2-Chloronicotine

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). 

Pyridylidenehydantoins such as 139, obtained from pyridinecarbaldehydes by Horner-Wadsworth-Emmons reactions, are cyclized under acidic conditions to tricycles of the type 140 (Scheme 39) <2004TL553>. Similar benzannulated ring systems can be prepared by the reaction of 2-benzimidazolylacetonitriles and, for example, 2-chloronicotinic esters or 2-chloronicotinamides under basic conditions (Equation 32) <1996JHC1147, 1997JHC397>. 

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]. 

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). 

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... 

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-... 

Frequently, the starting materials for the syntheses of 2-iminopyrido-TAs are 2-chloronicotinic acid derivatives—esters or isothiocyanates. The second reagent may be a substituted thiourea or it may be a primary or secondary amine. Imines 167 (73MI1), 168 (84POP122833), and 169 (86FES899) were prepared in this way (Scheme 58). 

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). 

C02H POCI3, PC15, 115-120°, 1.5 hours then H20 2-Chloronicotinic acid (41%) 4-Chloronicotinic acid (5%) No 6-Chloro derivative 345... 

Reaction between 2-chloronicotinic acid (130) and 2-amino-4-phenyl-thiazole furnishes 3-phenyl-5-H-pyrido[2,3,-d]thiazolo[3.2-a]pyximidin-5-one (131) (Scheme 86) (293). This reaction was extended to other pyridinyl compounds (294). 

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. 

Only a small substituent is tolerated at position 4 the (2 -S,4 -R)-methyl congener is the most potent of the entire series, but it is somewhat less potent than S-nicotine itself. None of the 3 - or 5 -substituted analogs approach this binding affinity. 2-Chloronicotine (65) is exponentially less potent than nicotine in an 0 4182 nicotinic receptor binding assay, whereas 6-chloronicotine (66) is twofold more potent... 

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). 

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