tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl]carbaMate

Synthesis

Tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate (8.9 g, 28.6 mmol) was dissolved in anhydrous methyl tert-butyl ether (90 mL), anhydrous toluene (9 mL) was added, and the reaction system was cooled down to -10 °C. Tetrahydrofuran solution of borane dimethyl sulfide (2 mol/L, 35.9 mL) was added slowly, and the reaction temperature was maintained at 0°C for 3.5 hours. Upon completion of the reaction, water (4 mL) was slowly added followed by dropwise addition of sodium hydroxide solution (1 mol/L, 89 mL) and stirred for 15 minutes. Sodium perborate (13.2 g, 85.8 mmol) was added in batches and stirred overnight at room temperature. After completion of the reaction, the reaction solution was left to partition and the aqueous phase was extracted with methyl tert-butyl ether (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. Toluene (50 mL) was added to the concentrate and heated to 90°C to dissolve. Slowly added n-hexane (200mL) dropwise to the reaction solution, precipitated white solid, filtered. The filter cake was washed with hexane (30 mL x 2) and concentrated to remove the solvent to give a white solid powder target product ((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester (7.9 g, 84% yield). Mass spectrum (ESI) m/z: 274.1 [M-55].

References

[1] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1760 - 1768
[2] Patent: EP3159344, 2017, A1. Location in patent: Paragraph 0096; 0097; 0104
[3] Patent: TW2017/8221, 2017, A. Location in patent: Page/Page column 33; 36
[4] Patent: TW2017/8224, 2017, A. Location in patent: Page/Page column 28; 32
[5] Patent: TW2017/8220, 2017, A. Location in patent: Page/Page column 56; 57; 60