Patent GB-723205-A (GB)
Title: Improvements in bis-quaternary salts and processes for their preparation
Inventor: SLACK RONALD
IPC: C07D295/02
Filed: 1950-12-15
Abstract: The invention comprises quaternary ammonium salts which contain the cation <FORM:0723205/IV (b)/1> where Z is O or a single bond and R is Me or Et and n 5 or 6. Bromide, chloride, iodide, bitartrate, citrate, phosphate and neutral sulphate are specified salts. Compounds mentioned are hexamethylene-bis-N-(N-methylpyrrolidinium) salts, e.g. the dibromide, pentamethylene - bis - N - (N - methylpyrrolidinium) salts, e.g. the di-iodide, hexamethylene-bis-N-(N - methylmorpholinium) salts, e.g. the diiodide and pentamethylene-bis-N-(N-methylmorpholinium) salts, e.g. the diodide.  They may be made by known general methods thus a compound X-(CH2)n-X in which X is an N-pyrrolidino or N-morpholino group or the acid residue of a reactive ester is treated with a compound Y which when X is pyrrolidino or morpholino is itself a reactive methyl or ethyl ester and when X is an ester is itself an N-methyl or N-ethyl-pyrrolidine or -morpholine followed by conversion to the required salt if necessary by metathesis or via the hydroxide.  In the case of salts in which the anion corresponds to that of a reactive ester, e.g. halide or p-toluenesulphonate, it is preferred either to form the polymethylene bis-pyrrolidine or morpholine and treat the free base with the appropriate methyl or ethyl ester, or condense a corresponding reactive polymethylene diester, e.g. dihalide, with an N-methyl or N-ethylpyrrolidine or morpholine.  The salts may be isolated or purified through their embonates.  Thus an aqueous solution of the salt is treated with a water-soluble salt of embonic acid (2,2-dihydroxy - 1,1 - dinaphthylmethane - 3,3 - di - carboxylic acid) to precipitate the embonate containing the polymethylene cation and which on solution in hot water and treatment with an acid corresponding to the required salt precitates embonic acid leaving a solution of the desired salt. The salts are sympathetic ganglionic blocking agents.  In examples, 1,6-dimorpholinohexane is treated with (1) methyl iodide and (2) ethyl iodide to yield hexamethylene bis-N-(N-methyl- or N-ethyl-morpholinium) di-iodide respectively; N-methylpyrrolidine is treated with (3) 1,6-dibromohexane, (4) 1,5-dibromopentane and sodium iodide and (5) 1,6-dibromohexane and sodium iodide to yield (4) pentamethylene-bis-N-(N-methyl-pyrrolidinium)di-iodide and the corresponding hexamethylene compound in (3) and (5); in (6) 1,4-dibromobutane and 1,6-diaminohexane are reacted to produce 1,6-bis-N-(N-pyrrolidino)-hexane which is treated with methyl iodide to yield hexamethylene-1,6-bis-N-(N - methylpyrrolidinium) - di-iodide; (7) N-methylmorpholine and 1,5 - dibromopentane yield pentamethylene - 1,5 - bis - N - (N - methylmorpholinium) dibromide; (8)N - methyl - morpholine and 1,6 - dibromohexane and sodium iodide yield hexamethylene-1,6-bis-N-(N - methyl - morpholinium) - di - iodide; (9 N - ethylpyrrolidine and 1,6 - dibromohexane yield hexamethylene - 1,6 - bis - N - (N - ethyl - pyrrolidinium) - dibromide and in (10 hexa - methylene - 1,6 - bis - N - (N - methylpyr - rolidinium)-dibromide is converted to the bitartrate via the carbonate.  In the examples the reaction is effected at elevated temperatures and often under pressure in the presence of such solvents as acetone and alcohol.  The 1,6-dimorpholinohexane of examples (1) and (2) is made by treating 1,6-dibromo-n-hexane with morpholine in benzene.  In the first Provisional Specification R may be lower alkyl and Z so selected to form any monocyclic saturated heterocyclic ring and in the second Provisional Specification Z is a single bond and R is lower alkyl.  The latter Specification also contains a reference to Specification 723,203.