Methanol → Methyl 4-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-2-fluoro-5-methylbenzoate

HRID 1502482

Reaction equation

HRID 1502482 reaction equation
Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)=[C:4]([CH3:25])[CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.[C:65](=[O:68])([O-])[O-:66].[K+].[K+].[CH3:71]O>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:22]1([C:20]([NH:19][C:14]2[N:15]=[CH:16][C:17]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([C:5]2[C:4]([CH3:25])=[CH:3][C:2]([C:65]([O:66][CH3:71])=[O:68])=[C:7]([F:8])[CH:6]=2)[CH:18]=3)=[O:21])[CH2:24][CH2:23]1

Participants

8

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 67974845N-(7-(4-bromo-5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamideHCID 71317487Phosphine, 1,1'-(1,3-propanediyl)bis[1,1-dicyclohexyl-, tetrafluoroborate(1-) (1:2)

Product 1

HCID 67974657Methyl 4-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-2-fluoro-5-methylbenzoateYield 78%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-[7-(4-bromo-5-fluoro-2-methyl-phenyl)-3-isoquinolyl]cyclopropanecarboxamide (385 mg, 0.964 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (61 mg, 0.096 mmol), palladium(II) acetate (11 mg, 0.048 mmol), potassium carbonate (202 mg, 1.45 mmol), and methanol (0.78 mL, 19.3 mmol) in DMF (1 mL) was evacuated and then filled with nitrogen (3×), and then evacuated and filled with carbon monoxide (2×). The reaction mixture was then heated at 100° C. for 2 hours under a balloon of carbon monoxide. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (285, 78%), which was used in the next step without further purification.

Workup

  1. customwas evacuated
  2. additionfilled with nitrogen (3×)
  3. customevacuated
  4. additionfilled with carbon monoxide (2×)
  5. customThe cooled reaction mixture
  6. washwashed with water (50 mL)
  7. customThe organic layer was separated
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto provide a residue that
  12. customwas purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane)
  13. customevaporated in vacuo

Sources & evidence

ORD record
ord-f41fba30a1f54f1a864481be2e4dd5d1
Source dataset
uspto-grants-2015_12
Patent number
US09206175B2

Linked notes

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