Potassium Phosphate, Tribasic → {4-Fluoro-2-[6-({4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}amino)-9-{[2-(trimethylsilyl)ethoxy]methyl}purin-2-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}phenyl}methyl Acetate

HRID 1024085Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1024085
[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].I[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[C:39]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:70][O:69][CH2:68]4)[CH2:63][CH2:62]3)=[CH:57][CH:56]=2)[N:38]=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].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:13](=[O:25])[C:14]3[S:20][C:19]4[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=4[C:15]=3[CH2:16][CH2:17]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:52])[CH3:53])=[C:39]([NH:54][C:55]2[CH:56]=[CH:57][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:68][O:69][CH2:70]4)[CH2:63][CH2:62]3)=[CH:59][CH:60]=2)[N:38]=1)(=[O:3])[CH3:2]

Komponenten

8

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 670162052-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-fluoro-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzyl AcetateHCID 866841532-Iodo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine

Produkt 1

HCID 86684157{4-Fluoro-2-[6-({4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}amino)-9-{[2-(trimethylsilyl)ethoxy]methyl}purin-2-yl]-6-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}phenyl}methyl AcetateAusbeute 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 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 103g (288 mg, 0.60 mmol), 2-iodo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine 117f (364 mg, 0.60 mmol), Pd(dppf)Cl2 (49 mg, 0.060 mmol), K3PO4 (254 mg, 1.20 mmol), sodium acetate (98 mg, 1.20 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the 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 119a (307 mg, 60%). MS-ESI: [M+H]+ 853.4

Aufarbeitung

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe resulting residue was purified by silica-gel column chromatography
  7. washeluting with 30:1 dichloromethane/methanol

Quellen und Nachweise

ORD-Eintrag
ord-22c03fb14f3d43c5b04d9dc6763e03c4
Quelldatensatz
uspto-grants-2014_05
Patentnummer
US08722676B2

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