Diphenylphosphinic chloride → 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 (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide

HRID 417192Notes

Reaction equation

HRID 417192 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(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH3:70])[C:66](=[O:71])[CH:65]=1>ClCCCl>[CH3:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[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])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][C:66]1=[O:71]

Participants

6

Reactant 4

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 133780004-Amino-1-methylpyridin-2-oneHCID 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 75985812rac-(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 (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

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 prepared in Example 4 (0.33 g, 0.57 mmol) in 1,2-dichloroethane (30 mL) was added diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (Aldrich) (0.54 g, 2.3 mmol) respectively. The mixture was stirred at room temperature for 0.5 h, then 4-amino-1-methyl-pyridin-2-one (Molbridge) (0.07 g, 0.57 mmol) was added. The reaction mixture was heated and stirred at 60° C. for 10 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 (5-10% of MeOH in EtOAc) 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 (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a off white solid (32 mg, 10%).

Workup

  1. temperatureThe reaction mixture was heated
  2. stirringstirred at 60° C. for 10 h
  3. concentrationThe mixture was concentrated
  4. customThe residue was partitioned between ethyl acetate and water
  5. customThe organic layer was separated
  6. washwashed with water, brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography (5-10% of MeOH in EtOAc)

Sources & evidence

ORD record
ord-31941d775360457a9d029cf001b6ef0f
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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