反应详情

Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-acetamido)-pyridyl))-propionate: A solution of 2-chloroisonicotinic acid (25.0 g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C., the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C. for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhdrous HCl in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhdrous HCl in dioxane was added and the reaction was warmed to reflux for an additional 20 h. Concentration with a stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2×200 mL), dried (Na2SO4). After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 mL) at 0 C. under an argon atmosphere was added acetyl chloride dropwise over 5 min. After 2 h at 0 C., the reaction was pored into over ice 300 g, extracted with ethyl acetate (2×300 mL), washed with water (2×100 ml) followed by brine (2×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of flash chromatography (step gradient ethyl acetate: hexane 1:4 then ethyl acetate: hexane 1:1) to afford ethyl 2-acetamidoisonicotinate.

1. temperatureAfter cooling to 23 C
2. filtrationsubsequently filtered
3. customto remove unreacted
4. concentrationThe solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo
5. filtrationthe desired 2-aminoisonicotinic acid was filtered off
6. additionTo a suspension of 2-aminoisonicotinic acid in ethanol (600 mL)
7. additionwas added 47.1 mL of 4 N anhdrous HCl in dioxane
8. temperatureAfter warming
9. temperatureto achieve reflux for 20 h
10. additionan additional 47.1 mL of 4 N anhdrous HCl in dioxane was added
11. temperaturethe reaction was warmed
12. temperatureto reflux for an additional 20 h
13. concentrationConcentration with a stream of nitrogen in the hood
14. concentrationwas followed by further concentration in vacuo
15. additionthe remaining solid was diluted with saturated bicarbonate (200 mL)
16. extractionextracted with ethyl acetate (2×200 mL)
17. dry with materialdried (Na2SO4)
18. concentrationAfter concentration in vacuo