p-Toluenesulfonic acid monohydrate → rac-(2'S,3'S,4'S)-4'-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one

HRID 2065418Notes

Reaction equation

HRID 2065418 reaction equation
[NH2:1][CH2:2][CH:3]([CH:18]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:28])[CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl:29][C:30]1[C:31]([F:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]([Si:9]([CH3:11])([CH3:10])[O:8][CH2:7][CH2:6][C:5]([CH3:17])([CH3:16])[CH2:4][CH:3]1[CH2:2][NH:1][CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=2[F:38])[C:18]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])([CH3:13])([CH3:14])[CH3:15]

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 7363353-Chloro-2-fluorobenzaldehydeHCID 58398996Racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one

Product 1

HCID 67336835rac-(2'S,3'S,4'S)-4'-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-oneYield 6.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 3.5 mmol) in toluene (30 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (0.56 g, 3.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol). The reaction mixture was heated at 130° C. for 2 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and aqueous NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (0.12 g, 6%)

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. custompartitioned between ethyl acetate and aqueous NaHCO3 solution
  3. customThe organic layer was separated
  4. extractionaqueous layer was extracted with ethyl acetate
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customThe residue was purified by chromatography (50-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-9b1b09eea51d457fb8a214018903f441
Source dataset
uspto-grants-2012_10
Patent number
US08288431B2

Reaction notes

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