The synthesis and biological activity of (l i?,5S,6S)-2-[(3SV5S)-5-substituted pyrrolidin-3-ylthio]-6-[(l i?)-l-hydroxyethyl]-l-methylcarbapen-2-em-3-carboxylic acids are described. These compounds exhibit potent antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. Of these new carbapenems, (lR,5S,6S)-2-[(3S,5S)-5sulfamoylammomethyl pyrrolidin-3-ylthio]-6-[(l i?)-l-hydroxyethyl]-l-methylcarbapen-2-em-3-carboxylic acid (S-4661) showed the most potent and well balanced activity and was selected as a candidate for further evaluation. The carbapenem compounds which have a (3S)pyrrolidin-3-ylthio group at the C-2 position in the carbapenem skeleton are noted for their broad and potent antibacterial activityJ), and a large numberof derivatives have been synthesized and investigated with enthusiasm. Amongthose compounds, panipenem2) was the first to be successfully launched in the market and clinical evaluations are in progress for meropenem3), BO-27274) and DX-87395) which have enhanced metabolic stability to renal dehydropeptidase-1 (DHP-1) because of the introduction of a l/?-methyl group to the carbapenem

The first synthesis using an original procedure and a practical large-scale process using an improved procedure for the synthesis of the N-PNZ-protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a novel parenteral 1 -methylcarbapenem antibiotic, are described. trans-4-Hydroxy-L-proline (4) was converted in an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-tertbutoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3) in 55-56% overall yield via a six-step sequence, which includes the two alternative routes to intermediate 13. This process requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvents, and short operating times and is amenable to a multikilogram-scale preparation. Several kilograms of the side chain 3 were successfully prepared by this process.

A practical large-scale process for the synthesis of doripenem hydrate (1), a novel parenteral 1β-methylcarbapenem antibiotic, from p-nitrobenzyl-protected enolphosphate 2b and N-(pnitrobenzyloxycarbonyl)-protected aminomethylpyrrolidine 3c is described. We found effective extraction conditions to remove p-toluidine and most other organic impurities using a THF/ water system containing an inorganic salt. Significant improvements have been made to the previous synthesis using a medicinal chemical procedure. The new process requires no chromatographic purification and affords the target compound 1 as a sterile crystalline powder. Several kilograms of compound 1 were successfully prepared by this process.