Patent GB-585729-A (GB)
Title: Manufacture of esters of 1-substituted 4-hydroxypiperidines
Filed: 1944-09-01
Abstract: Esters of 1-alkyl-4-hydroxypiperidines, of therapeutic value, are manufactured by reacting an aliphatic or cycloaliphatic monocarboxylic acid, which may be substituted by one aryl, aryloxy or alkoxy group, or a functional derivative (e.g. salt, halide, ester or anhydride) thereof, with a 1-alkyl-4-hydroxypiperidine or a reactive ester (e.g. halide or arylsulphonate) thereof.  In examples: (1) di-n-propylacetyl chloride is heated with 1-methyl-4-hydroxy-piperidine and the basic ester is liberated by concentrated ammonia; the di-n-butylacetic, di-isobutylacetic and n-propyl-isobutylacetic esters may be similarly prepared; (2) methyl-di-n-propylacetyl chloride is similarly treated, or the same ester is made from methyl-di-n-propylacetic acid salts and 1-methyl-4-bromo-piperidine; the methyl-di-isobutylacetic, methyl-n-propyl-n-butylacetic and methyl-n-butyl-isobutylacetic esters may be similarly prepared; (3) 1 - phenylcyclopentyl - 1 - carboxylic acid chloride is treated with 1-ethyl-4-hydroxy-piperidine as in (1); (4) a -phenylvaleryl chloride is treated as in (1); the a -phenylcaproic, a -phenyl - a  - methylvaleric and n - propylcyclo - hepten-1-yl-1-acetic esters may be similarly prepared; (5) 1-phenylcyclopentyl-1-carboxylic acid chloride is heated with 1-methyl-4-hydroxy-piperidine in chlorobenzene, and the basic ester is liberated by potassium carbonate; there may similarly be obtained the 1-methyl-4-hydroxy-piperidine esters of 1-(21-, 31- and 41-methyl-phenyl)- and 1 - (31 : 41 - dimethylphenyl)-cyclopentyl - 1 - carboxylic acids, 1 - phenyl - 2 : 5 - dimethylcyclopentyl - 1 - carboxylic acid, phen - oxy-cyclopentylacetic acid, 1-phenylcyclobutyl-1 - carboxylic acid, 1 - phenylcyclopropyl - 1 - carboxylic acid, a -(o-cresoxy)-isovaleric acid and cyclohexen - 1 - yl - 1 - phenylacetic acid, and the 1-ethyl-4-hydroxypiperidine ester of n-propyl - (4 - methylphenoxy) - acetic acid.  Additional starting materials specified are, on the one hand, 1-propyl- and 1-butyl-4-hydroxy-piperidine, and, on the other hand, acetic, propionic, diethylacetic, isopropyl-allyl-acetic, dimethyl - n - butyl - acetic, ethylidine - n - butyl - acetic, a  - benzylvaleric, dimethyl - n - butyloxy - acetic, n - butyl - (4 - methylphenoxy) - acetic and n - butylcyclohepten - 1 - yl - 1 -acetic acids. Methyl-n-butyl-isobutyl-, methyl-n-propyl-n-butyl- and methyl-di-isobutyl-acetic acids are obtainable by alkylation of acetonitrile with alkyl halides and sodium amide, followed by hydrolysis.  a -Benzlvaleric acid is similarly obtained from valeronitrile and benzyl chloride.  a -Phenyl-a -methylvaleric acid is obtainable by propylation and methylation of phenylacetonitrile with the corresponding alkyl halides and sodium amide, followed by hydrolysis.  Dimethyl-n-butyloxyacetic acid is obtainable by treatment of a -bromo-isobutyric acid ethyl ester with sodium butylate, and hydrolysis.  n - Butyl- and n - propyl - (4 - methylphenoxy) - acetic acids are obtainable by treatment of a -bromo-n-caproic- and n-valeric acid ethyl esters respectively with sodium p-cresolate, and hydrolysis.  n - Propyl- and n - butyl - cyclohepten - (1) - yl - (1) - acetic p  acids are obtainable by condensation of cycloheptanone with cyanacetic acid in the presence of piperidine, alkylation of the resulting cyclohepten - 1 - yl - 1 - cyanacetic acid with a propyl or butyl halide respectively, followed by hydrolysis and decarboxylation.  Cyclohexen - 1 - yl - 1 - phenylacetic acid is obtainable by condensation of phenylacetonitrile with cyclohexanone in the presence of piperidine, followed by hydrolysis.  1 - Phenyl-, 1-(21-, 31- and 41-methylphenyl)-and 1 - (31 : 41 - dimethylphenyl) - cyclopentane - 1 - carboxylic acids and 1 - phenyl-2 : 5-dimethylcyclopentane-1-carboxylic acid are obtainable by condensation of phenylacetonitrile or the appropriate homologues thereof with the requisite alkylene dibromide in the presence of sodium amide, followed by hydrolysis. Aryloxy-cycloaliphatic monocarboxylic acids, such as phenoxy-cyclopentylacetic acid, are obtainable by treatment of halogenated cycloaliphatic acid esters with sodium phenolates, and hydrolysis.  1-Propyl- and 1-butyl-4-hydroxypiperidine are obtainable by heating chelidonic acid with an aqueous solution of propylamine or butylamine respectively, followed by decarboxylation and hydrogenation of the resulting pyridone in the presence of a Raney nickel catalyst.