Patent GB-800718-A (GB)
Title: Novel substituted alkylamines and processes for their production
Filed: 1955-10-28
Abstract: The invention comprises compounds of the formula <FORM:0800718/IV (b)/1> and acid-addtion salts thereof (wherein R3 and R4 are alkylene groups of 2 to 6 carbon atoms, the latter of which may be substituted by a hydroxyl group and Y3 and Y4 are hydrogen atoms or one or two hydroxyl groups, which may be etherified by benzyl alcohol or an aliphatic alcohol of 1 to 4 carbon atoms or esterified by an aromatic sulphonic acid, but excluding the compound in which R3 and R4 each contain 2 carbon atoms and Y3 and Y4 are each hydrogen) and their preparation by the following methods: (1) reaction of a compound of the formula <FORM:0800718/IV (b)/2> (Hlg being a haloben atom) or an acid addition salt thereof with the appropriate phenoxyalkylamine, preferably in presence of an acid binder, e.g. a tertiary amine or an excess of the phenoxyalkylamine, or potassium bicarbonate, followed, if desired, by saponification of any esterified hydroxyl groups Y3 and/or Y4 or hydrogenolysis of any etherified hydroxyl groups Y3 and/or Y4, e.g. catalytic hydrogenation in the presence of a noble metal catalyst of benzyloxy groups; (2) for compounds wherein R4 is a hydroxylated alkylene group, by reacting a halogeno ketone corresponding to the phenyl alkyl halide starting material of method (1) but containing a keto group in place of the hydroxyl group to be present in the final product in the group R4 with the appropriate phenoxyalkylamine or an acid-addition salt thereof, the keto group being subsequently reduced, preferably by catalytic hydrogenation; (3) hydrogenation of a phenoxyalkanone of the general formula <FORM:0800718/IV (b)/3> (wherein R13 is an oxo-alkyl group, the oxo carbon atom being the carbon atom which will be linked to the nitrogen atom in the final product) in presence of an equimolar quantity of the appropriate phenyl alkylamine which may contain a keto group in the alkylene chain.  In examples: (1) 1-phenoxy-2-aminopropane and 1 - (41 - benzyloxyphenyl) - 2 - bromo - propanone - 1 give 1 - (41 - benzyloxyphenyl) - 2 - (11 - methyl - 21 - phenoxy - ethylamino)-propanone-1 hydrochloride and this is catalytically hydrogenated to give 1 - (41 - hydroxyphenyl) - 2 - (11 - methyl - 21 - phenoxyethylamino)-propanol-1 hydrochloride (free base also described); (2) the product of (1) is prepared by partial catalytic hydrogenation of the intermediate of (1) to give 1-(41-hydroxyphenyl)-2 - (11 - methyl - 21 - phenoxy - ethylamino) - propanone-1 hydrochloride with subsequent further hydrogenation of this compound; (3) 1-(41-hydroxyphenyl)-propanone-2 is hydrogenated in presence of 2-amino-1-phenoxy-propane to give 1 - (41 - hydroxyphenyl) - 2 - methyl - 2 - (11 - methyl - 21 - phenoxyethylamino) - ethane hydrochloride; (4) the product of (1) is prepared by hydrogenation of 1-phenoxy-propanone-2 in presence of 1-(41-hydroxyphenyl)-2-amino - propanone - 1; (5) 1 - phenyl - 2 - bromo - propanone - 1 and 1 - phenoxy - 2 - amino-propane give 1-phenyl-2-(11-methyl-21-phenoxy-ethylamino) -propanone-1 hydrochloride and this is hydrogenated to the corresponding secondary alcohol hydrochloride; (6) 1-(41-benzyloxyphenyl) - 2 - bromo - propanone - 1 and 2-phenoxyethylamine give 1-(41-benzyloxyphenyl) - 2 - (21 - phenoxy - ethylamino) - propanone-1 hydrochloride and this is then hydrogenated to 1-(41-hydroxyphenyl)-2-(21-phenoxyethylamino) -propanol-1 hydrochloride; (7) 1-(41 - benzyloxyphenoxy) - propanone - 2 oxime is prepared from the parent ketone and is then reduced