Synthesis
General procedure for the synthesis of (2-amino-6-fluorophenyl)methanol from 2-amino-6-fluorobenzoic acid:
Step 1. Preparation of (2-amino-6-fluorophenyl)methanol: Lithium aluminum hydride (1.0 M tetrahydrofuran solution, 18 mL, 18 mmol) was cooled under ice-bath conditions and a tetrahydrofuran (30 mL) solution of 2-amino-6-fluorobenzoic acid (2.00 g, 12.9 mmol) was added dropwise. Subsequently, the ice bath was allowed to melt naturally over a period of 18 hours to gradually warm the reaction mixture to about 25 °C. Upon completion of the reaction, the reaction was quenched by the addition of sodium sulfate decahydrate (2 g) and saturated aqueous sodium chloride solution (6 mL). The mixture was stirred for 1.5 hours and then filtered through diatomaceous earth. The filter pad was washed with ether (2 x 10 mL), the filtrate was combined and concentrated under reduced pressure. The concentrate was dissolved in tetrahydrofuran, treated with silica gel, and the solvent was removed under reduced pressure before the resulting material was loaded onto a silica gel column. Purification by dry column chromatography (elution gradient: 100% heptane to 2:1 ethyl acetate/heptane) gave (2-amino-6-fluorophenyl)methanol as a light yellow solid. Yield: 549 mg, 3.89 mmol, 30% yield. Mass spectrum (APCI) m/z 139.8 (M-1). 1H NMR (400 MHz, CDCl3) δ 1.59 (br s, 1H), 4.33 (br s, 2H), 4.79 (s, 2H), 6.48 (m, 2H), 7.05 (ddd, J = 8.2, 6.4, 2.0 Hz, 1H).
References
[1] Organic Letters, 2017, vol. 19, # 12, p. 3219 - 3222
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 25, p. 8079 - 8086
[3] Patent: WO2010/58314, 2010, A1. Location in patent: Page/Page column 59-60
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[5] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9603 - 9607,5
