Patent GB-803072-A (GB)
Title: Bis-ºÔ-aminophenoxy compounds of pharmaceutical value
Inventor: WALLS LESLIE PERCY
Filed: 1954-12-13
Abstract: The invention comprises compounds of the formula: <FORM:0803072/IV (b)/1> and acid addition salts thereof, wherein R1, R2, R3 and R4 are the same or different and are hydrogen atoms or alkyl groups of 1-4 carbon atoms and M is an aliphatic hydrocarbon chain of 2 to 7 carbon atoms having one double or triple bond.  The compounds are made by condensing an a  : o -disubstituted alkene or alkyne of the formula: <FORM:0803072/IV (b)/2> with a disubstituted benzene of the formula <FORM:0803072/IV (b)/3> wherein X and Y are groups capable of reacting together to form an ether linkage and Z is either a group NR1R2 or NR3R4 (where these groups are tertiary amino groups) or is a group convertible into a primary, secondary or tertiary amino group which is subsequently treated to effect the conversion.  The group Z may suitably be chosen from (a) as groups convertible into a primary amino group; nitro (convertible by reduction); acetamido, alkoxycarbonamido or aldimino (convertible by hydrolysis); or a halogen atom which may be aminated; (b) as groups convertible into secondary amino groups; a group R1WN or R3WN wherein W is a protecting group such as an acyl, p-toluenesulphonyl or alkoxycarbonyl group which is removed by hydrolysis, or a nitroso group which is removed by reduction or by reaction with urea and acid; a benzylideneamino group which is alkylated and hydrolysed; a carboxyalkylamino group which is decarboxylated; a primary amino group which is alkylated; an acylamido group (convertible by reduction with lithium aluminium hydride); or a halogen atom which may be aminated; and (c) as groups convertible into tertiary amino groups; a quaternary ammonium hydroxide or quaternary ammonium salt group which may be heated alone or with alcoholic alkali or alkali alcoholate; a primary or secondary amino group which is alkylated; an acylalkylamido-group which is reduced with lithium aluminium hydride; or a (carboxyalkyl) alkylamino group which is decarboxylated. Examples describe the preparation of p : p1-diamino-, p : p1-di (methylamino)-, p : p1-di(dimethylamino) -, p : p1 - di (diethylamino)-p : p1 - di(n - propylamino) -, and p : p1 - di (ethylamino) -, 1 : 4 - bis - phenoxy - but - 2-ene and similar derivatives of a  : o -bis phenoxy-but - 2 - yne, hept - 3 - ene, hex - 3 - ene, hex-3-yne, pent-2-ene and pent-2-yne.  Starting materials: a  : o  - Bis - acylaminophenoxy-alkenes and alkynes such as 1 : 4-bis-(p - ethoxycarbonamidophenoxy) but - 2 - ene, 1 : 4 - bis - (p - ethoxycarbonmethylamidophenoxy) but - 2 - ene, 1 : 4 - bis (p - acetamidophenoxy) but - 2 - yne, 1 : 4 - bis (p - ethoxycarbonamidophenoxy) but - 2 - yne, 1 : 4 - bis (p - acetmethylamidophenoxy) but - 2 - yne, 1 : 4 - bis (p - ethoxycarbonethylamidophenoxy) but - 2 - ene and similar derivatives of hex-3-ene, hept-3-ene, hex-3-yne, pent-2-yne and pent-2-ene are made by the action of the corresponding acylaminophenol on an a  : o -dihalo-, di-methanesulphonoxy - or di p - toluenesulphonoxy -, alkene or alkyne.  1 : 4 - Bis (p - nitroso - n - propylaminophenoxy) but - 2 - ene and 1 : 6 - bis (p - nitrosopropylaminophenoxy) hex - 3 - ene are made by the action of p-nitrosopropylaminophenol on 1 : 4 - dibromo - but - 2 - ene and 1 : 6 - di - p-toluenesulphonoxyhex - 3 - ene respectively.  The quaternary 1 : 4-bis (p-trimethylammoniumphenoxy) but - 2 - ene diiodide and 1 : 6 - bis (p-trimethylammoniumphenoxy) hex - 3 - ene and hex - 3 - yne diiodides are made by quaternating the corresponding primary or secondary amines.  1 : 6-Dibromo-hex-3-ene is made by the action of PBr3 on the 1 : 6-diol.  1 : 6-Ditoluenesulphonoxyhex - 3 - ene and 1 : 6 - ditoluenesulphonoxy - hex - 3 - yne are made by the action of p-toluenesulphonyl chloride on the diols. p-Ethoxycarbonethylamidophenol is made by the action of ethyl chloroformate on p-ethyl aminophenol.  3 - (Tetrahydro - 2 - pyranyloxy) prop - 1 - yne is condensed with ethylene oxide in the presence of lithamide to give 5-(tetrahydro - 2 - pyranyloxy) pent - 3 - yn - 1 - ol which is hydrolysed to pent-2-yn-1 : 5-diol.  The latter compound reacts with p-toluene sulphonylchloride to give 1 : 5-di-p-toluenesulphonoxy - pent - 2 - yne or is reduced by sodium in liquid ammonia to trans-pent-2-ene-1 : 5-diol which is converted in turn into 1 : 5-di-p - toluenesulphonoxy - pent - 2 - ene. Specifications 749,907, 749,923 and 758,382 are referred to. Reference has been directed by the Comptroller to Specification 761,888.