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Sodium Carbonate → 6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione

HRID 1513352
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1513352
Br[C:2]1[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C:15]3([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[C:13]([CH3:27])([CH2:14]3)[CH2:12]2)[N:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[F:30][C:31]1[C:36]([C:2]2[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C:15]4([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=5)[C:13]([CH3:27])([CH2:14]4)[CH2:12]3)[N:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

9

Edukt 4

HCID 10340Sodium Carbonate2×HCID 27342162-(Dicyclohexylphosphino)biphenyl2×HCID 27832702-Fluoropyridine-3-boronic acid2×HCID 686531246-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione

Produkt 1

HCID 59496095
6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione
Ausbeute 28,7 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418397HCID 178418397, VerbindungKatalysator2×HCID 962WaterLösungsmittelHCID 80711,2-DimethoxyethaneLösungsmittelHCID 18180031Water 1,2-dimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

6-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P16, 48 mg, 0.101 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (1.725 mL)/Water (0.345 mL). Then (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), sodium carbonate (32.2 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol) were added and the mixture was heated to 90° C. and stirred at that temperature for 3 hours. The mixture was cooled down to room temperature, diluted with 1.3 mL of a mixture of DME/Water (5:1) then 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol), (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and sodium carbonate (32.2 mg, 0.304 mmol) were added again. The reaction mixture was then heated to 90° C. and left stirring at that temperature for 40 minutes. The reaction mixture was cooled down to room temperature and evaporated under reduced pressure. The residue was partitioned between AcOEt and water and extracted. Organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by Preparative HPLC then further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) affording 6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (Enantiomer 2) (E11, 14 mg, 0.029 mmol, 28.2% yield).

Aufarbeitung

  1. temperatureThe mixture was cooled down to room temperature
  2. temperatureThe reaction mixture was then heated to 90° C.
  3. waitleft
  4. stirringstirring at that temperature for 40 minutes
  5. temperatureThe reaction mixture was cooled down to room temperature
  6. customevaporated under reduced pressure
  7. customThe residue was partitioned between AcOEt and water
  8. extractionextracted
  9. dry with materialOrganic phase was dried over sodium sulphate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customCrude product was purified by Preparative HPLC
  13. customthen further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1)

Quellen und Nachweise

ORD-Eintrag
ord-3fa5df04a8eb49249ef5251224972176
Quelldatensatz
uspto-grants-2012_07
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08217168B2

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