Synthesis
Oxalyl chloride (0.35 mL, 4.16 mmol) was dissolved in anhydrous dichloromethane (15.0 mL) under nitrogen protection and cooled to -78 °C. Subsequently, dimethyl sulfoxide (0.27 mL, 3.84 mmol) was slowly added dropwise and stirred at -78 °C for 15 min. Next, a solution of (4,4-difluorocyclohexyl)methanol (0.48 g, 3.20 mmol) in anhydrous dichloromethane (10 mL) was added dropwise. The reaction mixture was continued to be stirred at -78 °C for 1 hour. After that, triethylamine (1.27 mL, 9.60 mmol) was added slowly and dropwise. The reaction mixture was gradually warmed to room temperature and subsequently concentrated to dryness under reduced pressure. The crude product was dissolved in ether (30 mL) and washed sequentially with saturated aqueous sodium bicarbonate solution and ammonium chloride solution (30 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,4-difluorocyclohexanecarboxaldehyde (0.39 g, 82% yield), which could be used in subsequent reactions without further purification.1H NMR (DMSO-d6) δ: 9.61 (s, 1H), 2.05-1.73 (m, 7H), 1.64-1.51 (m, 2H).
References
[1] Patent: WO2014/144836, 2014, A2. Location in patent: Paragraph 0095; 0996
[2] European Journal of Medicinal Chemistry, 2016, vol. 111, p. 138 - 159
[3] Patent: WO2014/184561, 2014, A1. Location in patent: Page/Page column 72
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2780 - 2789
[5] Patent: WO2009/65035, 2009, A1. Location in patent: Page/Page column 81-82
