Isoamyl Nitrite → Nicotinic Acid
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[Na].C([C:5]1[C:6](CC(C)C)=[C:7]([C:18]([O:20]C)=[O:19])[C:8](C(F)F)=[N:9][C:10]=1C(F)(F)F)(=O)C.N(OCCC(C)C)=O>CO>[N:9]1[CH:10]=[CH:5][CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1[Na].C([C:5]1[C:6](CC(C)C)=[C:7]([C:18]([O:20]C)=[O:19])[C:8](C(F)F)=[N:9][C:10]=1C(F)(F)F)(=O)C.N(OCCC(C)C)=O>CO>[N:9]1[CH:10]=[CH:5][CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1This example illustrates the preparation of Compound 101, an example of the formation of the heterocycle by cycloaddition reaction. Sodium (7.87 g, 0.35 mol) was cautiously added in portions to 250 mL methanol under nitrogen. Methyl 5-acetyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (20 g, 0.057 mol) was added at 25° C., followed by dropwise addition of isoamyl nitrite (33.15 g, 0.283 mol). The mixture was stirred overnight at 25° C., then quenched with ice/concentrated HCl slush, and extracted with ether. The combined ether layers were washed with saturated sodium bicarbonate and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by HPLC with 10% ethyl acetate-hexane to give 22 g (99%) of 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-((hydroxyimino)acetyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester, as a yellow solid. m.p. 84°-86° C.
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