Practical Large-Scale Synthesis of Doripenem:  A Novel 1β-Methylcarbapenem Antibiotic

Abstract

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.

General Principles and Strategies for Salting-Out Informed by the Hofmeister Series

“…To illustrate the need for improved extraction methods, examples of pharmaceuticals or intermediates with high water solubility that posed difficulties in liquid–liquid extraction are presented (Figure ). In many of these processes, multiple back-extractions were required to compensate for poor partitioning ( 2a–2h, 2j ). At best, this approach is inefficient, but it can also present a significant liability when an intermediate with limited water stability such as sulbactam 2e is subjected to prolonged aqueous exposure.…”

Synthetic Approaches to the 2005 New Drugs

“…Commercially available (2S,4R)-(-)-4-hydroxy-2-pyrrolidinecarboxylic acid (17), anhydrous cyclohexanol and 2-cyclohexen-1-one were heated at 154 o C to give de-carboxylated compound 18 in 69 % yield. The tosyl group of 21 was removed with 48% HBr and phenol in refluxing water to yield 2,2diphenyl-2-[2(S)-pyrrolidinyl] acetonitrile as its corresponding hydrogen bromide salt (22), which was coupled to 2-(2, 3-dihydrobenzofuran-5-yl) acetic acid (23) by treatment with carbonyldiimidazole (CDI) in ethyl acetate to the corresponding amide 24 in a quantitative yield. The N-tosylated alcohol 19 was subjected to Mitsunobu reaction in the presence of methyl ptoluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF to afford N-tosyl-3(S)-(tosyloxy) pyrrolidine (20) in 70% yield, which was then condensed with 2,2-diphenylacetonitrile with NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(S)-yl]acetonitrile (21).…”

Practical One-Pot Synthesis of N-(tert-Butoxycarbonyl)sulfamide from Chlorosulfonyl Isocyanate via N-(tert-Butoxycarbonyl)aminosulfonylpyridinium Salt

“…Following conventional carbapenem retrosynthetic analysis of a carbapenem (Scheme 1), doripenem can be assembled from 4-nitrobenzyl-protected 1β-methylcarbapenem enolphosphate 2 3 and the aminosulfamoylcontaining side chain 3. 4,5 Enolphosphate 2 is also used for the synthesis of ertapenem as a starting material. 6 Both the enolphophate 2 and the side chain 3 are now commercially available.…”

“…6 Both the enolphophate 2 and the side chain 3 are now commercially available. Both N-(tert-butoxycarbonyl)sulfamide (4) 2,4 and trans-4-hydroxy-L-proline (5) are raw materials for the side chain 3.…”

“…Compound 1 exhibited potent, broad, and well-balanced antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa . Following conventional carbapenem retrosynthetic analysis of a carbapenem (Scheme ), doripenem can be assembled from 4-nitrobenzyl-protected 1β-methylcarbapenem enolphosphate 2 and the aminosulfamoyl-containing side chain 3 . , Enolphosphate 2 is also used for the synthesis of ertapenem as a starting material . Both the enolphophate 2 and the side chain 3 are now commercially available.…”