反应详情

Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) is dissolved in dichloromethane (30 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (990 mg, 3.33 mmol) is added, followed by hydroxybenzotriazole hydrate (510 mg, 3.33 mmol). The resulting mixture is stirred at rt for 40 min to give a suspension, which is treated with formyl hydrazide (231 mg, 3.85 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol) to give a solution. After stirring at rt for 23 hr, LC/MS shows the reaction to be incomplete. The reaction is allowed to stir for a further 97 hr at room temperature. The reaction is diluted with water and the mixture is extracted with six portions of dichloromethane, the combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1, increasing to 1:2). Fractions containing the product are combined, and the product triturated with ether to give 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-formylhydrazide (361 mg) as a white solid that was used without further purification. MS: m/e=238 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 9.05 (1H, br.s), 8.71 (1H, br.s), 8.20 (1H, s), 7.49 (1H, s), 3.97 (3H, s), 2.58 (3H, s), 2.56 (2H, q), 1.16 (3H, t).

1. customto give a suspension, which
2. customto give a solution
3. stirringAfter stirring at rt for 23 hr
4. customthe reaction
5. stirringto stir for a further 97 hr at room temperature
6. extractionthe mixture is extracted with six portions of dichloromethane
7. extractionthe combined extract
8. dry with materialis dried over magnesium sulfate
9. filtrationfiltered
10. customevaporated
11. customThe crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1, increasing to 1:2)
12. additionFractions containing the product
13. customthe product triturated with ether