Cesium carbonate → Methyl 2-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)pyrimidine-5-carboxylate

HRID 1662855Notes

Reaction equation

HRID 1662855 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.Br[C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[N:20]1([CH2:19][CH2:18][O:17][C:16]2[CH:25]=[CH:26][C:13]([NH:1][C:2]3[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 70657N-(2-(p-bromophenoxy)ethyl)pyrrolidineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 9793866Methyl 2-aminopyrimidine-5-carboxylate

Product 1

HCID 59652731Methyl 2-((4-(2-pyrrolidin-1-ylethoxy)phenyl)amino)pyrimidine-5-carboxylateYield 47%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

100 mL round-bottom flask was charged with methyl 2-aminopyrimidine-5-carboxylate (1.53 g, 10.0 mmol), 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (4.05 g, 15.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), XantPhos (694 mg, 1.2 mmol), Cs2CO3 (6.51 g, 20.0 mmol) and anhydrous dioxane (70 mL). The mixture was purged with argon gas for 15 min, and then refluxed under argon atmosphere for 2 days. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL). Combined EtOAc solutions were washed with H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous Na2SO4. The resulting solution was concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 0% to 20% MeOH gradient in DCM, 40 min method). Fractions, containing the product, were combined and concentrated in vacuo to give a yellow solid. The solid was re-crystallized from 20 mL of CH3CN to give the title compound as a beige powder (1.61 g, 47% yield).

Workup

  1. customThe mixture was purged with argon gas for 15 min
  2. temperaturerefluxed under argon atmosphere for 2 days
  3. customthe reaction mixture was partitioned between EtOAc and H2O
  4. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  5. washCombined EtOAc solutions were washed with H2O (2×100 mL), brine (2×100 mL)
  6. dry with materialdried over anhydrous Na2SO4
  7. concentrationThe resulting solution was concentrated in vacuo with ca. 15 g of silica gel
  8. customThe loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 0% to 20% MeOH gradient in DCM, 40 min method)
  9. additionFractions, containing the product
  10. concentrationconcentrated in vacuo
  11. customto give a yellow solid
  12. customThe solid was re-crystallized from 20 mL of CH3CN

Sources & evidence

ORD record
ord-b0c13d9ba0e24cd999283d8c8ef645cf
Source dataset
uspto-grants-2011_10
Patent number
US08030487B2

Reaction notes

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