P-Anisidine → N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridine-2,5-diamine

HRID 1621469

Reaktionsgleichung

Reaktionsgleichung von HRID 1621469
Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:2]2[CH:3]=[C:4]([C:17]3[N:25]=[C:24]([CH3:26])[N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:5]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)=[N:6][CH:7]=2)=[CH:37][CH:36]=1

Komponenten

8

Edukt 4

HCID 7732P-AnisidineHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 23676156Sodium t-butoxideHCID 595484095-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine

Produkt 1

HCID 66600577N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridine-2,5-diamine

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

A mixture of 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.115 g, 0.254 mmol) and 4-anisidine (0.117 mL, 1.018 mmol) (Aldrich, St. Louis, Mo.) in THF (10 mL) was treated with sodium tert-butoxide (0.073 g, 0.763 mmol) (Aldrich, St. Louis, Mo.) and 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (0.025 g) (Strem Chemicals, Inc., Newburyport, Mass.). The mixture was deoxygenated and Pd2(dba)3 (0.023 g, 0.025 mmol) (Strem Chemicals, Inc., Newburyport, Mass.) was added under N2. The flask was fitted with a reflux condenser, then placed into a pre-heated bath at 90° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with 4:1 CH2Cl2/MeOH (5×25 mL) and from brine. The combined organic extracts were washed with saturated aqueous NaHCO3 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as tan oil. This was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (80 g), eluting with a gradient of 1% to 5% MeOH in CH2Cl2 over 30 minutes to give N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridine-2,5-diamine as a tan oil. This was diluted with methanol (3 mL) and TFA (1.5 mL) and placed into a pre-heated (60° C.) bath. The mixture was allowed to stir under inert atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature, concentrated in-vacuo, then diluted with DCM. The mixture was made basic with 10N aqueous NaOH, diluted with water (15 mL) and extracted with CH2Cl2 (3×15 mL). The organic extract was washed with water (1×10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a tan oil. This was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 1% to 8% MeOH in CH2Cl2 over 25 minutes, to give N5-(4-methoxyphenyl)-N2-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridine-2,5-diamine (0.009 g, 0.020 mmol, 7.78% yield) as tan solid. MS (ESI pos. ion) m/z 455 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 9.62 (s, 1H); 8.59 (s, 1H); 8.51 (s, 1H); 8.14 (m, 2H); 7.00 (d, J=8.80 Hz, 2H); 6.84 (d, J=8.80 Hz, 3H); 3.84 (s, 3H); 3.70 (s, 3H); 2.86 (s, 3H).

Aufarbeitung

  1. customThe mixture was deoxygenated
  2. customThe flask was fitted with a reflux condenser
  3. customplaced into a pre-heated bath at 90° C.
  4. extractionextracted with 4:1 CH2Cl2/MeOH (5×25 mL) and from brine
  5. washThe combined organic extracts were washed with saturated aqueous NaHCO3 (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationThe solution was filtered
  8. concentrationconcentrated in vacuo
  9. customto give the crude material as tan oil
  10. custompurified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr
  11. wash, pre-packed silica gel column (80 g), eluting with a gradient of 1% to 5% MeOH in CH2Cl2 over 30 minutes

Quellen und Nachweise

ORD-Eintrag
ord-9636676100d64e82a3cfe6da06536ee2
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08772480B2

Verknüpfte Notizen

Wird geladen…