Triethylamine → (3aRS,7aRS)-7,7-bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone

HRID 1196289Notes

Reaction equation

HRID 1196289 reaction equation
[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][NH:28][CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 204661092-(2-(Dimethylamino)phenyl)acetic acidHCID 679159337,7-Bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride

Product 1

HCID 67916112(3aRS,7aRS)-7,7-bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindoloneYield 74.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

N,N'-Carbonyldiimidazole (0.44 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc). The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50:50) and collecting 10-cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(2 -fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (1 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (2 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.

Workup

  1. stirringThe reaction mixture is stirred for 20 hours at 25° C.
  2. washwashed with water (2×100 cc) and with saturated sodium chloride solution (100 cc)
  3. dry with materialThe organic phase is dried over magnesium sulphate
  4. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  5. customThe residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm)
  6. washeluting under a nitrogen pressure of 0.5 bar
  7. additionwith a mixture of cyclohexane and ethyl acetate (50:50)
  8. customcollecting 10-cc fractions
  9. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-93a96fad5c7441fc84c6cdcad3a1d0de
Source dataset
uspto-grants-1992_05
Patent number
US05112988

Reaction notes

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