Patent GB-1345184-A (GB)
Title: Phenyltetrafluoroethyl-benzylamines
IPC: C07F9/54
Filed: 1971-02-05
Abstract: 1345184 Phenyl - tetrafluoroethylbenzylamines; quaternary phosphonium salt MERCK & CO Inc 5 Feb 1971 4069/71 Headings C2C and C2P Compounds of the formula R 1 N(R).C(CH 3 ) 2 .(P-C 6 H 4 ).CF 2 CF 2 .C 6 H 5 , in which each of R and R 1  is H or a C 1-5  alkyl radical, are obtained (a) by fluorinating an N - R - N - R 1  - α,α - dimethyl - p - (2 - phenyl- 1,1,2,2 - tetrachloroethyl) - benzylamine by means of antimony fluoride or mercuric fluoride and anhydrous hydrogen fluoride, or (b) by fluorinating an N - R - N - R 1  - α,α - dimethylp - (2 - phenyl - 1 - chlorovinyl) - benzylamine, or an N - R - N - R 1  - α,α - dimethyl - p - (2- phenyl - 1,2 - difluorovinyl) - benzylamine or an N - R - N - R 1  - α,α - dimethyl - p - (1 - phenyl- 2,2 - difluorovinyl) - benzylamine by means of lead oxide and anhydrous hydrogen fluoride. The products are useful in treating or preventing cardiac arrhythmia. The preparation of the following intermediates is also described: 4-isopropylacetophenone is reacted with PCl 5  to form 1-chloro-1-cumylethylene which is aminated to p-(1-chlorovinyl)- α,α-dimethylbenzylamine using NCl 3  in the presence of AlCl 3  and t-butyl bromide, and dehydrohalogenation by ethanolic KOH yields 4 - ethynyl - α,α - dimethylbenzylamine which is converted to the copper derivative and condensed with iodobenzene to produce 4-(α-aminoisopropyl) - tolane; alternatively, α,α-dimethylbenzylamine is reacted with trifluoroacetic anhydride to give N - trifluoroacetyl - α,α-dimethylbenzylamine and then nitrated to 4-nitro- N - trifluoroacetyl - α,α - dimethylbenzylamine which is reduced to 4-amino-N-trifluoroacetyl- α,α-dimethylbenzylamine transformed to 4-iodo- N - trifluoroacetyl - α,α - dimethylbenzylamine, deacylated to 4 - iodo - α,α - dimethylbenzylamine which is condensed with copper phenylacetylide to give 4-(α-aminoisopropyl)-tolane; the hydrochloride of the latter is chlorinated to yield (2 - phenyl - 1,1,2,2 - tetrachloroethyl)-α,α- dimethylbenzylamine hydrochloride; N-trifiuoroacetyl - α,α- dimethylbenzylamine is chloromethylated with paraformaldehyde and HC1 and the resulting 4-(α-trifluoroacetamidoisopropyl) benzyl chloride is converted to 4-(α-trifluoroacetamidoisopropyl) benzyl triphenylphosphonium chloride by reaction with triphenylphosphine and condensed with benzaldehyde to yield 4 - (α - trifluoroacetamidoisopropyl) stilbene; alternatively, the 4-(α-trifluoroacetamidoisopropyl) benzyl chloride is oxidized with copper nitrate solution to 4-(α-trifluoroacetamidoisopropyl) benzaldehyde which is condensed with benzylidene triphenylphosphine to yield 4-(α- trifluoroacetamidoisopropyl) stilbene; the stilbene is chlorinated to the dichloride and dehydrochlorinated by heating in quinoline to yield a mixture of α- and α<SP>1</SP>-chloro-4-(trifluoroacetamidoisopropyl) stilbenes; the mixture is fluorinated with lead dioxide in HF to a mixture of α or α<SP>1</SP>-chloro - α,α<SP>1</SP> - difluoro - 4 - (trifluoroacetamidoisopropyl) diphenyl ethanes which is dehydrochlorinated and hydrolysed to give α,α<SP>1</SP>- difluoro-4-(aminoisopropyl) stilbene; iodocumene is converted to 4-cumyllithium which reacts with Cul to yield 4-cumylcopper which is treated with trifluorovinyl iodide to form α,#,#-trifluoro- 4-isopropyl styrene; reaction of the latter with phenyllithium produces α,α<SP>1</SP> - difluoro - 4 - isopropylstilbene. Alternatively, phenyllithium is converted to phenylcopper which condenses with trifluorovinyl iodide to yield α,#,#-trifluorostyrene which then reacts with 4-cumyllithium to form α,α<SP>1</SP>-difluoro-4-isopropylstilbene; N- trifluoroacetyl - α,α - dimethylbenzylamine condenses with benzoyl chloride to yield 4-(trifluoroacetamidoisopropyl)- benzophenone which condenses with difluoromethylene triphenylphosphine to give 1,1-difluoro-2-phenyl-2-(α-trifluoroacetamidocumyl)- ethylene which is saponified to give 1,1-difluoro-2-phenyl-2-(α- aminocumyl) ethylene; 4 - (α - trifluoroacetamidoisopropyl) benzoic acid is obtained by oxidation of the corresponding benzaldehyde, is converted to the acid chloride and condensed with benzene to give 4-(trifluoroacetamidoisopropyl)-benzophenone which is converted to 1,1 - difluoro - 2 - phenyl - 2 - (α - trifluoroacetamidocumyl) ethylene; this is deacylated and fluorinated in HF with lead dioxide with rearrangement to 4 - (2<SP>1</SP> -phenyl - 1<SP>1</SP>,1<SP>1</SP>,2<SP>1</SP>,2<SP>1</SP> - tetrafluorethyl) α,α - dimethylbenzylamine; 4 - (α - trifluoroacetamidoisopropyl) stilbene is hydrogenated to N-trifluoroacetyl-4-(2<SP>1</SP>-phenylethyl)- α,α-dimethylbenzylamine which is deacylated to 4 - (2 - phenylethyl) - α,α - dimethylbenzylamine.