Cesium carbonate → HCID 67103623, compound

HRID 2081021Notes

Reaction equation

HRID 2081021 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[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N: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[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[CH:18][N:17]=2)[C:3]1=[O:14]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 115428814-Chloro-6-(trifluoromethyl)pyrimidineHCID 671035641,1-Dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate

Product 1

HCID 67103623HCID 67103623, compoundYield 71%

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 (800 mg, 4.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-chloro-6-(trifluoromethyl)pyrimidine (729 mg, 4.00 mmol) in 1,4-dioxane (40 ml) was treated with cesium carbonate (1953 mg, 5.99 mmol), Xantphos™ (173 mg, 0.300 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction mixture was heated at reflux under argon overnight. After cooling the reaction was diluted with water and extracted with ethyl acetate (×2). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate and reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (983 mg, 67.5% yield). LC/MS [M+H]+=347. (ii) Trifluoroacetic acid (4 ml, 51.9 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (980 mg, 2.83 mmol) in dichloromethane (8 ml) and the solution was stirred at room temperature for 6 hours. The solvent was evaporated and the residue was co-evaporated with toluene. The residue was dissolved in saturated sodium hydrogen carbonate solution and the solution was loaded onto an amino column eluting with 10% 2N hydrochloric acid in methanol. Product-containing fractions were combined and reduced under vacuum and the residue was triturated with methanol and the solid was filtered off. The filtrate was reduced under vacuum to give 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid hydrochloride salt (893 mg, assume ˜2.8 mmol) which was used in the next step. LC/MS [M+H]+=291.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureat reflux under argon overnight
  3. temperatureAfter cooling the reaction
  4. extractionextracted with ethyl acetate (×2)
  5. washwashed with water and brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. customThe residue was purified by Flashmaster automated silica gel chromatography
  8. washeluting with 0-30% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-0f813d4f45964dbbba2c1eaaaa6cb8dc
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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