Patent GB-832286-A (GB)
Title: Improvements in or relating to processes for producing substituted alkylamines and acid-addition salts thereof
Filed: 1957-10-11
Abstract: Compounds of the formula <FORM:0832286/IV (b)/1> and acid addition salts thereof, wherein Y1 and Y2 are hydrogen or hydroxyl or esterified or etherified hydroxyl groups, R1 is an alkylene group of 2-6 carbon atoms which may bear a hydroxyl substituent and R2 is an alkylene group of 2-6 carbon atoms are made by reacting a compound of the formula <FORM:0832286/IV (b)/2> with a compound of the formula <FORM:0832286/IV (b)/3> or an acid addition salt thereof, wherein R11 is a group having the same carbon skeleton as R1, but containing a keto- or aldehydo-oxygen substituent and optionally a hydroxyl or a further keto-oxygen substituent, hydrogenating the resulting (Schiffs base) product, suitably by hydrogenating in situ immediately upon addition of the reactants either at atmospheric temperature and pressure in the presence of platinum or at 20-100 DEG  C. and a pressure of 2-2 DEG  atmospheres in the presence of Raney nickel and, if desired, converting any esterified or etherified group Y1 and/or Y2 into a hydroxyl group by hydrogenation or hydrolysis.  The condensation between the amine and the ketone or aldehyde preferably takes place in a solvent which may be an excess of one of the reaction components, a lower aliphatic alcohol such as methanol, ethanol, propanol-2 or butanol, an ether such as anisole, phenetol or diethyl diisopropyl or methyl ethyl ether, or aqueous acetic or propionic acid.  The groups Y1 and Y2 are preferably in the para position and may for example be benzyloxy groups, which are finally converted to hydroxy groups by catalytic hydrogenation, or they may be lower aliphatic acyloxy groups which are converted by saponification with acids or alkalis, or by reduction with a complex metal hydride such as lithium aluminium hydride or sodium borohydride.  The group R11 in the starting materials is suitably one of the groups -CHOH.COCH3, -CO-CO.CH3, -CHOH.CHO, -CO.CHO, -CHOH.CO.C2H5, -CO.CO.C2H5, -CH2, CO.CH3 or -COC2H5, the preferred products being compounds of which R1 is a group -CHOH-R6- wherein R6 is an alkylene group of 1-5 carbon atoms, or -CHOH.CHR7-wherein R7 is an alkyl group of 1-4 carbon atoms, e.g. -CHOH.CH(CH3)-, -CHOH.CH2- or -CHOH.CH(C2H5)-.  Suitably, R2 is one of the groups -CH2.CH2-, -CH(CH3).CH2-or -CH(CH3).CH2CH2-.  The compounds are used pharmaceutically (see Group VI).  Examples describe the preparation of 1-phenyl-and 1 - (41 - hydroxyphenyl)-, 2 - (11 - methyl - 21 - phenoxy - ethylamino) - propanol - (1); 1 - (41 - hydroxyphenyl) - 2 - (11 - methyl - 21 - phenoxyethylamino)-ethanol-1 and the intermediate p - hydroxy - a  - (11 - methyl - 21 - phenoxy - ethylamino) acetophenone; 1-(41-hydroxyphenyl) - 2 - [21 - (411 - hydroxyphenoxy) - ethylamino] - propanol - (1); 1 - (41-hydroxyphenyl) - 2 - [11 - methyl - 21 - (411-hydroxyphenoxy) - ethylamino] - propanol - 1; 1 - (41 - hydroxyphenyl) - 2 - [11 - methyl - 21 (411 - methoxyphenoxy) - ethylamino] - propanol - 1; 1 - (41 - methoxyphenyl) - 2 - (11-methyl - 21 - phenoxyethylamino) - propanol - 1, and 1 - (41 - methoxyphenyl) - N - (2 - phenoxy-ethyl)-propylamine.  2-(41-Benzyloxyphenoxy)-ethylamine is prepared by treating the sodium salts of 4-benzyloxyphenol with sodium chloracetate, converting the resulting 4-benzyloxyphenoxy-acetic acid into 4-benzyloxyphenoxy-acetyl chloride by treatment with thionyl chloride, adding ammonia to give 4-benzyloxyphenoxy-acetamide and reducing with lithium aluminium hydride.  1 - (41 - Hydroxyphenyl) - 2 - methyl - glyoxal is made by oxidizing a -4-dihydroxy propiophenone with copper sulphate in aqueous pyridine. 1 - Methyl - 2 - (41 - methoxyphenoxy) - ethyl - amine is made by reaction of chloracetone and p-methoxyphenol to give 1-(41-methoxyphenoxy)propanone-2 which is treated with ammonia and reduced.  Specifications 800,718, 832,287, 832,288 and 832,289 are referred to.ALSO:Pharmaceutical compositions comprise compounds of the formula <FORM:0832286/VI/1> or acid addition salts thereof (see Group IV (b)), wherein Y1 and Y2 are hydrogen, hydroxyl or esterified or etherified hydroxyl groups R1 is an alkylene group of 2-6 carbon atoms, optionally bearing a hydroxyl substituent and R2 is an alkylene group of 2-6 carbon atoms in admixture with a pharmaceutical carrier.  The preparations may take the form of tablets or solutions for oral use or injection.  A drip liquid is prepared by dissolving the active compound in admixture with sodium bisulphite, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and a small quantity of ethanol in distilled water.  A solution for injection is produced by mixing the active compound with glycerine and sodium metabisulphite and diluting with distilled water.  Specifications 800,718, 832,287, 832,288 and 832,289 are referred to.