反应详情

To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H).

1. additionwas added
2. washthe organics washed with water (20 mL)
3. extractionThe aqueous layer was back-extracted into EtOAc (15 mL)
4. washthe combined organics were then washed with brine (10 mL)
5. dry with materialdried (MgSO4)
6. customthe volatiles removed in vacuo
7. customThe residue was purified by preparative HPLC
8. washeluting with ACN