Patent GB-606181-A (GB)
Title: Improvements in or relating to substituted diamines
IPC: C07D405/12
Filed: 1945-05-17
Abstract: Therapeutically valuable di-tertiary diamines of the general formula <FORM:0606181/IV(b)/1> wherein "Het" represents a monocyclic heterocyclic nucleus (e.g. of pyridine, thiazole or pyrimidine), R represents an alkyl group, an aralkyl or aryl group in which the aryl nucleus may be substituted by alkyl or alkoxy groups, or a monocyclic heterocyclic group, and n is an integer equal to or greater than 2 (but excluding N-b 1-dimethylaminoethyl-N-p-methoxybenzyl-a -aminopyridine) are manufactured by (a) reacting a secondary-tertiary diamine Het-NH-(CH2)n.N(CH3)2 or its sodio derivative with a compound of the formula X.CH2R (X being a halogen atom, a hydroxy group or a sulphuric or sulphonic ester radical), or (b) reacting a secondary-tertiary diamine RCH2-NH-(CH2)n.N(CH3)2 with heterocyclic halogen compound Het-X (X being halogen), or (c) reacting an amine Het-NH-CH2-R or its sodio derivative with a compound of the formula X-(CH2)n-N(CH3)2 (X being as at (a) above).  Examples describe the preparation of: (1), (2) and (4) N-b 1-dimethylaminoethyl-N-benzyl-, -phenylethyl- and -p-isopropylbenzyl-a -aminopyridine from 1-dimethylamino-2-chloroethane and the sodio derivatives of N-benzyl-, N-phenylethyl- and N-p-isopropylbenzyl-a -aminopyridine respectively; (3) and (5) N-g 1-dimethylaminopropyl-N-benzyl- and -p-methoxybenzyl-a  - aminopyridine from 1 - dimethylamino - 3 - chloropropane and the sodio derivatives of N - benzyl- and N-p-methoxybenzyl-a -aminopyridine respectively; (6) to (8) N-b 1-dimethyl aminoethyl - N - benzyl-, -furfuryl- and -(2-methylthiazolyl - (4) - methyl) - a  - aminopyridine from the sodio derivative of N-b 1-dimethylaminoethyl - a  - aminopyridine and benzyl chloride, furfuryl bromide and 2-methyl-4-chloromethylthiazole respectively; (9) N-b 1-dimethylaminoethyl-N-benzyl-a -aminopyridine from N-b -dimethylaminoethylbenzylamine and a -bromopyridine (in the presence of copper powder).  Specifications 433,625 and 606,187 are referred to.  Samples have been furnished under Sect. 2(5) of: (A) 2-(N-b -dimethylaminoethyl-N-benzyl)-aminopyrimidine, prepared from the sodio derivative of 2-benzylaminopyrimidine and 1-dimethylamino-2-chloroethane; (B) 2-(N-b -dimethylaminoethyl - N - benzylamino) - 4 : 6 - dimethylpyrimidine, prepared similarly from the sodio derivative of 2-benzylamino-4 : 6-dimethylpyrimidine; (C) N-b 1-dimethylaminoethyl - N - butyl - a  - aminopyridine, prepared similarly from the sodio derivative of N-butyl-a -aminopyridine. N-Benzyl-, N-phenylethyl- and N-p-isopropylbenzyl a -aminopyridine are obtainable by the action of benzyl chloride, phenylethyl bromide and p-isopropylbenzyl chloride respectively on the sodio derivative of a -aminopyridine.  The first compound is alternatively made by warming a -aminopyridine with benzaldehyde and formic acid.  These amines are converted into their sodio derivatives by treatment with sodamide in toluene.  N-b 1-Dimethylaminoethyl-a -aminopyridine is obtainable by the action of 1-dimethylamino-2-chloroethane on the sodio derivative of a -aminopyridine, and is converted into its sodio derivative by the action of sodamide in xylene.  N-b -Dimethylaminoethylbenzylamine is obtainable by heating 1-dimethylamino-2-chloroethane hydrochloride with benzylamine. 2-Benzylaminopyrimidine is obtainable by the action of benzyl chloride on the sodio derivative of 2-aminopyrimidine. 2-Benzylamino-4 : 6-dimethylpyrimidine is obtainable by heating benzylguanidine bicarbonate with acetylacetone.  Benzylguanidine bicarbonate is obtainable by refluxing benzylamine with S-methylisothiourea sulphate, decomposing the resulting benzylguanidine sulphate with baryta solution, filtering and saturating the filtrate with carbon dioxide.  N-Butyl-a -aminopyridine is obtainable by the action of n-butyl bromide on the sodio derivative of a -aminopyridine, and is converted into its sodio derivative by treatment with sodamide in dioxane.  The Specification as open to inspection under Sect. 91 comprises also the manufacture of similar compounds in which the methylene groups of the alkylene chain may carry alkyl substituents, and the following alternative methods for preparing certain of the products: (d) condensation of dimethylamine with a compound of the general formula <FORM:0606181/IV(b)/2> (wherein "Het," R, X and n are as at (a) above, and R1 and R2 represent hydrogen atoms or alkyl groups); (e) methylation (e.g. with methyl halides, sulphate or sulphonates, formaldehyde in the presence of reducing agents, or diazomethane) or compounds of the formula <FORM:0606181/IV(b)/3> (obtainable by reduction of the nitrile produced by condensing Het-NH-CH2-R with X(CR1R2)n-1CN, or by Hoffmann or Curtius degradation of the amines or azides of acids of the formula <FORM:0606181/IV(b)/4> (f) condensation, in the presence of a reducing agent (e.g. formic acid), of an aldehyde R-CHO with a secondary base Het-NH-(CR1R2)n N(CH3)2, or of a secondary base Het-NH-CH2R with an aldehyde OHC-(CR1R2)n-1 N(CH3)2; (g) condensation of dimethylamine in the presence of a reducing agent with an aldehyde of the general formula <FORM:0606181/IV(b)/5> or its acetal (obtainable by condensing Het-NH-CH2R with X(CR1R2)n-1CH(OC2H5)2); (h) reduction of an amide of the general formula <FORM:0606181/IV(b)/6> or <FORM:0606181/IV(b)/7> (obtainable respectively from R-COCl and Het-NH-(CR1R2)nN(CH3)2 and from (CH3)2 N-(CR1R2)n-1COCl and Het-NH-CH2-R).  Additional examples are given, and reference is made to compounds in which "Het" is a radical of the piperidine, furane or tetrahydrofurane series.  This subject-matter does not appear in the Specification as accepted.