反应详情

温度

100 °C

To a solution of (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate (0.20 g, 0.32 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.97 mL, 1.9 mmol). The reaction mixture was heated at about 100° C. for about 3 h before it was allowed to cool to ambient temperature. The reaction was neutralized with 4N HCl in 1,4-dioxane (0.5 mL) and was concentrated under reduced pressure. To the residue was added MeCN (25 mL) before it was concentrated under reduced pressure. This procedure was repeated before the addition of 1-cyanocyclopropanecarboxylic acid (0.072 g, 0.65 mmol), HATU (0.111 g, 0.291 mmol) and DMF (2 mL) followed by DIEA (0.170 mL, 0.971 mmol). After stirring at room temperature for about 3 h, the reaction was partitioned between EtOAc (2×50 mL) and aqueous NaHCO3 (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction was purified by RP-HPLC (Table 2, Method j). The combined product-containing fractions were concentrated under reduced pressure to remove MeCN and then lyophilized to give (R)-1-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile as a white solid (0.010 g, 9%): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 335 (M+H)+.

1. temperatureto cool to ambient temperature
2. concentrationwas concentrated under reduced pressure
3. additionTo the residue was added MeCN (25 mL) before it
4. concentrationwas concentrated under reduced pressure
5. customthe reaction was partitioned between EtOAc (2×50 mL) and aqueous NaHCO3 (50 mL)
6. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe crude reaction
10. customwas purified by RP-HPLC (Table 2, Method j)
11. additionThe combined product-containing fractions
12. concentrationwere concentrated under reduced pressure
13. customto remove MeCN