4,4,4-TRIFLUORO-1-(3-OXO-3,4-DIHYDRO-2H-BENZO[B][1,4]OXAZIN-6-YL)BUTANE-1,3-DIONE synthesis

Yield:943994-23-8 80%

Reaction Conditions:

Stage #1: ethyl trifluoroacetate,with sodium hydride in tetrahydrofuran;
Stage #2: 6-acetyl-4H-benzo[1,4]oxazin-3-onewith dibenzo-18-crown-6 in tetrahydrofuran;ethanol; for 16 h;Heating / reflux;

Steps:

71.1

To a mixture of NaH (2.51 g, 105 mmol) in THF (100 mL) was carefully added ethyl 2, 2, 2-trifluoroacetate (12.5 mL, 105 mmol), observing both effervescence and a slight exotherm. To this resulting mixture were added sequentially 6-acetyl- 2H-benzo[b] [1, 4]oxazin-3 (4H) -one (5.00 g, 26.2 ?unol) , ethanol (2.50 mL) and a solution of [2, 4] -dibenzo-18-crown-6 (150 mg, 0.418 iranol) in THF (50.0 mL) . The mixture was refluxed for 16 hr, cooled, and partitioned between 10% H₂SO₄ (200 mL) and EtOAc (200 mL) . The organic layer was separated and washed with water (200 mL) , saturated aqueous NaHCO₃ (200 mL) , water (200 mL) and brine (200 mL) , dried (Na₂SO₄) and concentrated in vacuo. The residue was triturated with ether to give the title compound as a yellow solid (6.67 g, 80%) . ¹H-NMR (400 MHz, DMSO-d₆) δ: 10.88 (s, IH), 7.63 (dd, J = 8.5, 2.1 Hz, IH), 7.49 (d, J = 2.1 Hz, IH), 7.04 (d, J = 8.4 Hz, IH), 6.30 (s, IH), 4.69 (s, 2H) and 10.81 (s, IH), 7.58 (dd, J = 8.4, 1.6 Hz, IH), 7.48 (d, J = 1.9 Hz, IH), 7.11 (s, IH), 7.00 (d, J = 8.4 Hz, IH), 4.67 (s, 2H), consistent with a mixture of enolic tautomers; LCMS (ESI^"), M-H^": 286.

References:

WO2007/77961,2007,A2 Location in patent:Page/Page column 271-272