Triethylamine → (3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindolone

HRID 1029939Notes

Reaction equation

HRID 1029939 reaction equation
C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH2:41]2)[C:37](=[O:43])[CH2:36][CH2:35]1.C(N(CC)CC)C>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[F:50])[CH:42]2[CH:38]([CH2:39][NH:40][CH:41]2[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:13])[CH3:25])[C:37](=[O:43])[CH2:36][CH2:35]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 204661092-(2-(Dimethylamino)phenyl)acetic acidHCID 679159337,7-Bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride

Product 1

HCID 67915811(3aRS,7aRS)-7,7-bis-(2-fluorophenyl)-2-(2-dimethylaminophenyl)acetyl-4-perhydroisoindoloneYield 74.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

N,N-Carbonyldiimidazole (0.44 g) is added to a solution of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc) cooled to +4° C. The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis-(2-fluorophenyl)-4-perhydroisoindolone 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 silica gel column (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-4-perhydroisoindolone (1 g), from which the hydrochloride is prepared by dissolving in ethyl acetate (2 cc) and adding 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-4-perhydroisoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.

Workup

  1. temperaturecooled to +4° C
  2. stirringThe reaction mixture is stirred for 20 hours at 25° C.
  3. washwashed with water (2×100 cc) and with saturated sodium chloride solution (100 cc)
  4. dry with materialThe organic phase is dried 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 0.04-0.063 mm, diameter 2 cm, height 23 cm)
  7. washeluting under a nitrogen pressure of 0.5 bar
  8. additionwith a mixture of cyclohexane and ethyl acetate (50/50)
  9. customcollecting 10 cc fractions
  10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-89bc012ac04247138a89bdc421f59c29
Source dataset
uspto-grants-1992_04
Patent number
US05102667

Reaction notes

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