Acetonitrile → 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-isopropyl-6-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185209ノート

反応式

HRID 1185209 の反応式
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])C=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH:26]([N:29]1[C:34](=[O:35])[CH2:33][N:32]2[N:36]=[C:37]([NH:39][C:40]3[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44](B4OC(C)(C)C(C)(C)O4)[CH:45]=3)[CH:38]=[C:31]2[CH2:30]1)([CH3:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+].C(#[N:72])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:44]3[CH:45]=[C:40]([NH:39][C:37]4[CH:38]=[C:31]5[CH2:30][N:29]([CH:26]([CH3:28])[CH3:27])[C:34](=[O:35])[CH2:33][N:32]5[N:36]=4)[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=3)[C:18]=1[CH:19]=[O:20])[N:72]=[CH:8]2)([CH3:3])([CH3:4])[CH3:2]

参加物

8

反応物 5

HCID 6342AcetonitrileHCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866840642-(6-tert-butyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-4-chloronicotinaldehydeHCID 895521485-Isopropyl-2-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-3-ylamino)-4,5-dihydropyrazolo[1,5-a]pyrazin-6(7H)-one

生成物 1

HCID 866840592-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(5-(5-isopropyl-6-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde収率 48%

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 962Water溶媒2 回

反応条件

温度
80 °C

実験手順

A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-4-chloronicotinaldehyde 103b (108 mg, 0.30 mmol), 151g (256 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate.water (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), water (0.5 mL), and acetonitrile (8 mL). The reaction mixture was subjected to three cycles of vacuum/nitrogen flush and heated at 80° C. under N2 protection for 2 h. It was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 151h (90 mg, 48%) as yellow solid. MS-ESI: [M+H]+ 625.2.

後処理

  1. customA 25-mL round-bottomed flask equipped with a reflux condenser
  2. customflush
  3. temperatureIt was then cooled to room temperature
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with dichloromethane (20 mL) and water (10 mL)
  6. customThe organic layer was separated
  7. extractionthe water layer was extracted with dichloromethane (2×10 mL)
  8. extractionThe combined organic extract
  9. dry with materialwas dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe dark residue was purified by silica-gel column chromatography
  13. washeluting with dichloromethane/methanol (80:1 to 30:1)

出典と根拠

ORDレコード
ord-8bd9fdcc12da4dfd9c9873eaff25edc5
出典データセット
uspto-grants-2014_03
特許番号
US08669251B2

反応ノート

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