Patent GB-591992-A (GB)
Title: Manufacture of piperidine compounds
IPC: C07D211/64
Filed: 1944-06-22
Abstract: 4 - Aryl - piperidine - 4 - carboxylic acid nitriles are prepared by condensing an a -arylated - tertiary - g  - amino fatty acid nitrile in one or more stages with an alkylene-1 : 2-diol ester of a hydrohalic or a sulphonic acid in the presence of an acid binding agent.  The nitriles so obtained may be converted into the corresponding amides esters or ketones by a method known to be suitable for such a conversion.  In addition a hydrocarbon residue attached to the ring nitrogen may be removed at any stage of the process.  Specified nitriles which may be used as starting materials include a  - phenyl - g  - (N - methyl - N - benzylamino)-, a  - phenyl - g  - (dimethyl or diethylamino)-, a  - (benzyloxy or acyloxy-phenyl) - g  - (N - methyl - N - benzylamino)-, a  - (o - anisyl) - g  - (N - methyl - N - diphenylmethylamino)-, a -(m-anisyl) - g  - dimethylamino-, and a  - naphthyl - g  - dimethylamino - butyric acid nitriles and a  - phenyl - g  - (N - methyl - N - benzylamino)-valeric acid nitrile.  As esters of alkylene-1 : 2-diols there are mentioned the ethylene dibromide, ethylene chlorobromide, ethylene diiodide, propylene-1 : 2-dibromide, propylene-1 : 2-chlorobromide, butylene-1 : 2-dibromide esters, b  - chloroethanol - p - toluene sulphonic acid ester, glycol-di-p-toluene sulphonic acid ester and propane-1 : 2-diol dimethane sulphonic acid ester. Acid binding agents mentioned include sodium potassium, lithium, calcium or the alcoholates, amides, hydrides or hydrocarbon compounds thereof such as potassium tertiary butylate, potassium tertiary amylate, sodamide, sodium hydride, lithium butyl, sodium phenyl, or lithium phenyl. It is preferred to carry out the condensation in the presence of a solvent such as ether, benzene, toluene, xylene, or hexane, and to work in the presence of an inert gas such as nitrogen. The acids or their amides may be prepared from the nitriles by treatment with strong or mild hydrolysing agents respectively.  The amides may also be prepared from the acids or derivatives thereof such as halides or esters by reacting them with ammonia or amines. The esters may be obtained from the acids by esterification or direct from the nitriles by reaction with alcohols in the presence of strong acids.  The ketones may be obtained from the nitriles by the use of organo metallic compounds.  The compounds containing a quaternary nitrogen atom into the corresponding tertiary nitrogen compounds by splitting of halogen-alkyl by heating.  In examples: (1) a  - Phenyl - g  - (N - methyl - N - benzylamino)-butyric acid nitrile prepared from benzyl cyanide and b -chlorethyl-N-methyl-N-benzylamine is reacted with sodamide in ether solution and ethylene dibromide added to form 1 : 1-methylbenzyl-4 : 4-phenyl-cyano piperidinium bromide, which is purified and then heated with hydrogen and palladium black to give 1 - methyl - 4 : 4 - phenyl - cyano piperidine. Saponification with alkali and esterification with ethanol forms 1-methyl-4 : 4-phenyl-carbethoxy-piperidine.  (2) a  - Phenyl - g  - (N p  - methyl - N - benzylamino) - butyric acid nitrile is reacted with propylene-1 : 2-dibromide by means of sodamide as in example (1) to form 1 : 1 -methyl - benzyl - 2 - methyl - 4 : 4 - phenyl-cyanopiperidinium bromide which is worked up as in example (1) to form 1 : 2-dimethyl-4 : 4-phenyl - cyano - piperidine which may be converted into the carbethoxy compound or the amide.  An alternative starting material is a  - (m - nitrophenyl) - g  - (methylbenzylamino) butyric acid nitrile. (3) a -Phenyl-g -diethylamino-butyric acid nitrile is reacted with ethylene dibromide as in example (1) to form 1 : 1-diethyl-4 : 4-phenylcyanopiperidinium bromide, which may be converted to the piperidine compound as before, and finally into the corresponding ketone by alkyl magnesium halide. (4) a -Phenyl-g -dimethylamino-butyric acid nitrile obtained from benzyl cyanide and b -methyl-aminoethyl chloride is reacted with ethylene dibromide as in example (1) and further treated as in example (3).  (5) A toluene solution of a -(m-methoxyphenyl)-g -dimethylamino butyric acid nitrile is added to sodium phenyl and reacted with ethylene dibromide to form 1-methyl-4 : 4-(m-methoxyphenyl)cyano-piperidine.  Hydrolysis with caustic soda gives the corresponding 4-carboxylic acid which is then esterified. Alternative hydrolysis and esterifications are described.  (6) a  - Phenyl - g  - (N - methyl - N - benzylamino - butyric acid nitrile used in example (1) is replaced by a  - (o - methoxyphenyl) - g  - (N - methyl - N - benzylamino) buryic acid nitrile obtained from o-methoxy benzyl cyanide and b  - methyl - N - benzylamine.  (7) 2 : 3-Dimethoxybenzyl cyanide is reacted with b -chloroethyl-methylbenzylamine to form a -(2 : 3-dimethoxyphenyl) - g - (methylbenzylamino) butyric acid nitrile which is then reacted as before with ethylene dibromide in the presence of sodium phenyl to form 1 : 1-methylbenzyl-4 : 4-(21 : 31-dimethoxyphenyl)-cyano piperidinium bromide.  Samples have been furnished under Sect. 2 (5) of 1 - methyl - 4 - (m - hydroxyphenyl) - piperidyl - (4) - methyl ketone prepared (1) by reaction of a  - (m - methoxyphenyl) - g  - dimethylamino-butyric acid nitrile with p-toluene sulphonic acid-b -glycol-chlorhydrin ester in the presence of sodamide to form 1 : 1-dimethyl-4 : 4(m-methoxyphenyl)-cyano-piperidinium chloride, followed by heating to convert to the pyridine compound and treatment with magnesium methyl bromide; (2) by first preparing the quaternary cyano-piperidinium chloride as above followed by treatment with magnesium methyl bromide under varying experimental conditions and a purification step involving the use of sodium perchlorates.