反应详情

Sodium hydride (0.557 g, 13.93 mmol) was added portionwise to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (1.004 g, 3.48 mmol), in THF (30 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (0.602 g, 3.48 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (50 mL). The mixture was washed sequentially with water (50 mL), a saturated solution of NaHCO3 (50 mL), water (25 mL) and finally with a saturated solution of NaCl (20 mL). The mixture was filtered and the organic layer separated, dried over Na2SO4 and then evaporated. The residue was triturated in Et2O and MeOH and the mixture filtered. The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 5-10% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to leave 6-chloro-[[2-methyl-3-oxo-7-(4-propan-2-ylpiperazin-1-yl)-1H-isoindol-4-yl]amino]pyridine-3-carbonitrile (316 mg, 21% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 1.02 (6H, d), 2.60 (4H, t), 2.70 (1H, t), 3.02-3.08 (7H, m), 4.51 (2H, s), 7.04 (1H, d), 7.15 (1H, dd), 7.44 (1H, dd), 8.53 (1H, d), 9.68 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=425.30.

1. temperaturethe mixture heated overnight at 60° C
2. temperatureto cool to room temperature
3. washThe mixture was washed sequentially with water (50 mL)
4. filtrationThe mixture was filtered
5. customthe organic layer separated
6. dry with materialdried over Na2SO4
7. customevaporated
8. customThe residue was triturated in Et2O
9. filtrationMeOH and the mixture filtered
10. customThe filtrate was evaporated
11. customthe residue purified by chromatography on silica
12. washeluting with a gradient of 5-10% MeOH in CH2Cl2
13. additionFractions containing product
14. customevaporated