Patent GB-762442-A (GB)
Title: Improvements in or relating to 4-substituted-amino-10-hydroxy-1,7-phenanthrolines
IPC: C07D471/04
Filed: 1954-11-09
Abstract: The invention comprises: (1) 4-substituted-amino-10-hydroxy-1 : 7-phenanthrolines of the general formula <FORM:0762442/IV(b)/1> wherein X represents an alkylene radical of 2-8 carbon atoms having its two free valency bonds on different carbon atoms, a 2-hydroxy-1 : 3-propylene radical, or an oxa-alkylene radical of 4-8 carbon atoms having its oxygen atom at least one carbon atom removed from each terminal carbon atom bearing a free valency bond, and NR1R2 represents a di-(lower alkyl) amino, N-(lower alkyl)-N-(lower b -hydroxyalkyl) amino, N-(lower alkyl)-N-benzyl-, -lower alkylated-benzyl-, -lower alkoxylated-benzyl- or -halogenated-benzyl-amino, 1-piperidyl, (lower alkylated)-1-piperidyl, 1-pyrrolidyl, (lower alkylated)-1-pyrrolidyl or 4-morpholinyl group (the term "lower" indicating radicals of 1-6 carbon atoms); (b) their acid addition salts (e.g. mono-or poly-hydrochlorides, hydrobromides, hydriodides, phosphates, sulphates, sulphamates, ethanesulphonates, tartrates, citrates, succinates, acetates, benzoates and oleates) and their quaternary ammonium salts (especially those with one or two molar equivalents of a compound R3An, wherein R3 represents a lower alkyl, benzyl, (lower alkylated)-benzyl, (lower alkoxylated) - benzyl, halogenated - benzyl or nitrobenzyl group and An a non-toxic anion); (c) the preparation of (a) by heating 4-chloro-10-hydroxy-1 : 7-phenanthroline with a diamine H2N-X-NR1R2; (d) the quaternation of (a) by reaction with one or two molar equivalents of R3An.  If desired, the product of (d) may be converted into a salt of another anion by treating it with silver oxide and neutralizing the resulting quaternary ammonium hydroxide with the desired acid. Examples describe the preparation of compounds in which the 4-substituent is 3 - diethylamino - 2 - hydroxypropylamino, 2 - (4 - morpholinyl) - - (1 - piperidyl) - and - diethylaminoethylamino, 3 - diethylaminopropylamino, 4-diethylamino- and -di-n-butylaminobutylamino, 5-diethylaminopentylamino, 6-diethylaminohexylamino, 3 - (N - ethyl - N - b  - hydroxyethyl) - aminopropylamino, 3 - (3 - diethylaminopropoxy) - propylamino, 3 - (2 - dimethyl-, -diethyl- and -di-n-butyl-aminoethoxy) - propylamino, 3 - [2 - (1 - piperidyl) - ethoxy] - propylamino, 5 - (N - benzyl - N - methyl)-aminopentylamino, 3-[2-(N-benzyl-, -2-methoxybenzyl-, -2 : 3-dimethoxybenzyl- and -2-chlorobenzyl - N - methyl) - aminoethoxy] - propylamino, and 3-[2-(N-benzyl- and -2 : 3-dimethoxybenzyl - N - ethyl) - aminoethoxy] - propylamino, and in some cases their dihydrochlorides, dimethobromides, dimethiodides, diethiodides and di-2-chlorobenzochlorides. Additional products are listed.  The products possess anticholinesterase activity.  Starting materials.  4 - Chloro - 10 - hydroxy - 1 : 7-phenanthroline is prepared from 4 : 10-dihydroxy-1 : 7-phenanthroline, either directly by the action of a mixture of phosphorus oxychloride and pentachloride, or by converting it by the action of phosphorus oxychloride to 4 : 10 - dichloro - 1 : 7 - phenanthroline, which is then partially hydrolysed with dilute hydrochloric acid.  4 : 10 - Dihydroxy - 1 : 7 - phenanthroline is prepared from m-phenylenediamine by (a) heating it with ethyl ethoxalylacetate to produce 1 : 3 - bis - (a  : b  - dicarbethoxyvinylamino)-benzene, which is cyclized by heating to 2 : 8 - dicarbethoxy - 4 : 10 - dihydroxy-1 : 7 - phenanthroline and the latter hydrolysed and decarboxylated; or (b) condensing it with ethyl ethoxymethylenemalonate to yield m-bis-(b  : b -dicarbethoxyvinylamino)-benzene, which is cyclized by heating to 3 : 9-dicarbethoxy - 4 : 10 - dihydroxy - 1 : 7 - phenanthroline and the latter hydrolysed and decarboxylated. N - Benzyl - N - methylpentylenediamine is prepared by heating d -chlorovaleronitrile with N-methylbenzylamine and reducing the product.  3 - (N - Benzyl - N - alkylamino) - alkoxypropylamines are prepared by reacting an aromatic aldehyde ArCHO with a lower alkylamine R4NH2 and hydrogen in the presence of Raney nickel, reacting the resulting N-alkylbenzylamine with a chlorhydrin Cl(CH2)nOH (n=2-5) to form <FORM:0762442/IV(b)/2> condensing this with acrylonitrile and reducing the cyano group to form <FORM:0762442/IV(b)/3> The process is described in detail and physical properties given for compounds in which: Ar= phenyl, o - methoxyphenyl, 2 : 3 - dimethoxyphenyl and o-chlorophenyl, R4=methyl and ethyl, and n=2.