Cesium carbonate → 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide

HRID 600678Notes

Reaction equation

HRID 600678 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+].[CH3:78][N:79]([CH3:83])[C:80]([NH2:82])=[O:81]>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>[CH3:78][N:79]([CH3:83])[C:80](=[O:81])[NH:82][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

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 11737N,N-DimethylureaHCID 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 116267682-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamideYield 40.3%

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), Pd2 dba3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol) and 1,1-dimethylurea (232 mg, 2.63 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 and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica get (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1) to give 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide (93 mg, 40%) as a 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), 8.77 (1H, s), 8.26 (1H, s), 8.23 (1H, s), 8.13 (1H, d), 7.80 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m), 6.93 (1H, d), 6.73 (1H, t), 6.48 (1H, t), 6.29 (1H, d), 4.40 (2H, d), 4.14 (3H, s), 2.92 (6H, s); m/z (ES+) 462 [M+H]+.

Workup

  1. temperatureOn cooling the reaction
  2. customwas partitioned between EtOAc and water
  3. customThe organic phase was dried
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by chromatography on Isolute® Flash silica
  6. customget
  7. wash(Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 9:1)

Sources & evidence

ORD record
ord-b7d72a87cb034022a67857807743f8de
Source dataset
uspto-grants-2011_03
Patent number
US07902229B2

Reaction notes

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