2-Methoxyaniline → HCID 75985745, compound

HRID 417290Notes

Reaction equation

HRID 417290 reaction equation
F[C:2](F)(F)[C:3]([OH:5])=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:55])C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[NH2:71]>ClCCl>[OH:55][CH2:2][CH2:3][O:5][C:69]1[CH:68]=[CH:67][C:66]([NH:71][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[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])=[C:65]([O:64][CH3:63])[CH:70]=1

Participants

6

Reactant 4

HCID 70002-MethoxyanilineHCID 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 75985745HCID 75985745, compound

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 (0.4 g, 0.69 mmol) prepared in Example 4 in dichloromethane (9 mL) was added diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (Aldrich) (0.34 g, 1.42 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 442-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy-phenylamine (0.32 g, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (9 mL), and an aqueous solution (1N) of HCl (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. 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 Na2SO4, then concentrated. The residue was purified by chromatography (0-50% of EtOAc in CH2Cl2) 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 [4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-amide as a off white solid (0.18 g, 41%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 72 h
  2. concentrationThe mixture was concentrated
  3. dissolutionThe residue was dissolved into tetrahydrofuran (9 mL)
  4. additionan aqueous solution (1N) of HCl (1 mL) was added
  5. stirringThe reaction mixture was stirred at room temperature for 2 h
  6. concentrationconcentrated
  7. customThe residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution
  8. customThe organic layer was separated
  9. extractionaqueous layer was extracted with ethyl acetate twice
  10. extractionThe combined organic extract
  11. washwas washed with water, brine
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated
  14. customThe residue was purified by chromatography (0-50% of EtOAc in CH2Cl2)

Sources & evidence

ORD record
ord-cef449817e0c4bf4835e1dbbdbc58b07
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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