Patent GB-840094-A (GB)
Title: Improvements relating to keto-piperazines
IPC: C07D241/44
Filed: 1956-10-24
Abstract: Keto piperazino carboxylic acids of the general formula <FORM:0840094/IV(a)/1> where Z represents a tetramethylene or pentamethylene radical which may be alkyl-substituted, X1 and X2 represent hydrogen or aliphatic hydrocarbon radicals and Y1 and Y2 represent hydrogen, alkyl or the radical <FORM:0840094/IV(a)/2> at least one Y being such a carboxylic radical, may be esterified with higher alcohols such as octyl, decyl or dodecyl alcohol to form esters.  Keto-piperazino carboxylic acids of the above class containing two carboxylic groups may be condensed with polyhydric alcohols or aliphatic diamines such as ethylene glycol or 1 : 6-diamino hexane to form thermoplastic material.  The preparation of the acids is described (see Group IV (b)).  Specification 810,844 is referred to.ALSO:The invention comprises keto-piperazines having the general formula <FORM:0840094/IV(b)/1> wherein Z represents a tetra- or penta-methylene radical which may be alkyl substituted, X1 and X2 each represent hydrogen or an aliphatic hydrocarbon radical and Y1 and Y2 each represent hydrogen or an alkyl or <FORM:0840094/IV(b)/2> radical and a method for the preparation of keto-piperazines comprising reacting a cis1 : 2-diamino cyclohexane or cycloheptane containing at least one hydrogen atom on each nitrogen atom, and which can be alkyl substituted in the ring and/or mono-alkyl substituted on one or both amino-nitrogen atoms, with an a -halogen fatty acid or functional derivative thereof or with the nitrile of an a -hydroxy fatty acid, by heating the reagents together in an aqueous medium, preferably alkaline in reaction, thereby effecting both hydrolysis of any functional acid p  group present or carbimide group formed to a carboxylic acid group and carbonyl group respectively and a ring closure of the two amino groups.  The functional derivatives of the a -halogen fatty acids may be their salts, esters, anhydrides or halides; specified acids are a -chloro- and bromoacetic, propionic and butyric acids.  The a -hydroxy nitriles may be formed in situ from appropriate carbonyl compounds and hydrocyanic acid or its salts; specified nitriles are the cyano hydrides of formaldehyde, acetaldehyde, acetone and methyl ethyl ketone.  The cis-diamines, which can be prepared as described in Specification 810,844, may be diprimary, primary-secondary or di-secondary; these may be reacted with 1-3, 1-2 or 1 molar proportion(s) of the halo- or hydroxy acid reagent.  The resulting keto-piperazines containing carboxylic groups may be esterified with higher alcohols such as octyl, decyl or dodecyl alcohol to form plasticizers for polymers; those containing two carboxylic groups may be esterified with polyhydric alcohols or condensed with aliphatic diamines to form thermoplastic products (see Group IV (a)).  In examples: (1) cis-1 : 2-diamino cyclohexane is heated with monochloracetic acid (3 mols.) in aqueous NaOH solution for 5 hours, the mixture is then slightly acidified, reheated and thereafter neutralized with NH3 and the resulting 5 : 6 - tetramethylene - 2 - keto - piperazine-1,4-diacetic acid is isolated in the form of its copper salt from which the free diacetic acid is thereafter prepared by treatment with H2SO4 and H2S; its lead salt is mentioned; cis-1 : 2-diamino cycloheptane and cis-1 : 2-diamino-4-methyl cyclohexane may be reacted similarly; (2) cis-1 : 2-diamino-hexane, 1-methyl amino-or 1-ethylamino-2-amino-hexane are similarly reacted with 2 mols. chloracetic acid, yielding the corresponding keto-piperazine mono-acetic acids isolated by precipitation of their picrate salts which are converted via the hydrochloride salts into the free acids; (3) cis-1 : 2-diamino-cyclohexane or -cycloheptane is heated with 1 mol. of chloracetic acid in water yielding 5 : 6-tetramethylene or -pentamethylene-2-ketopiperazine; or (4) the former is reacted in similar fashion with a -bromo-propionic acid to yield the 3-methyl tetramethylene 2-ketopiperazine; (5) cis-1 : 2-diamino cyclohexane is refluxed in aqueous NaOH under reduced pressure and aqueous NaCN and aqueous formaldehyde are added dropwise yielding on acidification 5 : 6-tetramethylene-2-keto-piperazine-1-acetic acid; (6) glycol nitrile is similarly used in place of the cyanide and formaldehyde; a mixture of HCN and formaldehyde may replace the nitrile; acetaldehyde cyanhydrin and butyraldehyde cyanhydrin reacted similarly yield 3-methyl and 3-n-propyl-5,6-tetramethylene-2-keto-piperazine respectively; (7) acetone cyanhydrin is added dropwise to an aqueous solution of cis-1,2-diaminocyclohexane and the resulting dispersion is then heated yielding 3,3 - dimethyl - 5,6 - tetramethylene-2-ketopiperazine; methyl ethyl ketone cyanhydrin reacted similarly yields 3-methyl-3-ethyl-tetramethylene-keto-piperazine.