Patent GB-614567-A (GB)
Title: Manufacture of piperidyl ketones
Filed: 1946-07-12
Abstract: 4 - Aryl - piperidyl - (4) - ketones are prepared by reacting 4-aryl-piperidine-(4)-carboxylic acid esters with organo-metal compounds and decomposing the reaction products.  By "organo-metal compound" is meant a compound of the Grignard type, namely a halogen-organo-metal compound more especially of magnesium, but also of zinc or cadmium, and also alkali metal organic compounds such as those of sodium, potassium or lithium. The organic residues in these organo-metal compounds may be of aliphatic, alicyclic, aromatic or araliphatic character, e.g. methyl, ethyl, propyl, butyl, allyl, cyclohexyl, phenyl or benzyl residues.  Esters of any desired 4-aryl-piperidine-(4)-carboxylic acid, e.g. 4-phenyl- or 4-naphthyl-piperidine-(4)-carboxylic acids, and any oxy compound of alcoholic or phenolic character may be used.  They may also contain substituents, e.g. alkyl or aralkyl groups in the piperidine ring, or free, etherified or esterified hydroxyl groups such as alkoxy, aralkoxy or acyloxy groups in the aryl residue.  Lactones formed by internal esterification with an oxy group in the ortho-position in the aryl nucleus may also be used.  Esters specifically mentioned are 1-methyl-, 1-ethyl-, or 1-benzyl-4-phenyl piperidine carboxylic acid-(4)-methyl, ethyl, propyl or phenyl ester, 1 : 2-dimethyl-4-phenyl - piperidine - (4) - carboxylic acid ethyl ester, 1-methyl-, 1-ethyl-, or 1-benzyl-4-(meta-methoxyphenylmethoxyphenyl) or -(meta-benz or -(meta-acetoxyphenyl)- or -(meta-benzoyl - oxyphenyl)-piperidine-(4)-carboxylic acid ethyl or phenyl ester, 1-methyl-, 1-ethyl-, 1-propyl-, 1-allyl- or 1-benzyl-4-(ortho-oxyphenyl)-piperidine-(4)-carboxylic acid-g -lactone, or 1-methyl-, 1-ethyl-, 1-propyl-, 1-allyl- or 1-benzyl-4-(ortho : meta - dioxyphenyl) - piperidine - 4 - carboxylic acid-g -lactone.  The aforesaid lactones are obtainable by hydrolysis of the corresponding oxy-carboxylic nitriles and the nitriles and esters may be prepared by the processes described in Specifications 591,992 and 597,794.  The desired ketone may be isolated in the form of the base or of a salt thereof, and when the ketone contains a phenolic hydroxyl group, metal phenolates are formed by decomposition of the reaction product with water, e.g. magnesium, sodium or lithium phenolates.  When the desired ketone contains substituted or free hydroxyl groups, the ketone may be treated with a hydrolysing agent and/or an etherifying or esterifying agent.  In examples: (1) 1-methyl-4 - (ortho - methoxyphenyl) - piperidine - (4) - carboxylic acid nitrile (obtained by the process of Specification 591,992) is refluxed with hydrobromic acid to yield the lactone of 1-methyl-4-(ortho - oxyphenyl) - piperidine - (4) - carboxylic acid which is then reacted with methyl magnesium bromide to yield 1-methyl-4-(ortho-oxyphenyl)-piperidyl-(4)-methyl ketone, which is esterified with acetic anhydride or may be alkylated; instead of methyl magnesium bromide, ethyl, propyl or benzyl magnesium halide may be similarly reacted; (2) 1-methyl-4-(meta-methoxyphenyl) - piperidyl - (4) - methyl ketone is prepared by reacting methyl magnesium iodide and 1-methyl-4-(meta-methoxyphenyl) - piperidine - (4) - carboxylic acid ethyl ester, and may be dealkylated to yield the corresponding hydroxy compound; the methyl, propyl or benzyl ester of 1-methyl-4-(meta-methoxyphenyl) - piperidine - 4 - carboxylic acid may be similarly reacted; (3) 1-methyl-4-(ortho-oxyphenyl)-piperidyl-(4)-n-butylketone is prepared by reacting the hydrobromide of 1-methyl-4 - (ortho-oxyphenyl) - piperidine - (4) - carboxylic acid lactone and n-butyllithium.  The following compounds are also mentioned: 1-methyl-4-phenyl - piperidyl - (4) - methyl - ketone hydrochloride, 1-methyl-4-phenyl-piperidyl-(4)-ethyl-ketone, 1 - ethyl - 4 - phenyl - piperidyl - (4) - ethyl - ketone, 1 - methyl - 4 - (meta - methoxy - phenyl) - piperidyl - (4) - n - propyl - ketone hydrochloride, 1-methyl-4-(meta-oxy-phenyl)-piperidyl-(4)-n-propyl - ketone, 1 - methyl - 4 - (meta - acetoxy - phenyl) - piperidyl - (4) - n - propyl - ketone hydrochloride and 1 - methyl - 4 - (meta - oxy - phenyl) - piperidyl-(4)-benzyl-ketone.