with LiAlH4 to give 1-methyl-2-(41-benzyloxyphenoxy) - ethylamine - 1 (hydrochloride also described), this with 1-(41-benzyloxyphenyl)-2-bromo-propanone-1 gives 1-(41-benzyloxyphenyl) - 2 - [11 - methyl - 21 - (411 - benzyloxyphenoxy) - ethylamino] - propanone - 1 hydrochloride and this is hydrogenated to 1-(41-hydroxyphenyl) - 2 - [11 - methyl - 21 - (411 - hydroxyphenoxy) - ethylamino] - propanol - 1 hydrochloride; (8) 1-(31 : 41-dihydroxyphenyl)-2 - (21 - phenoxy - 11 - methyl - ethylamino) - ethanone-1 hydrochloride, prepared either from 2 - amino - 1 - phenoxypropane and 1 - (31 : 41-dihydroxyphenyl) - 2 - chloroethanone - 1 or by debenzylation of 1 - (31 : 41 - dibenzyloxyphenyl) - 2 - (11 - methyl - 21 - phenoxy - ethylamino) - ethanone - 1 hydrochloride, itself prepared from 1 - (31 : 41 - dibenzyloxyphenyl) - 2 - bromo-ethanone-1 and 2-amino-1-phenoxy-propane, is hydrogenated to the corresponding secondary alcohol; (9) 2-phenoxyethylamine and 1 - (41-methoxy-phenyl)-2-bromo-propanone-1 give 1-(41-methoxy-phenyl)-2-(21-phenoxyethylamino) - propanone - 1 hydrochloride and this is hydrogenated to 1-(41-methoxyphenyl)-2-(21-phenoxyethylamino) - propanol - 1 hydrochloride; (10) 1 - (41 - methoxyphenyl) - 2 - (11 - methyl - 21 - phenoxy - ethylamino) - propanol-1 hydrochloride is prepared by the method of (a) via 1 - (41-methoxyphenyl) - 2 - (11 - methyl - 21 - phenoxyethylamino) - propanone - 1 hydrochloride and is separated into its stereochemical isomers by recrystallization from water; (11) 1-methyl-2 - (41 - methoxyphenoxy) - ethylamine and 4 - benzyloxy - 21 - bromopropiophenone give 1 - (41 - benzyloxyphenyl) - 2 - [11 - methyl - 21 - (411 - methoxyphenoxy) - ethylamino] - propanone-1-hydrochloride and this on hydrogenation gives 1 - (41 - hydroxyphenyl) - 2 - [11 - methyl - 21 - (411 - methoxyphenoxy) - ethylamino] - propanol-1 hydrochloride; (12) 4-(41-tolylsulphonyloxy) - 211 - bromopropiophenone and 1-methyl - 2 - phenoxyethylamine give 4 - (41 - tolylsulphonyloxy) - 211 - (1 - methyl - 2 - phenoxyethylamino) - propiophenone hydrochloride and the free base on reduction with sodium borohydride gives 1 - [41 - (411 - tolylsulphonyloxy)phenyl] - 2 - (11 - methyl - 21 - phenoxyethylamino)-propanol-1, the resolution of which into two stereo isomeric hydrochlorides is described. Reference is also made to the resolution of the product of Example (1) prepared by the method of that example by fractional crystallization of acid-addition salts, e.g. hydrochlorides, from, for example, water or a mixture of ethanol and diethyl ether.ALSO:A pharmaceutical preparation comprises at least 0.1 per cent of a compound of the general formula <FORM:0800718/VI/1> (wherein R3 and R4 are alkylene groups of 2 to 6 carbon atoms, the latter of which may be substituted by a hydroxyl group and Y3 and Y4 are hydrogen atoms or one or two hydroxyl groups, which may be etherified by benzyl alcohol or an aliphatic alcohol of 1 to 4 carbon atoms or esterified by an aromatic sulphonic acid, but excluding the compound in which R3 and R4 each contain 2 carbon atoms and Y3 and Y4 are hydrogen) or an acid-addition salt thereof, together with a pharmaceutical carrier.  A dripping liquid comprising a compound of the above formula, sodium bisulphite, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and 96 per cent ethanol in distilled water, tablets comprising a compound of the invention with, for example, milk sugar, powder sugar, potato starch or talcum, and injection liquids comprising a compound of the invention, glycerine, sodium metabisulphite and distilled water are described.