反应详情

To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (66 mg, 0.27 mmol), (R)-6-trifluoromethyl-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (60.6 mg, 0.25 mmol), 4-dimethylaminopyridine (2.5 mg, 0.02 mmol) and N,N-diisopropylethylamine (153 μL, 0.88 mmol) in anhydrous DMF (4 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (102 mg, 0.27 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. The residue was dissolved in Methanol (20 mL) and 2N HCl (5 mL) was added. The reaction mixture was heated at 60° C. for 2 hours, then cooled and the methanol removed under vacuum. The remaining aqueous product was poured into saturated NaHCO3 solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 3% MeOH in DCM over 30 minutes) gave the product (43 mg) as a solid. m/z=391.8 (M+1), r.t.=2.96 and 3.04 mins. 1H NMR (400 MHz; DMSO-d6) δ 12.99 (1H, d), 8.68-8.60 (1H, m), 8.04 (0.5H, s), 7.94-7.87 (0.5H, m), 7.69 (0.5H, s), 7.53-7.16 (5H, m), 7.08-7.04 (0.5H, m), 5.12-4.90 (2H, m), 4.47-4.30 (2H, m), 1.46-1.41 (3H, m).

1. extractionextracted with EtOAc (3×30 mL)
2. washThe combined organics were washed with brine (3×30 mL)
3. dry with materialdried (MgSO4)
4. filtrationfiltered
5. concentrationconcentrated
6. dissolutionThe residue was dissolved in Methanol (20 mL)
7. addition2N HCl (5 mL) was added
8. temperatureThe reaction mixture was heated at 60° C. for 2 hours
9. temperaturecooled
10. customthe methanol removed under vacuum
11. additionThe remaining aqueous product was poured into saturated NaHCO3 solution (30 mL)
12. extractionextracted with EtOAc (3×30 mL)
13. washThe combined organics were washed with brine (3×30 mL)
14. dry with materialdried (MgSO4)
15. filtrationfiltered
16. concentrationconcentrated