反应详情
EQUATION
反应方程式
REACTANTS
反应物
PRODUCTS
生成物
AUXILIARIES
试剂、催化剂与溶剂
CONDITIONS
反应条件
- 温度
- 45 °C
PROCEDURE
实验过程
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70.0 mg, 0.135 mmol), trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanol (53.6 mg, 0.175 mmol), Pd(PPh3)4 (7.78 mg, 0.00673 mmol), K2CO3 (0.0558 g, 0.404 mmol) and 4:1 dioxane:H2O (5 mL, 50 mmol) was heated to 95° C. for 2 h. The solution was cooled to 45° C., and 12 M of HCl in H2O (0.2 mL, 2 mmol) was added, stirring for an additional 2 h. The solution was concentrated in vacuo and transferred to a separation funnel. The material was extracted with DCM and sat. NaHCO3. The organic layer was loaded onto silica gel for column chromatography, eluting with 2-4% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (1 mL, 2 mmol) was added at rt. The solution was stirred for 1 h, and concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (free base; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.84 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.22 (s, 3H), 3.67 (tt, J=10.8, 4.4 Hz, 1H), 4.18 (tt, J=11.0, 4.4 Hz, 1H), 5.11 (q, J=7.2 Hz, 1H), 6.44 (brt, J=73.8 Hz, 1H), 7.13 (dd, J=8.8, 4.4 Hz, 1H), 7.19 (dd, J=8.8, 8.4 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). 1H NMR(HCl salt; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.89 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.23 (s, 3H), 3.67 (tt, J=11.2, 4.2 Hz, 1H), 4.24 (tt, J=11.0, 4.4 Hz, 1H), 5.20 (q, J=7.2 Hz, 1H), 6.71 (brt, J=73.6 Hz, 1H), 7.19 (dd, J=8.8, 4.4 Hz, 1H), 7.26 (dd, J=8.8, 8.0 Hz, 1H), 7.64 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 8.38 (d, J=1.6 Hz, 1H). MS (ES+): m/z=519.16/521.18 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).
WORKUP
后处理
- concentrationThe solution was concentrated in vacuo
- customtransferred to a separation funnel
- extractionThe material was extracted with DCM and sat. NaHCO3
- washeluting with 2-4% (7N NH3 in MeOH)/DCM
- additionThe fractions containing the pure product
- concentrationwere concentrated in vacuo
- dissolutionredissolved in MeOH
- stirringThe solution was stirred for 1 h
- concentrationconcentrated in vacuo