Cesium carbonate → Methyl 5-[[2,3-dihydro-2,2-dimethyl-6-[[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl]-4-benzofuranyl]oxy]-3-fluoro-2-pyridinecarboxylate

HRID 1177154Notes

Reaction equation

HRID 1177154 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:32]=[C:31]([OH:33])[C:25]3[CH2:26][C:27]([CH3:30])([CH3:29])[O:28][C:24]=3[CH:23]=2)=[O:21])=[N:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:33][C:31]2[C:25]3[CH2:26][C:27]([CH3:29])([CH3:30])[O:28][C:24]=3[CH:23]=[C:22]([C:20](=[O:21])[NH:19][C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)[CH:32]=2)=[CH:7][N:6]=1)=[O:4]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 46311137Methyl 3,5-difluoropyridine-2-carboxylateHCID 595600842,3-Dihydro-4-hydroxy-2,2-dimethyl-N-(1-methyl-1H-pyrazol-3-yl)-6-benzofurancarboxamide

Product 1

HCID 59559964Methyl 5-[[2,3-dihydro-2,2-dimethyl-6-[[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl]-4-benzofuranyl]oxy]-3-fluoro-2-pyridinecarboxylateYield 57%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of 3,5-difluoro-pyridine-2-carboxylic acid methyl ester (175a) (422 mg, 2.44 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (700 mg, 2.44 mmol), and Cs2CO3 (1.59 g, 4.88 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 40-70% EtOAc in hexanes to give a white solid (607 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ 9.12 (br. s., 1 H) 8.31 (d, J=2.02 Hz, 1 H) 7.27 (d, J=2.27 Hz, 1 H) 7.12 (d, J=5.81 Hz, 2 H) 6.97-7.07 (m, 1 H) 6.78 (d, J=1.77 Hz, 1 H) 4.00 (s, 3 H) 3.73 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H21FN4O5 m/z 441.20 (M+H)+.

Workup

  1. temperaturecooled to room temperature
  2. customquenched with H2O
  3. extractionextracted with 3×EtOAc
  4. washThe combined organic layer was washed with 2×H2O
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by Biotage column chromatography with 40-70% EtOAc in hexanes

Sources & evidence

ORD record
ord-e672cace755240c0a6efc8fc137b9a12
Source dataset
uspto-grants-2010_11
Patent number
US07842713B2

Reaction notes

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