Dicyclohexylcarbodiimide → (3aR,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone

HRID 1029920Notes

Reaction equation

HRID 1029920 reaction equation
ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1

Participants

8

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11137716(S)-2-(2-Methoxyphenyl)propanoic acidHCID 22843247(3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride

Product 1

HCID 22843243(3aR,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindoloneYield 63.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

1-Hydroxybenzotriazole (0.59 g) is added to a solution of (S)-2-[2-methoxyphenyl]propionic acid (0.75 g) of 84% optical purity prepared by the method of T. Matsumoto et al: Bull. Chem. Soc. Jpn., 58, 340 (1985), in dry dimethylformamide (15 cc) and the solution is then cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (0.91 g) is added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.44 g) and N,N-diisopropylethylamine (0.76 cc) in dimethylformamide (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, diluted with ethyl acetate (100 cc) and concentrated to dryness under reduced pressure (2.7 kPa) after filtering off the precipitate. The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 125 cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolving in boiling isopropyl ether (60 cc) to which hexane (30 cc) had been added. The cooled solution is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone (1.2 g) in the form of a white meringue containing 10% of (3aR,7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone; [α]D20 =-181° (c=0.81, chloroform).

Workup

  1. customprepared by the method of T
  2. stirringThe reaction mixture is stirred at 20° C. for 16 hours
  3. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  4. filtrationafter filtering off the precipitate
  5. customThe residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm)
  6. washeluting under a nitrogen pressure of 0.7 bar
  7. additionwith a mixture of cyclohexane and ethyl acetate (50/50 by volume)
  8. customcollecting 125 cc fractions
  9. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  10. customThe residue is purified
  11. dissolutionby dissolving
  12. additionhad been added
  13. filtrationThe cooled solution is filtered
  14. concentrationthe filtrate is concentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-7151d568c33a4b9f9816ac6c7ab2a985
Source dataset
uspto-grants-1992_04
Patent number
US05102667

Reaction notes

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