Synthesis
Step 1. Preparation of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (i-12b). Dimethyl cyclohexane-1,4-dicarboxylate (i-12a) (8 g, 40 mmol) was reacted with barium hydroxide (6.3 g, 20 mmol) in 80% aqueous methanol (150 mL) for 12 h at 25 °C with stirring. Upon completion of the reaction, the mixture was diluted with water (200 mL) and washed with hexane (100 mL x 2) to remove unreacted starting materials. Subsequently, the aqueous layer was acidified to pH=3 with 2M HCl solution and extracted with ethyl acetate (EtOAc) (100mL x 3). The organic layers were combined, washed with water (100 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent ratio: petroleum ether (PE):ethyl acetate (EtOAc) = 50:1 to 3:1) to afford 4-(methoxycarbonyl)cyclohexanecarboxylic acid (3.2 g, 43% yield) as a white solid.LC-MS (ESI) analysis: calculated value of C9H14O4 [M+H]+ was 187, and the measured value was 187.
References
[1] Patent: WO2014/28597, 2014, A2. Location in patent: Page/Page column 54
[2] Patent: US2015/191434, 2015, A1. Location in patent: Paragraph 0294
[3] Liebigs Annalen der Chemie, 1993, # 8, p. 897 - 904
[4] Patent: WO2006/31959, 2006, A1. Location in patent: Page/Page column 13-14
[5] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1752 - 1761
