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

HRID 1196282Notes

Reaction equation

HRID 1196282 reaction equation
OC1C2N=NNC=2C=CC=1.[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 81531DiisopropylethylamineHCID 11137716(S)-2-(2-Methoxyphenyl)propanoic acidHCID 22843247(3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochlorideHCID 178418300HCID 178418300, compound

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

1H hydroxybenzotriazole (0.59 g) is added to a solution of 84% optically pure (S)-2-(2-methoxyphenyl)propionic acid (0.75 g), prepared according to 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 then added, the mixture is stirred for 1 hour at this temperature and a solution of (3aR, 7aR)-7,7-diphenylperhydro-4-isoindolone 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 the precipitate has been filtered off. The residue is chromatographed on a column of silica gel (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 dissolution in boiling isopropyl ether (60 cc) to which hexane (30 cc) is added. The cooled solution is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa) to give (3aR, 7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (1.2 g) in the form of a white meringue-like product containing (3aR, 7aR)-7,7-diphenyl-2-[(R)-2-(2-methoxyphenyl)propionyl]perhydro-4-isoindolone (10%); [α]D20 =-181° (c=0.81, chloroform).

Workup

  1. customprepared
  2. stirringThe reaction mixture is stirred at 20° C. for 16 hours
  3. concentrationconcentrated to dryness under reduced pressure (2.7 kPa) after the precipitate
  4. filtrationhas been filtered off
  5. customThe residue is chromatographed on a column of silica gel (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 by dissolution
  11. additionis added
  12. filtrationThe cooled solution is filtered
  13. concentrationthe filtrate concentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-d161a70b933f45ea9b3de5b9415ee6df
Source dataset
uspto-grants-1992_05
Patent number
US05112988

Reaction notes

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