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

HRID 2077459Notes

Reaction equation

HRID 2077459 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]([C:35]([F:38])([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.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.[Fe+2]>[CH3:32][C:29]1([CH3:33])[CH2:30][C:31]2[N:23]([C:21]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[CH:22]=3)[N:24]=[C:25]([C:35]([F:37])([F:38])[F:36])[C:26]=2[C:27](=[O:34])[CH2:28]1

Participants

9

Reactant 3

HCID 4192234-AminotetrahydropyranHCID 118541752-bromo-4-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenecarbonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 669529694-(6,6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrileYield 147.5%

Reagents, catalysts & solvents 5

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

Conditions

Temperature
120 °C

Procedure

4-Aminotetrahydropyran (245 mg, 2.42 mmol, 2.0 eq) and sodium tert-butoxide (233 mg, 2.42 mmol, 2.0 eq) were added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1.21 mmol, 1.0 eq), palladium (II) acetate (14 mg, 0.06 mmol, 0.05 eq), and DPPF (67 mg, 0.12 mmol, 0.10 eq) in 3.75 mL of toluene. The reaction vial was capped, and the reaction mixture was heated 20 minutes 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-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (772 mg, 49%) as a tan solid: LC/MS (m/z): [M+H]+ 433.7. Further elution with ethyl acetate afforded 4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (713 mg, 44%) as a yellow solid: LC/MS (m/z): [M+H]+ 451.2.

Workup

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

Sources & evidence

ORD record
ord-6c14eac714e94665ab01a75251e1a327
Source dataset
uspto-grants-2011_04
Patent number
US07928135B2

Reaction notes

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