Patent GB-794239-A (GB)
Title: Organic nitrogen compounds and process for producing the same
Filed: 1956-06-28
Abstract: The invention comprises compounds of the formula <FORM:0794239/IV (b)/1> (wherein R is an alkyl group of 1 to 4 carbon atoms, Z is hydrogen or an aliphatic carboxylic acid acyl group of 1 to 4 carbon atoms and n is 3, 4, 5 or 6), their acid-addition salts and their preparation by the following methods: (1) reacting an N -(R - phenyl) - N1 - unsubstituted piperazine with a compound of the formula Halogen-(CH2)nOZ, preferably by refluxing 2 equivalents of the piperazine with one equivalent of the halogen compound in an anhydrous organic solvent; (2) for the compounds in which Z is an acyl group, by acylation of the free alcohols, e.g. with an acyl halide or anhydride in an inert, anhydrous organic solvent or, when acetic anhydride is used, in acetic acid, preferably at reflux temperature; (3) for the compounds in which Z is hydrogen, by hydrolysis or alcoholysis of their esters, e.g. with an aqueous alkali or alkaline earth metal hydroxide in an organic solvent or with catalytic amounts of an alkali metal alcoholate in an anhydrous organic solvent, preferably at reflux temperature; (4) for the compounds in which Z is hydrogen, by reduction of compounds of the above general formula wherein the -(CH2)nOZ group is replaced by a group -Y-(CH2)n-2-COOR1 (Y being -CH2- or -CO- and R1 an alkyl group of 1 to 4 carbon atoms) e.g. by using hydrogen and a metal catalyst such as copper chromite in an inert organic solvent under pressure or by sodium and an alcohol or by lithium aluminium hydride in an anhydrous non-hydroxylic organic solvent; and (5) for the compounds wherein n is 3, by reacting an N-(R-phenyl)-N1-unsubstituted piperazine with allyl alcohol in presence of an alkali metal alcoholate of allyl alcohol, preferably at 75 DEG  to 100 DEG  C. The free base and acid-addition salt forms of the compounds of the invention are interconvertible by conventional procedures.  In examples (1) 1-o-methylphenylpiperazine is refluxed with sodium and allyl alcohol to give 4 - o - methylphenyl - 1 - piperazinepropanol which is subsequently acylated to the corresponding acetate; (2) 1-o-methylphenylpiperazine and tetramethylene bromohydrin give 4 - o - methylphenyl - 1 - piperazinebutanol; (3) 1 - o - methylphenylpiperazine and ethyl gamma-bromobutyrate give a product which on reduction with lithium aluminium hydride yields the product of (2); (4) 1-o-methylphenylpiperazine and delta-bromovaleronitrile are refluxed in benzene and the product is treated with absolute alcohol and dry hydrogen chloride and then refluxed in the presence of water to give a product which on reduction yields 4-o-methylphenyl-1-piperazine pentanol; (5) 1-o-ethylphenylpiperazine (prepared from o-ethylaniline and bis - (b  - bromoethyl)amine hydrobromide) and pentamethylene bromohydrin give 4 - o - ethylphenyl - 1 - piperazinepentanol; (6) 5-carbomethoxyvaleryl chloride (prepared from monomethyl adipate and thionyl chloride) and 1 - o - methylphenyl - piperazine are refluxed in benzene to give a product which on reduction yields 4-o-methylphenyl-1-piperazinehexanol; (7) 1-o-butylphenylpiperazine (prepared from o-n-butylaniline and bis-(b -bromoethyl) amine hydrobromide) and 5-carbomethoxyvaleryl chloride give a product which on reduction yields 4-o-butylphenyl-1-piperazine hexanol; (8) 1-o-ethylphenylpiperazine and methyl acrylate at 23 DEG C. give a product which on reduction with lithium aluminium hydride yields 4 - o - ethylphenyl - 1 - piperazinepropanol; (9) 1-o-ethylphenylpiperazine and diethyl adipate at 100 DEG  C. give a product which on reduction as in (8) yields 4-o-ethylphenyl-1-piperazine hexanol; and (10) 1-o-ethylphenylpiperazine and 5-bromopentan-1-ol acetate (prepared by heating acetyl bromide and tetrahydropyran in presence of granulated zinc and hydrogen bromide) give 4-o-ethylphenyl-1-piperazinepentanol acetate which on hydrolysis yields the free pentanol.  Acid-addition salts of some of the products are described.  Starting materials. Compounds of the formula <FORM:0794239/IV (b)/2> (R1 being alkyl group of 1 to 4 carbon atoms) are prepared from the corresponding phenylpiperazines and (1) a compound Halogen-(CH2)n-1-CN followed by treatment of the product with an anhydrous alcoholic hydrohalic acid and subsequent hydrolysis, or (2) a compound Halogen-(CH2)n-1-COOR1, or (3) when n is 3, an acrylic acid ester CH2=CHCOOR1.  Compound of the formula <FORM:0794239/IV (b)/3> are prepared from the appropriate phenylpiperazine and a compound Y1-CO-(CH2)n-2-COOR1 wherein Y1 is a halogen atom or an alkoxy group of 1 to 4 carbon atoms.