Methanesulfonic Acid → (4S,5R,6R,18R)-4,5-dihydroxy-3,8,8,15,15,18-hexamethyl-7,9-dioxapentacyclo[11.5.1.01,5.06,11.014,16]nonadeca-2,11-dien-19-one

HRID 1398279Notes

Reaction equation

HRID 1398279 reaction equation
[CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.CS(O)(=O)=O.C(N([CH2:36][CH3:37])CC)C.[C:38](OCC)(=O)C>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:36]([CH3:37])([CH3:38])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1

Participants

6

Reactant 4

HCID 6395Methanesulfonic AcidHCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 442042Ingenol

Product 1

HCID 91827745(4S,5R,6R,18R)-4,5-dihydroxy-3,8,8,15,15,18-hexamethyl-7,9-dioxapentacyclo[11.5.1.01,5.06,11.014,16]nonadeca-2,11-dien-19-one

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent3×

Conditions

Temperature
45 °C

Procedure

Dry ingenol (15.00 g, 90%, 38.75 mmol) was dissolved in acetone (630 mL) with stirring, and the solution was heated to 45° C. A solution of methanesulfonic acid (0.745 g, 7.75 mmol) in acetone (10 mL) was added during 5 seconds. The solution was stirred at 45° C. for an additional 95 seconds, before a solution of triethylamine (1.35 mL, 0.98 g, 9.69 mmol) in acetone (10 mL) was added during 5 seconds. The mixture was cooled to 20° C., and ethyl acetate (500 mL) was added. Most of the reaction solvent (650 mL) was distilled off under vacuum. Water (200 mL) was added to the remaining solution, and the mixture was agitated for 2 minutes. The water layer was removed, and the water wash was repeated once before the organic phase was concentrated under vacuum. The crude product contained 84% of the title compound as determined by 1H NMR spectroscopy. The residue was dissolved in toluene (75 mL) by heating to reflux temperature followed by slow cooling to 5° C. After 4 hours standing, the formed crystals were filtered off, rinsed with 5° C. toluene (2×5 mL) and dried under vacuum at 20° C. until constant weight. After 18 hours, ingenol-5,20-acetonide (8.97 g) was obtained.

Workup

  1. additionwas added during 5 seconds
  2. temperatureThe mixture was cooled to 20° C.
  3. distillationMost of the reaction solvent (650 mL) was distilled off under vacuum
  4. additionWater (200 mL) was added to the remaining solution
  5. stirringthe mixture was agitated for 2 minutes
  6. customThe water layer was removed
  7. washthe water wash
  8. concentrationwas concentrated under vacuum
  9. dissolutionThe residue was dissolved in toluene (75 mL)
  10. temperatureby heating
  11. temperatureto reflux temperature
  12. temperatureby slow cooling to 5° C
  13. filtrationthe formed crystals were filtered off
  14. washrinsed with 5° C. toluene (2×5 mL)
  15. customdried under vacuum at 20° C. until constant weight
  16. waitAfter 18 hours

Sources & evidence

ORD record
ord-fd7188c7042d4ab6bf824db7a2e2410a
Source dataset
uspto-grants-2014_12
Patent number
US08901356B2

Reaction notes

Loading…