Diphenylphosphinic chloride → HCID 76741098, compound

HRID 417351Notes

Reaction equation

HRID 417351 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](O)=[O:31])[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.C([Si](C)(C)[O:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH2:78])=[C:74]([O:79][CH3:80])[CH:73]=1)(C)(C)C>ClCCl>[OH:68][CH2:69][CH2:70][O:71][C:72]1[N:77]=[CH:76][C:75]([NH:78][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:31])=[C:74]([O:79][CH3:80])[CH:73]=1

Participants

6

Reactant 4

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 58286296HCID 58286296, compoundHCID 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 76741098HCID 76741098, compoundYield 46%

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 prepared in Example 4 (0.3 g, 0.52 mmol) in dichloromethane (9 mL) was added diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (Aldrich) (0.24 g, 1 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-methoxy-pyridin-3-ylamine prepared in Example 191 (0.23 g, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (3 mL), and an aqueous solution (1N) of HCl (1 mL) was added. The reaction mixture was stirred at room temperature for 1 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 (0-15% MeOH 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 [6-(2-hydroxy-ethoxy)-4-methoxy-pyridin-3-yl]-amide as a white solid (0.15 g, 46%).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 48 h
  2. concentrationThe mixture was concentrated
  3. dissolutionThe residue was dissolved into tetrahydrofuran (3 mL)
  4. additionan aqueous solution (1N) of HCl (1 mL) was added
  5. stirringThe reaction mixture was stirred at room temperature for 1 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 (0-15% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-05f46762ac284e7a84f0240641ca88c6
Source dataset
uspto-grants-2012_01
Patent number
US08088815B2

Reaction notes

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