Nitrogen → 4-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-6-yl)-2,2-dimethylmorpholine

HRID 1661980Notes

Reaction equation

HRID 1661980 reaction equation
Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[F:27])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.CCC(O)(C)C.N#N.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.Cl.[CH3:59][C:60]1([CH3:66])[O:65][CH2:64][CH2:63][NH:62][CH2:61]1.[OH-].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[C:2]([N:62]2[CH2:63][CH2:64][O:65][C:60]([CH3:66])([CH3:59])[CH2:61]2)=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:8]=2)[CH:4]=1

Participants

10

Reactant 6

HCID 947Nitrogen2×HCID 64052-Methyl-2-butanolHCID 14797Potassium HydroxideHCID 27349372-(Di-tert-butylphosphino)-2'-methyl-1,1'-biphenylHCID 220368882,2-Dimethylmorpholine hydrochlorideHCID 667671846-Bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole

Product 1

HCID 667668354-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-6-yl)-2,2-dimethylmorpholineYield 25.6%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent3×

Conditions

Temperature
80 °C

Procedure

6-Bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.5 g, 3.4 mmol) is added to a 50 mL Genevac Carousel® tube and is suspended into the amylene hydrate (10 mL, 91.4 mmol) and N2 is bubbled in suspension. To the mixture is added 2-(di-tert-butylphosphino)-2′-methylbiphenyl (97.7 mg, 309 μmol), Pd2(dba)3 (94.5 mg, 103 μmol) and DI water (0.3 mL), and N2 bubbling is continued for 10 min. To this mixture is added 2,2-dimethylmorpholine hydrochloride (1.04 g, 6.9 mmol) and a solution of KOH (617 mg, 11.0 mmol) dissolved in 0.3 mL of distilled water. The reaction mixture is heated at 80° C. for 2 hours and then cooled to RT. The mixture is then poured into EtOAc (300 mL), washed with distilled water (1×100 mL) and then saturated aqueous sodium chloride (100 mL). The combined aqueous layers are extracted with EtOAc (100 mL). The combined organic solution is dried with Na2SO4, filtered, and concentrated to dryness to give a gold solid. The solid is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 95%(A):5%(B) to 75%(A):25%(B) over 70 min to give a light yellow solid as the desired product (410 mg, 25% yield). MS (m/z): 470.8 (M+H).

Workup

  1. customis bubbled in suspension
  2. temperaturecooled to RT
  3. washwashed with distilled water (1×100 mL)
  4. extractionThe combined aqueous layers are extracted with EtOAc (100 mL)
  5. dry with materialThe combined organic solution is dried with Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customto give a gold solid
  9. customThe solid is purified on a silica gel column
  10. washeluting with hexanes (A) and EtOAc (B), gradient from 95%(A)

Sources & evidence

ORD record
ord-bffbc704516142a4bfec65dd027b0e4e
Source dataset
uspto-grants-2011_10
Patent number
US08030302B2

Reaction notes

Loading…