Potassium Phosphate, Tribasic → 5-[3-(6-Bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholin-3-one

HRID 925442Notes

Reaction equation

HRID 925442 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH2:27])=[N:22][N:23]2[CH3:26])=[CH:19][CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(O)=O.[Na+].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>[Br:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH:27][C:2]3[CH:3]=[C:4]([C:8]4([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[N:22][N:23]2[CH3:26])=[CH:19][CH:18]=1

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 468355496-Bromo-1-methyl-1H-indazol-3-amineHCID 581553055-(3-Bromophenyl)-5-methylmorpholin-3-one

Product 1

HCID 895001935-[3-(6-Bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholin-3-one

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one [Example 1, step f)] (CAS registry 1262858-67-2) (138.5 mg, 0.513 mmol), 6-bromo-1-methyl-1H-indazol-3-ylamine (CAS registry 1214899-85-0) (116 mg, 0.513 mmol), X-phos (78 mg, 0.164 mmol) and K3PO4 (218 mg, 1.025 mmol) in toluene (2.5 ml) and water (0.250 ml) was degassed with argon (5 min), then Pd2(dba)3 (37.6 mg, 0.041 mmol) was added and the reaction mixture was stirred at 120° C. for 20 h. The reaction mixture was diluted with water, sat. aq. NaHCO3 soln. and EtOAc. The layers were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 70% ACN+0.1% TFA) to yield the title compound as a pale yellow powder.

Workup

  1. customwas degassed with argon (5 min)
  2. customThe layers were separated
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting crude product was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 70% ACN+0.1% TFA)

Sources & evidence

ORD record
ord-7dc8aa5297e74ee299e2b9d0d522908f
Source dataset
uspto-grants-2016_03
Patent number
US09284284B2

Reaction notes

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