反应详情

A solution of 2,4-dichloro-5-trifluoromethylpyrimidine (59 mg, 0.27 mmol), diethyl[(5-aminopyridin-2-yl)methyl]phosphonate hydrochloride (Compound 260A, 76.6 mg, 0.27 mmol), and DIPEA (0.14 mL, 0.82 mmol) in THF (0.5 mL) was stirred at 60° C. for 2 h, after which, the solvents were removed in vacuo. The residue was treated with 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (71.1 mg, 0.27 mmol), TFA (0.063 mL, 0.82 mmol, TFE (0.8 mL). The resulting mixture was irradiated in a microwave reactor at 100° C. for 45 min. Solvents were removed in vacuo and the residue was dissolved in DCM (5 mL) and neutralized with sat. NaHCO3 (aq.) (5 mL). The organic phase was separated, aqueous phase extracted with DCM (2×5 mL). The organic phases were combined, dried over MgSO4, filtered, concentrated, and residue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM) to give 1.3 mg of diethyl[(5-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-pyridin-2-yl)methyl]phosphonate (Example 260) as the more polar spot on TLC (yield: 0.73%) and 3.8 mg of diethyl[(5-{[2-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}pyridin-2-yl)methyl]phosphonate (Compound 261) as the less polar spot on TLC (yield: 2.1%).

1. customafter which, the solvents were removed in vacuo
2. customThe resulting mixture was irradiated in a microwave reactor at 100° C. for 45 min
3. customSolvents were removed in vacuo
4. dissolutionthe residue was dissolved in DCM (5 mL)
5. customThe organic phase was separated
6. extractionaqueous phase extracted with DCM (2×5 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated
10. customresidue was purified by prep TLC (5% 7 N ammonia in MeOH in DCM)