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

HRID 468966ノート

反応式

HRID 468966 の反応式
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

参加物

8

反応物 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)

生成物 1

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

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
100 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-08cf49d7541348aca5e3e1b0d0c88db3
出典データセット
uspto-grants-2014_01
特許番号
US08623889B2

反応ノート

読み込み中…