Sodium Hydroxide → 7-Fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine

Temperature

65 °C

To a stirred solution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (I-22, 1 g, 5.98 mmol) in THF (25 mL) at 0° C. was added 3M CH3MgBr (8 mL, 24 mmol). After additon, the cooling bath was removed and the mixture was heated to 65° C. for 4 h. The reaction mixture was quenched with acetic acid (10 mL) at 0° C. and NaBH4 (568 mg, 15 mmol) was added to the solution. The resulting solution was stirred at rt for overnight. Subsequently, 3N aqueous NaOH solution was cautiously added until pH value of the mixture was adjusted to 10.0. The basic solution was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over neutral alumina (petroleum ether/EtOAc, 0-15% EtOAc) to afford 135 mg (14%) of 7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23) as a brown oil. 1H NMR (400 MHz, DMSO) δ 6.45-6.55 (m, 3H), 4.16-4.19 (m, 1H), 3.73-3.77 (m, 1H), 3.44-3.51 (m, 2H), 1.17 (d, J=6.34 Hz, 3H).

1. customAfter additon, the cooling bath was removed
2. customThe reaction mixture was quenched with acetic acid (10 mL) at 0° C.
3. extractionThe basic solution was extracted with ethyl acetate (2×30 mL)
4. washThe combined organic layers were washed with water, brine
5. dry with materialdried over Na2SO4
6. customthe solvent was removed under reduced pressure
7. customThe resulting crude product was purified by column chromatography over neutral alumina (petroleum ether/EtOAc, 0-15% EtOAc)

ORD record

ord-f4e04983cd394c5c8ff0cea7acb6db62

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08871754B2