反应详情

温度

100 °C

Into a flask was added (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (107 g, 219.29 mmol) and acetic acid (750 mL, 6.74 mol). The mixture was stirred for 5 min. Zinc powder (71.70 g, 1.10 mol) was added. An exotherm to 79° C. was observed over a period of 30 sec. The reaction mixture was warmed to 100° C. and stirred for 2 h. The mixture was cooled to 50° C. and water (750 mL) was added. The mixture was stirred for 10 min and cooled to 10° C. Ethyl acetate (500 mL) was added and the mixture was stirred for 20 min and filtered through Celite rinsing with ethyl acetate (300 mL). The filtrate was cooled to 10° C. and aqueous ammonium hydroxide (936.92 mL, 6.74 mol) was added dropwise over a period of 20 min. The layers were separated and the organics were washed with a mixture of water:brine (1:1, 500 mL), and concentrated under reduced pressure. Ethyl acetate (200 mL) was added and the mixture was concentrated under reduced pressure followed by the addition of acetonitrile (500 mL). The mixture was concentrated to dryness at 45° C. to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 g) as an amorphous material. 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; HPLC retention time: 4.450 min (Method: Same as for Step 1).

1. waitAn exotherm to 79° C. was observed over a period of 30 sec
2. stirringstirred for 2 h
3. temperatureThe mixture was cooled to 50° C.
4. stirringThe mixture was stirred for 10 min
5. temperaturecooled to 10° C
6. stirringthe mixture was stirred for 20 min
7. filtrationfiltered through Celite
8. washrinsing with ethyl acetate (300 mL)
9. temperatureThe filtrate was cooled to 10° C.
10. customThe layers were separated
11. washthe organics were washed with a mixture of water:brine (1:1, 500 mL)
12. concentrationconcentrated under reduced pressure
13. additionEthyl acetate (200 mL) was added
14. concentrationthe mixture was concentrated under reduced pressure
15. additionfollowed by the addition of acetonitrile (500 mL)
16. concentrationThe mixture was concentrated to dryness at 45° C.