Quinoline-3-carboxylates, 4-chloro

A benzene solution of 2.2 parts of a-chloro-y-quinoline-carboxylic acid chloride is gradually mixed, while cooling, with 2.3 parts of unsymmetrical diethylethylenediamine. When the reaction is at an end the solution is washed with water and the new base extracted by means of hydrochloric acid. The base is precipitated by means of sodium carbonate and extracted with benzene. The solvent is distilled and the base recrystallized from petroleum ether. The a-chloro-y-quinoline-carboxylic acid diethyl-amino-ethylene amide forms colorless lamina crystals of melting point 74°C. With acids the base forms neutral salts soluble in water. 

A solution of 2.5 parts of sodium in n-butylalcohol is boiled with 30 parts of a-chloro-y-quinoline-carboxylic acid diethyl-amino-ethylene-amide in a reflux apparatus, and when the reaction is over the excess of butylalcohol is distilled. The remaining base is taken up with ether the solution is washed with water and dried. The solvent is then distilled. The a-n-butoxy- quinoline-carboxylic acid diethyl-amino-ethylene-amide forms as colorless crystals, after recrystallization from petroleum ether melting point of it 64°C. 

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. 

Quinolinyl moiety has been applied in the Negishi reaction either as an electrophile or as nucleophile. 2- or 4-substituted quinolinyl triflates or bromides have been used extensively for introduction of aromatic rings at the C2 or C4 positions of the heterocycle. In a representative example, Murata et al. employed a Negishi reaction in his effort toward the formal synthesis of antitumor compound camptothecin. In accordance to that, 2-chloropyridine was allowed to react with lithium naphthalenide, followed by zinc chloride, to afford the corresponding zinc pyridine salt. Reaction of the resulting organozinc intermediate with 2-chloro-3-quinoline carboxylate provided the hetero biaryl core of camptothecin. ... 

Additional pyrimido[4,5-f ]quinoline syntheses include one involving the action of cyanogen bromide on 2-chloro-3-cyanoquinoline similar to that described for pyridines (Section 2.15.5.5.1) (78JHC877), and a synthesis of pyrimido[4,5-fe]quinoline-2-carboxylic... 

PyrimidoX4,5-6]quinoline-2-carboxylic acids synthesis, 3, 224-225 Pyrimido[4,5-6]quinoline-2,4-diones synthesis, 3, 224 Pyrimido[5,4-6]quinolinediones synthesis, 3, 219 Pyrimido[4,5-6]quinolines synthesis, 3, 219, 224, 227, 228, 230, 231 Pyrimido[4,5-c]quinolines synthesis, 3, 224, 227 tautomerism, 3, 205 Pyrimido[5,4-6]quinolines synthesis, 3, 227 Pyrimido[5,4-c]quinolines synthesis, 3, 219, 224, 227, 230 Pyrimido[5,4-6]quinoline-1,3,5-trione, 7-chloro-synthesis, 3, 221... 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

Raychaudhuri and Basu investigated the formation of side products in the large-scale cyclization of diethyl /V-(3-chlorophenyl)aminomethy-lenemalonate (250) in diphenyl ether (70J1C25). As side products, 7-chloro-1-ethyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (551), 7-chloro-4-ethoxyquinoline (552), and 7-chloro-l-ethyl-4(l//)-quinoline (553) could be isolated. These were probably formed from the primarily cyclized product, ethyl 7-chloro-4-hydroxyquinoline-3-carboxylate. The quantities of the side products depended on the reaction temperature during the cyclization, the duration of heating, and the purity of the starting N-(3-chlorophenyl)aminomethylenemalonate (250). 

It was later claimed that the thermal cyclization of bis(aminomethylene-malonates) (601, R = H, Me, Cl, N02, R1 = Et) by heating in refluxing diphenyl ether for 15-30 min under nitrogen afforded 8-(substituted amino)quinoline-3-carboxylates (603) in 31-75% yields (78USP4123536). In the cases of the methyl and chloro derivatives (601, R = Me, Cl, R1 = Et), l,10-phenanthroline-3,8-dicarboxylates (602, R = Me, Cl, R1 = Et) could also be isolated as byproducts in 3-4% yields. 

The cyclization of arylaminomethylenemalonates (701) on the action of phosphorus pentoxide in nitrobenzene gave quinoline-3-carboxylates (702) in 16-85% yields (74JMC137). Polyphosphoric acid proved to be a more effective cyclization agent than the phosphorus pentoxide-nitrobenzene system. For example, a chloro derivative (701, R = Et, R1 = Cl, R2 = R3 = R4 = H) gave quinoline-3-carboxylate (702, R = Et, R1 = Cl, R2 = R3 = R4 = H) in 46% yield on the action of polyphosphoric acid, whereas the yield was only 16% in the phosphorus pentoxide-nitrobenzene system. 

In the case of phosphoryl chloride, the primary products were 4-chloro-quinoline-3-carboxylates. As the quinoline-3-esters were very insoluble, the reaction products were hydrolyzed to quinoline-3-carboxylic acids, and the isomeric ratios were determined by H-NMR in trifluoroacetic acid. Thermal cyclization in Dowtherm A resulted mainly in formation of the 7-substituted isomer. In the case of chloro derivatives (250), only traces of 5-isomer could be detected. [Earlier, others observed and reported the formation of a small amount of the 5-isomer too (e.g., 46JA1204 47JA374]. 

