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

HRID 1746641Notes

Reaction equation

HRID 1746641 reaction equation
[F:1][C:2]1[C@H:3]([OH:33])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[C:11]=1[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:33][C@@H:3]1[C@H:4]2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[O:8]2)[C:11]([CH2:12][O:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:2]1[F:1])(=[O:44])=[O:43]

Participants

6

Reactant 4

HCID 962WaterHCID 8471Triethylamine3×HCID 31297Methanesulfonyl chloride2×HCID 90413083HCID 90413083, compound

Product 1

HCID 904119124H-Cyclopenta-1,3-dioxol-4-ol, 5-fluoro-3a,6a-dihydro-2,2-dimethyl-6-[(triphenylmethoxy)methyl]-, 4-methanesulfonate, (3aR,4R,6aR)-

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

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.

Workup

  1. temperaturewhilst maintaining the temperature at 0 to 5° C
  2. waitIPC analysis after 30 minutes indicated that the conversion
  3. temperaturehad increased to 97.3%
  4. waitAfter a further 30 minutes
  5. temperaturethe mixture warmed to 15 to 25° C
  6. customthe phases separated
  7. additioncharged
  8. additionthe two phases mixed for 10 to 20 minutes
  9. customseparated
  10. dry with materialThe organic phase was dried over Na2SO4 (787 g, 1 wt) for 10 minutes
  11. filtrationfiltered
  12. washthe filter cake washed with DCM (2×787 mL, 2×1 vol)
  13. concentrationThe combined filtrate and washes were concentrated at up to 30° C.
  14. customon a rotary evaporator under vacuum

Sources & evidence

ORD record
ord-51c9f92422d9409a8aed7212ece9d9a9
Source dataset
uspto-grants-2015_10
Patent number
US09150520B2

Reaction notes

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