Cesium carbonate → 4-((3-(Difluoromethoxy)-2-methoxy-6-(1-oxoisoindolin-5-yl)phenoxy)methyl)benzamide

HRID 2171114Notes

Reaction equation

HRID 2171114 reaction equation
Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([O:19][CH3:20])[C:5]([O:21][CH:22]([F:24])[F:23])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:23][CH:22]([F:24])[O:21][C:5]1[C:6]([O:19][CH3:20])=[C:7]([C:2]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[C:44](=[O:48])[NH:43][CH2:42]3)=[CH:3][CH:4]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 219557955-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-oneHCID 674639064-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide

Product 1

HCID 674655434-((3-(Difluoromethoxy)-2-methoxy-6-(1-oxoisoindolin-5-yl)phenoxy)methyl)benzamideYield 17.7%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

To a stirring solution of 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzamide (500 mg, 1.24 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (1.2 g, 3.73 mmol), tetrakis(triphenylphosphine) palladium(0) (72 mg, 0.06 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (386 mg, 1.49 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (100 mg, 17.7%).

Workup

  1. customthe resultant reaction mixture
  2. temperatureThe reaction mixture was cooled to RT
  3. filtrationfiltered
  4. additionthe filtrate was diluted with water
  5. extractionextracted with ethyl acetate (3×)
  6. washThe combined ethyl acetate layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulphate
  8. concentrationconcentrated under reduced pressure
  9. customPurification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether)

Sources & evidence

ORD record
ord-a6502d2f25034ddc9fdca096117e37ca
Source dataset
uspto-grants-2015_06
Patent number
US09051290B2

Reaction notes

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