(R)-(+)-1-Boc-3-aminopyrrolidine → (3R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)pyrrolidine-1-carboxylate

HRID 1529284Notes

Reaction equation

HRID 1529284 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.[C:31]([N:38]1[CH2:42][CH2:41][C@@H:40]([NH2:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[N:7]=[C:2]([NH:43][C@@H:40]2[CH2:41][CH2:42][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)[CH:3]=[N:4][CH:5]=1

Participants

6

Reactant 3

HCID 854070(R)-(+)-1-Boc-3-aminopyrrolidineHCID 23676156Sodium t-butoxideHCID 867097633-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 67959703(3R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)pyrrolidine-1-carboxylateYield 83%

Reagents, catalysts & solvents 2

HCID 25112666BrettPhos PalladacycleCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

A glass microwave reaction vessel was charged with 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (250 mg, 0.586 mmol) and (R)-(+)-1-boc-3-aminopyrrolidine (149 μL, 0.879 mmol, CNH technologies) in p-dioxane (2.5 mL) followed by chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst) (23.39 mg, 0.029 mmol), sodium tert-butoxide (143 μL, 1.171 mmol) and BrettPhos precatalyst (15.72 mg, 0.029 mmol). The reaction mixture was stirred and heated in an oil bath at 85° C. for 2 h, and then solvent was removed. The residue was purified by silica gel chromatography (eluting with 5-30% EtOAc in DCM with 1% MeOH) to give (3R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)pyrrolidine-1-carboxylate (280 mg, 83% yield). MS (ESI, pos. ion) m/z: 577 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. customsolvent was removed
  3. customThe residue was purified by silica gel chromatography (eluting with 5-30% EtOAc in DCM with 1% MeOH)

Sources & evidence

ORD record
ord-7e4e18bba43d448dbab6ea5791bd0cb2
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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