反应详情

(S)-3-Amino-1-methylpiperidin-2-one hydrochloride (56 mg, 0.34 mmol) was dissolved in triethylamine (95 μL, 0.68 mmol) and N,N-dimethylformamide (1.5 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; 152 mg, 0.34 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 a silica gel column, eluting with 70% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ie) (94 mg, 60%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 8.61 (br, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.90 (m, 1H), 4.48 (ddd, 1H), 4.22 (d, 2H), 3.36 (m, 2H), 2.97 (s, 3H), 2.73 (m, 1H), 2.36 (m, 1H), 1.99 (m, 2H), 1.66 (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 a silica gel column
6. washeluting with 70% ethyl acetate/hexanes