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

HRID 417307Notes

Reaction equation

HRID 417307 reaction equation
[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C@@H:18]1[NH:22][C@@H:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[C@H:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[C:9]([OH:11])=O)[CH2:2][CH2:3][CH3:4].CC[N:48]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:9](=[O:11])[NH2:48])[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([CH:18]1[NH:22][CH:21]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[CH2:2][CH2:3][CH3:4]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 53237755rac-3-butoxy-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-benzoic acid

Product 1

HCID 75985950rac-(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (2-butoxy-4-carbamoyl-phenyl)-amideYield 89.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid (0.1 g, 0.15 mmol) prepared in Example 151 in anhydrous DMF (2 mL) were added EDCI (59 mg, 0.31 mmol), HOBt (41 mg, 0.31 mmol), NH4Cl (81 mg, 1.5 mmol), and triethylamine (31 mg, 0.31 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-butoxy-4-carbamoyl-phenyl)-amide as a white solid (88 mg, 89%).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. custompartitioned between ethyl acetate and water
  3. customThe organic layer was separated
  4. extractionaqueous layer was extracted with ethyl acetate twice
  5. extractionThe combined organic extract
  6. washwas washed with water, brine
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography (25-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-962a6f86669a45f1acfa53be683d063d
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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