Potassium bis(trimethylsilyl)amide → (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester

To a mixture of 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol).

1. additionwas added
2. customThe reaction mixture was quenched by the addition of water (1000 mL)
3. customThe organic phase was separated
4. extractionthe aqueous solution was extracted with EtOAc (4×500 mL)
5. washThe combined organic phase was washed with brine (1 L)
6. dry with materialdried over Na2SO4
7. concentrationconcentrated in vacuo
8. customThe residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

ORD record

ord-e02319b6bd2142f898be1593c5368cab

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115151B2