反应详情

温度

2.5 °C

To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N,N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) δ 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).

1. customTo a oven dried 2 L round bottom flask
2. customequipped with the overhead
3. customthe ice bath was removed
4. temperatureto warm gradually to room temperature
5. waitwas complete after 22 h
6. concentrationthe reaction mixture was concentrated under reduced pressure
7. customto remove about 400 mL of solvent
8. additionThe residue was treated with ethyl acetate (EtOAc, 500 mL)
9. washthe resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL)
10. extractionThe aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL)
11. dry with materialThe combined organic fractions were dried over magnesium sulfate (MgSO4)
12. concentrationconcentrated under reduced pressure
13. customto yield the crude product (25) as an amber oil
14. customThe crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution)