2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1529377Notes

Reaction equation

HRID 1529377 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[CH:22]=[N:21][CH:20]=[C:19]([CH:23]5[CH2:25][CH2:24]5)[N:18]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[CH:101]1([Zn+])[CH2:103][CH2:102]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:101]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH:23]6[CH2:25][CH2:24]6)[N:18]=5)[CH:15]=4)[N:10]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)[N:9]=3)[CH:5]=[N:4][CH:3]=2)[CH2:103][CH2:102]1

Participants

6

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 21081571Dicyclohexyl(2',4',6'-tripropyl-[1,1'-biphenyl]-2-yl)phosphineHCID 867097793-(6-chloropyrazin-2-yl)-5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleHCID 178419765HCID 178419765, compound

Product 1

HCID 679598073,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 21.4%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Procedure

A microwave tube was charged with 3-(6-chloropyrazin-2-yl)-5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Ex. 243e, 111 mg, 0.256 mmol), Pd(OAc)2 (3 mg, 0.013 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl, (X-Phos) (12 mg, 0.026 mmol) and the tube was sealed. The tube was evacuated under vacuum and backfilled with N2 (3×). THF (1.7 mL) was added and the mixture was cooled in an ice-water bath. Cyclopropylzinc bromide solution (0.5 M in THF, 0.62 mL, 0.31 mmol, Sigma-Aldrich) was added and the mixture was warmed to RT and stirred for 2 h. The mixture was filtered and the crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 24 mg of 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The column was eluted with 2-10% MeOH in CH2Cl2 to afford 50 mg of 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The two portions were combined to give 3,5-bis(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (74 mg, 0.17 mmol, 66% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 439.2 (M+1).

Workup

  1. customthe tube was sealed
  2. customThe tube was evacuated under vacuum
  3. additionTHF (1.7 mL) was added
  4. temperaturethe mixture was cooled in an ice-water bath
  5. filtrationThe mixture was filtered
  6. customthe crude was purified by silica gel chromatography
  7. washeluting with a gradient of 0-50% EtOAc in hexanes

Sources & evidence

ORD record
ord-5e1b1eaf95b5493e846b93d3763c86f0
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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