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) of Step 2, Example 14 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 45 min to give a suspension, which is treated with acetic hydrazide (285 mg, 3.85 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 32 hr, LC/MS shows the reaction to be complete. 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 evaporated to obtain 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-acetylhydrazide (give 923 mg) as a white solid. MS: m/e=252 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.72 (1H, d), 8.50 (1H, d), 7.49 (1H, s), 3.96 (3H, s), 2.59 (3H, s), 2.54 (2H, q), 2.12 (3H, s), 1.17 (3H, t).

1. customto give a suspension, which
2. stirringThe resulting solution is stirred at rt for 32 hr
3. customthe reaction
4. extractionthe mixture is extracted with six portions of dichloromethane
5. extractionthe combined extract
6. dry with materialis dried over magnesium sulfate
7. filtrationfiltered
8. customevaporated
9. 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)
10. additionFractions containing the product
11. customevaporated