Cesium carbonate → morpholine-4-carboxylic acid (4-{[3-fluoro-2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide

HRID 2100415Notes

Reaction equation

HRID 2100415 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[N:78]1([C:84]([NH2:86])=[O:85])[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>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].CN(C=O)C>[F:29][C:25]1[C:11]([C:12](=[O:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[C:10]([NH:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:86][C:84]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[O:85])[CH:7]=2)[CH:28]=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 75088Morpholine-4-carboxamideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 231189892-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide

Product 1

HCID 11584229morpholine-4-carboxylic acid (4-{[3-fluoro-2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amideYield 52.4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide (227 mg, 0.5 mmol) was suspended in dioxane (4 mL) and treated consecutively with DMF (1.6 mL), Pd2dba3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol) and morpholine-4-carboxylic acid amide (244 mg, 0.75 mmol). The reaction mixture was placed under an argon atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give morpholine-4-carboxylic acid (4-{[3-fluoro-2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (132 mg, 52%) as a pale yellow resin. Further purification was accomplished by preparative reverse phase HPLC [Column: Kromasil C8 5μ, 125×20 mm. Eluant: 38% CH3CN in H2O (containing 0.2% NH3) to 95% CH3CN in H2O (containing 0.2% NH3)]; 1H-NMR (300 MHz, d6-DMSO) 10.43 (1H, s), 9.15 (1H, s), 8.26 (1H, s), 8.23 (1H, s), 8.15 (1H, d), 7.79 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m),-6.95 (1H, d), 6.73 (1H, t), 6.48 (1H, t), 6.29 (1H, d), 4.40 (2H, d), 4.14 (3H, s), 3.56-3.59 (4H, m), 3.42-3.45 (4H, m); m/z (ES+) 504 [M+H]+.

Workup

  1. temperatureOn cooling the reaction
  2. customwas partitioned between EtOAc and water
  3. customThe organic phase was dried
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1)

Sources & evidence

ORD record
ord-141f8f8d8b264e068053f532c008084b
Source dataset
uspto-grants-2009_08
Patent number
US07572794B2

Reaction notes

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