400827-64-7

80-48-8

400827-68-1

400827-64-7

To a glass round bottom flask was added 35 g (51.7 mmol) of 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 8-oxo-7-[(2-phenylacetyl)amino]-3-[[4-(4-pyridinyl)-2-thiazolyl]thio]-, (6R,7R)-diphenylmethyl ester, and 75 mL of methylene chloride, and the temperature of the reaction was controlled at 25°C. To this solution was added 48 g (258.5 mmol) of methyl p-toluenesulfonate, and the mixture was heated to reflux and maintained at reflux for 12 hours and subsequently cooled to room temperature. In another glass-lined reactor, 32.3 g (155.1 mmol) of phosphorus pentachloride and 75 mL of methylene chloride were added. This suspension was cooled to -5°C to 0°C and 12.3 g (155.1 mmol) of pyridine was added dropwise while maintaining the temperature at -5°C to 0°C. After addition, stirring was continued at the same temperature for 15 minutes. The solution in the round-bottomed flask was carefully added to a glass-lined reactor that had been cooled to -10°C to -5°C while maintaining the temperature in the range of -10°C to -5°C; the resulting mixture was stirred at the same temperature for 2 hours. Subsequently, 105 mL of isobutanol was slowly added over about 30 minutes while maintaining a temperature in the range of -5°C; the mixture was heated to 28°C to 30°C and reacted at this temperature for 3.5 hours. Upon completion of the reaction, the mixture was concentrated under vacuum to 1/3 of the original volume, diluted with 200 mL of acetone, and stirred at 25°C to 30°C for 1 hour. 70 mL of 32% hydrochloric acid was added, the temperature was maintained at 25°C to 30°C and the mixture was stirred overnight. The resulting suspension was filtered and the filter cake was washed with acetone (2 x 35mL). The wet solid was dried under vacuum at 40 °C overnight to give 18.4 g (38.4 mmol) of 4-[2-[[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3- yl]thio]-4-thiazolyl]-1-methylpyridinium chloride hydrochloride (1:1:1) as a crystalline solid. Yield 74.3%.