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

HRID 1502482

반응식

HRID 1502482 반응식
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

참가 물질

8

반응물 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)

생성물 1

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

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

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온도
100 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-f41fba30a1f54f1a864481be2e4dd5d1
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09206175B2

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