Patent GB-788126-A (GB)
Title: Quaternary salts of piperidyl esters
Inventor: PAPA DOMENICK
IPC: C07D211/46
Filed: 1955-09-29
Abstract: The invention comprises quaternary salts of the general formula <FORM:0788126/IV (b)/1> wherein R is a phenyl, cyclopentenyl, cyclopentyl, cyclohexenyl or cyclohexyl group, R1 and R2 are alkyl groups of 1-6 carbon atoms, and Y is a pharmaceutically acceptable anion, and their preparation by the following methods: (a) for compounds in which R is phenyl, by heating diphenylchloroacetyl chloride with the appropriate N-alkyl-4-piperidinol or its hydrohalide, basifying the diluted reaction product and converting the basic ester into a quaternary salt; (b) for compounds in which R is cyclohexyl, by selective hydrogenation of the corresponding N-alkyl-4-piperidyl benzilate with hydrogen in the presence of platinum oxide and converting the basic ester into a quaternary salt; and (c) for the preparation of the quaternary salts, by reacting the free basic ester in ether or benzene with an alkyl halide or ester R2Y, or by treating a quaternary ammonium hydroxide with an acid HY, or when Y is a chloride or bromide ion by reacting the corresponding quaternary iodide with silver chloride or bromide.  When the group R is a cycloalkyl or cycloalkenyl group the free bases corresponding to the quaternary salts of the invention may be prepared by trans-esterification, e.g. by heating at 150-160 DEG  C. an ethyl ester of the appropriately disubstituted glycollic acid with the N-alkyl-4-piperidinol in presence of sodium.  Other anions referred to are sulphate, methosulphate, tartrate, citrate, maleate, acetate, benzoate, phthalate, hexahydrophthalate, salicylate, p-aminobenzoate and veratrate ions.  In examples: (1) N-methyl-4-piperidinol hydrochloride and diphenyl chloroacetyl chloride give N-methyl-4-piperidyl benzilate which on refluxing with methyl iodide in benzene gives the methiodide; (2) N-ethyl-4-piperidyl benzilate is prepared by the method of Example 1 and is quaternized with methyl iodide, or the product of Example 1 is quaternized with ethyl iodide; (3) the iodide of Example (1) is converted to the corresponding bromide with silver bromide, the same product being prepared from the free ester of Example (1) and methyl bromide, quaternary methochlorides are prepared similarly and the following salts are also referred to:-the methosulphate, ethobromide and isopropiodide of N-methyl-4-piperidyl benzilate and the butobromide and iso-amyloiodide of N-ethyl-4-piperidyl benzilate; (4) N-methyl-4-piperidyl phenylcyclopentyl-glycollate is prepared by alkaline trans-esterification of ethyl phenylcyclopentylglycollate with N-methyl-4-piperidinol and is quaternized with methyl iodide, and other quaternary salts and the corresponding N-ethyl and N-propyl compounds are referred to; (5) N-methyl-4-piperidyl benzilate is selectively reduced to N-methyl-4-piperidylcyclohexyl glycollate which is then quaternized with methyl iodide; (6) N-methyl-4-piperidyl phenyl - D 1 - cyclohexenyl glycollate is prepared from ethyl phenyl-D 1-cyclohexenylglycollate and N-methyl-4-piperidinol and then quaternized with methyl iodide; (7) N-methyl-4-piperidyl phenyl-D 1-cyclopentenylglycollate and its methiodide are similarly prepared; (8) N - methyl - 4 - piperidyl phenyl D 2 - cyclohexenylglycollate is similarly prepared and quaternized with methyl iodide.  Starting materials.  Ethyl phenyl-D 1-cyclohexenyl-, and D 1-cyclopentenyl glycollates are prepared by reacting ethyl benzoyl formate with D 1-cyclohexenyl or D 1-cyclopentenyl lithium, and ethyl phenyl-D 2-cyclohexenyl glycollate is prepared from D 2-cyclohexenyl magnesium bromide and ethyl benzoyl formate or benzoyl formic acid.  Specification 765,607 is referred to.ALSO:A pharmaceutical preparation comprises a quaternary salt of the formula:  <FORM:0788126/VI/1> (wherein R is phenyl, cyclopentenyl, cyclohexenyl, cyclopentyl or cyclohexyl, R1 and R2 are alkyl groups of 1 to 6 carbon atoms and Y is a pharmaceutically acceptable anion) and a non-toxic pharmaceutical carrier.  The preparation may be in the form of a tablet containing 1 to 10 mg. of the salt, or an administrable dose may contain this amount of the salt dissolved or suspended in a non-toxic liquid vehicle.  The tablets may contain inert carriers such as gums, starches, metal soaps, calcium and magnesium carbonates or clay.  Elixirs may be prepared in an aqueous alcohol mixture which is suitably flavoured. The salts alone or mixed with inert diluents may be filled into gelatin or other capsules or the salts may be suspended in edible oils, e.g. sesame, peanut or hydrocarbon oils.  The solutions or suspensions preferably contain a small amount of a non-toxic preservative such as an ester of p-hydroxybenzoic acid. Specification 765,607, [Group IV (b)], is referred to.