1,1'-Carbonyldiimidazole → (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-(benzyloxyphenylacetyl)perhydroisoindol-4-ol

HRID 1599151Notes

Reaction equation

HRID 1599151 reaction equation
[C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]C(O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[OH:32][CH2:33][CH:34]1[CH2:42][CH:41]2C(CNC2)[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])([OH:43])[CH2:35]1.C(N(C(C)C)CC)(C)C>ClCCl>[OH:32][CH2:33][CH:34]1[CH2:42][CH:41]2[CH:11]([CH2:12][N:8]([C:1](=[O:2])[CH:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:27]=3)[CH2:9]2)[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])([OH:43])[CH2:35]1

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 519916(2-Benzyloxyphenyl)acetic acidHCID 67660643(3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol hydrochloride

Product 1

HCID 67660681(3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-(benzyloxyphenylacetyl)perhydroisoindol-4-olYield 55.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

0.54 g of carbonyldiimidazole is added to a solution of 0.8 g of 2-benzyloxyphenylacetic acid in 10 cm3 of dichloromethane, cooled to 0° C. The mixture is stirred at this temperature for 2 hours and then 0.8 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol hydrochloride and 1.04 cm3 of diisopropylethylamine are added. The reaction mixture is stirred at room temperature for 18 hours, and then the organic phase is washed with 10 cm3 of water, then with 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with ethyl acetate and collecting fractions of 25 cm3. Fractions 18 to 50 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.72 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-(benzyloxyphenylacetyl)perhydroisoindol-4-ol is obtained in the form of a thick white foam.

Workup

  1. stirringThe reaction mixture is stirred at room temperature for 18 hours
  2. washthe organic phase is washed with 10 cm3 of water
  3. dry with materialwith 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate
  4. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  5. customThe residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 20 cm)
  6. washeluting under a pressure of 0.5 bar of nitrogen with ethyl acetate
  7. customcollecting fractions of 25 cm3
  8. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-ea1b2ed406e54d2598879c86f2ef4614
Source dataset
uspto-grants-1998_04
Patent number
US05739351

Reaction notes

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