反应详情

To a suspension of 7-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 308C, 200 mg, 0.45 mmol. 36:64 mixture of regioisomers with the minor as the desired one), diethyl [(6-aminopyridin-3-yl)methyl]phosphonate (Compound 309A, 111 mg, 0.45 mmol), Pd(OAc)2 (5.09 mg, 0.023 mmol), Xantphos (26.2 mg, 0.045 mmol), and Cs2CO3 (296 mg, 0.91 mmol) in dry dioxane (2.8 mL) was bubbled nitrogen for 2 min. This mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography (1-5% MeOH in DCM) to give 32.6 mg of the title compound (yield: 11%), the more polar of the two regioisomers on the TLC. 1H NMR (CDCl3, 400 MHz): δ=1.28 (t, J=7.2 Hz, 6 H), 1.44 (m, 2 H), 1.63 (m, 2 H), 1.91 (m, 2 H), 2.16 (m, 2 H), 2.50 (m, 1 H), 3.12 (d, J=21.2 Hz, 2 H), 3.22 (s, 3 H), 3.77 (m, 1 H), 4.02-4.10 (m, 4 H), 4.39 (s, 2 H), 7.32 (d, J=8.4 Hz, 1 H), 7.68 (d, J=8.4 Hz, 1 H), 7.98 (s, 1 H), 8.22 (s, 1 H), 8.36 (d, J=8.4 Hz, 1 H), 8.45 (s, 1 H), 8.62 (d, J=8.4 Hz, 1 H), 10.59 (s, 1 H). MS (ES+): m/z 649.18 [MH+]. HPLC: tR=3.38 min (ZQ3, polar—5 min).

1. customwas bubbled nitrogen for 2 min
2. customThis mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor
3. filtrationthe reaction mixture was filtered
4. concentrationthe filtrate was concentrated
5. custompurified by silica gel chromatography (1-5% MeOH in DCM)