Water → 4H-Cyclopenta-1,3-dioxol-4-ol, 5-fluoro-3a,6a-dihydro-2,2-dimethyl-6-[(triphenylmethoxy)methyl]-, 4-methanesulfonate, (3aR,4R,6aR)-

Participants

Reaction Conditions

Reaction Steps

Compound 10 (787 g (corrected), 1 wt), (gross input 1292 g), was dissolved in DCM (7.87 L, 10 vol) and cooled to 0 to 5° C. Triethylamine (368 mL, 0.468 vol, 1.5 eq) was charged followed by MsCl (164 mL, 0.208 vol, 1.3 eq) whilst maintaining the temperature at 0 to 5° C. IPC by 1H NMR analysis after 30 minutes indicated that 94.2% conversion had been achieved. An additional charge of triethylamine (28 mL) and MsCl (16 mL) (2 mol % per 1% conversion remaining) was made. IPC analysis after 30 minutes indicated that the conversion had increased to 97.3%. A second additional charge of triethylamine (13 mL) and MSCl (7.5 mL) was made. After a further 30 minutes IPC by 1H NMR analysis indicated that 100% conversion had been achieved. Water (7.87 L, 10 vol) was charged to the reaction and the mixture warmed to 15 to 25° C. Once the reaction was within the temperature range it was stirred for 10 minutes and the phases separated. The organic phase was returned to the flask, saturated NaHCO3 (7.87 L, 10 vol) charged and the two phases mixed for 10 to 20 minutes, then separated. The organic phase was dried over Na2SO4 (787 g, 1 wt) for 10 minutes, filtered and the filter cake washed with DCM (2×787 mL, 2×1 vol). The combined filtrate and washes were concentrated at up to 30° C. on a rotary evaporator under vacuum to obtain 11 as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 7.7 ppm, d, 4H, TBDPS-F stage 1 by-product, δ 7.25 to 7.5 ppm, 21H. Trityl group and TBDPS-F by-product, δ 5.23 ppm, (d, J=5.8 Hz, 1H) (CH), δ 5.10 ppm, (t, J=7.1 Hz, 1H) (CH), δ 4.77 ppm, (m, J=2.8 Hz, 1H) (CH), δ 4.0 ppm, (d, J=12.6 Hz, 1H), 3.9 ppm, (d, J=12.6 Hz, 1H) (CH2), δ 3.1 ppm, s, 3H, Mesylate, (CH3), δ 1.4 ppm, 6H, Acetonide, (2×CH3), δ 1.1 ppm, 3, 9H, (3×CH3, TBDPSF), Solvents δ 5.8 ppm, s, 2H DCM.

Provenance & Evidence