反应详情

温度

98 °C

A 3 L flask was charged with 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (50 g, 240 mmol), 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-43) (158 g, 290 mmol), Cs2CO3 (133 g, 408 mmol) and 1,4-dioxane (1125 mL). The reaction was heated to 98° C. and maintained for 30 minutes. Pd(OAc)2 (3.5 g, 15.6 mmol) and Xantphos (9.5 g, 16.4 mmol) were added and the reaction was heated to 102° C., and maintained for 3 hours. After 3 hours, additional 5-iodo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (1-43) (7 g, 13.3 mmol) was added and maintained at 102° C. for 1 hour. HPLC analysis (UV=215 nm) was used to monitor the reaction. The mixture was cooled to 20° C. and water (500 mL) and EtOAc (2 L) were added. The above procedure was repeated on the same scale and the two runs were combined. The suspension was filtered through 200 g of silica gel and concentrated to dryness under vacuum to give a dark brown sticky solid. The solids were dissolved in i-PrOAc (3 L) with heat and washed with water (500 mL). The organic layer was concentrated to dryness to give a dark brown solid. The solids were purified by column chromatography on silica gel with 50% EtOAc in heptanes as eluant to yield 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). Melting point: 90° C. (dec.). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=7.6 Hz, 1 H), 7.78 (s, 1 H), 7.38 (s, 1 H), 7.30-7.26 (m, 1 H), 7.25-7.23 (m, 1 H), 7.22-7.16 (m, 5 H), 6.92-6.87 (m, 4 H), 6.6 (dd, J=2.4, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.09 (dd, J=6.8, 9.2 Hz, 1 H), 4.74 (d, J=16.0 Hz, 2 H), 4.50 (d, J=15.6 Hz, 2 H), 4.22-3.94 (m, 2 H), 3.82 (s, 6 H), 2.96-2.84 (m, 1 H), 2.18-2.05 (m, 1 H).

1. temperaturemaintained for 30 minutes
2. temperaturethe reaction was heated to 102° C.
3. temperaturemaintained for 3 hours
4. temperaturemaintained at 102° C. for 1 hour
5. customthe reaction
6. temperatureThe mixture was cooled to 20° C.
7. filtrationThe suspension was filtered through 200 g of silica gel
8. concentrationconcentrated to dryness under vacuum
9. customto give a dark brown sticky solid
10. temperaturewith heat
11. washwashed with water (500 mL)
12. concentrationThe organic layer was concentrated to dryness
13. customto give a dark brown solid
14. customThe solids were purified by column chromatography on silica gel with 50% EtOAc in heptanes as eluant