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

HRID 1502482

Reaktionsgleichung

Reaktionsgleichung von HRID 1502482
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

Komponenten

8

Edukt 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)

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 167845palladium(II) acetateKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-f41fba30a1f54f1a864481be2e4dd5d1
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206175B2

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