Water → rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid 4-methoxycarbonyl-phenyl ester

HRID 2065429Notes

Reaction equation

HRID 2065429 reaction equation
[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]2[NH:21][C:22](=[O:44])[C:23]3([CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:26][N:25]([C:33](Cl)=[O:34])[CH:24]3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])[C:18]2=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:33]([N:25]2[CH2:26][CH:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]3([C:18]4[C:19](=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)[NH:21][C:22]3=[O:44])[CH:24]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:34])=[CH:11][CH:10]=1)=[O:7]

Participants

6

Reactant 4

HCID 962WaterHCID 7456MethylparabenHCID 24758Sodium hydrideHCID 76776161rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-1'-carbonyl chloride

Product 1

HCID 67337314rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid 4-methoxycarbonyl-phenyl esterYield 18%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of methyl 4-hydroxybenzoate (Aldrich) (20 mg, 0.13 mmol) in N,N-dimethylforamide (3 mL) was added NaH (60%, 7.8 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 10 min, then rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride prepared in Example 8 (56 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water was added. The mixture 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 triturated with dichloromethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-phenyl ester as a white solid (Yield 14 mg, 18%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 3 h
  2. customThe mixture was partitioned between ethyl acetate and water
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with ethyl acetate
  5. washwashed with water, brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was triturated with dichloromethane and hexanes

Sources & evidence

ORD record
ord-c7aa36c23bc94c03828c267be0c2c3d1
Source dataset
uspto-grants-2012_10
Patent number
US08288431B2

Reaction notes

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