反应详情

温度

0 °C

60% sodium hydride in mineral oil (0.96 g, 24.1 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (2.97 g, 20.1 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (5.87 g, 22.1 mmol) in tetrahydrofuran (50 mL) was added dropwise over a period of 2 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hour. The reaction was cooled to ˜10° C., 1M citric acid (20 mL) added and the mixture was extracted with EtOAc (2×50 mL). The organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to give the methyl (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxypropanoate (5.7 g, 70% ee). This was further purified by chiral HPLC on Chiralcel OJ eluting with isohexane/isopropanol/triethylamine (70:30:0.1) at 60 mL/min. to give the enantiomerically pure product (3.8 g, 50%) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.60-3.73 (2H, m), 3.79 (3H, s), 4.00-4.11 (2H, m), 5.85 (1H, dd), 7.45 (1H, dd), 8.00 (1H, dd), 8.42 (1H, s), 8.58 (1H, s), 8.61 (1H, dd), m/z (ESI+) (M+H)+=378; HPLC tR=1.84 min.

1. temperatureto warm to ambient temperature
2. stirringstirred for 2 hour
3. temperatureThe reaction was cooled to ˜10° C.
4. extractionthe mixture was extracted with EtOAc (2×50 mL)
5. washThe organic extracts were washed with water (25 mL) and saturated brine (25 mL)
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. customevaporated
9. customThe residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane