Patent GB-803403-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:0803403/IV (b)/1> (wherein R is an alkyl group of 1 to 4 carbon atoms or an allyl group, Z is hydrogen or an aliphatic carboxylic acid acyl group of 1 to 4 carbon atoms and n is 2, 4, 5 or 6) and acid-addition salts thereof and their preparation by the following methods: (1) by reacting the appropriate N - unsubstituted - N1 - alkoxy- or allyloxy-phenyl-piperazine with a compound Halogen-(CH2)n-OZ, preferably using a molar excess of the piperazine compound and an anhydrous organic solvent; (2) for compounds where Z is an acyl group, by acylation of the corresponding substituted alkanols with, for example, an acyl halide or anhydride in an inert anhydrous organic solvent; (3) for compounds where Z is a hydrogen atom, by hydrolysis, e.g. with an aqueous alkali or alkaline earth metal hydroxide in an organic solvent, or by alcoholysis, e.g. with catalytic amounts of an alkali metal alcoholate in an anhydrous organic solvent, of the compounds in which Z is an acyl group; (4) for compounds where Z is a hydrogen atom, by reduction of a compound of formula <FORM:0803403/IV (b)/2> (wherein Y is -CH2- or -CO- and R1 is an alkyl group of 1 to 4 carbon atoms), for example by means of a complex oxidizable metal hydride, e.g. LiAlH4, in an anhydrous nonhydroxylic organic solvent, or by gaseous hydrogen and a metal catalyst such as copper chromite, in an inert organic solvent, preferably at 200-300 atmospheres and 200-300 DEG  C., or by using metallic sodium and an alcohol, preferably at reflux; and (4) for compounds where Z is hydrogen and n is 3, by reacting the appropriate N - unsubstituted - N1 - alkoxy - or allyloxy-phenylpiperazine with allyl alcohol in presence of an alkali metal allylate.  In examples: (1) 1-o-methoxyphenylpiperazine and d -bromovaleronitrile are condensed to 4-o-methoxy - phenyl - 1 - piperazinevaleronitrile by refluxing in toluene, the product (not isolated) is treated with anhydrous HCl at 0-5 DEG  C., the solution is hydrolysed with water to give ethyl 4 - o - methoxyphenyl - 1 - piperazinevalerate (not isolated) and this is reduced with LiAlH4 to 4 - o - methoxyphenyl - 1 - piperazinepentanol (hydrobromide also prepared); (2) 1-o-methoxyphenylpiperazine and diethyl adipate are heated at 100 DEG C. and the resulting 4-o-methoxyphenyl - 1 - d  - carbethoxyvaleryl-piperazine (not isolated) is reduced with LiAlH4 to 4 - o - methoxyphenyl - 1 - piperazine hexanol (dihydrochloride described); (3) 5-carbomethoxyvaleryl chloride, prepared from monomethyl adipate and thionyl chloride, and 1-o-methoxyphenyl-piperazine give 4-o-methoxyphenyl-1-d -carbomethoxyvalerylpiperazine (not isolated) which is reduced to give the product of (2); (4) 1-o-methoxyphenylpiperazine and ethyl g -bromobutyrate give ethyl 4-o-methoxyphenyl-1-piperazine butyrate which is then reduced to 4 - o - methoxyphenyl - 1 - piperazinebutanol (monohydrochloride also prepared); (5) 1-o-methoxyphenylpiperazine and trimethylene bromohydrin give 4-o-methoxyphenyl-1-piperazinepropanol (monohydrochloride also prepared); (6) 1-o-ethoxyphenylpiperazine, prepared from o-phenetidine and bis-(b -bromoethyl) - amine hydrobromide, and pentamethylene bromohydrin give 4-o-ethoxyphenyl-1-piperazinepentanol, the acetate (monohydrochloride) of which is prepared by acylation with acetic acid and acetic anhydride; (7) 1-o-propoxyphenylpiperazine (prepared as the corresponding ethoxy compound in (6)) and 5-bromopentan-1-ol acetate ester (prepared by heating tetrahydropyran and acetyl bromide containing HBr with zinc) give 4-o-propoxyphenyl-1-piperazinepentanol acetate (monohydrochloride) which is hydrolysed to the free pentanol (monohydrochloride also prepared); (8) 1-o-butoxyphenylpiperazine, prepared as in (6), and 5-bromopentan-1-ol acetate ester are condensed and the product (not isolated) is hydrolysed to give 4 - o - butoxyphenyl - 1 - piperazinepentanol (hydrochloride also prepared); (9) 1-o-allyloxyphenylpiperazine, prepared as in (6), and 5 - bromopentan - 1 - ol give 4 - o - allyloxyphenyl - 1 - piperazine pentanol acetate (monohydrochloride) which is hydrolysed to the free pentanol (monohydrochloride); (10) 1-o-ethoxyphenylpiperazine and methyl acrylate are condensed at 23-25 DEG  C. and the product (not isolated) is reduced to 4-o-ethoxyphenyl-1-piperazinepropanol; (11) 1-o-ethoxyphenylpiperazine and allyl alcohol in presence of sodium give 4 - o - ethoxyphenyl - 1 - piperazine propanol (hydrogen sulphate prepared) which is acylated to the acetate (monohydrochloride and free base).  Compounds of formula II wherein Y is a -CH2-group are prepared by reacting the appropriate N-phenylpiperazine with (1) an o  - haloalkyl nitrile, Hal-(CH2)n-1CN, treating the product with anhydrous alcoholic hydrohalic acid and hydrolysing the imine ester hydrohalide so produced, or (2) an o -haloalkanoic ester Hal-(CH2)n-1-COOR1, or (3) when n is 3, an acrylic acid ester CH2=CH-COOR1. Compounds of formula II wherein Y is a -CO-group are prepared by reacting the appropriate N-phenylpiperazine with a compound Y1-CO-(CH2)n-COOR1, wherein Y1 is halogen or an alkoxy group of at most 4 carbon atoms.