反应详情

温度

-20 °C

A flask was charged with TfOH (136.4 g, 909 mmol) and DCM (505 mL) and cooled to −20° C. Anisole (45 g, 416 mmol) was added followed by a solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (101 g, 166 mmol) in DCM (303 mL). The mixture was warmed to 20° C., and maintained for 15 hours. HPLC showed consumption of (I-53). The reaction was cooled to <0° C. and DCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10). The aqueous layer was separated and extracted with DCM (500 mL). The rag layer was filtered through Celite and the two layers were separated. The organic layers were combined and concentrated to dryness. The resulting solid was triturated with TBME (250 mL) at 20° C. to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). Melting point: 140° C. (dec.). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61-7.58 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.3, 23.8 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H).

1. temperatureThe mixture was warmed to 20° C.
2. temperaturemaintained for 15 hours
3. customconsumption of (I-53)
4. temperatureThe reaction was cooled to <0° C.
5. additionDCM (1 L) and an aqueous saturated K2CO3 (1 L) was added (aqueous layer pH=9-10)
6. customThe aqueous layer was separated
7. extractionextracted with DCM (500 mL)
8. filtrationThe rag layer was filtered through Celite
9. customthe two layers were separated
10. concentrationconcentrated to dryness
11. customThe resulting solid was triturated with TBME (250 mL) at 20° C.