Patent GB-826496-A (GB)
Title: Substituted piperazines and methods for obtaining same
Inventor: PARCELL ROBERT FORD
Filed: 1956-09-14
Abstract: The invention comprises N-o-halophenyl-N1-alkylated piperazines of the general formula <FORM:0826496/IV (b)/1> and acid addition salts thereof, wherein X is a chlorine or bromine atom and Y is a methyl group or a straight chain alkylene group containing 2 to 5 carbon atoms having attached to the o -carbon atom thereof a hydrogen atom or a hydroxy, lower acyloxy or lower acylamido radical, together with the following processes for their manufacture.  In general the compounds (I) are prepared by alkylating a halophenyl piperazine (II) <FORM:0826496/IV (b)/2> with a compound Hal-Y, wherein Hal is a halogen atom and, if desired, converting the product into an acid addition salt. Alternatively, when Y is (CH2)n-OH, compounds (III) <FORM:0826496/IV (b)/3> are subjected to hydrolysis or alcoholysis; when Y is (CH2)nNH-Acyl, compounds (II) are reacted with an o -haloalkyl nitrile and the resulting N - o - halophenyl - N1 - o  - cyanoalkyl piperazine is reduced to the corresponding amine, which is in turn reacted with an aliphatic acyl halide or anhydride; when Y is methyl, compounds (II) are reacted with formaldehyde in the presence of formic acid; when Y is (CH2)3OH, compounds (II) are reacted with allyl alcohol in the presence of an alkali metal allylate; when Y is (CH2)3NH-Acyl, compounds (II) are reacted with acrylonitrile, the resulting N - o - halophenyl - N1 - (2 - cyanoethyl)-piperazine is reduced and the product acylated; in each case the final product (I) may, if desired, be converted into an acid addition salt.  Examples describe the preparation of N - o - chlorophenyl - N1 - methylpiperazine monohydrochloride (by the action of formaldehyde and formic acid on N-o-chlorophenylpiperzine), N - o - chlorophenyl - N1 - n - amylpiperazine monohydrochloride (from N-o-chlorophenylpiperazine and n-amyl bromide), N-o-chlorophenyl - N1 - (3 - hydroxypropyl) - piperazine (by reacting N-o-chlorophenylpiperazine with allyl alcohol in the presence of sodium allylate), N - o - chlorophenyl - N1 - (5 - hydroxyamyl)-piperazine and its hydrochloride (from N - o - chlorophenyl - piperazine and pentamethylene chlorohydrin), N-o-chlorophenyl-N1-(3 - acetamidopropyl) - piperazine (by hydrogenating N - o - chlorophenyl - N1 - (2 - cyanoethyl)-piperazine over platinum oxide in a mixture of acetic acid and acetic anhydride), N - o - chlorophenyl - N1 - (5 - formamidoamyl)-piperazine (from N - o - chlorophenyl - N1 - (5 - aminoamyl)-piperazine and formic acid), N-o-bromophenyl - N1 - (5 - hydroxyamyl) - piperazine monohydrochloride (by condensing N-o-bromophenylpiperazine with 5-bromopentanol-1 acetate, followed by alcoholysis), N-o-bromophenyl - N1 - (3 - acetamidopropyl) - piperazine (by acetylating N-o-bromophenyl-N1-(3-aminopropyl)-piperazine) and N-o-bromophenyl-N1-(3-hydroxypropyl)-piperazine (by the addition of N-o-bromophenylpiperazine to methyl acrylate followed by reduction with lithium aluminium hydride).  N - o - Chlorophenylpiperazine is prepared by reacting o-chloroaniline and diethanolamine.  N - o - Chlorophenyl - N1 - 2 - cyanoethyl) - piperazine is prepared by the addition of N-o-chlorophenylpiperazine to acrylonitrile.  N - o - Chlorophenyl - N1 - (5 - aminoamyl) - piperazine is prepared by condensing N-o-chlorophenylpiperazine with d  - bromovaleronitrile and reducing the resulting N-o-chlorophenyl - N1 - d  - cyanobutylpiperazine with lithium aluminium hydride.  N - o - Bromophenylpiperazine is obtained by condensing o-bromoaniline with bis-(b -bromoethyl)-amine hydrochloride.  5 - Bromopentanol - 1 acetate is prepared by treating tetrahydropyran with acetyl bromide containing traces of hydrogen bromide in the presence of zinc.  N - o - Bromophenyl - N1 - (3 - aminopropyl) - piperazine is obtained by adding N-o-bromophenylpiperazine to acrylonitrile and reducing the resulting N-o-bromophenyl-N1-(2-cyanoethyl)-piperazine with lithium aluminium hydride.