Diisopropylethylamine → p-nitrobenzyl (1R,5S,6S)-2-[1-(4-cyano-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

Participants

Reaction Steps

To a solution of 3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)azetidine (760 mg, 3.18 mmol) (obtained as described in Reference Example 4) in dimethylformamide (38 ml) was added hydrazine acetate (351 mg, 3.81 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.89 g, 3.18 mmol) in acetonitrile (95 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (2.21 ml, 12.7 mmol). The mixture was stirred for 4 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M aqueous sodium chloride solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:4) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-cyano-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (1.65 g, yield 96%).

Provenance & Evidence