Phosgene → 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-benzyl ester

HRID 2065422Notes

Reaction equation

HRID 2065422 reaction equation
[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(Cl)=[O:14].[Cl:17][C:18]1[CH:23]=[C:22]2[NH:24][C:25](=[O:44])[C:26]3([CH:30]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:29][NH:28][CH:27]3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])[C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:13]([N:28]2[CH2:29][CH:30]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[C:26]3([C:21]4[C:22](=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[NH:24][C:25]3=[O:44])[CH:27]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:14])=[CH:12][CH:11]=1)=[O:8]

Participants

7

Reactant 4

HCID 6371PhosgeneHCID 8471TriethylamineHCID 81325Methyl 4-(hydroxymethyl)benzoateHCID 67336394rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3'-pyrrolidin]-2-one

Product 1

HCID 67337493rac-(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-benzyl esterYield 74.7%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of methyl 4-(hydroxymethyl)benzoate (20 mg, 0.12 mmol) in tetrahydrofuran (3 mL) was added a toluene solution (Aldrich, 20%) of phosgene (0.25 mL, 0.48 mmol) dropwise via a syringe. The reaction mixture was stirred at room temperature for 1 h, then the solvents were removed. The residue was dissolved into tetrahydrofuran (3 mL), and rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 6 (56 mg, 0.13 mmol) and triethylamine (0.04 mL, 0.29 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 18 h. The solvents were removed, and 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 (35% EtOAc in 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-benzyl ester as a white solid (Yield 55 mg, 68%).

Workup

  1. customthe solvents were removed
  2. additionwere added sequentially
  3. stirringThe reaction mixture was stirred at room temperature for 18 h
  4. customThe solvents were removed
  5. customthe residue was partitioned between ethyl acetate and water
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was extracted with ethyl acetate
  8. washwashed with water, brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated
  11. customThe residue was purified by chromatography (35% EtOAc in hexanes)

Sources & evidence

ORD record
ord-e5515a816b9d4e87b1c044e6fc650a3a
Source dataset
uspto-grants-2012_10
Patent number
US08288431B2

Reaction notes

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