Water → 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

HRID 1811844

Reaktionsgleichung

Reaktionsgleichung von HRID 1811844
Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[C:22]([F:25])=[N:23][CH:24]=1.C([O-])(=O)C.[K+].O>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:22]([F:25])=[N:23][CH:24]=1

Komponenten

6

Edukt 4

HCID 962WaterHCID 517044Potassium AcetateHCID 249017795-Chloro-2-fluoropyridine-3-boronic AcidHCID 595482686-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

Produkt 1

HCID 595482256-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purineAusbeute 73 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.979 mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388 g, 7.91 mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25 ml) were added to a 100 mL round-bottomed flask. Potassium acetate (0.583 g, 5.94 mmol) was added to the mixture, followed by water (1 mL). The mixture was evacuated, then backfilled with Nitrogen gas. Then bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture. The mixture was evacuated, then backfilled with nitrogen gas. The flask was fitted with a reflux condenser, then placed into a pre-heated (90° C.) oil bath and allowed to stir under inert atmosphere for 2 h. The progress of the reaction was monitored by LCMS, which showed mostly desired product. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were washed with satd aqueous Na2CO3 (1×20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2, to give 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.502 g, 1.443 mmol, 73.0% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.37-8.45 (m, 1H); 8.27-8.33 (m, 2H); 5.79-5.92 (m, 1H); 4.14-4.26 (m, 1H); 3.74-3.91 (m, 1H); 2.89 (s, 3H); 1.96-2.25 (m, 3H); 1.63-1.91 (m, 3H). m/z (ESI, +ve) 348 (M+H)+.

Aufarbeitung

  1. customThe mixture was evacuated
  2. additionThen bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture
  3. customThe mixture was evacuated
  4. customThe flask was fitted with a reflux condenser
  5. temperatureto cool to room temperature
  6. additiondiluted with water (10 mL)
  7. extractionextracted with CH2Cl2 (3×25 mL)
  8. washThe organic extracts were washed with satd aqueous Na2CO3 (1×20 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationThe solution was filtered
  11. concentrationconcentrated in vacuo
  12. customto give the crude material as a tan oil
  13. custompurified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr
  14. wash, pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-d228024e6ee040f5a66b10c7af99213a
Quelldatensatz
uspto-grants-2013_01
Patentnummer
US08362241B2

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