Triethylamine → rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid tert-butyl ester

HRID 417256Notes

Reaction equation

HRID 417256 reaction equation
[C:1]([O:5][C:6](=[O:23])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[C:32]2[C:28](/[C:29](=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])/[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:21])([CH3:22])[CH2:12][OH:13])[C:29]2([C:28]3[C:32](=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)[NH:31][C:30]2=[O:34])[CH:35]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[F:43])=[O:23])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 71464325(3Z)-6-Chloro-3-[(3-chloro-2-fluorophenyl)methylidene]-1,3-dihydro-2H-indol-2-oneHCID 178446421HCID 178446421, compound

Product 1

HCID 66625192rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 6386tert-ButanolSolvent

Procedure

To a solution of [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid-tert-butyl ester (3.1 g, 9.0 mmol) prepared in Example 100 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (2.5 g, 8.1 mmol) prepared in Example 2 in dichloromethane (100 mL) were added triethylamine (7.5 mL, 54 mmol) and AgF (1.9 g, 15 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (15 mL), and DBU (16 g, 65 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (10-80% EtOAc in hexanes) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.0 g, 23%)

Workup

  1. concentrationThe mixture was concentrated
  2. customthe residue was partitioned between ethyl acetate and brine
  3. customThe organic layer was separated
  4. washwashed with water
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. additionwas added
  8. temperatureThe reaction mixture was heated at 120° C. for 2 h
  9. temperatureThe mixture was then cooled to room temperature
  10. concentrationconcentrated
  11. customThe residue was partitioned between ethyl acetate and water
  12. customThe organic layer was separated
  13. extractionthe aqueous layer was extracted with ethyl acetate
  14. washwashed with water, brine
  15. dry with materialdried over MgSO4
  16. concentrationconcentrated
  17. customThe residue was purified by chromatography (10-80% EtOAc in hexanes)

Sources & evidence

ORD record
ord-6aa1a5af35df412c938c4c35a4acfaf5
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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