Potassium Phosphate, Tribasic → 2-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 592727Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 592727
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:30]=[C:21]3[CH2:22][N:23]([CH:26]4[CH2:29][O:28][CH2:27]4)[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:31].Cl[C:33]1[C:38]([CH:39]=[O:40])=[C:37]([N:41]2[CH2:54][CH2:53][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[C:51]([F:52])=[C:43]3[C:42]2=[O:55])[N:36]=[CH:35][CH:34]=1.[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].O.C(#N)C>[F:52][C:51]1[C:50]2[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=2[N:44]2[CH2:53][CH2:54][N:41]([C:37]3[N:36]=[CH:35][CH:34]=[C:33]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:30]=[C:21]6[CH2:22][N:23]([CH:26]7[CH2:29][O:28][CH2:27]7)[CH2:24][CH2:25][N:20]6[N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:38]=3[CH:39]=[O:40])[C:42](=[O:55])[C:43]=12

Komponenten

8

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866842384-Chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehydeHCID 866842921-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Produkt 1

HCID 866842912-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeAusbeute 60 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittelHCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 163a (354 mg, 0.83 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (289 mg, 0.83 mmol), PdCl2(dppf) (68 mg, 0.08 mmol), K3PO4 (352 mg, 1.66 mmol), sodium acetate (136 mg, 1.66 mmol), acetonitrile (50 mL), and water (3 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 166a (305 mg, 60%) as a brown solid. MS-ESI: [M+H]+: 613.6.

Aufarbeitung

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customThe system was evacuated
  4. additionrefilled with N2
  5. temperatureIt was then cooled to room temperature
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customthe resulting residue was purified by silica-gel column chromatography
  9. washeluting with 30:1 dichloromethane/methanol

Quellen und Nachweise

ORD-Eintrag
ord-57588aa36dfc46d2a3e8471072a137ad
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09238655B2

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