Patent GB-749907-A (GB)
Title: Improvements in bis-(p-aminophenoxy) alkane derivatives
Inventor: RAISON CLIFFORD GORDON
Filed: 1952-12-04
Abstract: The invention comprises compounds of the formula <FORM:0749907/IV(a)/1> and their acid addition salts where n is an integer from 3 to 10 and R is an alkyl or alkenyl radical of 1 to 5 carbon atoms.  The compounds are made by the following methods.  (1) A compound of the formula <FORM:0749907/IV(a)/2> where Z is a substituent which is convertible into a secondary amino group is converted by known methods for introducing a secondary amino group into an aromatic compound; e.g. a protecting group W is removed from a group RWN- such as by hydrolysis of an acyl, toluene-p-sulphonyl, or alkoxycarbonyl group, or removal of a nitroso group by reduction or by reaction with urea and acid or of a benzyl group by hydrogenation; a benzylidene amino group is treated with an alkylating agent containing the group R and the product is hydrolysed; a carboxyalkylamino group is decarboxylated; a primary amino group is alkylated either directly or by reductive alkylation with an aldehyde; an aliphatic acyl amido group is reduced for example by lithium aluminium hydride; a group WHN-, where W is a protecting group such as an acyl, e.g. acetyl, formyl or toluene-p-sulphonyl, group is alkylated and the protecting group W is removed or a compound in which Z is a halogen atom, e.g. chlorine, is aminated.  (2) An a :o  - disubstituted alkane of the general formula X-(CH2)n -X is reacted with a disubstituted benzene of the formula <FORM:0749907/IV(a)/3> where X and Y are groups capable of reacting together to form an ether linkage, e.g. Y is a hydroxy group and X is a halogen atom such as bromine or chlorine or a mesyl or tosyl group. (3) A monophenoxy compound of the formula <FORM:0749907/IV(a)/4> is reacted with a disubstituted benzene of the formula given under (2) above.  The compounds are used in the treatment of schistosomiasis. Examples describe the use of the above methods in the preparation of a :o -bis-(p - methylaminophenoxy), - propane, - butane, - pentane, - hexane, - heptane, - octane, - nonane and - decane; a :o  - bis-(p - ethylaminophenoxy), - propane, - pentane, - hexane, - heptane, - octane and - nonane; a :o  - bis-(p - n - propylaminophenoxy), - pentane, - hexane, - heptane, -octane and - nonane; a :o  - bis - (isopropylaminophenoxy), - hexane, - heptane and - octane; a :o  - bis - p( - n - and isobutylaminophenoxy), -hexanes, -heptanes and octanes; a :o  - bis - (p - n - amylaminophenoxy), -hexane, -heptane and -octane and a :o  - bis - (p - allylaminophenoxy), - hexane, -heptane and -octane.  Some of these products are isolated in the form of the acid addition salts.  Acid amides.-p - Hydroxyacetethylanilide prepared from acetic anhydride and p-ethylaminophenol is reacted with 1:6-dibromohexane to give 1:6 - bis - (p acetethylamino phenoxy) hexane.  p - Hydroxyacet - n - propylanilide, p - hydroxyacet - n - butylanilide, p-hydroxyacet - n - amylanilide, p - hydroxyacetallylanilide, and p - hydroxyacet - isobutylanilide are similarly prepared and reacted with 1:6-dibromohexane or with other a :o -dibromoalkanes.  1:5 - Bis - (p - formamidophenoxy) pentane is made by heating 1:5-bis-(p-aminophenoxy) pentane with formic acid. 6-(p-Acetmethylamidophenoxy) hexyl bromide is made by the reaction of p-acetmethylamidophenol with an excess of 1:6-dibromohexane. p-Ethoxycarbonmethylamidophenol is prepared by the reaction of ethyl chloroformate and p-methylaminophenol sulphate in the presence of sodium acetate and is subsequently condensed with 1:5-dibromopentane. Sulphonamides.-p - (Toluene - p - sulphonmethylamido) phenol is heated with 1:5 - dibromopentane to give 1:5-bis-(p-(toluene-p-sulphonmethylamido) phenoxy) pentane.  The same product is obtained by reaction of toluene-p-sulphonyl chloride with 1:5-bis-(p-aminophenoxy) pentane.  1:5 - Bis - (p - benzylideneaminophenoxy) pentane is made by reaction of benzaldehyde with 1:5-bis-(p-aminophenoxy) pentane.  1:5 - Bis - (p - benzylaminophenoxy) pentane is made by catalytic reduction of 1:5-bis-(p-benzylideneamino phenoxy) pentane. Reaction of the product with n-propyl iodide gives 1:5-bis - (p - benzyl - n - propylaminophenoxy) pentane.  1:5 - Bis - (p - carbethoxymethylaminophenoxy) pentane is made by reacting 1:5-bis-(p-aminophenoxy) pentane with ethyl chloroacetate in the presence of sodium acetate.  Hydrolysis of this ester gives bis-(p-carboxymethylaminophenoxy) pentane.  Nitroso compounds.-N-Nitroso-p-isopropylaminophenol, N - nitroso - p - ethylaminophenol, N - nitroso - p - methylaminophenol and N-nitroso - p - n - propylaminophenol are made by the action of nitrous acid on the corresponding alkylaminophenols.  These compounds are reacted with a :o -dibromoalkanes to give inter alia:  N:N1 - dinitroso - 1:6 - bis - (p - methylaminophenoxy) hexane and N:N1 - dinitroso-1:5 - bis - (p - methylaminophenoxy) pentane.  The former compound is also prepared by the reaction of N-nitroso 6-(p-methylaminophenoxy) hexyl bromide with N-nitroso-p-methylaminophenol.  Specifications 722,980, [Group III], and 749,923 are referred to.