Patent GB-501135-A (GB)
Title: Manufacture of piperidine compounds
IPC: C07D211/64
Filed: 1937-08-21
Abstract: 501,135. Piperidine derivatives. GROVES, W. W. (I. G. Farbenindustrie Akt.- Ges. ) , Aug. 21, 1937, No. 22979. [Class 2 (iii)] Substitution products of 4-oyanopiperidine are obtained by condensing an arylacetonitrile having a free methylene group, in the presence of an agent capable of eliminating hydrogen halide, with a tertiary amine of the formula NRR<1>R<11>, in which R and R<1> are #-halogenalkyl groups and R<11> is an aryl, alkyl, aralkyl or cycloalkyl group. The cyanopiperidine derivatives so obtained may be converted by standard processes into the corresponding piperidinecarboxylic acids or their esters or amides. When R<1> is an aralkyl. group, the products may be treated with hydrogen in the presence of a hydrogenation catalyst, whereby the aralkyl group is replaced by hydrogen. The following examples are given: (1) benzylcyanide is condensed with methyl-di(#-chlorethyl) amine, in the presence of sodium amide to yield 1-methyl-4-phenyl-4-cyanopiperidine the later may be saponified with methyl alcoholic potash to yield 1-methyl-4-phenylpiperidine-4-oarboxylic acid, which loses carbon dioxide when heated and yields 1-methyl-4- phenylpiperidine; the chloride of 1-methyl-4- phenylpiperidine-4-carboxylic acid is obtainable from the acid and thionyl chloride, and may be condensed with hydroxy or amino compounds to yield esters or amides of the acid ; the methyl, ethyl, butyl, benzyl, phenyl and #-diethylaminoethyl esters, the amide, diethylamide and #-diethylaminoethyl amide, and a urea derivative of the acid are described ; (2) benzyl cyanide is condensed with benzyl-di(#- chlorethyl) amine in the presence of sodium amide to yield 1-benzyl-4-phenylÀ4-cyanopiperidine, which can be saponified with methyl alcoholic caustic soda to yield 1-benzyl-4- phenylpiperidine-4-carboxylic acid; the chloride of the acid is obtainable from the acid and thionyl chloride, and may be treated with ethyl alcohol to yield the ethyl ester of the acid ; the benzyl group may be eliminated from 1-benzyl- 4-phenylpiperidine-4-carboxylic acid and its derivatives by treating these compounds, as hydrochlorides in alcoholic solution, with hydrogen and palladium; the preparation in this way of the ethyl ester of 4-phenylpiperidine- 4-carboxylic. acid from the ethyl ester of 1-benzyl-4-phenylpiperidine-4-carboxylic acid is mentioned, and it is indicated that the preparation of 4-phenylpiperidine-4-carboxylic acid and its derivatives in this way gives better yields than the method wherein benzyl cyanide and di(#-chlorethyl) amine are first condensed in the presence of sodium amide to yield 4- phenyl-4-cyanopiperidine; (3) 4-methoxybenzyl cyanide is condensed with methyl-di(#-bromethyl) amine or methyl-di(#-chlorethyl)amine to yield 1 - methyl- 4 - (4<1>-methoxyphenyl)-4- oyanopiperidine ; (4) benzyl cyanide is condensed with methyl-di(#-chloropropyl) amine in the presence of potassium amide to yield 1 : 3: 5- trimethyl - 4 -phenyl - 4 - cyanopiperidine, which can be saponified to yield 1:3: 5-trimethyl-4- phenylpiperidine-4-carboxylic acid ; (5) benzyl cyanide is condensed with methyl-di(gamma-methoxy- #-chloropropyl) amine in the presence of sodium amide to yield 1-methyl-3 : 5-di(methoxymethyl) - 4 - phenyl - 4 - cyanopiperidine ; (6) alphanaphthylacetonitrile and methyl-di(#-chlorethyl) amine similarly yield 1-methyl-4-(alphanaphthyl)-4-cyanopiperidine, which can be converted successively into the corresponding acid and its ethyl ester; (7) benzyl cyanide and di(#-chlorethyl)aniline similarly yield 1:4- diphenyl - 4 - cyanopiperidine, which can be saponified with sulphuric acid to yield 1 : 4- diphenylpiperidine - 4 - carboxylic acid ; the chloride of the acid is obtainable from the acid and phosphorus pentachloride, and may be condensed (a) with #-diethylaminoethanol to yield the #-diethylaminoethyl ester of the acid, or (b) with asym. diethylethylenediamine to yield the #-diethylaminoethylamide of the acid ; (8) benzyl cyanide and cyclohexyl-di(#-chlorethyl) amine yield 1-cyclohexyl-4-phenyl-4- cyanopiperidine, which can be converted succÚssively into the corresponding acid and its ethyl ester. Methyl-di(#-chlorethyl) amine is obtainable from methyldiethanolamine and thionyl chloride. Benzyl-di(#-chlorethyl) amine is obtainable from thionyl chloride and benzyldiethanolamine, which may be prepared from benzyl chloride and diethanolamine. Methyl-di(#-bromethyl) amine is obtainable from methyldiethanolamine hydrobromide and hydrogen bromide. Methyl-di(#-chloropropyl) amine is obtainable from thionyl chloride and methyl-di(#-oxypropyl) amine, which may be prepared from aqueous methylamine and propylene oxide. Methyl-di(gamma-methoxy-#-chloropropyl) amine is obtainable from thionyl chloride and methyldi(gamma-methoxy-#-oxypropyl) amine, 'which may be prepared from methylamine and methyl- (#, gamma-epoxypropyl) ether. Cyclohexyl-di(#-chlorethyl) amine is obtainable from thionyl chloride and cyclohexyldiethanolamine, which may be prepared from cyclohexylamine and ethylene chlorhydrin in the presence of caustic soda.