Patent GB-1147068-A (GB)
Title: Phenyl-pyridine derivatives
Inventor: DOYLE PETER
IPC: C07D213/57
Filed: 1966-12-02
Abstract: 1,147,068. Pyridine derivatives. IMPERIAL CHEMICAL INDUSTRIES Ltd. 30 Oct., 1967 [2 Dec., 1966], No. 54135/66. Heading C2C. [Also in Division A5] Novel compounds of Formula I, wherein X is hydrogen, C 1-3  alkyl, C 1-3  alkoxy or halogen, Y is phenyl optionally substituted by one or two halogen atoms, R<SP>1</SP> is hydrogen or C 1-3  alkyl, R<SP>2</SP> is hydrogen, C 1-3  alkyl or C 2-6  alkoxycarbonyl, R<SP>3</SP> is a radical of formula -CONH 2  or -COOR<SP>4</SP>, where R<SP>4</SP> is hydrogen or C 1-5  alkyl, and wherein the Y and -CR<SP>1</SP>R<SP>2</SP>R<SP>3</SP> radicals are linked to non-adjacent carbon atoms of the pyridine nucleus, and salts thereof, are prepared by the following methods: the amides (R<SP>3</SP>= -CONH 2 ) are prepared by hydrolysis of a cyano compound of Formula II; the acids (R<SP>3</SP> = CO 2 H) are prepared by hydrolysis of (a) a compound of Formula II, (b) a corresponding amide or (c) a corresponding alkyl, aralkyl or aryl ester; the acids of Formula III are prepared by reacting a compound of Formula IV, in which R<SP>4</SP> is C 1-5  alkyl and R<SP>7</SP> is cyano or C 2-6  alkoxy carbonyl, with an inorganic base or acid in the presence of water and under the influence of heat; the esters (R<SP>3</SP>=-COOC 1-5  alkyl) are prepared by esterification of a corresponding acid or by reacting a compound of Formula II with a C 1-5  alkanol; the esters of Formula V, in which R<SP>1</SP> is hydrogen, are prepared by reacting a compound of Formula VI, in which R<SP>1</SP> is hydrogen, with a carbonate of formula CO.(OR<SP>4</SP>) 2 , in which R<SP>4</SP> is C 1-5  alkyl, in the presence of sodium or potassium or a hydride, amide or alkoxide thereof; the compounds in which R<SP>1</SP> is C 1-3  alkyl are prepared by alkylating a corresponding compound in which R<SP>1</SP> is hydrogen; the compounds in which Y is unsubstituted phenyl are prepared by treating a corresponding compound in which Y is halophenyl with hydrogen in the presence of a hydrogenation catalyst. Cyanoalkyl-pyridine starting materials of Formula II are generally prepared by reducing a corresponding pyridine carboxylic ester to form the corresponding hydroxymethyl compound treating this with thionyl chloride to form the chloromethyl compound and, if necessary, alkylating and/or alkoxycarbonylating the cyanomethyl group. 6 - (4 - Chlorophenyl) - 2 - methylpyridine N-oxide is prepared by treating 6-(4-chlorophenyl) - 2 - methylpyridine with m-chloroperbenzoic acid. 2 - Methyl - 4 - (4 - chlorophenyl)- pyridine N-oxide is similarly prepared. Ethyl 5 - (4 - chlorophenyl - 2 - methylpyridine- 3 - carboxylate is prepared by reacting 4- cholorophenylacetic acid with dimethylformamide and phosphorus oxychloride to form α - (4 - chlorophenyl) - # - dimethylaminopropenal, treating this with phosgene to form #-chloro- α - (4 - chlorophenyl) - propenal, and treating this with ethyl #-aminocrotonate and cyclohexene to form the desired compound. The corresponding 4-bromophenyl and 2,4-dichlorophenyl compounds are similarly prepared. 5 - (4 - Chlorophenyl) - 2 - methylpyridine is prepared by treating 2-bromo-3-(4-chlorophenyl) - 6 - methylpyridine with powdered zinc. 2 - (4 - Chlorophenyl) - 5 - hydroxymethylpyridine and 2 - methyl - 4 - (4 - chlorophenyl)- pyridine are similarly prepared. 2 - Bromo - 3 - (4 - chlorophenyl) - 6 - methylpyridine is prepared by treating 3 - (4 - chlorophenyl) - 1,2 - dihydro - 6 - methyl - 2 - oxopyridine with phosphorus tribromide. 2 - Bromo - 3 - carbomethoxy - 6 - (4 - chlorophenyl)- pyridine and 2 - bromo - 4 - (4 - chlorophenyl) - 6 - methylpyridine are similarly prepared. 3 - (4 - Chlorophenyl) - 1,2 - dihydro - 6 - methyl - 2 - oxopyridine is prepared by reacting α - (4 - chlorophenyl) - α - hydroxy-metbyleneacetonitrile with acetone in the polyphosphoric acid. 6 - (4 - Chlorophenyl) - 3 - cyano - 2 - pyridone and 4 - (4 - chlorophenyl) - 6 - methyl- 2 - pyridone are similarly prepared. A mixture of 2-chloromethyl- and 2-hydroxymethyl - 6 - (4 - chlorophenyl) - pyridine is obtained by reacting 6 - (4 - chlorophenyl) - 2 - methylpyridine N-oxide with acetyl to form a mixture of 2 - acetoxymethyl- and 2 - chloromethyl - 6 - (4 - chlorophenyl) - pyridine hydrochloride and treating this mixture with sodium hydroxide. 3 - Carbomethoxy-6-(4-chlorophenyl) -2-p yridone is prepared by treating 6-(4-chlorophenyl)-3- cyano-2-pyridone with methanol. 4 - (4 - Chlorophenyl) - 2 - hydroxy - methylpyridine is prepared by treating 2- methyl-4-(4-chlorophenyl)pyridine N-oxide with acetic anhydride. 2 - (4 - Chlorophenyl) - 4 - cyanomethyl-pyridine is prepared by reacting 4-chlorobromobenzene with magnesium followed by 4-picoline N- oxide to produce 2-(4-chlorophenyl)-4-methylpyridine, reacting this with ethyl oxalate to form ethyl 3 - [2 - (4 - chlorophenyl) - pyrid - 4 - yl] - pyruvate, reacting this with hydroxylamine hydrochloride to form the oxime of 3 - [2 - (4 - chlorophenyl) - pyrid - 4 - yl] - pyruvic acid and reacting this with acetic anhydride.