Synthesis Of Doripenem And Key Raw Material 4AA For Carbapenem Antibiotics

Doripenem , developed by SHIONOGI & Co., Ltd, is a novel 1β-methylcarbapenem antibiotic with the replacement of a sulfamoylaminomethyl substituted pyrrolidylthio group at C-2 position. It shows broad and potent antibacterial activity by combining with PBP-2 of bacterials to restrain the synthesis of their cell wall. Doripenem is stable to most β-lactamase as well as DHP-I. It has potent antibacterial activity towards kinds of anaerobe and aerobe. Doripenem was launched in Sept. 2005.In this assay, we have synthesized Doripenem by two methods both from trans-4-hydroxy-proline. In method 1, we have introduced comparably cheap reagent-Boc anhydride as protecting group and synthesized intermediate 18 through 6 reactions, which then condensed with 24, and followed by deprotection to obtain Doripenem with an overall yield of 17.0%. In this work, we have synthesized a new compound 28. Besides, we take out the protection of nitrogen and active hydroxyl group through"one-pot"synthesis; in reduction of 27, we use KBH₄/ZnCl₂ instead of NaBH₄; after deprotection of PNZ and PNB, Doripenem was recrystalled from isopropanol, thus we avoided using resin column to purefy title compound.In method 2, according to literature, we synthesized Doripenem through 6 reaction started from trans-4-hydroxy-proline. But we have done some research work on the reduction, Mitsunobu reaction and deprotection steps, and optimized some of the procedures. In addition, we've tried several recrystallization conditions so as to obtain comparatively high quality product. The overall yield for this method is 27.6% (from L-proline) .We have also synthesized another compound 4AA. It is gained through 7 reactions from L-threonine andp-phenylenediamine. We have used GC to follow up the formation of epoxy acid and established the acidify condition; we have done series of parallel experiments to better the pivotal condensation reaction between acid and amine; In the cyclization step, we use cheap and available reagent-Lithium amide , rather than expensive LiHMDS, to proceed the reaction; and at last, we introduced green reagent-ozone to clear the phenyl group of nitrogen to avoid using heavy metal reagent-CAN. The total yield for this method is 29.8%.The structure of Doripenem was confirmed by MS, IR, Element Analysis, ¹H-NMR, ¹³C-NMR, DEPT and HMQC. The content of 4AA was above 98.0% by HPLC. The structures of other key intermediates were confirmed by ¹H-NMR and HPLC.