Patent GB-742819-A (GB)
Title: New aliphatic acid amide derivatives and processes for the production thereof
IPC: C07D295/15
Filed: 1953-05-20
Abstract: The invention comprises amides of the general formula <FORM:0742819/IV(a)/1> wherein R1 and R2 represent hydrogen or an alkyl or aralkyl radical; R3, R4 and R5 represent hydrogen, halogen or an alkyl, alkoxy, hydroxy, amino or acylamino group and Am represents an alkylamino, dialkylamino or cycloalkylene amino group, the latter also containing, if desired, hetero-atoms additional to the nitrogen atom, e.g. oxygen or sulphur, and salts of the amides with organic or inorganic acids non-toxic to warm-blooded animals. The compounds produce local anaesthesia.  The amides may be produced by treating a phenoxy-amino-alkane of the general formula <FORM:0742819/IV(a)/2> with an approximately equimolar proportion of a reactive functional derivative of a halogeno-substituted aliphatic carboxylic acid, e.g. a halide, anhydride or ester, and treating the resulting halo-acylated product with a primary or secondary amine Am.H, where Am and the Rs have the above meanings.  The reaction with the amine Am.H is preferably effected with aid of a basic condensing agent or an excess of the amine.  A solvent may be present.  The amides of the above type wherein "Alkyl" contains at least 2 carbon atoms and "Am" is in the b -position may also be prepared by reacting the amine Am.H with an amide of the general formula <FORM:0742819/IV(a)/3> wherein "Alkenyl" denotes an a ,b -unsaturated alkenyl group, in the presence of a quaternary ammonium base.  In examples (1) a -pipecoline is added dropwise to 1-(p-chlorophenoxy)-2-(N - methyl - N - chloracetyl) - amino propane, prepared from the free amine and chloracetyl chloride as in (4) or (5), and the mixture is then refluxed in benzene to yield 1-(p-chlorophenoxy) - 2 - [N - methyl - N - (21 - methylpiperidino - acetyl)] - amino propane; (2) a -pipecoline is similarly reacted with 1-phenoxy-2 - (N - chloroacetylamino) - propane, prepared from the free amine and chloro acetyl chloride as in (4) or (5), to yield 1-phenoxy-[N-(21-methyl piperidino - acetyl)] - aminopropane; (3) morpholine is similarly reacted with 1-(21.41.61 - trimethylphenoxy) - 2 - (N - methyl-N - chloracetyl) - amino ethane, prepared from the free amine and chloroacetyl chloride as in (4) or (5), to yield 1-(21,41,6-trimethyl-phenoxy)-2 - (N - methyl - N - morpholino - acetyl)-amino ethane; (4) chloracetyl-chloride is reacted with 1 - (21,41 - dimethyl - phenoxy) - 2-N - ethyl amino propane in presence of triethylamine in benzene and the resulting chloracetamido product reacted as in (1) with pyrrolidine to yield 1 - (21,41 - dimethyl - phenoxy)-2 - (N - ethyl - N - pyrrolidino - acetyl) - aminopropane; (5) in like manner, chloracetyl chloride is reacted with 1-phenoxy-2-methylamino propane and the chloracetylamino product reacted with diethylamine to yield 1-phenoxy - 2 - (N - methyl - N - diethylaminoacetyl) - amino propane; (6) 1 - phenoxy - 2-methyl amino propane is reacted in ether with b -bromo-propionic acid chloride in the presence of triethylamine and the resulting b -bromopropionyl amide is reacted in ethanol with dimethyl amine or diethylamine to yield 1-phenoxy - 2 - (N - methyl - N - b  - dimethylamino or diethylaminopropionyl) - amino propane; (7) 1- (21-acetamino phenoxy)-2-N-methylamino propane is similarly reacted with b -bromo propionyl chloride in benzene and the mixture is then heated on the steam bath so yielding 1 - (2 - acetamino phenoxy) - 2 - (N-methyl - N - acroyl) - aminopropane which is isolated and reacted with excess of diethylamine in the presence of benzyl trimethyl ammonium hydroxide as catalyst, yielding 1-(21-acetamino phenoxy) - 2 - (N - methyl - b  - diethylamino propionyl) amino propane; its picrate is described.  Numerous other examples of such compounds are listed. Salts of the bases are obtained on reacting with acids.