Cesium carbonate → 1,1-Dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate

HRID 2081049Notes

Reaction equation

HRID 2081049 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]=[C:20]([O:22][CH3:23])[CH:19]=[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]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 5889352-Chloro-4-methoxypyrimidineHCID 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 671032461,1-Dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylateYield 13%

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 (500 mg, 2.497 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-4-(methyloxy)pyrimidine (361 mg, 2.497 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1220 mg, 3.75 mmol), Xantphos™ (108 mg, 0.187 mmol) and tris(dibenzylideneacetone)dipalladium(0) (57.2 mg, 0.062 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (×2, 20 ml). The organic layers were combined, washed with water (20 ml) and brine (20 ml), dried over magnesium sulphate and then evaporated in vacuo. The residue was purified by flash-silica gel chromatography eluting with 0-10% methanol in dichloromethane. The fractions containing product were combined and solvent evaporated in vacuo to give a yellow oil. The residue was purified again by flash-silica gel chromatography, eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate as a yellow oil (100 mg, 13% yield). LC/MS [M+H]+309. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylate (100 mg, 0.324 mmol) in dichloromethane (0.6 ml)/trifluoroacetic acid (0.300 ml) was stirred at room temperature for 24 hours. The solution was evaporated and the residue was co-evaporated with toluene (×3) and then dichloromethane (×4). The product was then dried in a vacuum oven (50° C.) to give crude 3-methyl-1-[4-(methyloxy)-2-pyrimidinyl]-2-oxo-4-imidazolidinecarboxylic acid as a yellow gum (95 mg, ˜0.3 mmol) which was used in the next reaction. LC/MS [M+H]+253.

Workup

  1. temperaturethe mixture was heated
  2. temperatureat reflux under argon for 3 hours
  3. extractionextracted with ethyl acetate (×2, 20 ml)
  4. washwashed with water (20 ml) and brine (20 ml)
  5. dry with materialdried over magnesium sulphate
  6. customevaporated in vacuo
  7. customThe residue was purified by flash-silica gel chromatography
  8. washeluting with 0-10% methanol in dichloromethane
  9. additionThe fractions containing product
  10. customsolvent evaporated in vacuo
  11. customto give a yellow oil
  12. customThe residue was purified again by flash-silica gel chromatography
  13. washeluting with 0-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-c67bf12360974272ad13d4123fe22acc
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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