GB789704A - Piperazine derivatives and their preparation - Google Patents

Abstract

The invention comprises piperazine derivatives of the formula: <FORM:0789704/IV (b)/1> and their acid addition and quaternary ammonium salts (R1 and R2 are monocyclic alicyclic groups including cyclohexyl and cyclohexenyl; monocyclic aromatic groups including phenyl and halophenyl; monocyclic heterocyclic groups including thienyl and pyridyl, or higher alkyl groups (6-14 carbon atoms) including hexyl; R3 is hydrogen, lower alkyl (1-5 carbon atoms), benzyl or lower alkyl substituted benzyl); also a process for their preparation by reacting an R1 halide with magnesium to form the Grignard reagent R1Mg halide and reacting this with a ketone of the formula: <FORM:0789704/IV (b)/2> decomposing the resulting Grignard complex, and if desired when the base so obtained contains an aromatic group, subjecting it to hydrogenation to reduce the aromatic group to an alicyclic group, and/or if desired forming a salt of the base. Specified quaternizing agents include methyl iodide, methyl bromide, methyl sulphate, methyl p-toluene sulphonate, benzyl bromide, and ethyl chloride; suitable salt-forming acids are sulphuric, hydrochloric, phosphoric, levulinic, mucic, acetic and tartaric acids. In examples: (1) N-methyl-N1-phenacylpiperazine in ether is added dropwise to ethereal cyclohexyl magnesium bromide and the reaction mixture decomposed with aqueous NH4Cl to yield N-(b -cyclohexyl-b -hydroxy-b -phenyl) ethyl - N1 - methyl - piperazine, characterized (2)-(4) as its dihydrochloride hemihydrate, methiodide, and methosulphate; N - methyl - N1 - phenacylpiperazine is similarly reacted; (5) with phenyl magnesium bromide to give N-(b : b -diphenyl-b -hydroxy) ethyl - N1 - methylpiperazine, characterized as its dihydrochloride; and (6) as its methosulphate; (7) with p-chlorophenyl magnesium bromide to give N - [b - (p - chlorophenyl) - b -phenyl - b - hydroxy) ethyl - N1 - methylpiperazine, its di-HCl, and (8) its methiodide; (9) with the Grignard reagent from 2-bromothiophene to yield N-(b -hydroxy-b -phenyl-b -[2-thienyl]) ethyl-N1-methylpiperazine; and (10) with the reagent from 2-bromopyridine to give N - (b - hydroxy - b - phenyl - b - [2 - pyridyl]) ethyl-N1-methylpiperazine; (11) the product of (5) is hydrogenated over a platinum catalyst to give N - (b : b - dicyclohexyl - b - hydroxy) ethyl - N1 - methylpiperazine; other compounds obtainable by the process of the invention include N - (b - cyclohexen - 1 - yl-b - phenyl - b - hydroxy) ethyl - N1 - methylpiperazine; N - (b ,b - diphenyl - b - hydroxy) ethyl - piperazine; N - (b ,b - diphenyl - b - hydroxy) - ethyl - N1 - benzylpiperazine and N - (b - n - hexyl - b - hydroxy - b - phenyl) ethyl-N1-methylpiperazine. The starting material N-phenacyl-N1-methylpiperazine is prepared by the dropwise addition of phenacyl bromide in toluene to a refluxing mixture of N-methylpiperazine, sodium carbonate and xylene. Triethylamine may replace sodium carbonate as the base.