4-Aminotetrahydropyran → 4-(6,6-Dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile

HRID 1875402Notes

Reaction equation

HRID 1875402 reaction equation
[NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].Br[C:15]1[CH:22]=[C:21]([N:23]2[C:31]3[CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]=3[C:25]([CH:35]([F:37])[F:36])=[N:24]2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:32][C:29]1([CH3:33])[CH2:30][C:31]2[N:23]([C:21]3[CH:22]=[CH:15][C:16]([C:17]#[N:18])=[C:19]([NH:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[CH:20]=3)[N:24]=[C:25]([CH:35]([F:36])[F:37])[C:26]=2[C:27](=[O:34])[CH2:28]1

Participants

9

Reactant 3

HCID 4192234-AminotetrahydropyranHCID 118546862-Bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-benzonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 669522624-(6,6-Dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrileYield 284.8%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

The following reaction was conducted at the 300 mg scale and in duplicate at the 500 mg scale: 4-Aminotetrahydropyran (154 mg, 1.52 mmol, 2.0 eq.) and sodium tert-butoxide (146 mg, 1.52 mmol, 2.0 eq.) were added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (300 mg, 0.76 mmol, 1.0 eq.), palladium (II) acetate (8.5 mg, 0.04 mmol, 0.05 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (42 mg, 0.08 mmol, 0.1 eq.) in toluene (2.25 mL). The reaction vial was capped, and the reaction mixture was heated for 20 min at 120° C. under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate and combined. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage system (SiO2, hexanes-ethyl acetate) to afford 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (897 mg, 65% yield) as a tan solid: LC/MS (m/z): [M+H]+ 415.2. Further elution with ethyl acetate afforded the title compound, 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, (131 mg, 9%) as a yellow solid: LC/MS (m/z): [M+H]+ 433.3.

Workup

  1. customThe following reaction
  2. customThe reaction vial was capped
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (3×)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified on a Biotage system (SiO2, hexanes-ethyl acetate)

Sources & evidence

ORD record
ord-30f78bf01ee7452e9f69c138dd154296
Source dataset
uspto-grants-2012_11
Patent number
US08309548B2

Reaction notes

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