Cesium carbonate → 2-Chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

HRID 2234407

Reaktionsgleichung

Reaktionsgleichung von HRID 2234407
Br[C:2]1[C:3]([N:9]([CH2:16][CH2:17][O:18][CH3:19])[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[CH2:16][CH2:17][O:18][CH3:19])=[CH:7][N:6]=1

Komponenten

6

Edukt 3

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)2×HCID 866175793-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methoxyethyl)amino]-N-methyl-propanamide2×

Produkt 1

HCID 866175782-Chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-oneAusbeute 18,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysator2×HCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methoxyethyl)amino]-N-methyl-propanamide (Intermediate 110; 1.12 g, 3.185 mmol) was suspended in dioxane (70 mL), Caesium Carbonate (2.08 g, 6.37 mmol) added and the mixture bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.151 mmol) and XANTPHOS (166 mg, 0.287 mmol) were added and the mixture heated to 100° C. for 20 hrs. A further 0.06 equivalent of Tris(dibenzylideneacetone)dipalladium(0) and 0.09 equivalent of XANTPHOS were added and heating continued for a further 2 hrs. The reaction mixture was cooled to room temperature filtered and the filter cake washed with DCM. The filtrate was evaporated and dissolved in DCM and purified on silica eluting with a gradient of 40-55% Ethyl Acetate/iso-hexane then 55% Ethyl Acetate/iso-hexane and finally 70% Ethyl Acetate/iso-hexane. Fractions containing product were combined and evaporated to a yellow solid. Which was purified by base modified reverse phase HPLC to yield the title compound as a white solid (157 mg, 18%)

Aufarbeitung

  1. customthe mixture bubbled with nitrogen for 10 minutes
  2. temperatureheating
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationfiltered
  5. washthe filter cake washed with DCM
  6. customThe filtrate was evaporated
  7. dissolutiondissolved in DCM
  8. custompurified on silica eluting with a gradient of 40-55% Ethyl Acetate/iso-hexane
  9. additionFractions containing product
  10. customevaporated to a yellow solid
  11. customWhich was purified by base modified reverse phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-c09119b498a549f9aea3c5dc8ed49eb3
Quelldatensatz
uspto-grants-2010_05
Patentnummer
US07709471B2

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