Patent GB-793899-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:0793899/IV (b)/1> (wherein R is an allyl group or an alkyl group of 1 to 4 carbon atoms, Z is hydrogen or an aliphatic carboxylic 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 a N-(R-mercaptophenyl)-N1-unsubstituted piperazine with a compound of formula Halogen-(CH2)OZ, preferably by refluxing 2 equivalents of the piperazine with 1 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 temperatures; (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 sodium and an alcohol or lithium aluminium hydride in an anhydrous non-hydroxylic organic solvent; and (5) for the compounds wherein n is 3, by reacting an N-(R - mercaptophenyl) - N1 - unsubstituted piperazine with allyl alcohol in presence of an alkali metal alcoholate of allyl alcohol, preferably at 75 DEG  to 150 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-methylmercapto-phenylpiperazine (prepared from o-methylmercaptoaniline and bis-(b -bromethyl) amine hydrobromide) and 5-bromopentan-1-ol acetate (prepared by heating acetyl bromide and tetrahydropyran in presence of granulated zinc and hydrogen bromide) give 4-o-methylmercaptophenyl - 1 - piperazine pentanol acetate which is subsequently hydrolysed to the free pentanol; (2) 1-o-ethylmercaptophenylpiperazine (prepared from bis-(b -bromoethyl)amine hydrobromide and o-ethylmercapto aniline, the latter being prepared from 2-amino benzenethiol and diethyl sulphate) and methyl acrylate at 23-25 DEG  C. give a product which on reduction with lithium aluminium hydride yields 4-o-ethylmercaptophenyl - 1 - piperazine propanol; (3) 5 - carbomethoxyvaleryl chloride (prepared from monomethyl valerate and thionyl chloride) is reacted with 1-o-ethylmercaptophenylpiperazine and the product is reduced with lithium aluminium hydride to give 4-o-ethylmercaptophenyl - 1 - piperazine hexanol which on esterification with acetic anhydride in acetic acid gives the acetate; (4) 4-o-ethylmercaptophenyl - 1 - piperazine pentanol acetate is prepared as in (1) and is then hydrolysed to the free pentanol; (5) 1-o-ethylmercaptophenyl piperazine and diethyl adipate are reacted together at 100 DEG  C. and the product reduced to give the hexanol of (3); (6) 1-o-methylmercaptophenyl piperazine and deltabromovaleronitrile are refluxed in toluene and the product is then treated with absolute alcohol and anhydrous hydrogen chloride and subsequently refluxed in the presence of water to give a product which on reduction yields 4 - o - methylmercaptophenyl - 1 - piperazinepentanol; (7) 1-o-methylmercaptophenyl piperazine, sodium and allyl alcohol are refluxed to give 4 - o - methylmercaptophenyl - 1 - piperazinepropanol; (8) the pentanol product of (4) is prepared from 1-o-ethylmercaptophenylpiperazine and pentamethylene bromohydrin; (9) 4 - o - allylmercaptophenyl - piperazine pentanol acetate is prepared from 1-o-allylmercaptophenylpiperazine (prepared from bis(b  - bromoethyl)amine hydrobromide and o-allylmercapto aniline, the latter being prepared from 2-aminobenzene thiol and allyl bromide) by the method of (1) and is then hydrolysed to the free pentanol; (10) 4-o-butylmercaptophenyl-1-piperazine pentanol acetate is prepared as in (1), the 1-o-butylmercaptophenylpiperazine starting material being prepared from o-butylmercaptoaniline, itself prepared from 2-aminobenzenethiol and butyl bromide, and is hydrolysed to the free pentanol; (11) 1 - o - ethylmercaptophenylpiperazine and ethyl gammabromobutyrate give a product which on reduction yields 4-o-ethylmercaptophenyl - 1 - piperazinebutanol.  Acid - addition salts of some of the products are described.  Starting materials.  Compounds of the formula: <FORM:0793899/IV (b)/2> (R1 being an 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 alcohol 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.  Compounds of the formula: <FORM:0793899/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.