Process Development on (3S,4S)-[(R)-1‘-((tert-Butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone: 1-β-Methylcarbapenem Key Intermediate

The process for the stereoselective synthesis of the 1-β-methylcarbapenem key intermediate 2 via the Reformatsky-type reaction employing a dihydro-oxazinone derivative has been developed for large-scale production. The most difficult problem involved in the development was the exothermic nature of the reaction. Change of acidification order avoided the heat release in the hydrolysis of 5 to 2.