Patent GB-762689-A (GB)
Title: Novel piperidine compounds and their production
Inventor: STERN EDWARD SEVERIN
IPC: C07D211/64
Filed: 1955-01-04
Abstract: The invention comprises compounds of the general formula <FORM:0762689/IV(b)/1> where XN- is the residue of an alkyl-substituted or unsubstituted non-aromatic heterocyclic base XNH which contains the >NH group as a part of the ring system or another norpethidine residue, and -R- is the residue of a straight or branched chain aliphatic hydrocarbon containing from one to four carbon atoms, and their acid-addition salts; and their preparation by reacting a compound XN-Y with a compound <FORM:0762689/IV(b)/2> where one of Y and Y1 represents the radical -R-Z, Z being chlorine, bromine, iodine or hydroxyl, and the other of Y and Y1 is hydrogen. The invention also comprises the preparation of compounds of the first general formula above in which XN- is the residue of an alkyl-substituted or unsubstituted piperidine or pyrrolidine by condensing a compound XN-R-N-(CH2CH2Cl)2 with benzyl cyanide in the presence of a hydrogen chloride acceptor such as sodamide or an alkali or alkaline earth metal carbonate or bicarbonate with subsequent hydrolysis and esterification of the nitrile so formed. In examples: (1) morpholinoethyl-norpethidine, isolated as the dihydrochloride, is prepared from ethyl 4-phenylpiperidine-4-carboxylate (norpethidine) and chlorethyl morpholine; (2) ethyl 4-phenyl-1-piperidinoethylpiperidine-4-carboxylate, isolated as the dihydrochloride, is prepared from norpethidine and chloroethylpiperidine; (3) piperidinoethyl chloride and diethanolamine are condensed together and the product is chlorinated with thionyl chloride to yield di-(2-chloroethyl)-piperidinoethylamine hydrochloride which, as the free base, is condensed with sodamide and benzyl cyanide to yield 1-piperidinoethyl-4-phenylisonipecotonitrile; this is hydrolysed with concentrated sulphuric acid to give the corresponding acid and this on esterification by azeotropic distillation with ethanol and xylene yields the same product as Example (3); (4) the condensation product of pyrrolidine and ethylene chlorhydrin is chlorinated to yield chloroethylpyrrolidine hydrochloride which, as the free base, is condensed with norpethidine to give pyrrolidinoethyl-norpethidine, isolated as the dihydrochloride; (5) the condensation product of norpethidine and ethylene chlorohydrin is chlorinated to yield chloroethylnorpethidine which is then condensed with norpethidine to yield 4-phenyl-4-carbethoxypiperidinoethylnorpethidine dihydrochloride; (6) chlorethylnorpethidine and piperazine give piperazinoethylnorpethidine, isolated as the trihydrochloride; (7) morpholine and propylene chlorohydrine give 1-morpholinopropan-2-ol, this is chlorinated to yield 1-morpholino-2-chloro-propane hydrochloride and the latter as the free base is condensed with norpethidine to yield 1-morpholino-prop-2-ylnorpethidine dihydrochloride; (8) morpholine and 3-chloropropanol give 3-morpholinopropan-1-ol, this is chlorinated to 3-morpholinopropyl chloride hydrochloride and the latter, as the free base, with norpethidine gives 3-morpholino propylnorpethidine dihydrochloride; (9) chloroethylnorpethidine and 4-methyl piperidine give 4-methyl piperidinoethylnorpethidine, isolated as the dihydrochloride; (10) chloroethylnorpethidine and D 3-tetrahydropyridine give D 3-tetrahydropyridinethyl norpethidine, isolated as the dihydrochloride; (11) hydroxymethylmorpholine and norpethidine give morpholinomethylnorpethidine, isolated as the hydrobromide.