Yield:477933-12-3 84%

Reaction Conditions:

with triphenylphosphine;diethylazodicarboxylate in tetrahydrofuran;toluene at 20;Product distribution / selectivity;

Steps:

2; 20 1-(2-cyclopropylethyl)-6-fluorobenzo[d]-[1,3]oxazine-2,4-dione

Under nitrogen atmosphere, 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (2.2 g, 12.3 mmol), triphenylphosphine (3.5 g, 13.4 mmol) and cyclopropyl ethanol were stirred together in THF and treated with diethyl azodicarboxylate (40% in toluene, 6.14 ml, 13.4 mmol). The reaction was stirred overnight at room temperature and under nitrogen atmosphere. The THF was evaporated, and the crude compound was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give intermediate 2 (2.54 g, 84%) which was a white powder. Intermediate 2 was characterized by the following spectroscopic data: ¹H NMR (d₆-DMSO, 400 MHz) δ (ppm) 0.34-0.41 (m, 3H), 0.65-0.89 (m,2H), 1.54 (q, J=7.28 Hz, 2H), 4.08 (t, J=7.28 Hz, 2H), 7.17 (td, J=8.54 Hz and J=2.14 Hz, 1H), 7.47 (dd, J=11.3 Hz and J=2.14 Hz, 1H), 8.07 (dd, J=8.54 Hz and J=6.22 Hz, 1H); and MS (ESI, EI^-) m/z=222 (MH^-) mass of acid derivate.; Under nitrogen atmosphere, intermediate 19 (12.3 mmol), triphenylphosphine (13.4 mmol) and cyclopropyl ethanol were stirred together in THF and treated with diethyl azodicarboxylate (40% in toluene, 13.4 mmol). The reaction was stirred overnight at room temperature and under nitrogen atmosphere. The THF was removed, and the crude compound was purified by silica gel chromatography to give intermediate 20, which was a white powder. Intermediate 20 was characterized by the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 0.34-0.41 (m, 3H), 0.65-0.89 (m,2H), 1.54 (q, J=7.28 Hz, 2H), 4.08 (t, J=7.28 Hz, 2H), 7.17 (td, J=8.54 Hz and J=2.14 Hz, 1H), 7.47 (dd, J=11.3 Hz and J=2.14 Hz, 1H), 8.07 (dd, J=8.54 Hz and J=6.22 Hz, 1H); and MS (ESI, EI^-) m/z=222 (MH^-) mass of acid derivate.

References:

US2009/60866,2009,A1 Location in patent:Page/Page column 52; 56