With 2-chloronicotinic acid

The reaction of hydrazines with 2-chloronicotinic acid derivatives affords pyrazolones 9 either directly or via the isolated hydrazines or hydrazides. 

Condensation of unsymmetrical hydrazines with 2-chloronicotinic acid derivatives has generally yielded 1-substituted products, but the acid chloride 10a and benzylhydrazine afforded, via the hydrazide lOd, 2-benzyl compound 13.23 The isomer 12 (R = CH2Ph) was obtained either directly from the ester lOe or from 14 via the hydrazide 10c.23... 

Condensation of 3-(2-thienyl)-4-amino-5-thiol-l,2,4-triazole (174) with 2-chloronicotinic acid (175) in refluxing ethanol in the presence of sodium acetate produced the sulfide (176), which was treated with phosphorus oxychloride to result in cyclization giving rise to the triazolo[3,4-fe]pyrido[3,2-/]-l,3,4-thiadiazepine (177) (45% yield). The triazole (174) also reacted with the a,jS-unsaturated ketones (178) to give the triazolo-l,3,4-thiadiazepines (179) (75% yield) (Scheme 32) <91SUL201>. 

Cyclocondensation of 2-chloronicotinic acid with 2-amino-5-iodobenzoic acid and methyl 2-amino-4-bromobenzoate in boiling EtOH in the presence of cone. HCl for 18 h gave the 2-iodo and 3-bromo derivatives of 11-0X0-1 l/f-pyrido[2,l-6]quinazoline-6-carboxylic acid (98MIP1, 98MIP2, 99USP5908840, 99USP5914327). 

Interestingly, a substance somewhat closely related to flunixin, triflocin (30), is a diuretic rather than an antiinflammatory agent. It can be prepared by nucleophilic aromatic displacement on 4-chloronicotinic acid (29) with m-trifluoromethyl-aniline.8... 

Niflumic acid Niflumic acid, 2-3-(trifluoromethyl)anilino nicotinic acid (3.2.21), is synthesized either by the reaction of 2-chloronicotinic acid with 3-trifluoromethylaniline [84-86], or 2-aminonicotinic acid with l-bromo-3-trifluoromethylbenzene [87]. 

N-Substituted amides derived from 2-chloro- or4-chloronicotinic acid react with CH-acidic nitriles in the presence of base to yield amino derivatives of [l,6]naphthytid-5(6//)-ones and [2,7]naphthyrid-l(2//)-ones <1997JHC397>. 3-(l-Alkylamino)pyridines react with electron-deficient alkynes (acetylene dicatboxylates) in the presence of acid to give l,2-dihydro[2,7]naphthyridine-3,4-dicarboxylates in up to 72% yield compounds unsubstituted at C-1 were readily oxidized with potassium permanganate to naphthyridine-l-ones <2005TL3953>. 

In a related vein, one of the benzene rings in dibenzepin (36-7) can be replaced by pyridine. In a one-pot reaction, condensation of the 2-chloronicotinic acid (43-2) with ortho-phenylenediamine (43-1) leads to the lactam (43-3). The order in which the two steps, aromatic displacement and amide formation, take place has not been elucidated. Simple alkylation of the anion from the product with 3-chloro-2-(AA -drmethylamino)propane (43-4) affords the antidepressant agent propizepine (43-5) [43]. 

Synthesis Condensation of 2-chloronicotinic acid with 3-trifluoromethylaniline or reaction of 2-aminonicotinic acid with 1-bromo-3-trifluoromethylbenzene yields niflumic acid (Sherlock and Sperber (Schering Corp.), 1967 Faure and Hoffman (Labs. U.P.S.A.), 1968 Kleemann et al., 1999). 

MI1). Triazocine 199 (R = R = Ts) was obtained by reacting 1,2-dibromoethane with 200 (obtained from 2-chloronicotinic acid) (85MI3). 

Dihydropyrido[2,3-6][l,5]benzothiazepin-5(6//)-ones (104) were obtained by cyclocondensation of 5 and 2-chloronicotinic acid (103) the reaction of compounds 104 with phosphorus oxychloride and phosphorus pentachloride afforded the corresponding iminochlorides which were refluxed in toluene with piperazines and triethylamine to give compounds 105. These products showed antihistaminic, orexigenic, and antianaphy-... 

Certain pyridines react with Grignard reagents in the 1,4-manner when substituted by electron-withdrawing groups such as a carboxamide <2000J(P1)4245, 2005JOC2000>. The intermediate dihydropyridine can conveniently be oxidized to the pyridine structure. An example of this is seen in the reaction of 6-chloronicotinic acid derivative 125 with an excess of o-tolylmagnesium chloride, followed by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone... 

