Diisopropylethylamine → 4-Methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid [1-(1H-indazol-5-yl)ethyl]amid

A stirred solution of 4-methyl-6-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (50 mg, 0.2 mmol), HBTU (73 mg, 0.2 mmol) and DIPEA (67 μL, 1.5 mmol) in anhydrous DMF (2 mL) was added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethanamine (43 mg, 0.17 mmol) in anhydrous DMF (0.5 mL). The reaction was stirred overnight at room temperature, then 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 resulting product was redissolved in MeOH (10 mL), and 2N HCl (1 mL) was added. After stirring overnight at 50° C., the methanol was removed by evaporation, and the aqueous residue 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 3.5% MeOH in DCM) gave the title compound (22 mg, 31%) as a solid, containing a mixture of diastereomers. m/z=405.5 (M+1), r.t.=3.36, 3.42 mins. 1H NMR (400 MHz; d6-DMSO) δ 13.00 (1H, s), 12.98 (1H, s), 8.51 (1H, d), 8.44 (1H, d), 8.04 (1H, s), 7.95 (1H, s), 7.68 (1H, s), 7.54-7.51 (2H, m), 7.42 (1H, d), 7.36 (1H, d), 7.25 (1H, d), 7.03-6.89 (6H, m), 5.12-5.04 (2H, m), 4.87-4.81 (2H, m), 3.48-3.43 (2H, m), 3.34-3.30 (2H, m), 2.88 (6H, d), 1.47-1.43 (6H, 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 resulting product was redissolved in MeOH (10 mL)
7. addition2N HCl (1 mL) was added
8. stirringAfter stirring overnight at 50° C.
9. customthe methanol was removed by evaporation
10. additionthe aqueous residue poured into saturated NaHCO3 solution (30 mL)
11. extractionextracted with EtOAc (3×30 mL)
12. washThe combined organics were washed with brine (3×30 mL)
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. concentrationconcentrated

ORD record

ord-7978e51fbd0e48748d4f936db4f4645b

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08163901B2