Trifluoroacetic acid → 3-Methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxylic acid

Participants

Reaction Steps

To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloropyrazine (0.179 ml, 1.998 mmol) in 1,4-dioxane (20 ml) was added cesium carbonate (2604 mg, 7.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and Xantphos™ (87 mg, 0.150 mmol) and the reaction mixture was stirred at reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was washed with saturated sodium hydrogen carbonate solution, water and brine and separated by hydrophobic frit. The solution was reduced under vacuum and the residue purified by silica gel chromatography eluting with 10-75% ethyl acetate in isohexane to give the crude 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxylate (322 mg, 38.2% yield) which was used in the next step. LC/MS [M+H]+=279. (ii) Trifluoroacetic acid (1 ml) was added to a solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxylate (290 mg, 0.709 mmol) in dichloromethane and the solution was stirred at room temperature overnight. The reaction mixture was reduced to dryness azeotroping with toluene and dried under heated vacuum. The residue was taken up in dichloromethane and extracted with saturated sodium hydrogen carbonate solution (×3) and aqueous layer reduced under vacuum. The residue was taken up in water and the solution acidified to pH 4 by the slow addition of 2N hydrochloric acid. The solution was washed with dichloromethane (×2) and the solvent was reduced under vacuum. The residue was triturated with the minimal amount of methanol, the solid was filtered off and the filtrate reduced under vacuum to leave a white solid which was dried under heated vacuum to give 3-methyl-2-oxo-1-(2-pyrazinyl)-4-imidazolidinecarboxylic acid (242 mg, ˜0.7 mmol) which was used in the next step. LC/MS [M+H]+=223.

Provenance & Evidence