Synthesis
Under nitrogen protection, tert-butyllithium (2.14 mL, 1.6 M toluene solution, 3.42 mmol) was slowly added dropwise to an anhydrous THF solution (6 mL) of 4-bromo-1-isopropoxy-2-methoxybenzene (400 mg, 1.63 mmol) at a reaction temperature of -78 °C. The reaction mixture was stirred continuously at -78 °C for 1 hour. Subsequently, the reaction solution was slowly added dropwise to a flask containing solid carbon dioxide (1.8 g, 40.8 mmol) in anhydrous THF solution (2 mL). The reaction mixture was continued to be stirred for 30 min and then gradually warmed up to room temperature. Water (20 mL) was added to the reaction mixture and the volatiles were removed under reduced pressure. The resulting aqueous layer was acidified to pH 1 with 1N HCl solution and subsequently extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-isopropoxy-3-methoxybenzoic acid (310 mg, 85% yield) as a white solid.ESI-MS m/z calculated value 210.1, measured value 211.1 ([M + H]+); retention time: 1.23 min (run time 3 min).1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.67 (dt, J = 12.1, 6.0 Hz, 1H), 3.78 (s, 3H), 1.28 (d J = 6.0 Hz, 6H).
References
[1] Patent: WO2013/109521, 2013, A1. Location in patent: Paragraph 00300
[2] Patent: WO2014/22639, 2014, A1. Location in patent: Paragraph 00188-00190
[3] Patent: US2012/196869, 2012, A1. Location in patent: Paragraph 0350; 0351; 0352
