The Synthesis Of Biapenem

Biapenem 1, 6-[[(4R, 5S, 6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6, 7-dihydro-5H-pyrazolo[1, 2-a][1, 2, 4] triazol-4-ium hydroxide, inner salt, is a new non-natural 1β-methylcarbapenem antibiotic which exhibits a wide range of antibacterial activity, remarkable chemical stability, and extensive stability against human renal dehydropeptidase-I (DHP-I).The dihydrobenzoxazone 4, which is easily prepared from salicylamide and cyclohexanone, serves as an efficient auxiliary in the synthesis of the 1β-methyl-carbapenem key intermediate bicyclic nucleus 2. The stereocontrolled Reformatsky-type reactions of the acetoxyazetidinone 6 with the carboximides 5 gave the intermediates 7 with high diastereoselectivities in 70% yield. The auxiliary 4 also acts as a good leaving group in the TMSCl-promoted Dieckmann-type cyclization leading to a 1β-methylcarbapenem skeleton. By using this auxiliary, 2 was synthesized in 55% overall yield and four steps from salicylamide.Biapenem 1 bearing a bicyclotriazolium thio group at C-2 as the pendant moiety is strikingly different from that of other 1β-methylcarbapenems. Mercaptobicyclo-triazolium chloride 3 useful for the pendant moiety of 1 was successfully synthesized starting from hydrazine hydrate along an economically available synthetic route in 20% yield.The thiol 3 was efficiently exploited for an expeditious synthesis of Biapenem 1 in 73% total yield.