反应详情

A round bottom flask under a nitrogen atmosphere is charged with 5-ethyl-6-methoxy-2-methyl-nicotinic acid (1.00 g, 5.13 mmol) of Step 2, Example 14 dissolved in dichloromethane (50 mL). To this is added O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.676 g, 5.64 mmol) followed by hydroxybenzotriazole hydrate (785 mg, 5.13 mmol). The resulting mixture is stirred at rt for 30 min then treated with a solution of ammonia in 1,4-dioxane (0.5 M, 10.3 mL, 5.15 mmol) followed by N-ethyl-diisopropylamine (2.32 mL, 13.3 mmol) to give a suspension. After stirring at rt for 23 hr, LC/MS shows the reaction to be incomplete. A solution of ammonia in 1,4-dioxane (0.5 M, 10 mL, 5.00 mmol) is added and stirred for an additional period of 24 hr. LC/MS shows the reaction is still incomplete and so more ammonia (0.5 M, 5 mL, 2.5 mmol) is added and allowed to stir for 68 hr to give a solution. LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with seven 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 (1:0, increasing to 1:2). Fractions containing the product are combined and re-purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2). Fractions containing the product are combined, the solvent evaporated and the residue triturated with ether to give 5-ethyl-6-methoxy-2-methyl-nicotinamide (1.22 g) as a fluffy, pink solid. MS: m/e=195 (M+H); 1H NMR (CDCl3, δ, ppm): 7.50 (1H, s), 5.77 (2H, s), 3.96 (3H, s), 2.61 (3H, s), 2.56 (2H, q), 1.18 (3H, t).

1. customto give a suspension
2. stirringAfter stirring at rt for 23 hr
3. customthe reaction
4. stirringstirred for an additional period of 24 hr
5. stirringto stir for 68 hr
6. customto give a solution
7. customthe reaction
8. extractionthe mixture is extracted with seven portions of dichloromethane
9. extractionThe combined extract
10. dry with materialis dried over magnesium sulfate
11. filtrationfiltered
12. customevaporated
13. customThe crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2)
14. additionFractions containing the product
15. customre-purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:0, increasing to 1:2)
16. additionFractions containing the product
17. customthe solvent evaporated
18. customthe residue triturated with ether