反应详情

(S)-3-Amino-1-(2-hydroxyethyl)pyrrolidin-2-one hydrochloride (101 mg, 0.558 mmol) was dissolved in triethylamine (0.141 mL, 1.01 mmol) and N,N-dimethylformamide (2.5 mL). To this solution was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 225 mg, 0.507 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel, loaded and eluted with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide (Ig) (177 mg, 74%). Mass spec: 473 (M+1). 1H NMR (CDCl3) δ 8.37 (br, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.16 (m, 1H), 7.01 (m, 2H), 6.92 (m, 1H), 4.53 (m, 1H), 3.83 (m, 3H), 3.56 (m, 3H), 3.44 (m, 1H), 3.15 (t, 1H), 2.74 (m, 1H), 2.36 (m, 1H), 2.08 (m, 1H), 0.92 (d, 6H).

1. washwashed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine
2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
3. filtrationfiltered
4. concentrationconcentrated
5. customThe crude product was purified by flash chromatography on silica gel
6. washeluted with 100% acetone