5,6-Disubstituted nicotinic acid

Table 1. Yield and Purity of a 25-Membered Rehearsal Library of 5,6-Disubstituted Nicotinic Acids...

In conclusion, a series of 10 combinatorial libraries consisting of 11,528 total conq)ounds were designed, prepared, and screened as potential herbicide leads. The libraries were chosen to deliver confounds with desirable physical properties, in diis case polar weak acids. The approach was illustrated with a series of 5,6-disubstituted nicotinic acids, prepared usii solid phase, combinatorial techniques. 

The final library consisted of 1320 nicotinic acids of general structure 2 derived from, in part, 36 amines as nucleophiles (2 of which failed), 24 boronic acids, and 5 stannanes. Each MiniKan contained 80 mg of resin, which, with a measured loading of 1.36 mmol/g, was capable of yielding 0.1088 mmol of disubstituted nicotinic acid product. The final product acids were cleaved from the resin with trifluoroacetic acid and isolated as discrete sanq>les. Each sanq>le was analyzed by LCMS and the expected molecular ion was found in >80% of the sanples (92% when failed iiq)uts were eliminated). In selected instances, H NMR analyses were also used to ascertain the success of individual reactions. Members of a 25-membered rehearsal library were hilly characterized the yield and purity of each member of this library are shown in Table 1. 

A number of syntheses of substituted 2,3 -bipyridines are worthy of note. Tetracyclone heated at 215°C with nicotinonitrile affords 3,4,5,6-tetraphenyl-2,3 -bipyridine, whereas 3,4-di(2-pyridyl)pyridine is obtained by an oxidative degradation of the corresponding 6,7-disubstituted thiazolo[3,2-a]-pyridinium salt. Nicotinic acid on UV irradiation in aqueous solution at pH 4-6 gives 2,3 -bipyridine-5-carboxylic acid, whereas irradiation of picolinic acid in the same pH range in the absence of metal ions gives some 2,3 -bipyridine. 6,6 -Diphenyl-2,3 -bipyridine is thought to be formed from... 

Solvent effects on the dissociation of 11 2,6-disubstituted benzoic acids have been analysed by chemometric analysis.66 The acid-base behaviour of the three zwitterionic pyridinecarboxylic acids (picolinic, nicotinic, and isonicotinic acid) has been studied. The cationic form of picolinic acid converts partially into the corresponding zwitterion within a borderline acidity range (pH/acidity function). The various pXa values were determined for the three isomers by spectrophotometric and potentiometric methods and reasonable agreement was found.67... 

Suitable cyclization partners are 2-(acylamino)nicotinic acids and primary amines, giving 2,3-disubstituted pyrido[2,3-r7]pyriinidin-4(3//)-ones. Thus, 3-aryl-2-methylpyrido[2,3-c/]pyrimidin-4(3/f)-ones 22 are synthesized by fusion of 2-acetamidonicotinic acid with arylamines.33... 

The 3,6-diposition-substituted pyridine compounds are important intermediates for industrial synthesis, especially for production of some agricultural chemicals. This compound can be obtained by chemically synthesized from pyridine, but the process is accompanied by some by-products. Microbial hydroxylation of aromatic compounds is a very efficient method of regioselective reaction. Several methods have been reported for the preparation of 3,6-disubstituted pyridine using microorganisms. In 1985, Lehky et al. reported the microbial production of 6-hydroxynicotinic acid (6-HNA) from nicotinic acid (NA) by Achromobacter xylosoxydans Nagasawa et al. also prepared 6-HNA from NA by using Pseudomonas fluorescens TN5. 

Dimethyl acetonedicarboxylate or ethyl acetoacetate can provide the 3-, 4-, and 5-carbons to give 3,5-disubstituted-4-pyridones (XI-177, Rs = CH3CO, CO2CH3). s-Triazine has been used to provide the 2- and 6-carbons. A compound, previously described as 4-hydroxy-3-pyridinecai o lic acid (XII-177, R = Rj = H) ° was shown to be nicotinic acid-l-oxide(XII-I78). ° ... 

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