Patent GB-765957-A (GB)
Title: Bis (4-aminophenoxy) alkane derivatives
Inventor: RAISON CLIFFORD GORDON
Filed: 1953-08-28
Abstract: The invention comprises compounds of the formula <FORM:0765957/IV(b)/1> in which R1 is hydrogen, R2 is an alkyl or alkoxy group of 1 to 4 carbon atoms, R3 and R4 may be hydrogen atoms or alkyl groups of 1 to 4 carbon atoms and n is an integer from 3 to 9 and acid addition salts thereof.  The products are made by treating a compound of the formula <FORM:0765957/IV(b)/2> where Z is a group convertible to the group -NR3R4, by known methods for introducing an amine group into an aromatic compound.  Thus, a primary amino group may be formed by reducing a compound wherein Z is a nitro, nitroso, azo or aldimine group or by hydrolysing a compound wherein Z is an acylamido, alkoxycarbonamido or aldimine group.  A secondary amino group may be introduced by (1) removing a protecting group W from a group R3WN, e.g. an acyl, toluene-p-sulphonyl or alkoxycarbonyl group may be removed by hydrolysis, a nitroso group by reduction or by reaction with urea and acid, or a benzyl group may be removed by hydrogenation; (2) treating a benzylidene amino group with an alkylating agent and hydrolysing the product; (3) decarboxylating a carboxyalkylamino group; (4) alkylating a primary amino group; (5) reducing an aliphatic acylamido group by lithium aluminium hydride, and (6) aminating a compound wherein Z is a halogen atom.  A tertiary amino group may be introduced by (1) heating a quaternary amine salt or hydroxide alone or with alcoholic alkali or alkali alcoholate, or by reductive catalytic debenzylation of a quaternary ammonium salt containing a benzyl group; (2) alkylating a primary or secondary amine; (3) reducing a nitro group in the presence of an aldehyde; (4) reduction, e.g. with lithium aluminium hydride of an alkylacylamino group and (5) decarboxylation of a (carboxyalkyl) alkylamino group. An amino group may also be formed from carb-amido group by the Hofmann or Curtius reaction.  Examples describe the preparation of products of the general formula (I) above, in which NR3R4 is an amino group, R2 is methyl and n has all values from 3 to 9; NR3R4 is a methylamino group, R2 is methyl and n has all values from 3 to 9; NR3R4 is an ethylamino group, R2 is methyl and n is 3, 4, 5, 6 and 8; NR3R4 is dimethylamino group, R2 is methyl and n is 3,4,5,6,8 and 9; NR3R4 is an amino group, R2 is methoxy and n has all values from 3 to 9 and NR3R4 is a dimethylamino group, R2 is methoxy and n is 3, 4, 6, 7 and 8.  Hydrochlorides of these products are also isolated.  Bis - acylamido - phenoxy - alkanes and other intermediate products of the general formula (II) above, are made by treating an a  : o -substituted alkane of the general formula (III) X-(CH2)n-X with a compound of the formula <FORM:0765957/IV(b)/3> where X and Y are substituents capable of reacting together to form an ether linkage. Alternatively a compound of the formula (IV) is reacted with a compound of the formula <FORM:0765957/IV(b)/4> Acetyl derivatives corresponding to the primary and secondary amines obtained in the examples are isolated.  Bis-quaternary ammonium-phenoxy alkanes, for example the dimethiodides of 1 : 3 - bis - (2 - methyl - 4 - dimethylaminophenoxy) propane and the corresponding a  : o -substituted butane, pentane, hexane, octane and nonane and the dimethiodides of 1 : 3 - bis - (2 - methoxy - 4 - dimethylaminophenoxy), propane and the corresponding a  : o -substituted butane, hexane, heptane and octane are prepared from the corresponding a  - o  - bis - (2 - methyl - 4 - methylaminophenoxy) alkanes and a  : o -bis-2-methoxy-4-dimethylaminophenoxy) alkanes respectively.  1 : 6 - Bis - (2 - methyl - 4 - N - nitrosoethylaminophenoxy) hexane is made by treating 2-methyl - 4 - N - nitrosoethylaminophenol (obtained by treating 4-ethylamino-2-methylphenol with nitrous acid) with 1 : 6-dibromohexane.  1 : 7 - Bis - (4 - benzeneazo - 2 - methoxyphenoxy) heptane is made by treating 4-benzeneazo - 2 - methoxy phenol with 1 : 7-dibromoheptane.  1 : 8 - Bis - (4 - ethoxycarbonamido - 2 - methoxyphenoxy) octane is made by treating 4-ethoxycarbonamido-2-methoxyphenol (obtained by the action of ethyl chloroformate on 4-amino guaiacol) with 1 : 8-dibromooctane. 2-Methyl-4-methylaminophenol is obtained as its sulphate by heating 1-methyl-2 : 5-dihydroxybenzene with aqueous methyl-amine in an autoclave and neutralizing the product with sulphuric acid. 4-Ethylamino-2-methylphenol sulphate is similarly obtained by using ethylamine in place of methylamine.  Both these products are converted into their N-acetyl derivatives. 4-Acetamido-2-methylphenol is prepared by catalytic reduction of 2-methyl-4-nitrosophenol and acetylation of the resulting amine. Specifications 749,907, 749,923 and 758,382 are referred to.