Quinoline-4-carboxylic acids, ring

The design and s)mthesis of the new oxime-functionalized pyrrolidine derivative of gemifloxacin, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, was first described in Scheme 4.1 starting from step (a) to step (i) in the scheme. Then, the new pyrrolidine derivative moiety was coupled with a certain quinoline carboxylic acid derivative (7-chloro (or fluoro)-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid) to form the new fluoroquinolone drug, gemifloxacin as described in Scheme 4.1. 

Potassium t-butoxide in t-butyl alcohol requires powerful electron-attracting substituents at C-4 to effect ring opening of pyrazoles but sodamide does not (Scheme 26) (B-76MI40402). As the key to the transformation is the generation of the anion, similar results were obtained by heating some pyrazole-3-carboxylic acids with quinoline. 

The result is explained by considering the stacking structure between the quinoline moiety and the benzene ring linked to the carboxylic acid, which gives the cavity size adequate for Li+. (Fig. 3) Several selective host molecules for Li+ such as [13]crown-4 18), [14]crown-4 19), [16]crown-4 20>, or noncyclic polyether amide derivatives 21) also possess trimethylene moiety, and this is an interesting finding from the point of view of molecular design of new host molecules for Li+. 

V-(3-trifluoromethylphenyl)aminomethylenemalonate (749, R = 3-CF3) proved unsuccessful in boiling phosphoryl chloride. The thermal cycliza-tion of ZV-ethyl-N-arylaminomethylenemalonates (749) and their ring closure in acetic acid, in acetic anhydride with zinc chloride, or in a melt of aluminium chloride were likewise unsuccessful (71JHC357). The corresponding quinoline was not obtained in a one-pot version when N-ethylani-line and EMME were reacted in polyphosphoric acid. Table V shows the yields of quinoline-3-carboxylic acid derivatives obtained from /V-ethyl-N-phenyl- and iV-ethyl-7V-(3,4-methylenedioxyphenyl)aminomethylene-malonates (749, R = H and 3,4-0CH20) under various acidic cyclization conditions. 

Cyclization of diethyl [3-(4-acetyl-l-piperazinyl)-4-fluorophenyl-l,3-thiazetidin-2-ylidene]malonate (1291) in polyphosphoric acid at 120°C for 1 hr gave a mixture of l,3-thiazeto[3,2-a]quinoline-3-carboxylate (1292, R = Et 25%) and 3-carboxylie acid (1292, R = H 20%) (87BRP2190376). Ring closure was also carried out in fuming sulfuric acid at 100°C for 5 min to afford l,3-thiazeto[3,2-fl]quinoline-3-carboxylic acid (1292, R = H) in 98% yield. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Carbonation of lithiofurans is a useful method for obtaining these compounds. Furan-2-carboxylic acid (pKa 3.15) is a stronger acid than the 3-carboxylic acid (pKa 4.0) because of the inductive effect of the ring oxygen, and both are stronger than benzoic acid. Furancarboxylic acids can be decarboxylated by the copper-quinoline method or merely by heating. The 2-carboxylic acids are more easily decarboxylated than the 3-isomers, so furan-3-carboxylic acid can be obtained by stepwise decarboxylation of the tetracarboxylic acid via the 2,3,4-tricarboxylic acid and the 3,4-dicarboxylic acid. A more convenient source of the 3-carboxylic acid is by partial hydrolysis and decarboxylation of the readily available diethyl furan-3,4-dicarboxylate (71S545). 

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