[Synthesis]
Example 7. Synthesis of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22)
To a 250 mL four-necked round-bottomed flask (equipped with a mechanical stirrer, thermocouple, dosing funnel and nitrogen inlet) was added compound 21 (9.25 g, 13.52 mmol, 3.50% water content) and acetonitrile (74 mL) and the temperature was controlled to be at 20 ± 5 °C. The resulting white suspension was cooled to below 5 °C. Boron trifluoride diethyl ether compound (BF3-OEt2, 6.46 mL, 51.37 mmol, 3.80 eq.) was slowly added, keeping the internal temperature below 5.0°C. The reaction mixture was then warmed to 20 ± 5 °C and stirred for 18 hours.
After completion of the reaction, the mixture was cooled to 0-5 °C and BF3-OEt2 (0.34 mL, 2.70 mmol, 0.2 eq.) was added again, keeping the temperature below 5.0 °C. Warm up to 20±5 °C and continue stirring for 5 hours. Cool again to 0-5 °C, slowly add water (12.17 mL, 0.676 mol, 50 eq.) and keep the internal temperature below 5.0 °C. Warmed to 20±5°C and stirred for 2 hours.
Cool to 0-5 °C, add aqueous ammonium hydroxide (NH4OH, 5N, 121.7 mmol, 9.0 eq.) and keep the internal temperature below 5.0 °C. The temperature was raised to 20 ± 5 °C and stirred for 20 h. After completion of SEM-deprotection, the reaction mixture was filtered and the solid was washed with EtOAc (9.25 mL). The filtrates were combined, diluted with EtOAc (74 mL) and washed with 13% aqueous NaCl (46.2 mL). The organic phase was diluted with EtOAc (55.5 mL) and concentrated under reduced pressure to a minimum volume. EtOAc (120 mL) was added and stirred at 20±5°C for 30 min. Wash sequentially with 7% aqueous sodium bicarbonate (2 x 46 mL) and 13% aqueous sodium bicarbonate (46 mL). The organic phase was diluted with EtOAc (46 mL) and treated with water (64 mL) at 50±5°C for 30 min. Cooled to 20±5°C and partitioned. The organic phase was again treated with water (64 mL) at 50±5°C for 30 min, cooled and partitioned. The organic phase was concentrated to give the crude product 22 (free base), which was purified by column chromatography (SiO2, 330 g, 0-10% MeOH/EtOAc gradient elution) to give analytically pure free base 22 (7.00 g, 93.5%) as an off-white solid.
Identification data for 22:
1H NMR (400 MHz, (CD3)2SO) δ 12.17 (d, J = 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J = 4.7 Hz, 1H), 7.63 (dd, J = 3.6, 2.3 Hz, 1H), 7.09 (dd, J = 3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J = 7.9 Hz, 2H), 3.61 (t, J = 7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J = 10.5 Hz, 1H), 3.09 (ddd, J = 13.2, 9.5, 3.1 Hz , 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm.
13C NMR (101 MHz, (CD3)2SO) δ 160.28, 153.51, 150.86, 152.20, 150.94, 149.62, 146.30, 146.25, 139.48, 134.78, 134.61, 135.04, 134.92, 134.72, 134.60, 134.38, 134.38, 134.60, 134.40, 134.40, 134.40, 134.40 134.38, 134.26, 134.03, 133.92, 129.22, 127.62, 126.84, 121.99, 122.04, 124.77, 122.02, 119.19, 116.52, 117.39, 113.00, 99.99, 61.47, 60.49, 57.05. 44.23, 28.62, 27.88, 27.19 ppm.
Molecular formula: C26H23F4N9O (MW 553.51), LCMS (EI) m/e 554.1 (M+ + H). |