2,6-Lutidine → (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane

Participants

Reaction Steps

In 420 ml of anhydrous tetrahydrofuran was dissolved 30.00 g of (3R,4R)-4-[1-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-1-(p-nitrobenzyloxycarbonyl)methylthio]-1-hydroxymethyl-3-phenylacetamidoazetidin-2-one. To the solution were added, with ice cooling, 6.72 ml of 2,6-lutidine and 3.95 ml of thionyl chloride in this order. The mixture was stirred at room temperature for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 600 ml of anhydrous tetrahydrofuran. To the solution was added 13.6 ml of N,O-bis(trimethylsilyl)acetamide. The mixture was stirred at room temperature for 15 minutes and cooled to -60° C. To the reaction mixture were added, at 40° C. or below, 40.4 ml of hexamethylphosphoric triamide and 69.6 ml of tetrahydrofuran solution lithium bis(trimethylsilyl)amide (0.8 mmol/ml), in this order. The temperature of the mixture was elevated to -15° C. in 1 hour. To the reaction mixture was added 3.16 ml of acetic acid while maintaining the temperature at -15° C. The mixture was added to a mixed solvent consisting of 500 ml of water and 500 ml of ethyl acetate. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with diluted hydrochloric acid of pH 2.0, mixed with 200 ml of water, and adjusted to pH 7.0 with an aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 2/1) to obtain 13.32 g (yield: 45.7%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia- 1-azabicyclo[3.2.0]heptane.

Provenance & Evidence