Cesium carbonate → Methyl 2-((3-(2-pyrrolidin-1-ylethoxy)phenyl)amino)pyrimidine-5-carboxylate

HRID 1662856Notes

Reaction equation

HRID 1662856 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:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]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:19]1([CH2:18][CH2:17][O:16][C:15]2[CH:14]=[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:26]=[CH:25][CH:24]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 211452Pyrrolidine, 1-(2-(m-bromophenoxy)ethyl)-HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 9793866Methyl 2-aminopyrimidine-5-carboxylate

Product 1

HCID 59652715Methyl 2-((3-(2-pyrrolidin-1-ylethoxy)phenyl)amino)pyrimidine-5-carboxylateYield 104.2%

Reagents, catalysts & solvents 2

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

Procedure

Two 20 mL microwave vials were each charged with methyl 2-aminopyrimidine-5-carboxylate (460.0 mg, 3.0 mmol), 1-[2-(3-bromo-phenoxy)-ethyl]-pyrrolidine (811.0 mg, 3.0 mmol), Pd2(dba)3 (110.0 mg, 0.12 mmol), XantPhos (208.3 mg, 0.36 mmol), Cs2CO3 (1.95 g, 6.0 mmol) and anhydrous dioxane (20 mL). The mixture was purged with argon gas for 15 min, then sealed and irradiated in a microwave (Initiator, Biotage) at 180° C. for 60 min. After cooling to room temperature, the cap was removed and the reaction mixtures were combined and 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 reddish oil. The oil was re-crystallized from 10 mL of CH3CN to give the title compound as a light-yellow solid (1.07 g, 35% yield).

Workup

  1. customThe mixture was purged with argon gas for 15 min
  2. customsealed
  3. customirradiated in a microwave (Initiator, Biotage) at 180° C. for 60 min
  4. customthe cap was removed
  5. customthe reaction mixtures
  6. custompartitioned between EtOAc and H2O
  7. extractionThe aqueous layer was extracted with EtOAc (3×100 mL)
  8. washCombined EtOAc solutions were washed with H2O (2×100 mL), brine (2×100 mL)
  9. dry with materialdried over anhydrous Na2SO4
  10. concentrationThe resulting solution was concentrated in vacuo with ca. 15 g of silica gel
  11. 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)
  12. additionFractions, containing the product
  13. concentrationconcentrated in vacuo
  14. customto give reddish oil
  15. customThe oil was re-crystallized from 10 mL of CH3CN

Sources & evidence

ORD record
ord-222fe0b069594ba186dfac5e8779f6d5
Source dataset
uspto-grants-2011_10
Patent number
US08030487B2

Reaction notes

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