2,3-Dimethylacrylic acid, (Z)- → Ingenol Mebutate

HRID 1482752Notes

Reaction equation

HRID 1482752 reaction equation
[CH3:1][C@H:2]1[C:18]23[CH:21]=[C:22]([CH3:25])[C@H:23]([OH:24])[C@@:17]2([OH:26])[C@H:16]2[C:11]([CH2:12][O:13]C(C)(C)[O:15]2)=[CH:10][CH:9]([C:19]3=[O:20])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1.[C:29](O)(=[O:34])/[C:30](=[CH:32]\[CH3:33])/[CH3:31]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:33]/[CH:32]=[C:30](\[C:29]([O:24][C@@H:23]1[C@@:17]2([OH:26])[C@H:16]([OH:15])[C:11]([CH2:12][OH:13])=[CH:10][C@H:9]3[C@@H:5]4[C:6]([CH3:7])([CH3:8])[C@@H:4]4[CH2:3][C@@H:2]([CH3:1])[C@:18]2([C:19]3=[O:20])[CH:21]=[C:22]1[CH3:25])=[O:34])/[CH3:31]

Participants

5

Reactant 2

HCID 6439152,3-Dimethylacrylic acid, (Z)-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

Product 1

HCID 6918670Ingenol MebutateYield 71.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1140TolueneSolvent

Procedure

A solution of ingenol-5,20-acetonide (100 mg, 0.26 mmol), angelic acid (39 mg, 0.39 mmol, 1.5 mol. equiv.) and DMAP (48 mg, 0.39 mmol, 1.5 mol. equiv.) in toluene (4 ml), was stirred at room temperature for 2 hours and was then filtered through a bed of celite and evaporated. The resulting material was filtered in silica gel (ca. 5 g) and evaporated. The residue was purified by means of silica gel gravity column chromatography (5 g, petroleum ether:EtOAc 85:15) until obtaining over 80 mg of ingenol-3-angelate with a purity>99%. For physical and spectroscopic data, see Hohmann J et al. Planta Medica 2000, 66, 291-294.

Workup

  1. filtrationwas then filtered through a bed of celite
  2. customevaporated
  3. filtrationThe resulting material was filtered in silica gel (ca. 5 g)
  4. customevaporated
  5. customThe residue was purified by means of silica gel gravity column chromatography (5 g, petroleum ether:EtOAc 85:15)

Sources & evidence

ORD record
ord-08d3a0aab1fc47198e497ac3199b9d1c
Source dataset
uspto-grants-2016_08
Patent number
US09416083B2

Reaction notes

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