反应详情

A mixture of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (540 mg, 1.25 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (416 mg, 1.38 mmol), Pd(PPh3)4 (7 mg, 0.06 mmol), LiCl (159 mg, 3.75 mmol) and 1M Na2CO3 (6.3 mL, 6.3 mmol) in dioxane (20 mL) was heated to reflux in an oil bath until the iodide had been consumed as determined by LCMS. The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give an orange solid. The title compound was purified by silica gel chromatography (95:3:2 to 85:13:2 CH2Cl2/MeOH/NH3) to yield a yellow solid. HCl (1M in diethyl ether, 3.1 mL, 3.1 mmol) was added in a dropwise manner to a solution of (1R,2S)-5′-methoxy-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (240 mg, 0.500 mmol) in THF (1 mL). A yellow precipitate formed and the solid was then filtered and washed with ether (2 mL) giving the title compound (256 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.19 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (d, J=7.7 Hz, 1H), 5.62 (s, 1H), 4.01-3.98 (m, 2H), 3.67-3.64 (m, 2H), 3.39-3.32 (m, 3H), 3.28 (s, 3H), 3.18-3.11 (m, 2H), 3.00 (s, 3H), 2.28-2.25 (m, 1H), 2.21-2.18 (m, 1H); MS ESI 480.4 [M+H]+, calcd for [C29H29N5O2+H]+ 480.23.

1. temperaturewas heated
2. customhad been consumed
3. additionwas diluted with EtOAc and water
4. additionwas added
5. extractionThe resulting mixture was extracted with EtOAc
6. washthe combined organic extracts were washed with brine
7. dry with materialdried over MgSO4
8. concentrationconcentrated
9. customto give an orange solid
10. customThe title compound was purified by silica gel chromatography (95:3:2 to 85:13:2 CH2Cl2/MeOH/NH3)
11. customto yield a yellow solid
12. customA yellow precipitate formed
13. filtrationthe solid was then filtered
14. washwashed with ether (2 mL)