2-Methoxyphenylacetic acid → (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-(phenylacetyl)perhydro-4-isoindolone

HRID 1196286Notes

Reaction equation

HRID 1196286 reaction equation
CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[F:37][C:33]1[CH:32]=[C:31]([C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:36]=[CH:35][CH:34]=1

Participants

5

Reactant 3

HCID 71342-Methoxyphenylacetic acidHCID 8471TriethylamineHCID 679158007,7-Bis(3-Fluorophenyl)-4-perhydroisoindolone hydrochloride

Product 1

HCID 67916043(3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-(phenylacetyl)perhydro-4-isoindoloneYield 62.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of (2-methoxyphenyl)acetic acid (0.46 g) in dry dichloromethane (15 cc) is cooled to 0° C., then treated with N,N'-carbonyldiimidazole (0.45 g) and stirred for 1 hour at 0° C. A solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dichloromethane (20 cc) is added dropwise. The reaction mixture is stirred for 3 hours at 25° C. and then washed with water (2×50 cc) and with saturated sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered 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 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting 15-cc fractions. Fractions 4 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa), and the product obtained is recrystallized in acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-(phenylacetyl)perhydro-4-isoindolone (0.76 g) is obtained. M.p. 194° C.

Workup

  1. stirringThe reaction mixture is stirred for 3 hours at 25° C.
  2. washwashed with water (2×50 cc) and with saturated sodium chloride solution (50 cc)
  3. dry with materialThe organic phase is dried over magnesium sulphate
  4. filtrationfiltered
  5. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  6. customThe residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm)
  7. washeluting under a nitrogen pressure of 0.5 bar
  8. additionwith a mixture of cyclohexane and ethyl acetate (70:30 by volume)
  9. customcollecting 15-cc fractions
  10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  11. customthe product obtained
  12. customis recrystallized in acetonitrile
  13. washwashed with isopropyl ether
  14. customdried

Sources & evidence

ORD record
ord-e3b62c0b0e3844f9a7aaae3aae0f773b
Source dataset
uspto-grants-1992_05
Patent number
US05112988

Reaction notes

Loading…