Acetamide → [6-[[1-[[4-(4-Morpholinyl)-3-(trifluoromethyl)phenylamino]carbonyl]-1H-indol-5-yl]oxy]-4-pyrimidinyl]acetamide

HRID 2264607Notes

Reaction equation

HRID 2264607 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])[CH2:13][CH2:12]3)[CH:3]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([O:8][C:4]5[N:5]=[CH:6][N:7]=[C:2]([CH2:38][C:37]([NH2:40])=[O:39])[CH:3]=5)=[CH:17][CH:16]=4)[CH:12]=[CH:13]3)=[O:19])=[CH:22][C:23]=2[C:33]([F:35])([F:36])[F:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1

Participants

7

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866182902,3-dihydro-5-(6-chloro-4-pyrimidinyloxy)-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]-1H-indole-1-carboxamide

Product 1

HCID 67531453[6-[[1-[[4-(4-Morpholinyl)-3-(trifluoromethyl)phenylamino]carbonyl]-1H-indol-5-yl]oxy]-4-pyrimidinyl]acetamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 2,3-dihydro-5-(6-chloro-4-pyrimidinyloxy)-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]-1H-indole-1-carboxamide (Intermediate IIa; 1.30 g, 2.5 mmol), acetamide (0.22 g, 3.75 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine] (90 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (45 mg, 0.05 mmol), caesium carbonate (1.14 g, 3.5 mmol) in dry dioxan (10 mL) is heated under an argon atmosphere at 70° C. for 15 h. The cooled suspension is filtered and the residue is dissolved in DMF (50 mL). The resulting solution is filtered (hyflo) and the solvent is evaporated off under reduced pressure to afford the crude product which is purified by preparative HPLC (VP Reprosil 100 Å-5 μm; eluent 0.1% TFA/H2O→0.09% TFA/CH3CN) and neutralised with saturated aqueous NaHCO3 to give the title compound as a colourless crystalline solid, m.p. 272-275° C.

Workup

  1. filtrationThe cooled suspension is filtered
  2. dissolutionthe residue is dissolved in DMF (50 mL)
  3. filtrationThe resulting solution is filtered (hyflo)
  4. customthe solvent is evaporated off under reduced pressure
  5. customto afford the crude product which
  6. customis purified by preparative HPLC (VP Reprosil 100 Å-5 μm; eluent 0.1% TFA/H2O→0.09% TFA/CH3CN)

Sources & evidence

ORD record
ord-531bff4363e6453cb220043f494e27ab
Source dataset
uspto-grants-2010_12
Patent number
US07855215B2

Reaction notes

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