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

Participants

Reaction Steps

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).

Provenance & Evidence