反应详情

温度

100 °C

A solution of (S)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0804 g, 0.221 mmol), 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (0.065 g, 0.18 mmol), potassium carbonate (0.0815 g, 0.590 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) in previously degassed DME/Water (4:1) (2.05 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil. This material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=508.9/510.8 (76/24) [MH+]. This compound was dissolved in DCM (2.0 mL) and charged with 1.0 M of HCl in Et2O (1.1 mL) and stirred at 40° C. for 5 then at rt for an additional 16 h. The solid that formed was filtered off and washed with diethyl ether (3×), yielding the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.23-2.36 (m, 1H), 2.39-2.49 (m, 1H), 3.33-3.48 (m, 1H), 3.51-3.62 (m, 2H), 3.62-3.82 (m, 2H), 5.14-5.28 (m, 1H), 7.66 (t, J=9.2 Hz, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.17 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.54 (d, J=11.7 Hz, 2H), 8.67 (br. s., 1H), 9.41 (br. s., 1H), 9.54 (br. s., 1H), 9.68 (s, 1H). MS (ES+): m/z=408.88/410.77 (76/24) [MH+]. HPLC: tR=1.84 min (ZQ2, polar—5 min).

1. customevacuated
2. additioncharged with N2 (2×)
3. additionThe reaction mixture was diluted with EtOAc
4. washwashed with H2O (2×), brine (2×)
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customto give a brown oil
9. customThis material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3]
10. customresulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester
11. customThe solid that formed
12. filtrationwas filtered off
13. washwashed with diethyl ether (3×)