Methanol → Dimethyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate

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Reaction Steps

Lesher and Carabateas U.S. Pat. No. 3,907,808, issued Sept. 23, 1975, show as antibacterial agents 1-alkyl-1,4-dihydro-4-oxo-5(or 6)-(halo, lower-alkyl or lower-alkoxy)-7-(pyridinyl)-3-quinolinecarboxylic acids. Illustrative of these compounds is 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 57A), which was prepared in six steps starting with 2-fluoro-5-nitrobenzaldehyde as follows: (1) a mixture containing 2-fluoro-5-nitrobenzaldehyde, methyl acetoacetate, methanol and concentrated ammonium hydroxide was refluxed to produce dimethyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Example 57B); (2) oxidizing the product of Example 57B by heating it with 4N nitric acid to produce dimethyl 4-(2-fluoro-5-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (Example 57C); (3) catalytically hydrogenating Example 57C to produce dimethyl 4-(5-amino-2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (Example 57D); (4) reacting Example 57D with diethyl ethoxymethylenemalonate to produce 3-(3,5-dicarbomethoxy)-2,6-dimethyl-4-pyridinyl)-4-fluoroanilinomethylenemalonate (Example 57E); (5) heating Example 57E in Dowtherm A to produce ethyl 7-(3,5-dicarbomethoxy-2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example 57F); and, (6) heating Example 57F with ethyl iodide in dimethylformamide in the presence of anhydrous potassium carbonate and saponifying the resulting compound to produce 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 57A). Example 56F of this patent shows the conversion of 4-(2-methoxy-5-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid to 4-(2-methoxy-5-nitrophenyl)-2,6-dimethylpyridine by heating it in Dowtherm A. Also, Example 64C shows the conversion of 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-6-methyl-4-oxo-3-quinolinecarboxylic acid to 7-(2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-6-methyl-4-oxo-3-quinolinecarboxylic acid by heating it in diethyl phthalate at 240°-255° C.

Provenance & Evidence