Patent GB-716556-A (GB)
Title: Improvements in salts of penicillin
IPC: C07D499/00
Filed: 1951-07-02
Abstract: The invention comprises: (a) salts of penicillin with N-substituted diamines of the general formula RR1N.Y.NHR2 (wherein R and R1 represent aliphatic, alicyclic, araliphatic, aromatic or heterocyclic groups, with or without substituents, or R1 may also represent hydrogen, R2 represents hydrogen, or, when R1 is hydrogen, an aliphatic, alicyclic, araliphatic, aromatic or heterocyclic group, with or without substituents, and Y represents an alkylene group of 2-12 carbon atoms), which diamines may have been prepared by (i) reacting an alkylene diamine with a ketone or aldehyde and hydrogenating the resulting di-imine, (ii) reacting an alkylene dihalide with an amine, (iii) reacting a salt of ethylenediamine with formaldehyde and a compound containing a reactive hydrogen atom, (iv) reacting ethylene diamine diformate with an aldehyde or ketone in a solvent, or (v) reacting an aliphatic, araliphatic, aromatic or heterocyclic halide with an alkylene diamine and treating the resulting hydrohalide with an alkali; and (b) the manufacture of the diamine salts of penicillin by bringing penicillin into contact with the diamine (preferably in an organic solvent, e.g. ether, acetone, ethyl acetate or amyl acetate) or by reacting a penicillin salt (e.g. an alkali or alkaline earth metal salt of penicillin G, dihydro-F, X or K), preferably in an aqueous medium, with a salt of the diamine, especially a carboxylic acid salt obtained by preparing the diamine as in (v) above and reacting it with an aliphatic carboxylic acid or anhydride.  The products may be recrystallized from solution in dimethyl formamide by addition of water or acetone.  They are useful for therapeutic purposes and also afford a means of isolating or purifying penicillin, e.g. by adding an aqueous solution of a water-soluble salt of the diamine (e.g. a diacetate) to a buffered aqueous penicillin extract, or by adding the free diamine to an amyl acetate extract.  In examples: (1) ethylenediamine is condensed with benzaldehyde and the product is hydrogenated in methanol in the presence of Adams' platinum catalyst to N : N1-dibenzylethylenediamine, which may be converted to its diacetate, dihydrochloride, dinitrate, phosphate, sulphate, thiocyanate, salicylate, picrate, oxalate or lactate; (2) the same base, together with some monobenzyl compound (isolated as dipicrate) is prepared by adding ethylene diamine to formic acid and refluxing the product with benzaldehyde; (3) piperonal is reacted as in (1) to give N : N1 p  - dipiperonylethylenediamine, which may be converted to its dihydrochloride, diacetate or flavianate; (4) as examples (1) and (2) of Specification 716,598; (5) ethylenediamine is condensed with furfural in benzene, and the product, without isolation, is reduced with sodium and alcohol to N : N1-difurfurylethylenediamine, which may be converted to its diacetate or dipicrate; (6) ethylene bromide is heated with 2-heptylamine to produce N : N1-bis-(2-heptyl)-ethylenediamine dihydrobromide; the free base and its picrate are also described; (7) cinnamaldehyde is reacted somewhat as in (1) to form N : N1-bis-(g -phenylpropyl)-ethylenediamine, which may be converted to its dihydrochloride; (8) cyclohexylamine is heated with ethylene chloride and the product is treated with aqueous alkali to liberate N : N1-dicyclohexylethylenediamine, which may be converted to its dihydrochloride, dihydrobromide, dinitrate, diflavianate, phosphate, picrate, sulphate, acetate, bis-urea or dinitroso derivative; (9) 2-amino-4-methylpentane and ethylene bromide similarly yield N : N1-bis-(4-methyl-2-2 - pentyl) - ethylenediamine; (10) 3 : 5 : 5-trimethylhexylamine similarly gives N : N1-bis-(3 : 5 : 5 - trimethylhexyl) - ethylenediamine, which may be converted into its diacetate, dihydrobromide, dihydrochloride, nitrate, phosphate or sulphate; (11) p-chlorobenzyl chloride is heated with ethylenediamine in xylene, to produce N : N1 - bis - (p - chlorobenzyl) - ethylenediamine, which is isolated as its diacetate; the picrate is also described; (12) 2 : 4-dichlorobenzyl chloride similarly yields N : N1-bis-(2 : 4-dichlorobenzyl)-ethylenediamine (as picrate); (13) N : N1 - bis - (p - nitrobenzyl) - ethylenediamine is prepared (as dihydrochloride) as in example (3) of Specification 716,598, or from p-nitrobenzyl chloride and ethylenediamine as in (11); the o- and mnitrobenzyl compounds may be similarly prepared; (14) p-hydroxybenzaldehyde is reacted as in (2) to produce N - mono - (p - hydroxybenzyl) - ethylenediamine, the dihydrochloride and dipicrate of which are described; (15) the first product of (13) is converted to its monoacetate, which is hydrogenated in methanol in the presence of platinum oxide to form N : N1-bis-(p-aminobenzyl)-ethylenediamine (isolated as hydrochloride); (16) anisaldehyde is reacted as in (2) to give N : N1-bis-(p-methoxybenzyl)-ethylenediamine, which may be converted to its dihydrochloride, dipicrate or dinitrate; (17) ethylenediamine dihydrochloride or sulphate is reacted with aqueous formaldehyde and thiophene to produce N : N1-bis-(2-thenyl)-ethylenediamine (isolated as diacetate); the thiophene may be replaced by cyclohexanone, 2-, 3- and 4-methylcyclohexanone, 4 - methoxycyclohexanone, cyclopentanone, 2-methylthiophene, isoquinoline, 3-methylisoquinoline or quinaldine; (18) dimethyl benzylaminoacetal and 1-phenylpropylamine are reacted in the presence of formic acid to give N-benzyl-N1-a -ethylbenzyl-ethylenediamine, which may be converted to its dihydrochloride, dipicrate or dinitrate; (19) ethylene bromide is refluxed with p-, o- or m-xylylamine in butanol to produce N : N1-bis-(p-, o- or m-methylbenzyl)-ethylenediamine dihydrobromide; the diacetate of the p-compound is also described; (20) decamethylene iodide is refluxed with benzylamine in isopropanol to form 1 : 10-bis-(benzylamino)-decane dihydriodide; the diacetate is also described; (21) trimethylene bromide is warmed with benzylamine to produce 1 : 3-bis-(benzylamino)-propane dihydrobromide; the free base and diacetate are also described; (22) pentamethylene iodide similarly yields 1 : 5-bis-(benzylamino)-pentane and its diacetate; (23) b -phenylethylamine is reacted as in (6) to produce N : N1 - bis - (b  - phenylethyl) - ethylenediamine, which may be converted to its diacetate; similarly alkylene dihalides such as ethylene chloride may be reacted with laurylamine, 3 - methylcyclohexylamine, m-nitraniline, 2-amino-3-, -4-, -5- or -6-methylpyridine, 2-aminothiazole or 2-amino-5-methylfuran; (24) N - (p - hydroxybenzyl) - ethylenediamine dihydrochloride and p-hydroxybenzaldehyde are refluxed with formic acid and sodium formate to produce N : N1-bis-(p-hydroxybenzyl)-ethylenediamine, isolated as dihydrochloride; the dipicrate is also described; (25) the same compound is obtained (as dihydrobromide) by refluxing N : N1 - bis - (p - methoxybenzyl) - ethylenediamine dihydrochloride with hydrobromic acid in acetic acid; (26) ethylenediamine diformate is refluxed with piperonal in ethanol to give N : N1-dipiperonylethylenediamine (isolated as dihydrochloride); (27) ethanolamine is heated with benzyl chloride, the resulting 2-dibenzylaminoethanol is treated with thionyl chloride, and the product is heated with ammoniacal ethanol under pressure to form N : N-dibenzylethylenediamine, the dipicrate of which is described; (28) and (29) N-monobenzyl- or -(p-hydroxybenzyl)-ethylenediamine dihydrochloride is reacted with sodium penicillin in aqueous solution; (30) N : N-dibenzylethylenediamine is dissolved in aqueous acetic acid and the product reacted with potassium penicillin; (31) N : N1-dibenzylethylenediamine diacetate is reacted with sodium penicillin G in aqueous solution; (32) and (33) N : N1-dipiperonyl- and -difurfuryl-ethylenediamine diacetates are reacted with sodium penicillin in aqueous solution.  Tables give the properties of the dipenicillin salts of N-octyl- and N : N1-di-n-, -iso- and -sec.-butyl-, -phenyl-, -benzhydryl-, -p-chlorobenzyl-, -2 : 4-dichlorobenzyl-, - p - nitrobenzyl -, - p - hydroxybenzyl -, - p - methoxybenzyl-, -p-aminobenzyl-, -phenylethyl-, -g -phenylpropyl-, -2-thenyl-, -cyclohexyl-, -4-methyl-2-pentyl-, -2-heptyl-, -3 : 5 : 5-trimethylhexyl- and -p-methylbenzyl-ethylenediamine, N : N1 - dibenzyl - 1 - methylethylenediamine, N - benzyl - N1 - (a  - ethylbenzyl) - ethylenediamine, 1 : 3 - bis - (benzylamino) - propane, 1 : 5 - bis - (benzylamino) - pentane and 1 : 10-bis-(benzylamino)-decane.  Still further penicillin salts and substituted diamines are listed.ALSO:Salts of penicillin with N-substituted diamines of the general formula RR1N.Y.NHR2 (wherein R and R1 represent aliphatic, alicyclic, araliphatic, aromatic or heterocyclic groups, with or without substituents, or R1 may also represent hydrogen, R2 represents hydrogen, or, when R1 is hydrogen, an aliphatic, alicyclic, araliphatic, aromatic or heterocyclic group, with or without substituents, and Y represents an alkylene chain of 2-12 carbon atoms), which are sparingly soluble in water and consequently capable of producing a prolonged antibiotic effect, are employed therapeutically, e.g. for injection either with a spreading agent such as hyalurodinase, with a suspending agent such as carboxymethyl cellulose or pectin, or in vegetable oil vehicle with beeswax or aluminium stearate gel.  Faster-acting and slower-acting compounds may advantageously be mixed, whether this involves combinations of different diamine penicillins or combinations of diamine penicillins with procaine penicillin or other known compounds. Specification 716,598, [Group IV(b)], is referred to.