1,1'-Carbonyldiimidazole → (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindole

HRID 2400004Notes

Reaction equation

HRID 2400004 reaction equation
C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][NH:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.C(N(CC)CC)C>[C:43]1([C:33]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][N:36]([C:22](=[O:24])[C@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH3:25])[CH2:37]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1

Participants

6

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 11137716(S)-2-(2-Methoxyphenyl)propanoic acidHCID 67746156(3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride

Product 1

HCID 54246184(3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindoleYield 20.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 8471TriethylamineSolvent

Procedure

0.32 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.36 g of (S)-2-(2-methoxyphenyl)-propionic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydro-isoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine, is added. The reaction mixture is stirred at room temperature for 20 hours, diluted with 200 cm3 of dichloromethane and then washed with 50 cm3 of water, dried over magnesium sulphate, filtered 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 cm, height 20 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (60/40 by volume) and collecting fractions of 20 cm3. Fractions 10 to 15 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 0.6 cm3 of isopropyl oxide. The crystals obtained are drained, washed with isopropyl oxide and then dried. 0.19 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindole is obtained in the form of white crystals; melting point 195° C.

Workup

  1. stirringThe reaction mixture is stirred at room temperature for 20 hours
  2. washwashed with 50 cm3 of water
  3. dry with materialdried over magnesium sulphate
  4. filtrationfiltered
  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 3 cm, height 20 cm)
  7. washeluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (60/40 by volume)
  8. customcollecting fractions of 20 cm3
  9. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  10. customThe residue is crystallized from 0.6 cm3 of isopropyl oxide
  11. customThe crystals obtained
  12. washwashed with isopropyl oxide
  13. customdried

Sources & evidence

ORD record
ord-2d683fd1b2e24b4fbabe024d248b965f
Source dataset
uspto-grants-1995_09
Patent number
US05451601

Reaction notes

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