3,4-Dihydro-2H-benzo[1,4]oxazine-7-carboxylic acid

Synthesis

The general procedure for the synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid from methyl 3,4-dihydro-2H-1,4-benzoxazine-7-carboxylate was as follows: methyl 3,4-dihydro-2H-benzo[1,4]oxazine-7-carboxylate (52 mmol) was dissolved in methanol (20 mL) and 2M aqueous sodium hydroxide (20 mL). The reaction was stirred at 60 °C for 48 hours. Upon completion of the reaction, the methanol was removed by rotary evaporation. The remaining aqueous phase was acidified with 4 M hydrochloric acid to pH < 3. The acidified aqueous phase was extracted three times with ethyl acetate and the organic phases were combined. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography on silica gel with heptane/ethyl acetate gradient elution. The final product yield was 31%. The structure of the product was confirmed by 1H NMR (D6-DMSO): δ 3.33 (t, 2H); 4.10 (t, 2H); 6.51 (d, 1H); 7.16 (d, 1H); 7.30 (dd, 1H).

References

[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8219 - 8248
[2] Patent: WO2005/39572, 2005, A1. Location in patent: Page/Page column 33
[3] Patent: US2016/355483, 2016, A1. Location in patent: Paragraph 0382-0383