Sodium Hydroxide → 4-{5-[(2,2-Dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(1H-indol-4-yl)-1H-indazole

HRID 38885Notes

Reaction equation

HRID 38885 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][CH:48]=[C:47]3[C:43]=2[CH:44]=[CH:45][NH:46]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.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]>[CH3:33][C:28]1([CH3:32])[O:29][CH2:30][CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:42]4[CH:50]=[CH:49][CH:48]=[C:47]5[C:43]=4[CH:44]=[CH:45][NH:46]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][N:23]=2)[CH2:27]1

Participants

8

Reactant 4

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 113224711H-Indole-4-boronic acid, pinacol esterHCID 666956776-Bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole

Product 1

HCID 666957204-{5-[(2,2-Dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(1H-indol-4-yl)-1H-indazoleYield 24.3%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of 6-bromo-4-{5-[(2,2-dimethyl-4-morpholinyl)methyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazole (176 mg, 0.298 mmol) in dioxane (2.5 ml) and water (0.25 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (102 mg, 0.420 mmol, available from Frontier Scientific Europe), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (43.5 mg, 0.060 mmol) and potassium phosphate tribasic (198 mg, 0.933 mmol). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The crude residue was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC. The product-containing fractions were blown down under a stream of nitrogen to give a yellow solid. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 3 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen to give a brown solid (31 mg) that was dissolved in DMSO (750 μL) and purified by Mass Directed Automated Preparative HPLC. The solvent was removed under a stream of nitrogen. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a pale yellow gum (2.4 mg).

Workup

  1. washwashing with MeOH
  2. customThe solvent was removed under a stream of nitrogen
  3. customthe residue was partitioned between DCM (10 ml) and water (10 ml)
  4. customseparated with a hydrophobic frit
  5. customthe solvent again removed under a stream of nitrogen
  6. dissolutionThe crude residue was dissolved in DMSO (2 ml)
  7. custompurified by Mass Directed Automated Preparative HPLC
  8. customto give a yellow solid
  9. customThe mixture was evaporated to dryness under a stream of nitrogen
  10. customThe residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml)
  11. customseparated with a hydrophilic frit
  12. customThe solvent was removed under a stream of nitrogen

Sources & evidence

ORD record
ord-8b7700de66fa4f7ca90f18ee2c7513be
Source dataset
uspto-grants-2013_09
Patent number
US08524751B2

Reaction notes

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