Patent GB-1356795-A (GB)
Title: Preparation of tetrafluorophenethyl benzylamines
IPC: A61K31/40
Filed: 1971-02-05
Abstract: 1356795 Tetrafluorophenethyl benzylamines MERCK & CO Inc 7 July 1971 [5 Feb 1971] 4068/71 Heading C2C α,α - Dimethyl - 4 - (α,α,#,# - tetrafluorophenethyl)-benzylamine and N-alkyl or N,N-dialkyl derivatives thereof may be obtained (1) by reacting a 2-halo-2-[p-α,α,#,#-tetrafluorophenethyl] phenyl propane with Mg and heating the resulting Grignard reagent with either o-methyl hydroxylamine or monochloramine dissolved in an ether; (2) by reacting the starting material of (1) with ammonia, or a C 1-5  alkylamine or di- (C 1-5  alkyl)amine; (3) by contacting α-methyl- 4 - (α,α,#,# - tetrafluorophenylethyl) - styrene with hydrogen in the presence of a nickel, platinum or palladium catalyst and contacting the product with NCl 3 , sulphoxamic acid, or a mixture of hydroxylamine and sulphuric acid; (4) contacting 4 - (α,α,#,# - tetrafluorophenethyl)aniline with nitrous acid to form the diazonium salt, contacting with 2-nitropropane to form 1 - (1<SP>1</SP> - nitro - isopropyl) - 4 - (α,α,#,#- tetrafluorophenethyl)-benzene and reducing this with an alkali metal aluminium hydride or with hydrogen in the presence of a catalyst; (5) contacting a a,a-dimethyl-4-(α,α,#,#-tetrafluorophenethyl)phenyl propionic acid or C 1-5  alkyl ester with hydrazoic acid in acidic medium; (6) contacting 2-methyl-2-[4-(α,α,#,#-tetrafluorophenethyl)-phenyl]-propionamide with ahalogen (e.g. bromine) in a strongly alkaline medium; (7) contacting 2 - [4 - (α,α,#,# - tetrafluorophenethyl) - phenyl] - 2 - methyl - 3 - oxo - n - butane with NH 2 OH and contacting the resulting oxime with an acidic reagent (e.g. sulphuric acid); (8) contacting [4 - (α,α,#,# - tetrafluorophenethyl) - phenyl] - dimethylcarbinol with benzylamine or an N-(C 1-3  alkyl)benzylamine in the presence of a halogen acid and reducing the resulting N-benzylamine compound with hydrogen in the presence of a catalyst or with an alkali metal aluminium hydride; (9) contacting the carbinol of (8) with urea in the presence of sulphuric acid and hydrolysing the resulting ureide; or (10) contacting the ureide formed in (9) with phthalic anhydride and converting the resulting phthalimide by treatment with hydrazine; (11) contacting α - methyl - 4 - (α,α,#,# - tetrafluorophenethyl)-styrene with chlorine and acetonitrile followed by hydrolysis to yield a compound R-C(CH 3 )(CH 2 Cl)-NHCOCH 3  (where R is 4-(α,α,#,#-tetrafluorophenethyl)-phenyl-) converting this to a Grignard reagent and hydrolysing the Grignard reagent; (12) contacting 4 - (α,α,#,# - tetrafluorophenethyl) - acetophenone with alkali metal cyanide and ammonium chloride to form R-C(CH 3 )(CN)-NH 2  and reducing this with alkali metal aluminium hydride to an imine, converting to a hydrazone and decomposing the hydrazone; (13) reacting the starting material of (12) with ammonia in contact with molecular sieves to form 1-acetimidoyl - 4 - (α,α,#,# - tetrafluorophenethyl)benzene and contacting this with methyl lithium under anhydrous conditions; (14) heating 4- (α,α,#,# - tetrafluorophenethyl) - isopropyl benzene with isopropylamine under pressure, either under U.V. irradiation or in the presence of a peroxide and air; (15) contacting RLi with an equimolar amount of the N-benzylimine of acetone in the presence of a dehydrating agent and hydrolysing the resulting benzylamine RC(CH 3 ) 2 N=CHC 6 H 5 ; (16) diazotizing a α,α,- dimethyl - 4 - (α,α,#,# - tetrafluorophenethyl)- benzylamine which is amino-substituted in one or both of the benzene rings and treating the diazonium salt with hypophosphorous acid. In all of the above processes, the resulting 4-(α,α, #,# - tetrafluorophenethyl) - benzylamine is optionally converted into the corresponding N- alkyl or N,N,-dialkyl benzylamine.