Diisopropylethylamine → p-nitrobenzyl (1R,5S,6S)-2-[1-(4-pyrrolidinocarbonyl-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-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (235 mg, 0.84 mmol) (obtained as described in Reference Example 26) in dimethylformamide (12 ml) was added hydrazine acetate (103 mg, 110 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 3 hours. 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 (499 mg, 0.84 mmol) in acetonitrile (25 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.56 ml, 3.36 mmol). The mixture was stirred overnight 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 hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (240 mg, yield 46%) as a pale yellow solid.

Provenance & Evidence