N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide → 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin

Participants

Reaction Steps

3 mol/L hydrogen chloride-ethyl acetate (30 mL) was added to N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide (Compound of Reference Example 5; 11.8 g) while the solution was chilled on an ice bath. The reaction mixture was stirred for 1 hour and then additional 1 hour at room temperature. The solvent was removed and the resulting residue was dissolved in N,N-dimethylformamide (20 mL). To this solution, potassium carbonate (5.37 g) was added and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin (6.22 g, 68%).

Provenance & Evidence