Cesium carbonate → 1,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate

HRID 2081046Notes

Reaction equation

HRID 2081046 reaction equation
[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Cl[C:16]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=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.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]>[F:22][C:19]1[CH:18]=[N:17][C:16]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[N:21][CH:20]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 5834662-Chloro-5-fluoropyrimidineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 671035641,1-Dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate

Product 1

HCID 671031911,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylateYield 52.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.498 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-5-fluoropyrimidine (0.194 ml, 1.573 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (732 mg, 2.247 mmol), Xantphos™ (65.0 mg, 0.112 mmol), and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.037 mmol) and then heated at reflux for ˜3 hrs. The mixture was cooled to room temperature, diluted with water (˜25 ml) and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water and then with brine and evaporated to give a yellow/brown residue. This was purified by automated silica-gel column chromatography (Biotage SP-4), eluting with a 0-100% gradient of ethyl acetate in isohexane (8 column volumes), to give 1,1-dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 52.3% yield) as a white solid. (ii) 1,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml, 26.0 mmol) and dichloromethane (4 ml) at 0° C. and then left to warm to room temperature and stirred overnight. The mixture was evaporated (azeotroping with toluene and then with dichloromethane to remove all TFA traces) to give 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (211 mg) as a white solid which was used without further purification in subsequent chemistry. LC/MS MH+=240.85.

Workup

  1. temperatureheated
  2. temperatureat reflux for ˜3 hrs
  3. extractionextracted with ethyl acetate (3×)
  4. washThe combined ethyl acetate layers were washed with water
  5. customwith brine and evaporated
  6. customto give a yellow/brown residue
  7. customThis was purified by automated silica-gel column chromatography (Biotage SP-4)
  8. washeluting with a 0-100% gradient of ethyl acetate in isohexane (8 column volumes)

Sources & evidence

ORD record
ord-a8914478e8f64dd7bc22b7db7f6332f2
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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