Benzylamine → N2-{5-[5-(benzylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}-N-(2,2,2-trifluoroethyl)valinamide

HRID 510205Notes

Reaction equation

HRID 510205 reaction equation
Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.ClC1C=[C:41]2[C:47]([C:48]3[CH:49]=[C:50](NC(C(C)C)C(NCC(F)(F)F)=O)[CH:51]=[N:52][CH:53]=3)=CN(COCC[Si](C)(C)C)C2=NC=1.C(N)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:53]([NH:52][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)[C:48]1[CH:47]=[CH:41][CH:51]=[CH:50][CH:49]=1

Participants

7

Reactant 4

HCID 7504Benzylamine2×HCID 23714775LiHMDS tetrahydrofuran2×HCID 1238640952-(5-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamideHCID 131733258N2-[5-(5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide

Product 1

HCID 131733257N2-{5-[5-(benzylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}-N-(2,2,2-trifluoroethyl)valinamide

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a nitrogen gas purged microwave vial of N2-[5-(5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide, 2-1a (1380 mg, 2.482 mmol), palladium(II) acetate (80 mg, 0.356 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (188 mg, 0.339 mmol) in DME (5 mL) was added benzylamine (0.407 mL, 3.72 mmol) followed by 1M lithium bis(trimethylsilyl)amide/THF (3.72 mL, 3.72 mmol). The reaction mixture was sealed and heated in an oil bath at 100° C. in a sealed microwave vessel for 18 h. An additional amount of palladium(II) acetate (80 mg, 0.356 mmol) and (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (188 mg, 0.339 mmol), benzylamine (0.407 mL, 3.72 mmol) followed by 1M lithium bis(trimethylsilyl)amide/THF (3.72 mL, 3.72 mmol) was added and the reaction was allowed to stir at 100° C. for 2 h. The reaction was quenched with aq. KHSO4, diluted with ethyl acetate. The organic layer was washed with aq. NaHCO3, dried over sodium sulfate, filtered and concentrated to an oil. The oil purified on silica gel (EtOAc/hexane; 50-100%) to afford the title compound, 5-1a.

Workup

  1. customThe reaction mixture was sealed
  2. additionwas added
  3. customThe reaction was quenched with aq. KHSO4
  4. additiondiluted with ethyl acetate
  5. washThe organic layer was washed with aq. NaHCO3
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated to an oil
  9. customThe oil purified on silica gel (EtOAc/hexane; 50-100%)

Sources & evidence

ORD record
ord-685716bdc8d24a009330fef71f647c4b
Source dataset
uspto-grants-2015_08
Patent number
US09096598B2

Reaction notes

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