Patent GB-578342-A (GB)
Title: Improvements in processes for producing substituted piperazines and salts thereof
IPC: C07D295/185
Filed: 1944-05-22
Abstract: Piperazines, N - or N1-monosubstituted and N,N1-unsymmetrically disubstituted, of the general formula <FORM:0578342/IV/1> wherein, in the monosubstituted compounds, R represents hydrogen and R represents a substituent radical and in the unsymmetrically disubstituted compounds the two N - substituents R and R1 are two different radicals, the nature of the radicals being hereinafter defined, are produced: (a) by treating piperazine or p  its hexahydrate in a solvent, e.g. absolute ethanol with an aralkyl halide, or with an alkyl halide containing 8 to 18 carbon atoms per molecule to form mixtures containing in addition to unreacted piperazine and symmetrical di-aralkyl or di-alkyl substituted piperazine, considerable quantities of mono-aralkyl or mono-alkyl substituted piperazine having relatively high stability and a boiling point or solubility differing substantially from the corresponding properties of the other reaction products and separating out the mono-aralkyl or mono-alkyl substituted piperazine by fractional distillation or selective solution. Suitable aralkyl halides are benzyl chloride, p-chlorobenzyl chloride, anisyl chloride or a phenyl ethyl halide, specified monosubstituted piperazines so obtainable being: mono-N-benzylpiperazine, mono-N-p-chlorbenzylpiperazine, mono-N-anisyl piperazine and mono-N-b -phenethyl piperazine.  The separated mono-aralkyl or mono-alkyl piperazine may then be treated to introduce on to the second nitrogen atom as R1:alkyl, an aralkyl different from that present in the monosubstituted compound, phenacyl or substituted phenacyl, hydroxyphenylalkyl, carbamido or substituted carbamido, carbamidino or acyl.  Specified compounds are: N-benzyl-N1-methyl-, N-b -phenethyl-N1-ethyl-, N-anisyl-N1-(3 : 4-dihydroxyphenaryl)-, N - anisyl - N1 - (b  - 3 : 4 - dihydroxyphenyl - b  - hydroxyethyl)-, N - anisyl - N1 - carbamido-, N - anisyl - N1 - phenylcarbamido - N - benzyl-N1-carbamidino-, N-benzyl-N1-acetyl-, N - p - chlorobenzyl - N1 - p - nitrobenzoyl-, N - b  - phenethyl - N1 - propionyl- and N - anisyl-N1 - p - aminobenzoyl piperazine; (b) by treating piperazine with a benzyl- or substituted benzyl halide, e.g. a p-chlorobenzyl, anisyl-, 4-phenylbenzyl- or a -naphthyl methyl halide, or with an alkyl halide containing from 8 to 18 carbon atoms per molecule as in (a) separating the N-mono-substituted compound, introducing the desired second substituent on to the N1-nitrogen atom, then removing the benzyl or substituted benzyl group by catalytic hydrogenation, using nickel, platinum or, preferably, palladium as catalyst and optionally obtaining unsymmetrically disubstituted piperazines by introducing on to the nitrogen atom freed by catalytic hydrogenation the requisite substituent, differing from that present in the monosubstituted compound, but which may be selected from the same group. Monoalkyl, monoacyl, and other monosubstituted piperazines may thus be prepared, and also mono-substituted piperazines in which R1 represents, for example, an alkyl radical having less than 8 carbon atoms, which when introduced into unreacted piperazine will not produce a separable mixture of mono- and disubstituted compounds, or a radical such as an acyl, arylsulphonyl or substituted arylsulphonyl, producing such separable mixtures only under certain conditions, or a radical having relatively small inherent stability, e.g. an acyloxyalkyl, hydroxyphenalkyl (produced by reducing the corresponding phenacyl compound), nitrobenzoyl, carbamido, substituted carbamido, carbamidino, acyloxyalkyl, phenacyl, substituted phenacyl, thiocarbamido or thiocarbamidino radical.  Numerous examples are given.