Synthesis
The general procedure for the synthesis of 2-fluoro-5-methoxybenzoic acid from 4-fluoroanisole and carbon dioxide was as follows: 1-fluoro-4-methoxybenzene (5 g, 39.6 mmol, 1.0 eq.) and PMDTA (7.56 g, 43.62 mmol, 1.1 eq.) were dissolved in anhydrous THF (100 mL) under nitrogen protection and cooled to -60 °C. A solution of s-BuLi (1.3 M, 36.6 mL, 47.5 mmol, 1.2 eq.) was added slowly over 1 hr. The reaction mixture continued to be stirred at -60 °C for 2 hours. Subsequently, carbon dioxide gas was passed into the solution for 1 hour. After completion of the reaction, the mixture was slowly warmed to room temperature, acidified with 1 M HCl solution and extracted with EtOAc. The organic phases were combined, washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc/petroleum ether, gradient from 0:1 to 1:1) to afford 2-fluoro-5-methoxybenzoic acid as a yellow solid (5.4 g, 80% yield).LC-MS: m/z 171.1 [M+H]+, 193.0 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ. 13.33 (s, 1H), 7.31 (m, 1H), 7.24 (m, 1H), 7.20-7.16 (m, 1H), 3.78 (s, 3H).
References
[1] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1271 - 1275
[2] Patent: WO2013/37705, 2013, A2. Location in patent: Page/Page column 61; 62
[3] Patent: WO2004/14856, 2004, A1. Location in patent: Page 21
[4] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7495 - 7498
