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 (60 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (838 mg, 2.82 mmol) is added, followed by hydroxybenzotriazole hydrate (392 mg, 2.56 mmol). The resulting mixture is stirred at rt for 30 min to give a suspension, which is treated with hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (509 mg, 2.69 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 135 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with five portions of dichloromethane, the combined extract is washed with saturated aqueous sodium bicarbonate (30 mL), then 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 (3:1). Fractions containing the product are combined and evaporated and repurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1) to obtain {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (686 mg, 73% yield) as a white solid. MS: m/e 755 (100%) (2M+Na), 367 (70%) (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.97 (1H, br.s), 8.22 (1H, br.s), 7.44 (1H, s), 5.21 (1H, br.t), 3.96 (5H, m), 2.59 (3H, s), 2.53 (2H, q), 1.48 (9H, s), 1.18 (3H, t).

1. customto give a suspension, which
2. stirringThe resulting solution is stirred at rt for 135 hr
3. customthe reaction
4. extractionthe mixture is extracted with five portions of dichloromethane
5. extractionthe combined extract
6. washis washed with saturated aqueous sodium bicarbonate (30 mL)
7. dry with materialdried over magnesium sulfate
8. filtrationfiltered
9. customevaporated
10. customThe crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1)
11. additionFractions containing the product
12. customevaporated
13. customrepurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1)