Potassium Phosphate, Tribasic → 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate

HRID 2081011Notes

Reaction equation

HRID 2081011 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].Br[C:16]1[N:17]=[CH:18][N:19]([CH3:21])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.ClCCl.[Cu]I>[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:17]=[CH:18][N:19]([CH3:21])[CH:20]=2)[C:3]1=[O:14]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 12776534-Bromo-1-methyl-1H-imidazoleHCID 11275066(1R,2R)-N1,N1-Dimethylcyclohexane-1,2-diamineHCID 671035641,1-Dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate

Product 1

HCID 671033991,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylateYield 101.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred mixture of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-bromo-1-methyl-1H-imidazole (193 mg, 1.199 mmol) in 1,4-dioxane (8 ml) was added potassium phosphate (1060 mg, 4.99 mmol), copper(I) iodide (190 mg, 0.999 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.158 ml, 0.999 mmol) and the reaction mixture was stirred at reflux under argon for 3 hours. The mixture was cooled to room temperature and diluted with dichloromethane (20 mL) and filtered and washed through with dichloromethane. The filtrate was concentrated under vacuum and taken up in dichloromethane. The solution was washed with 0.880 ammonia (×3), water then brine and separated by hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-20% methanol in dichloromethane to leave an oil which crystallised on standing. The residue was dried under vacuum overnight to give 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (285 mg, 87% yield). LC/MS [M+H]+=281. (ii) Trifluoroacetic acid (1.0 ml, 12.98 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylate (220 mg, 0.785 mmol) in DCM (2 ml) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated under vacuum, azeotroping with toluene and the residue was dried under vacuum over the weekend to give crude 3-methyl-1-(1-methyl-1H-imidazol-4-yl)-2-oxo-4-imidazolidinecarboxylic acid trifluoroacetate salt which was taken through to next step without further purification. LC/MS [M+H]+=225.

Workup

  1. temperatureat reflux under argon for 3 hours
  2. filtrationfiltered
  3. washwashed through with dichloromethane
  4. concentrationThe filtrate was concentrated under vacuum
  5. washThe solution was washed with 0.880 ammonia (×3), water
  6. custombrine and separated by hydrophobic frit
  7. customThe residue was purified by Flashmaster automated silica gel chromatography
  8. washeluting with 0-20% methanol in dichloromethane
  9. customto leave an oil which
  10. customcrystallised
  11. customThe residue was dried under vacuum overnight

Sources & evidence

ORD record
ord-b4e5e823fe0645c2806ec250a19d449b
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

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