Triethylamine → HCID 178519655, compound

HRID 1013843Notes

Reaction equation

HRID 1013843 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][N:18](S(C(F)(F)F)(=O)=O)[N:19]=3)[CH2:15]2)[C:10]1=[O:30].Cl.[F:41][C:42]1([F:48])CCNCC1.[CH2:49]([N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])C.[C]=[O:57]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:31][C:6]1[CH:5]=[C:4]([C:49]([N:51]2[CH2:54][CH2:55][C:42]([F:48])([F:41])[CH2:53][CH2:52]2)=[O:57])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][NH:18][N:19]=3)[CH2:15]2)[C:10]1=[O:30]

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 87354083HCID 87354083, compoundHCID 178418416HCID 178418416, compound2×

Product 1

HCID 178519655HCID 178519655, compound

Reagents, catalysts & solvents 1

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Procedure

Dissolve (3R,5S)-Trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 43) (0.304 g, 0.48 mmol) in 5 ml of argon-sparged dimethylformamide. Treat with 4,4-difluoropiperidine-HCl salt (0.22 g, 1.41 mmol), catalyst: [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.02 g, 0.024 mmol) and triethylamine (0.21 ml, 1.48 mmol). Stir under 40 psi carbon monoxide pressure at 80° C. for 5 hr. Add more catalyst (0.02 g, 0.024 mmol) and more triethylamine (0.25 ml, 1.76 mmol). Heat at 85° C. for 4 hrs at 50 psi carbon monoxide pressure. LCMS shows consumption of starting material. Cool to ambient temperature and add ethyl acetate (50 ml) and water (10 ml). Extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Dissolve the crude product in 5 ml of dimethoxyethane and treat with 2 M aqueous lithium hydroxide solution (1 ml). Stir for 2 hrs at ambient temperature. Dilute with ethyl acetate (50 ml) and water (10 ml) and extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Chromatography (silica, 98:2 CH2Cl2/2M NH3 in MeOH) yields 0.028 g as a foam MS (m/z): 511 (M+1).

Workup

  1. customsparged dimethylformamide
  2. customconsumption of starting material
  3. additionadd ethyl acetate (50 ml) and water (10 ml)
  4. extractionExtract the aqueous phase with ethyl acetate (50 ml)
  5. washWash the organic phases with water (10 ml) and brine (10 ml)
  6. dry with materialCombine the organic phases, dry over sodium sulfate
  7. concentrationconcentrate under reduced pressure
  8. dissolutionDissolve the crude product in 5 ml of dimethoxyethane
  9. additiontreat with 2 M aqueous lithium hydroxide solution (1 ml)
  10. additionDilute with ethyl acetate (50 ml) and water (10 ml)
  11. extractionextract the aqueous phase with ethyl acetate (50 ml)
  12. washWash the organic phases with water (10 ml) and brine (10 ml)
  13. dry with materialCombine the organic phases, dry over sodium sulfate
  14. concentrationconcentrate under reduced pressure
  15. customChromatography (silica, 98:2 CH2Cl2/2M NH3 in MeOH) yields 0.028 g as a foam MS (m/z)

Sources & evidence

ORD record
ord-a62049c16f214b59903b962269296398
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

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