Synthesis
General steps:
1. ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) was dissolved in dichloromethane (DCM, 5 mL) and Deoxo-Fluor (0.881 mL) and ethanol (EtOH, 0.038 mL) were added.
2. The reaction mixture was stirred at room temperature for 16 hours.
3. Upon completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate (NaHCO3) solution and extracted with ethyl acetate (EtOAc).
4. The organic phase was separated, washed with water and then with saturated sodium chloride (NaCl) solution.
5. The organic phase was dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated to give ethyl 2-(4,4-difluorocyclohexyl)acetate (0.4 g).
6. 2-(4,4-difluorocyclohexyl)ethyl acetate was dissolved in tetrahydrofuran (THF, 2 mL) and 1N sodium hydroxide (NaOH, 1 mL) solution was added.
7. The reaction mixture was stirred at room temperature for 16 hours.
8. Upon completion of the reaction, the reaction mixture was concentrated and then diluted with ethyl acetate (EtOAc) and acidified with 1N hydrochloric acid (HCl).
9. The organic phase was washed with saturated aqueous sodium bicarbonate (NaHCO3) solution and then with saturated sodium chloride (NaCl) solution.
10. The organic phase was dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated to give 2-(4,4-difluorocyclohexyl)acetic acid as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (1H, br.s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1H, m), 1.10-1.31 (2H, m).
References
[1] Patent: US2006/264489, 2006, A1. Location in patent: Page/Page column 78
[2] Patent: WO2010/103429, 2010, A1. Location in patent: Page/Page column 34-35
[3] Patent: US2013/183269, 2013, A1. Location in patent: Paragraph 1216; 1217
[4] Patent: US2015/23913, 2015, A1. Location in patent: Paragraph 1461-1462
[5] Patent: WO2015/5901, 2015, A1. Location in patent: Page/Page column 517; 518
