Patent GB-789033-A (GB)
Title: Improvements in or relating to substituted aralkyl-phenyl-alkylamines
Filed: 1955-10-20
Abstract: The invention comprises compounds of the formula <FORM:0789033/IV (b)/1> (wherein R is a divalent alkylene group of 2-5 carbon atoms and Y1 and Y2 are either each OH or one of them is H and the other OH) and acid-addition salts thereof, and their preparation by reduction of ketones of the formula <FORM:0789033/IV (b)/2> or acid-addition salts thereof (wherein R1O is OH or esterified or etherified OH capable of being converted into OH by saponification with dilute acids or alkalis or of being de-etherified by catalytic hydrogenation or by treatment with strong inorganic acids, and Y11 and Y21 are as Y1 and Y2 or, when OH, are similarly protected) with saponification or de-etherification when necessary.  When the aromatic OH groups are protected by etherification with benzyl alcohol or diphenyl or triphenyl methanol then they may be converted into free OH groups in the same reaction step as that in which the keto group is reduced, by hydrogenation in the presence of a noble metal catalyst, e.g. finely-divided palladium on carbon, barium sulphate or calcium carbonate.  In an alternative procedure in which OR1 is a benzyloxy or a diphenylmethoxy or triphenylmethoxy group and Y11 and/or Y21 is or are OH etherified by a lower aliphatic alcohol, e.g. methanol, the group R1O is de-etherified by catalytic hydrogenation without substantial reduction of the keto group, Y11 and/or Y21\h is or are then de-etherified with a strong inorganic acid, e.g. HBr or HI, and, finally, the keto group is reduced by hydrogenation in presence of a noble metal.  In a further modification in which R1O, Y11 and/or Y21 are hydroxyl groups etherified with a lower aliphatic alcohol these groups are de-alkylated with a strong inorganic acid prior to reduction of the keto group as before.  Other conventional reducing methods are also referred to.  Reference is also made to the preparation of the compounds of the invention by reacting a compound of the general formula <FORM:0789033/IV (b)/3> (R1O being OH or an ether group) with a compound of the structure <FORM:0789033/IV (b)/4> (O = (R) being an aldehyde group with the same number of carbon atoms as R) or by reacting a compound of the general formula <FORM:0789033/IV (b)/5> with a compound of the general formula <FORM:0789033/IV (b)/6> with, in each case, subsequent reduction of the Schiff's base so formed. In examples: (1) 2-(p-methoxyphenyl) - ethylamine with formalin and sodium cyanide in presence of aqueous sodium bisulphite at 60 DEG  C. gives, after addition of HCl, 2 - [21 - (p - methoxyphenyl)ethylamino]-acetonitrile hydrochloride, this is reacted with veratrole in presence of HCl gas and AlCl3 in nitrobenzene to give 1-(31:41-dimethoxyphenyl)-2 - [21 - (p - methoxyphenyl) ethylamino] - ethan - 1-one hydrochloride, this is boiled with HBr to give, on addition of HCl, 1-(31:41-dihydroxyphenyl) - 2 - [21 - (p - hydroxyphenyl) ethylamino]-ethan-1-one and this is catalytically reduced to the corresponding secondary alcohol; (2) the processes are as in (1), the intermediates being 2 - [11 - methyl - 21 - (p - methoxyphenyl) ethylamino]-acetonitrile hydrochloride, 1-(31:41-dimethoxyphenyl) - 2 - [11 - methyl - 21 - (p - methoxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride and 1 - (31:41 - dihydroxyphenyl) - 2 - [11 - methyl - 21 - (p - hydroxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride, this last compound then being reduced to the corresponding secondary alcohol; (3) the processes are as in (1), the intermediates being 2-[11-methyl - 31 - (p - methoxyphenyl) propylamino]-acetonitrile hydrochloride, 1 - (31:41 - dimethoxyphenyl) - 2 - [11 - methyl - 31 - (p - methoxyphenyl) - propylamino] - ethan - 1 - one and 1 (31:41 - dihydroxyphenyl) - 2 - [11 - methyl - 31 - (p - hydroxyphenyl) - propylamino] - ethan - 1 - one hydrochloride, this last compound then being reduced to the corresponding secondary alcohol; (4) the processes are as in (1), the intermediates being 2 - [11:11 - dimethyl - 21 - (p - methoxyphenyl) - ethylamino] - acetonitrile hydrochloride, 1 - (31:41 - dimethoxyphenyl) - 2 - [11:11 - dimethyl - 21 - (p - methoxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride and 1 - (31:41 - dihydroxyphenyl) - 2 - [11:11 - dimethyl-21 - (p - hydroxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride, this last compound then being reduced to the corresponding secondary alcohol; (5) 1 - methyl - 2 - (31:41 - dimethoxyphenyl) - ethylamine and 1-(31:41-dibenzyloxyphenyl)-2-bromo-ethan-1-one are condensed in presence of HCl to yield 1-(31:41-dibenzyloxyphenyl)-2-[11-methyl - 21 - (311:411 - dimethoxyphenyl) ethylamino] - ethan - 1 - one hydrochloride, this is catalytically hydrogenated to give 1-(31:41-dihydroxyphenyl) - 2 - [11 - methyl - 21 - (311:411-dimethoxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride, this is boiled with HBr to yield 1 - (31:41 - dihydroxyphenyl) - 2 - [11 - methyl 21 - (311:411 - dihydroxyphenyl) - ethylamino] - ethan-1-one, this is converted to the hydrochloride and this is catalytically hydrogenated to the corresponding secondary alcohol; (6) by similar processes to (5) the following intermediates are prepared:-1-(31:41-dibenzyloxyphenyl) - 2 - [21 - (311 - methoxyphenyl) - - 11 - methyl - ethylamino]-, 1 - (31:41 - dihydroxyphenyl) - 2 - [21 - (311 - methoxyphenyl) - 11 - methyl - ethylamino] - and 1 - (31:41 - dihydroxyphenyl) - 2 - [21 - (311 - hydroxyphenyl) - 11 - methyl - ethylamino] - ethan - 1 - one hydrochlorides, this last compound then being reduced to the corresponding secondary alcohol; (7) similarly 1 - (31:41 - dibenzyloxyphenyl) - 2 - [21 - (211 - methoxyphenyl) - 11 - methyl - ethyl amino]-, 1 - (31:41 - dihydroxyphenyl) - 2 - [21 - (211 - methoxyphenyl) - 11 - methyl - ethylamino] - and 1 - (31:41 - dihydroxyphenyl) - 2 - [21 - (211-hydroxyphenyl) - 11 - methyl - ethylamino] - ethan-1-one hydrochlorides are prepared, the last compound then being reduced to the corresponding secondary alcohol; and (8) 1-methyl-2-(41-benzyloxyphenyl) - ethylamine and 1 - (31:41-dibenzyloxyphenyl) - 2 - bromo - ethan - 1 - one are condensed to yield 1-(31:41-dibenzyloxyphenyl) - 2 - [11 - methyl - 21 - (411 - benzyloxyphenyl) - ethylamino] - ethan - 1 - one hydrochloride and this is catalytically hydrogenated to yield 1-(31:41-dihydroxyphenyl)-2-[11-methyl-21 - (411 - hydroxyphenyl) - ethylamino] - ethanol.  Specifications 640,492 and 684,781 are referred to.