Methyl Anthranilate → rac-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 methyl ester

HRID 417176Notes

Reaction equation

HRID 417176 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C([N:42]([CH:45]([CH3:47])[CH3:46])CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.N[C:64]1C=CC=[CH:70][C:65]=1[C:66]([O:68][CH3:69])=[O:67]>ClCCl>[CH3:69][O:68][C:66](=[O:67])[C:65]1[CH:70]=[CH:46][C:45]([NH:42][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:47][CH:64]=1

Participants

6

Reactant 4

HCID 8635Methyl AnthranilateHCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 78158843rac-(2'R,3'S,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 trifluoroacetic acid

Product 1

HCID 53236633rac-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 methyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 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 trifluoroacetic acid (0.86 g, 1.48 mmol) in dichloromethane (20 mL) was added diisopropylethylamine (1.53 g, 11.9 mmol), diphenylphosphinic chloride (Aldrich) (1.41 g, 5.94 mmol) respectively. The mixture was stirred at room temperature for 0.5 h, then methyl aminobenzoate (Acros) (0.22 g, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (3-10% of EtOAc in CH2Cl2) to give rac-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 methyl ester as a off white solid (0.34 g, 38%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 20 h
  2. concentrationThe mixture was concentrated
  3. customThe residue was partitioned between ethyl acetate and water
  4. customThe organic layer was separated
  5. washwashed with water, brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by chromatography (3-10% of EtOAc in CH2Cl2)

Sources & evidence

ORD record
ord-c6d51ce04e17427db3a8f2b3833a9e91
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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