred and warmed with mercuric oxide and a solution of ammonia in ethanol to give N1 : N2-di-p-chlorophenyl-N5-isopropylbiguanide (as acetate); (34) and (35) N1-(N-p-chlorophenyl-N1-phenyl- and -N1 - p - methylphenyl - guanyl) - N2 - isopropyl - thiourea are similarly treated; (36) N1-p-chlorophenyl-N2-ethylguanylthiourea similarly yields N1-p-chlorophenyl-N5-ethylbiguanide acetate; (37) to (39) the ammonia in (36) is replaced by n-propylamine and n- and iso-butylamine, producing N1 - p - chlorophenyl - N2 - n - propyl- and -n- and -iso-butyl-N5-ethylbiguanides (as hydrochlorides); there may similarly be produced the hydrochlorides of N1-p-chlorophenyl-N2-methyl - N5 - ethyl-, - N2 : N5 - diethyl- and -dimethyl- and - N2-ethyl-N5-methyl - biguanides; (40) N1-p-chlorophenyl-N2-ethylguanylthiourea is stirred and warmed with isopropylamine and mercuric oxide in ethanol to form N1-p-chlorophenyl - N2 - isopropyl - N5 - ethylbiguanide (as hydrochloride); (41) N1 - p - chlorophenyl - N2 - isopropylguanylthiourea is treated as in (33) to give the same product, which (42) is also obtained from N1-p-chlorophenyl-N2-isopropylguanyl-5 -ethylisothiourea hydrobromide and a solution of ammonia in ethanol by heating in a sealed vessel; (43) to (46) N1-p-chlorophenyl-N2-n- or -isopropylguanylthiourea is stirred and warmed with mercuric oxide and a solution of methylamine or ethylamine in water, ethanol and b -ethoxyethanol, yielding N1-p-chlorophenyl-N2-methyl- or -ethyl-N5-n- or -isopropylbiguanide (as hydrochlorides); (47) and (48) there are similarly prepared N1-p-chlorophenyl-N2 : N5 - diisopropyl- and - N2 - n - butyl - N5 - isopropyl-biguanide hydrochlorides; (49) to (51) N1 - p - chlorophenyl - N2 - n - butylguanylthiourea is stirred and warmed with ammonia, methylamine or ethylamine in ethanol; (52) N1-p-bromophenyl - N2 - isopropylguanylthiourea is treated as in (33) to give N1-p-bromophenyl-N5-isopropylbiguanide (as hydrochloride); (53) to (56) there are similarly prepared N1-p-bromo-and -iodo-phenyl-N2-methyl- and -ethyl-N5-isopropylbiguanide hydrochlorides; (57) N1-p-chlorophenyl - N2 - (N : N - dimethylguanyl) - thiourea is treated as in 33) to form N1-p-chlorophenyl-N5 : N5-dimethylbiguanide; (58) the same product is obtained from N1-p-chlorophenyl - N2 - (N : N - dimethylguanyl) - S - ethylisothiourea hydrobromide as in (42); (59) and (60) the ammonia in (57) is replaced by an aqueous solution of methylamine or ethylamine, producing the corresponding N2 : N5 : N5-trimethyl-and N2-ethyl-N5 : N5-dimethyl compounds (as acetates); (61) to (63) there are similarly prepared the N2-methyl- and -ethyl-N5-methyl-N5-isopropyl and N2-methyl-N5 : N5-diethyl compounds (as acetates); (64) N1-phenyl-N2-(N : N - dimethylguanyl)-thiourea is treated as in (33) to yield N1-phenyl-N5 : N5-dimethylbiguanide (as hydrochloride); (65) N1-p-chlorophenyl-N2-(p-chlorophenylguanyl)-thiourea similarly gives N1 : N5 - di - p - chlorophenylbiguanide hydrochloride; (66) and (67) the ammonia in (65) is replaced by methylamine or ethylamine, producing N1 : N5-di-p-chlorophenyl - N2 - methyl - and -ethyl-biguanide hydrochlorides; (68) there is similarly made N1-p-chlorophenyl-N2-methyl-N5 - p - methylphenylbiguanide hydrochloride (and acetate); (69) N-p-chlorophenylguanyl-S-methylisothiourea hydriodide is stirred with isopropylamine in methanol to form N1-p-chlorophenyl - N5 - isopropylbiguanide (as acetate); (70) to (72) methylisopropylamine, dimethylamine and methylamine similarly give the corresponding N5 - methyl - N5 - isopropyl, N5 : N5-dimethyl and N5-methyl compounds (as acetate, free base and hydrochloride respectively); (73) N-p-tolylguanyl-S-ethylisothiourea hydriodide is treated as in (69); (74) N-p-chlorophenyl-S-benzylisothiourea hydrochloride is refluxed with n-butylamine in methanol; (75) N-isopropylguanyl-S-methylisothiourea hydriodide is refluxed with p-chloroaniline and water to yield N1-p-chlorophenyl-N5-isopropylbiguanide hydriodide; (76) N-methyl-N-isopropylguanyl-S-methylisothiourea hydriodide similarly gives N1-p-chlorophenyl-N5-methyl-N5-isopro pylbiguanide hydriodide; (77) N : N-diethylguanyl-S-methylisothiourea hydriodide and m-chloroaniline similarly yield N1-m-chlorophenyl-N5 : N5-diethylbiguanide hydriodide; (78) the p-chloraniline in (75) is replaced by p-anisidine; (79) N-n-butylguanylthiourea is treated with methyl iodide and the product refluxed with p-bromoaniline and water to produce N1-p-bromophenyl - N5 - n - butylbiguanide (as hydrochloride); (80) p-chlorophenylguanylthiourea is stirred and heated with isopropylamine hydrochloride and mercuric oxide in nitrobenzene to yield the product of (2) (as hydrochloride); (81) p-iodophenylguanylthiourea hydrochloride and isopropylamine are similarly reacted; (82) isopropylguanylthiourea and mercuric oxide are stirred and warmed with a solution of p-bromoaniline in dilute hydrochloric acid; (83) the p-bromoaniline in (82) is replaced by 3 : 4-dichloroaniline hydrochloride; (84) N1-p-methoxyphenyl - N2 - isopropylguanylthiourea is treated as in (33); (85) N1-(N-p-chlorophenyl-N\sv-methylguanyl) -N2-isopropylthiourea hydrochloride is similarly treated, giving N1-p-chlorophenyl - N2 - methyl - N5 - isopropylbiguanide (as dihydrochloride hydrate); (86) the ammonia in (85) is replaced by aqueous methylamine, producing N1-p-chlorophenyl-N2 : N4-dimethyl-N5-isopropylbiguanide (as hydrochloride); (87) and (88) N1-(N-p-chlorophenyl-N\sv-ethylguanyl) -N2-isopropylthiourea is treated as in (84) and (86) respectively; (89) the methylamine in (88) is replaced by ethylamine; (90) N1-p-chlorophenyl - N2 - (N - methyl - N\sv - isopropylguanyl) - thiourea is treated as in (86) to form N1-p-chlorophenyl - N2 : N4 - dimethyl - N5 - isopropylbiguanide (as hydrochloride); (91) N1-(N : N\sv - di - p - chlorophenylguanyl)-N2-isopropylthiourea is treated as in (89) to produce N1 : N2-di-p-chlorophenyl-N4-ethyl-N5 -isopropylbiguanide; (92) N1 - p - chlorophenylguanyl - N2 - methylthiourea is treated as in (30); (93) N1-p-chlorophenylguanyl - N2 - isopropyl - S - methylisothiourea (lib