Quinolines carboxylation

The present method for preparing aromatic dicarboxylic acids has been used to convert phthalic or isophthalic acid to tereph-thalic acid (90-95%) 2,2 -biphenyldicarboxylic acid to 4,4 -biphenyldicarboxylic acid 3,4-pyrroledicarboxylic acid to 2,5-pyr-roledicarboxylic acid and 2,3-pyridinedicarboxylic acid to 2,5-pyridinedicarboxylic acid. A closely related method for preparing aromatic dicarboxylic acids is the thermal disproportionation of the potassium salt of an aromatic monocarboxylic acid to an equimolar mixture of the corresponding aromatic hydrocarbon and the dipotassium salt of an aromatic dicarboxylic acid. The disproportionation method has been used to convert benzoic acid to terephthalic acid (90-95%) pyridine-carboxylic acids to 2,5-pyridinedicarboxylic acid (30-50%) 2-furoic acid to 2,5-furandicarboxylic acid 2-thiophenecar-boxylic acid to 2,5-thiophenedicarboxylic acid and 2-quinoline-carboxylic acid to 2,4-quinolinedicarboxylic acid. One or the other of these two methods is often the best way to make otherwise inaccessible aromatic dicarboxylic acids. The two methods were recently reviewed. ... 

Buu-Hoi has shown that n-alkyl methyl ketones excluding ethyl methyl ketone, yield primarily 2-monosubstituted cinchoninic acids. It has been demonstrated that the products of the condensation of isatin with aryloxyketones are the corresponding 3-aryloxy-4-quinoline carboxylic acids rather than the isomeric 2-aryloxymethylcinchoninic acids.In the case of simple a-alkoxyketones such as 1-alkoxyethyl methylketones, the preferred products are the 2-alkoxyalkylcinchoninic... 

Finally, the quinoline ring can be methylated at the 3 position with retention of biologic activity. The starting quinoline is prepared by the same scheme as that used for the desmethyl compound by substituting the methylated oxosuccinate ester, S6, in the sequence. The initial quinoline carboxylate (87) is taken on to the dichloro compound (88) by the standard reactions. Condensation with the ubiquitous diamine (76) affords sontoquine (89)... 

A mixture of 26 parts of 3-carbethoxy-6,7-methylenedioxy-4-hydroxy-quinoline, 16 parts of sodium hydroxide and 50 parts of dimethylformamide is heated at 70° to 75°C for 2 hours, then 31 parts of ethyl iodide is added over 1 hour with continued heating and stirring. After an additional 3 to 4 hours of heating (at 70° to 75°C) and stirring, the mixture is diluted with 500 parts of water, refluxed for 3 to 4 hours, acidified with concentrated hydrochloric acid and filtered to yield 18 to 22 parts of 1-ethyl-1,4-dihydro-6,7-methylene-dioxy-4-oxo-3-quinoline-carboxylic acid, MP 309° to 314°C (decomposes). The analytical sample from dimethylformamide melts at 314° to 316°C (decomposes). 

C23H,i,FN04 124863-78-1) see Cerivastatin sodium diethyl 1,1 -(dithiodi-2,1 -elhanediyl)bis[6,8-difiuoro-l, 4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinoline-carboxylic acid diethyl ester]... 

Indolylaminomethylenemalonate (617) was cyclized to pyrrolo[3,2-/i]quinolinecarboxylate (618) in 54% yield by heating in diphenyl ether for 5 min. The dihydro derivative (619, R = H) failed to cyclize under similar conditions, but its 7V-(4-methylphenylsulfonyl) derivative (619, R = 4-MePhS02) gave the expected pyrrolo[3,2-/i]quinoline carboxylate (620) in 44% yield [75JCS(P 1)2409]. 

The thermal ring closure of 4-benzothiazolylaminomethylenemalonates (629) in boiling Dowtherm A for 10-30 min gave thiazolo[5,4-/i]quinoline-carboxylates (630) in 61-78% yields [77JAP(K)83596, 77JAP(K)125196 79CPB1],... 

The cyclization of yV-(2,2,2-trifluoroethyI)-/V-(3,4-methylenedioxyphe-nyl)aminomethylenemalonate (836, R = CF3) proceeded smoothly in polyphosphoric acid at 115-120°C for 25 min to give (2,2,2-trifluoroethyl)-l,3-dioxino[g]quinoline carboxylate (837) (76GEP2534869 78USP-4086236). 

Supplement XXII, 2nd Supplement 1935 3032-3457 Quinoline carboxylic acid, 74. Cin-chomeromc acid, 155. 

It contains a quinoline carboxylic acid derivative and has beer recorded as alkaloidal. Two of seven samples gave positive tests ir this study. 

Besides quinoline, carboxylic acid reactions of anilines with arylidenepyruvic acids can yield other heterocyclic compounds (Scheme 3.78), in particular 5-aryl-3-(2-arylamino)furan-2-ones 280 (by stirring the starting materials in ethanol at room temperature) [214, 215] and l,5-diarylpyrrolidine-2,3-dione 281 (by refluxing in ethanol) [216]. 

The three-component reaction of pyruvic acid, aldehydes and anilines can also yield pyrrolidine-2,3-dione [198], but in most cases the products of such multicomponent condensations are quinoline carboxylic acids identical to compounds obtained via the reaction of arylidenepyruvic acids [217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228]. 

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. 

Domagala JM, et al. l-Ethyl-7-[3-[(ethyl-amino)methyl]-l-pyrrolidinyl]-6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid. New quinolone antibacterial with potent gram-positive activity. J. Med. Chem., 1986, 29, 445-448. 

Ifenprodil (= l-Methyl-2-hydroxy-2-(4-hydroxyphenyl) ethyl-1 -(4-benzyl-piperidine)] -(aryl piperidine) [at(/o-3-(Indol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane] (indolotropane) [Kynurenic acid (= 4-Hydroxy-2-quinolinecarboxylic acid)] (quinoline carboxylic acid) [Memantine (= 1-Amino-3,5 dimethyladamantane)] (amino adamantane, amino cyclic aliphatic) [Methadone (= 6-Dimethylamino-4,4-diphenyl-3-heptanone)] (aryl tertiary amine) [em/o-3-(l -Methylindol-2-yl)-8-methyl-8-azabicyclo-[3.2.1] octane(indolotropane) exo- 3-( 1 -Methylindol-2-yl)-8-methyl-8-... 

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. 

Cinchoninic Acid.—(2) Carboxylic acids. The only quinoline carboxylic acid of importance is known as cinchoninic acid because it is obtained by oxidizing cinchonine, one of the alkaloids of cinchona bark. It is the quinoline 4-carboxylic acid and by loss of carbon dioxide yields quinoline. By oxidation cinchoninic acid yields pyridine 2-3-4 tricarboxylic acid (p. 858) which by loss of carbon dioxide (3 mol.) yields pyridine. 

Brequinar (DUP 785, NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis by inhibiting dihydro-orotate dehydrogenase. It was originally developed as an anticancer drug, but has also been investigated for its immunosuppressant activity after transplantation. Some data suggest that that the immunosuppressant activity of brequinar may be partly due to inhibition of tyrosine phosphorylation in lymphocytes (1). 

Ciprofloxacin (l,4-dihydro-l-cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-3-Quinoline-carboxylic acid) is a fluoroquinolone antibiotic drug used mainly to treat respiratory infections and septicemia. It also enjoyed a brief period of notoriety in 2001 as the... 

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