Cesium carbonate → (S)-1-(5-fluoro-6-methyl-pyridin-2-yl)-5-oxo-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)amide

HRID 469750Notes

Reaction equation

HRID 469750 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].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+].Br[C:68]1[N:73]=[C:72]([CH3:74])[C:71]([F:75])=[CH:70][CH:69]=1>O1CCOCC1.C(OCC)(=O)C.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]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[C:68]2[CH:69]=[CH:70][C:71]([F:75])=[C:72]([CH3:74])[N:73]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27831806-Bromo-3-fluoro-2-methylpyridineHCID 67454707(S)-5-oxo-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide

Product 1

HCID 67457597(S)-1-(5-fluoro-6-methyl-pyridin-2-yl)-5-oxo-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)amideYield 27.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

(S)-5-Oxo-pyrrolidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide (300 mg, 1.19 mmol), tris(dibenzylideneacteone)dipalladium (0) (32.80 mg, 0.036 mmol), Xantphos ® (62.20 mg, 0.011 mmol), caesium carbonate (654.16 mg, 2.01 mmol) and 6-bromo-3-fluoro-2-methylpyridine (226.90, 1.20 mmol) are charged to a vessel, diluted with dioxane (anhydrous, 3 ml) and heated to 100° C. overnight. On completion, the reaction is diluted with ethyl acetate and partitioned between water. The organic phase is separated, dried over sodium sulphate and the solvents removed under vacuum. The crude residue is purified by flash column chromatography eluting with a gradient solution of heptane/ethyl acetate 0-50% to isolate 117 mg of title compound as a white solid, yield 27%. ESI m/z 361=MH+

Workup

  1. custompartitioned between water
  2. customThe organic phase is separated
  3. dry with materialdried over sodium sulphate
  4. customthe solvents removed under vacuum
  5. customThe crude residue is purified by flash column chromatography
  6. washeluting with a gradient solution of heptane/ethyl acetate 0-50%

Sources & evidence

ORD record
ord-987aff7be2f44470ad9d48f03e47a9df
Source dataset
uspto-grants-2014_01
Patent number
US08629157B2

Reaction notes

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