Reactions of 2-mercaptobenzimidazole and 2-mercapto-l//-imidazo[4,5-bjpyridine with 2-chlorobenzoic or 2-chloronicotinic acids lead to tetracyclic heterosystems 195 and 196, respectively [88IJC(B)1142] (Scheme 69). 

Chloronicotinic acid (5.0 mmol) and 1.6 ml triethylamine were dissolved in 50 ml THF at 0°C, then treated with ethyl chloroformate (5.0 mmol), and stirred 60 minutes while the mixture warmed to ambient temperature. The mixture was further treated with 4-phenoxyaniline (5.0 mmol), then stirred 14 hours, and partitioned between water and EtOAc. The aqueous layer was extracted twice with 50 ml EtOAc and combined organic layers were washed with brine, dried over Na2S04, then concentrated. The residue consisted of a brown oil and was used without further purification. 

Reaction of 2-aminobenzyl alcohol 483 with 2-chloronicotinoyl chloride 484 in the presence of Et3N yielded the 2-hydroxymethylphenylamide-2 -chloronicotinic acid 485 (32%). Such an intermediate underwent a base promoted to give the pyridobenzo[3/][l,5]oxazocin-6-one 486 in 36% yield (Scheme 97) <1997FA751>. 

Boscalid was shown to be an effective fungicide and its industrial production is expected to begin soon. The biphenyl intermediate, 4 -chloro-2-nitrobiphe-nyl, is prepared by palladium-catalyzed coupling of 2-nitrochlorobenzene with 4-chloroboronic acid according to Equation 19. Other details are not available. Boscalid is the 2-chloronicotinic acid amide derivative of the amine obtained by reduction of the nitrobiphenyl product. 

The action of mineral acids on 2-(2 -oxocyclohexyl)methyl-6-chloronicotinic acid (140) yields 6-(4 -carboxy)butyl-2-hydroxy-5-oxo-6,7-dihydro-5/7-1 -pyrindine (141).98a 98e Chemical and spectra data, as well as an unequivocal synthesis starting with ethyl 2-bromomethyl-... 

Demethylation by phase I biotransformation is the major pathway, with 6-chloronicotinic acid being the major metabolite. Compounds can then undergo phase II transformation with glycine conjugation representing the major pathway. 

Aminobenzothiazoles (164) react with 2-chloronicotinoyl chloride (165) to give the corresponding 2-chloronicotinamides (166). When 2-chloronicotinic acid (167) is used the amide (168) is obtained (Scheme 40). This behavior can be explained by the low reactivity of 2-chloronicotinic... 

Ialo-l,8-naphthyridin-2(17/)-ones, readily available from 2-chloronicotinic acid, were subjected to Suzuki coupling with aryl boronic acids to give a diversity of 4-aryl-l,8-naphthyridin-2(17/)-ones ((2003T6021). 

The 2-chloronicotinoylchloride (5)was easily prepared from 2-chloronicotinic acid, which was commercially available in multi-ton quantities. The most significant initial concern was with the ability to obtain pilot-scale quantities of CAPIC (4). Gram quantities of this material were initially obtained by the reduction of 2-chloro-4-methyl-3-nitropyridine. Small quantities of this material were initially obtained from laboratory supply houses, but significant scale-up quantities were not com-merciallv available. 

The condensation reaction required significant process development modifications from the procedure used to produce the initial drug development requirements. 2-Chloronicoti-noylchloride (5) was prepared in situ during medicinal and chemical development runs by adding 2-chloronicotinic acid to a 5 molar excess of thionyl chloride as a neat reaction mixture. Upon completion of the reaction, excess thionyl chloride was removed by distillation. The residue was then redissolved in toluene, followed by the addition of CAPIC in toluene and sodium carbonate to neutralize the excess HCl liberated from the condensation. An alternative procedure was developed with the use of a 10% molar excess of thionyl chloride in toluene to produce (5). The excess thionyl chloride was removed by distillation and to the... 

The simple structure of the alkaloid cerpegin (118) has attracted a lot of synthetic attention. The first synthesis (229) was completed in six steps beginning with 3-iV,(V-diisopropylcarbamoyl-2-methoxypyridine (344), itself prepared from 2-chloronicotinic acid. Treatment of 344 with TMPLi... 

In an alternative synthesis (230), 2-chloronicotinic acid (348) was converted to its tert-butyl amide 349, which was readily converted to its methoxy derivative 350. Treatment with butyl lithium, then acetone and acidification afforded 351, and the methyl group was effectively transposed from oxygen to nitrogen by heating with methyl iodide at 140°C to afford 118 (Scheme 40). 

AminonicOtiniC Acid, 6-Amino-3 pyridinecar-boxylic acid 6 -amtno-3 -car boxy pyridine. CjHjNjOv mol wt 138.12. C 52.17%, H 4.38%, N 20.28%, O 23.17%. Prepd by heating 6-chloronicotinic acid with ammonia Marck-... 

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