Patent GB-609763-A (GB)
Title: Manufacture of piperidyl ketones
IPC: C07D211/32
Filed: 1946-03-21
Abstract: Piperidyl ketones are prepared by reacting a 4-aryl-piperidine-4-carboxylic acid halide with a compound which contains at least one reactive hydrogen atom bound to carbon, or with a metal derivative of such a compound.  Examples of such compounds are ethyl malonate, malonitrile, ethyl acetoacetate, benzoylacetic acid ethyl ester, pyridoylacetic acid ethyl ester, ethyl acetate, benzyl cyanide, acetyl acetone, diazomethane, diazoethane, diazobutane, phenyldiazomethane and ethyl diazoacetate.  The condensation products so obtained may be subjected to a process of degradation or synthesis while retaining the newly-formed keto group, for example, a nitrile or esterified carboxyl group may be hydrolysed and the compound de-carboxylated, a benzyl group attached to the ring nitrogen atom may be split off, an esterified or etherified hydroxyl group may be hydrolysed, a diazo-keto compound may be converted into an oxyketone or an ester or ether thereof, or a diazo group may be replaced by halogen or hydrogen.  The following examples are given: (1) Sodium is reacted with ethyl malonate in ether and the product mixed with the hydrochloride of 1-methyl-4-phenylpiperidine-4-carboxylic acid chloride.  After acidifying, separating the ether layer and adding ammonia (1-methyl-4-phenylpiperidyl-4)-dicarboxymethyl ketone is precipitated, extracted with ether and converted to its hydrochloride which, on heating, is decarboxylated to give (1 - methyl - 4 - phenylpiperidyl-4) methyl ketone.  Instead of using the tertiary acid chloride, a quaternary compound may be used, such as the chlorobenzylate.  Starting with monomethylmalonic acid ethyl ester, there is obtained (1-methyl-4-phenylpiperidyl-4) ethyl ketone.  (2) Magnesium is reacted with ethyl malonate and absolute alcohol and the resulting magnesium compound dissolved in ether is added to the hydrochloride of 1 - methyl - 4 - phenylpiperidine - 4 - carboxylic acid chloride; (1-methyl-4-phenylpiperidyl-4) methyl ketone is separated as in (1).  (3) The sodium compound of ethyl acetoacetate is reacted with the hydrochloride of 1-methyl-4-phenylpiperidine-4-carboxylic acid chloride to yield the hydrochloride of (1-methyl-4-phenylpiperidyl-4) acetylcarbethoxymethyl ketone.  (4) 1-Methyl-4-(m-phenoxyphenyl)-piperidine-4-carboxylic acid is heated with thionyl chloride and ethyl acetate and the hydrochloride of the acid chloride so obtained is added to ethoxy-magnesium-malonic acid ethyl ester to yield [1 - methyl - 4 - (m - methoxyphenyl) - piperidyl - 4] dicarbethoxymethyl ketone which is then hydrolysed and decarboxylated to give [ [1 - methyl - 4 - (m - oxyphenyl) - piperidyl - 4] methyl ketone.  (5) The hydrochloride of 1-methyl-4-phenylpiperidine-4-carboxylic acid chloride is added to diazomethane in ether and the [1-methyl - 4 - phenylpiperidyl - 4] diazomethyl ketone formed is evaporated with HCl to give the hydrochloride of [1 - methyl - 4 - phenyl - piperidyl-4] chloromethyl ketone.  The latter may be de-halogenated by treatment with hydrogen in presence of palladium black.  By treating the diazo ketone with an organic acid instead of hydrochloric acid, the corresponding ester of the oxyketone is obtained.  (6) The sodium compound of ethylmalonic acid diethyl ester is reacted with the hydrochloride of 1-methyl - 4 - (m - methoxyphenyl) - piperidine - 4 - carboxylic acid chloride to give [1-methyl-4-(m-methoxyphenyl) -piperidyl-4]-(a a -dicarbethoxypropyl) ketone which is then hydrolysed and decarboxylated, and finally acetylated to produce [1-methyl-4-(m-acetoxyphenyl)-piperidyl-4]-n-propyl ketone.  (7) Sodamide is reacted with benzyl cyanide and added to the hydrochloride of 1 - methyl - 4 - (m - methoxyphenyl) - piperidine-4-carboxylic acid chloride to yield [1-methyl-4-(m-methoxyphenyl)-piperidyl-4]-(a -cyanobenzyl) ketone which is hydrolysed to [1-methyl-4-(m-oxyphenyl)-piperidyl-4]-benzyl ketone.  (8) The hydrochloride of 1-methyl-4-(m - methoxyphenyl) - piperidine - 4 - carboxylic acid chloride is added to a solution of diazomethane and the product, after separation, is heated with hydrochloric acid to give [1-methyl-4-(m-methoxyphenyl)-piperidyl-4]-chloromethyl ketone hydrochloride.  By dehalogenation with palladium and hydrogen followed by hydrolysis with HBr, [1-methyl-4-(m-oxyphenyl)-piperidyl-4]-methyl ketone is obtained. Specification 597,794 is referred to.