Under acidic conditions, the formation of a nearly 1 1 mixture of 5- and 7-substituted quinoline-3-carboxylates, with a slight excess of the former, was observed from the 3-chloro- and 3-methyl derivatives. The cycliza-tions of 3-nitro, 3-trifluoromethyl, and methoxy derivatives were carried out only in polyphosphate to give mainly the 7-substituted isomers. 

The cyclization of N-(3-substituted 4-ethylphenyl)aminomethylenema-lonates (757, R = 4-BrPhOCH2, octadecyloxy, R1 = Et) in phosphoryl chloride at 100-130°C for 4 hr afforded 7-substituted 6-ethyl-4-chloro-quinoline-3-carboxylates (778, R = 4-BrPhOCH2, octadecyloxy) in 94-98% yields (79EGP134225, 79EGP136742). 

The ring closure of A-(3-chlorophenyl)aminomethylenemalona-mate (781, R = Cl) and the 4-chloro derivative in boiling benzene on the action of phosphoryl chloride for 6-10 hr afforded the corresponding 4-(arylamino)quinoline-3-carboxylate (e.g., 783) in 57-65% yield... 

The cyclization of N-( 1,3-benzodioxan-6-yl)aminomethylenemalonates (827, R2 = H) in boiling phosphoryl chloride for 6-18 hr afforded angular 7-chloro-l,3-dioxino[5,4-/]quinoline-9-carboxylates (829) in 25-85% yields (72GEP2139212, 72MI4). Earlier, the reaction product of compound 827 (R = R1 = R2 = H) was incorrectly given as the linearly anelated tricycle 828 (R = R2 = H) (70GEP1936393 72BRP1283900). 9-Chloro-l,3-dioxino[4,5-g]quinoline-8-carboxylates (828, R2 = Me) were obtained un-... 

Chloroquinolines are reactive groupings due to electron-deficient carbon to which the halogen is attached. This carbon is electron-deficient due to the combined electron-withdrawing effects of the chlorine substituent and the quinoline nitrogen. The electrophilic carbon is thus able to react readily with nucleophiles present in the body. The impact of this grouping on a molecule is illustrated by 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (Figure 8.28). In contrast to many related compounds (chromone-carboxylates) lacking the chloroquinoline, 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate is excreted as a... 

Ethyl 4,5-difluoro-7-oxo-2,3-dihydro-7//-pyrido[3,2,l-i)][2,l]benzox-azinone-6-carboxylate (98) was formed when ethyl 6,7-fluoro-4-hydroxy-8-(2-hydroxyethyl)quinoline-3-carboxylate (97) was treated with m-chloro-peroxybenzoic acid in chloroform [92JAP(K)92/208287, 92JAP(K)92/ 210656],... 

Reacting 3-chloro-4-fluoroaniline and ethyl ethoxymethylenmalonate gives the snbsti-tntion prodnct (33.2.15), which upon heating in diphenyl ester cyclizes into ethyl ester of 6-flnoro-7-chloro-l,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.16). Direct treatment of the prodnct with ethyl iodide in the presence of triethylamine and snbseqnent hydrolysis with a base gives l-ethyl-6-flnoro-7-chloro-l,4-dihydro-3-qninolin-4-on-carboxylic acid (33.2.17). Reacting this with piperazine gives norfloxacin (33.2.18) [70-75]. 

Interestingly, when carboxylate derivatives are considered, the SET process is irreversible (due to release of CO ) and the degradation rate is maximum when this mechanism is supposed to be operating. On the contrary, when a radical cation or a semiquinone intermediate is invoked, as in the case of quinoline or hydroxy-methoxy-chloro benzenes [60,64], the rate is minimum due to the back reaction. 

The amino groups of isomeric 5-aminomethyl-8-chloro-6-phenyl-3-methyl-l-oxo-1/7- and -l-methyl-3-oxo-3//-pyrimido[l,2-a]quinolines were acylated with acetic anhydride at room temperature for 1 h (79CPB2927). 5,8,9-Trihydroxy-2,3-dihydro-l//-pyrimido[l,2-a]quinoline-l-carboxylic acid was acylated with acetic anhydride in pyridine at room temperature for 24 h (87T2261). 

Cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydro-3-quinolinecarboxylic acid was synthesized by heating of a mixture of 7-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinolin-3-carboxylic acid and 30.1 g dry piperazine in 100 ml DMSO for 2 hours at 135-140°C. DMSO was evaporated in high vacuum. The residue was heated with 100 ml of water, and was dried over CaCI2 in vacuum. Cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydro-3-quinolinecarboxylic acid obtained has a temperature of decomposition 255-257°C. 

Decarboxylation of 5,7-dimethyl-8-oxo-6-aza-8//-indeno[2,1 - ]thiophene-4-carboxylic acid could be effected by heating an admixture of it and copper powder <87H(26)1535). Direct sublimation in vacuo afforded the desired product (58%). 9-Chloro-2- and 3-methyltriazolo[4,5-/]quinoline-7-carboxylic acids are decarboxylated under similar conditions <93H(36)259>. The cyano group of 8-cyano-7-oxo-4,5,6,7-tetrahydrothiazolo[4,5-/]quinolines can be converted into an amino group by cone. HC1 mediated hydrolysis to the amide, followed by Hofmann rearrangement <89H(29)I517>. 

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