Methanol → methyl 3-fluoro-5-(3-((1S,2S)-2-fluorocyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpicolinate

HRID 1502454ノート

反応式

HRID 1502454 の反応式
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([C@@H:21]4[CH2:23][C@@H:22]4[F:24])=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:25])[C:3]=1[F:26].F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.[C:66](=[O:69])([O-])[O-:67].[K+].[K+].[CH3:72]N(C)C=O.CO.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:26][C:3]1[C:2]([C:66]([O:67][CH3:72])=[O:69])=[N:7][CH:6]=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([C@@H:21]4[CH2:23][C@@H:22]4[F:24])=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[C:4]=1[CH3:25]

参加物

8

反応物 6

HCID 887MethanolHCID 6228DimethylformamideHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 71317487Phosphine, 1,1'-(1,3-propanediyl)bis[1,1-dicyclohexyl-, tetrafluoroborate(1-) (1:2)HCID 86674978(1S,2S)-N-(7-(6-chloro-5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)-2-fluorocyclopropanecarboxamide

生成物 1

HCID 71115156methyl 3-fluoro-5-(3-((1S,2S)-2-fluorocyclopropanecarboxamido)isoquinolin-7-yl)-4-methylpicolinate収率 45%

試薬・触媒・溶媒 1

HCID 167845palladium(II) acetate触媒

反応条件

温度
100 °C

実験手順

A flask charged with (1S,2S)-N-(7-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-isoquinolin-3-yl)-2-fluoro-cyclopropanecarboxamide (261 mg; 0.5237 mmol), palladium(II) acetate (13.7 mg; 0.0610 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (66.8 mg; 0.106 mmol), potassium carbonate (136.1 mg; 0.9749 mmol), N,N-dimethylformamide (3.0 mL; 38 mmol) and methanol (0.75 mL; 18 mmol) was evacuated and backfilled with CO gas 3 times, and then stirred under a balloon of CO gas at 100° C. for 20 hours. To the reaction mixture was then added triethylamine (0.20 mL; 1.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (64.9 mg; 0.0795 mmol). The reaction vessel was re-purged with CO gas and stirred at 100° C. for an additional 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 134.9 mg (70% pure, 45% yield) of the title compound. LCMS (ESI): M+H=398.2.

後処理

  1. customwas evacuated
  2. customThe reaction vessel was re-purged with CO gas
  3. stirringstirred at 100° C. for an additional 3 hours
  4. additionThe reaction mixture was diluted with ethyl acetate
  5. washwashed with water and brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-10% methanol in dichloromethane)

出典と根拠

ORDレコード
ord-410123abf0eb43d88f7d709dda947293
出典データセット
uspto-grants-2015_12
特許番号
US09206175B2

反応ノート

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