Cyclohexanemethanol, 4,4-difluoro- (9CI)

Uses

(4,4-Difluorocyclohexyl)methanol acts as a reagent in the preparation and anti-HIV activity of fluorinated betulinic acid derivatives.

Synthesis

General procedure for the synthesis of (4,4-difluorocyclohexyl)methanol from methyl 4,4-difluorocyclohexanecarboxylate: LiAlH4 (2.0 M THF solution, 11.2 mL, 22.47 mmol) was suspended in anhydrous Et2O (55 mL) under the protection of nitrogen and cooled to 0 °C. Subsequently, methyl 4,4-difluorocyclohexanecarboxylate (1.0 g, 5.62 mmol) was dissolved in dry Et2O (10 mL) and the above suspension was added dropwise. The reaction mixture was stirred at room temperature for 1 h and then cooled to 0 °C again. H2O (1.0 mL) was added slowly and carefully, followed by 3.0 M KOH solution (1.0 mL) and additional H2O (4.5 mL). The mixture was continued to be stirred at 0 °C for 1 h, followed by filtration. The organic layer was dried with Na2SO4, filtered and concentrated to dryness to afford (4,4-difluorocyclohexyl)methanol (0.68 g, 81% yield), which could be used in the subsequent steps without further purification.1H NMR (DMSO-d6) data: δ 4.51 (t, 1H, J=5.6 Hz), 3.26 (t, 2H, J=7.5 Hz), 2.05- 1.93 (m, 2H), 1.86-1.66 (m, 4H), 1.55-1.41 (m, 1H), 1.21-1.08 (m, 2H).

References

[1] Patent: WO2014/144836, 2014, A2. Location in patent: Paragraph 0986; 0987; 0993; 0994
[2] European Journal of Medicinal Chemistry, 2016, vol. 111, p. 138 - 159
[3] Patent: EP3299371, 2018, A1. Location in patent: Paragraph 0096; 0097; 0098
[4] Patent: WO2009/65035, 2009, A1. Location in patent: Page/Page column 81-82