Synthesis
To a stirred mixed solution of methyl 4-cyclopropyl-2-methylbenzoate (1.3 g, 6.84 mmol) in tetrahydrofuran (THF, 9 mL), methanol (MeOH, 6 mL) and water (3 mL) was added lithium hydroxide monohydrate (0.842 g, 20.52 mmol). The reaction mixture was stirred at 70 °C for 2 hours. After completion of the reaction, excess solvent was removed by distillation under reduced pressure. The residue was dissolved in water and acidified to pH < 7 with 10% hydrochloric acid (HCl) solution, followed by three extractions with ethyl acetate (EtOAc). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the target product 4-cyclopropyl-2-methylbenzoic acid (1.2 g, 99% yield). The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 7.52 (d, J = 7.6 Hz, 1H), 6.75-6.74 (m, 2H), 1.84-1.81 (m, 1H), 0.92-0.87 (m, 2H), 0.64-0.60 (m, 2H).
References
[1] Patent: WO2014/125408, 2014, A2. Location in patent: Page/Page column 24
[2] Patent: US2006/205773, 2006, A1. Location in patent: Page/Page column 22
[3] Patent: US2010/222325, 2010, A1. Location in patent: Page/Page column 118
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
