Potassium Phosphate, Tribasic → (R)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1185133ノート

反応式

HRID 1185133 の反応式
[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[CH3:24])=[O:17])=[CH:12][N:11]=2)=[CH:5][C:4](B(O)O)=[CH:3]1.[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48](Cl)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48]([C:4]3[CH:5]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][C@H:19]5[CH3:24])=[O:17])=[CH:12][N:11]=4)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:29])[CH3:30]

参加物

7

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866839152-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehydeHCID 86683988(R)-1-Methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-ylboronic Acid

生成物 1

HCID 86683987(R)-2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(1-methyl-5-(5-(3-methylmorpholine-4-carbonyl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde収率 37%

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 18373917Acetonitrile--water (1/1)溶媒

反応条件

温度
100 °C

実験手順

A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 132c (260 mg, 0.70 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotin-aldehyde 103b (180 mg, 0.50 mmol), K3PO4 (297 mg, 1.4 mmol), sodium acetate (114 mg, 1.4 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (57 mg, 0.070 mmol), and acetonitrile/water (10/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 132d (120 mg, 37%) as a yellow solid. MS-ESI: [M+H]+ 652.3

後処理

  1. customA 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/N2 flush
  3. custom1.5 h
  4. temperatureThe reaction mixture was cooled to room temperature
  5. concentrationconcentrated under reduced pressure
  6. additionThe residue was diluted with dichloromethane (20 mL) and water (20 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with dichloromethane (3×20 mL)
  9. dry with materialThe combined organic layer was dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe dark residue was purified by silica-gel column chromatography
  13. washeluting with 60:1 dichloromethane/methanol

出典と根拠

ORDレコード
ord-bda1e3b73e19437ab78e0922299df3a9
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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