Patent GB-1299100-A (GB)
Title: Substituted pyridines and dihydropyridines
Inventor: WITZEL BRUCE EDWARD
IPC: C07D213/70
Filed: 1970-11-09
Abstract: 1299100 Substituted pyridines and dihydropyridines MERCK & CO Inc 9 Nov 1970 [12 Nov 1969] 53254/70 Heading C2C Novel compounds I and II in which L is H, alkyl, alkenyl, alkynyl, aralkyl, substituted benzyl, aryl, substituted phenyl, hydroxyalkyl, amino, dialkylamino, dialkylaminoalkyl, carboxyalkyl, alkylaminoalkyl, haloalkyl, alkylamino, alkanoylaminoalkyl, hydroxy, N - alkanoylalkylaminoalkyl, aralkenyl, alkoxy or heterocyclyl; each R<SP>0</SP> is H, acyl or alkoxycarbonyl; X is O or S; Z is H, alkyl or aryl; and each of R 1 , R 2  and R 3  is H, haloalkyl, alkylthio, alkylsulphinyl, alkylsulphonyl, OH, sulphonamido, sulpho, carboxyalkyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkoxyalkyl, arylthio, aralkylthio, acylamino, hydroxyalkyl, acyl, alkenyl, alkynyl, alkyl, cycloalkyl, NO 2 , carbamoyl, N-alkyl or N,N- dialkyl - carbamoyl or N - arylcarbamoyl with the provisos that if one of R 1 -R 3  is alkyl or NO 2  the other two must be H; that if one of R 1 -R 3  is acyl, the other two must be other than alkyl and that at least one of R 1 -R 3  must be other than H; are prepared (1) by reduction of compounds III (2) by reaction of compounds IV with P 2 S 5  to give I where L is H, R is H and X is S; (3) by introducing a radical L<SP>1</SP> at the 1- position of a compound III by normal methods followed by reduction of the NO 2  group; (4) by reduction of compounds V (5) by acylation of the amino group in a compound VI (6) by cleaving the ether or thioether group in a compound II to give a compound I in which L is H. 2 - Amino - 4 - ethyl - pyridine (A) is prepared by reacting 4-ethylpyridine with sodamide. 2 - Amino - 3 - nitro - 4 - ethyl - pyridine (B) is prepared by nitration of (A). Similarly to B are prepared 2 - amino - 3 - nitro - 5 - methyl-; 2 - amino - 3 - nitro - 4,5,6 - trimethyl-; 2- amino - 3 - nitro - 4 - ethyl - 5 - fluoro and 2- amino - 3 - nitro - 5 - ethyl - 6 - trifluoromethylpyridine. 4 - Ethyl - 3 - nitro - 2[1H] - pyridone is prepared by diazotization of 2-amino-4-ethyl- 3 - nitropyridine. 4 - t - Butyl - pyridine - N- oxide is prepared by reacting 4 - t - butyl. pyridine with H 2 O 2 . 4-t-Butyl-2[1H]-pyridone is prepared by reacting the previously named intermediate with acetic anhydride or by reaction with SO 2 Cl 2  and hydrolysis of the 2- chloro-derivative formed. 4-t-Butyl-5-nitro- 2[1H] - pyridone - 5 - methyl - 3 - nitro - 2[1H]- pyridone and 4 - ethyl - 5 - fluoro - 3 - nitro- 2[1H]-pyridone are prepared by nitration of the corresponding non-nitrated compounds. 5- Bromo - 4 - ethyl - 3 - nitro - 2[1H] - pyridone is prepared by bromination of the non-brominated compound, e.g. with Br 2  or N-bromosuccinimide. 5 - Methylthio - 4 - ethyl - 3 - nitro- 2[1H]-pyridone is prepared by reacting the corresponding 5-bromo-derivative with copper methylthiolate. 4 - t - Butyl - 5 - cyano - 3 - nitro- 2[1H]-pyridone is prepared by reaction of the 5-bromo-derivative with cuprous cyanide. 5- Chloro - 3 - nitro - 4 - methyl - 2[1H] - pyridone is prepared by reaction of the non-chlorinated compound with N-chlorosuccinimide under N 2 - 2 - Chloro - 6 - methyl - nicotinoyl chloride is prepared by reaction of 3-carboxy-6-methyl. 2[1H]-pyridone with PCl 5  and POCl 3 . 2-Chloro- 6 - methyl - 3 - trifluoromethyl - pyridine is prepared by reacting the previously mentioned acid chloride with HF. 6-Methyl - 3 - trifluoromethyl-2[1H]-pyridone is prepared from the last named intermediate by reaction with silver acetate and acetic acid followed by hydrolysis. 3 - Acetyl - 6 - methyl - 2[1H] - pyridone, is prepared by reaction of 3-cyano-6-methyl- 2[1H]-pyridone with methyl magnesium iodide. 3 Acetyl - 5 - nitro - 6 - methyl - 2[1H] - pyridone is prepared by nitration of the non-nitrated com - pound. 5 - Methylsulphinyl and 5 - methylsulphonyl - 4 - ethyl - 3 - nitro - 2[1H] - pyridone is prepared by oxidation of the 5-methylthio compound. 3 - Amino - 6 - ethyl - 5 - nitro - 2[1H]-pyridone is prepared by nitration of the corresponding non-nitrated compound. 5- Carbamoyl - 4 - methyl - 3 - nitro - 2[1H]- pyridone is prepared by partial hydrolysis of the 'relevant 5 - cyano compound. 4 - Carboxymethyl - 3 - nitro 2[1H] - pyridone is prepared by reaction of the corresponding 4-methyl compound with butyl lithium and solid CO 2 . 4 - t - Butyl - 1 - methyl - 3 - nitro - 2[1H]- pyridone is prepared by N-methylation. 4-t- Butyl 1 - phenyl - 3 - nitro - 2[1H] - pyridone is prepared by N-phenylation. 5-Ethyl-3-nitro- 1 - tetrahydropyran - 2 - yl - 2[1H] - pyridone is prepared by reaction of the N-unsubstituted compound with dihydropyran- 3-Amino-6- methyl 2[1H] - pyridone - 5 - sulphonic acid is prepared by reacting chlorosulphonic acid with 3 - nitro - 6 - methyl - 2[1H] - pyridone. 3- Nitro - 6 - methyl - 2[1H] - pyridone - 5 - sulphonamide is prepared by reaction of the above sulphonic acid with diazomethane followed by concentrated NH 4 OH. 6-Benzylthio-3-nitro- 2[1H]-pyridone is prepared by reaction of benzene thiol with the appropriate 6-chloro-compound. 2 - Chloro - 3 - nitro - 5 - ethyl - pyridone is prepared by reacting 3-nitro-5-ethyl-2[lH]- pyridone with PCl 5  and POCl 3 . 3-Nitro-5-ethyl- 2-methoxypyridine is prepared by reaction of the 2-chloro compound with CH 3 ONa. 3-Fluoro- 4 - methyl - pyridine - N - oxide is prepared by reaction of 3 - fluoro - 4 - methyl - pyridine with H 2 O 2 . 2 - Chloro - 3 - fluoro - 4 - methyl - pyridine is prepared by reaction of the above N- oxide with SO 2 Cl 2 . 3-Fluoro-4-methyl-2[1H]- pyridone is prepared by hydrolysis of the 2- chloro - derivative. 1 - Amino - 4 - t - butyl- 3 - nitro - 2[1H] - pyridone is prepared by reaction of sodium salt of 4-(-butyl-3-nitro- 2[1H]-pyridone and chloramine. Pharmaceutical compositions useful as antiinflammatory agents for enteral and parenteral administration comprise a compound I together with a suitable excipient.