Patent GB-720593-A (GB)
Title: Improvements in or relating to the production of ª-phenylethyl-amine ethers
Inventor: MCCOUBREY ARTHUR
Filed: 1951-03-29
Abstract: The invention comprises an a -phenylethylamine having a m- or p-ether group of which the etherifying radical is an alkyl, cycloalkyl or aryl radical containing from 4 to 8 carbon atoms, said a -phenylethylamine containing at least 15 carbon atoms when the etherifying radical is an aromatic radical.  Preferably the phenyl nucleus is substituted by a non-ortho hydroxy group and/or a non-ortho alkyl group containing 1 to 3 carbon atoms.  For therapeutic use the compounds may be used as their salts, e.g. hydrochlorides.  One process of preparing certain of such compounds comprises reacting m- or p-hydroxy acetophenone with the appropriate alkyl or cycloaliphatic halide in the presence of an alkali to produce the corresponding acetophenone ether, reacting the ether with hydroxylamine or its salt to produce the corresponding oxime and reducing the oxime to the a -phenylethylamine ether, e.g. with sodium amalgam in alcoholic acetic acid.  To produce the meta-etherified compound from an acetophenone having both a m- and a p-hydroxy group, the p-hydroxy group may be benzylated by reaction with a benzyl halide in the presence of an alkali before the etherifying group is introduced, and the benzyl radical is removed by hydrogenation, e.g. with hydro gen in the presence of a palladium black catalyst supported on charcoal.  As an alternative the acetophenone ether may be hydrogenated to the corresponding secondary carbinol, which is reacted with a phosphorus trihalide and halide produced is reacted with ammonia or a primary or secondary amine, the latter being chosen so as to yield a product containing at least 15 carbon atoms in the molecule.  In examples (1) p-cyclohexoxyacetophenone (prepared by reacting p-acetylphenol and cyclo hexyl bromide) is reacted with an alkaline solution of hydroxylamine and the p-cyclohexoxy acetophenone oxime obtained is reduced with sodium amalgam and acetic acid to give (\sB)-a -(4-cyclohexoxyphenyl)ethylamine.  Similarly produced are ethylamines having as a -substituents p-n-butyloxyphenyl, p-n-heptyloxyphenyl, p-n-octyloxyphenyl, m-n-hexyloxyphenyl, m-active-amyloxyphenyl, and p-diethyl-m-methoxyphenyl substituents; (2) p-phenoxyacetophenone is hydrogenated using Raney nickel to a -p-phenoxyphenylethanol, which is reacted with phosphorus tribromide to give the corresponding bromide.  The bromide is reacted with dimethylamine to give (\sB)-a -(p-phenoxyphenyl) - ethyldimethylamine.  Similarly produced are a  - (p - cyclohexyloxy - phenyl)ethyl ethylamine, a  - (p - cyclo - hexyloxyphenyl)ethyl dimethylamine, a  - (p - cyclohexyloxy - phenyl)ethyl diethylamine, a - (p - phenoxyphenyl)ethyl methylamine, a  - (p - phenoxylphenyl)ethyl ethylamine, a  - (p-phenoxyphenyl)ethy diethylamine, and a -(m - cyclohexyloxyphenyl)ethyl diethylamine; (3) 4-acetocatechol and benzyl chloride are reacted and the 4-benzyloxy-3-hydroxyacetophenone (separated from 3 : 4-dibenzyloxyacetophenone by-product) is reacted with cyclohexyl bromide.  The 4-benzyloxy-3-cyclohexoxyacetophenone obtained is hydrogenated to give 3-cyclohexyloxy-4-hydroxyacetophenone which is reacted with allyl bromide and the product is heated at 200 DEG  C. to effect a rearrangement.  The resulting 3-cyclohexoxy-4-hydroxy-5-allyacetophenone is converted to its oxime, which on reduction with sodium amalgam gives (\sB) - a  - (3 - cyclohexoxy - 4 - hydroxy - 5 - n - propylphenyl)ethylamine.  The corresponding 3-n-hexyl-compound is produced by a similar series of reactions.