Ammonium Chloride → (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol

HRID 1599148Notes

Reaction equation

HRID 1599148 reaction equation
C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[C:18](=[O:32])[CH2:17]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22]2)[C:18]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:32])[CH2:17]1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 612591-Bromo-2-fluorobenzeneHCID 18931561(3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-oneHCID 178418339Butyllithium

Product 1

HCID 67661831(3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

94.4 cm3 of a 1.6M solution of butyllithium in hexane are added dropwise to a solution of 16.5 cm3 of 2-fluorobromobenzene in 200 cm3 of tetrahydrofuran, cooled to -78° C. The reaction mixture is stirred at -78° C. for 2 hours, and then a solution of 8.1 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one in 20 cm3 of tetrahydrofuran is added. The reaction mixture is subsequently stirred at room temperature for 48 hours, then treated with 50 cm3 of saturated aqueous ammonium chloride solution and subjected to extraction with 200 cm3 of ethyl acetate, and the organic phase is washed with 100 cm3 of saturated 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 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 75 cm3. Fractions 21 to 45 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.35 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol are obtained in the form of a thick white foam.

Workup

  1. stirringThe reaction mixture is subsequently stirred at room temperature for 48 hours
  2. extractionsubjected to extraction with 200 cm3 of ethyl acetate
  3. washthe organic phase is washed with 100 cm3 of saturated sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  6. customThe residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm)
  7. washeluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume)
  8. customcollecting fractions of 75 cm3
  9. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-69c26b3beabc4bd19c7efd1988c56287
Source dataset
uspto-grants-1998_04
Patent number
US05739351

Reaction notes

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