Ceftibuten: Development of a Commercial Process Based on Cephalosporin C. Part II. Process for the Manufacture of 3-Exomethylene-7(R)-glutaroylaminocepham-4-carboxylic Acid 1(S)-Oxide

Abstract

Analysis of several options for the synthesis of Ceftibuten from cephalosporin C-derived starting materials led to the conclusion that the most practical option, leading to the lowest costs, would be realized by trying to resurrect the previously discarded electrochemical reduction process. This contribution describes the preparation of 3-exomethylene-7(R)-glutaroylaminocepham-4-carboxylic acid 1(S)-oxide (10,1(S)-oxide) in almost quantitative yield by the electrochemical reduction of 3-acetoxymethyl-7(R)-glutaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide (9,1(S)-oxide) using a high-surface area tin mesh cathode. The new product has been shown (see Bernasconi, E.; Lee, J.; Sogli, L.; Walker, D. Org. Process Res. Dev. 2002, 6, 169) to be a superior new intermediate for the preparation of orally active cephalosporins such as Ceftibuten.

Cathodic Corrosion of Metal Electrodes—How to Prevent It in Electroorganic Synthesis

“…As a final note, we do not review corrosion through anodic oxide formation that is followed by cathodic reduction of the metal oxides, 44 − 46 cathodic corrosion of nanoparticles, 47 or open-circuit corrosion. 48 It is noteworthy that the latter can be an important aspect to consider when setting up electrosynthesis.…”

Breaking and Making of Rings: A Method for the Preparation of 4‐Quinolone‐3‐carb­oxylic Acid Amides and the Expensive Drug Ivacaftor

“…[6] The recent advancements in technologies and experimental approaches for ozonolysis have allowed the large-scale production of drugs and useful building blocks at the industrial scale. [7] The prospects of 4-quinolone-3-carboxylic acid derivatives in drug discovery and the existing harsh conditions for their synthesis prompted us to develop a simple and mild method that is similar to the underexplored Witkop-Winterfeldt oxidation (WWO). [8] This reaction involves oxidative cleavage of the C2-C3 double bond of the indole skeleton (Witkop oxidation) followed by an aldol-type condensation (Camps cyclization) to form a quinolone ring system.…”

Electrochemical Alcohol Oxidation Mediated by TEMPO-like Nitroxyl Radicals

“…The electrochemical synthesis of aldheydes, ketones, and carboxylic acids (including polymers) throughe lectrochemical oxidation of the primary alcohol functionm ediated by TEMPOlike nitroxyl radicals provides numerous key advantages. [4,9,19,11,15] As briefly shown by the selected studies reviewed in this Minireview,the reaction can be run at affordable cost under mild reaction conditions, affording highlyp ure oxidized reaction productsa longw ith little or no waste, getting rid of environmentally unfriendly hypochlorite used in the Anelli-Montanari process;o ro ft he potentialh azards associated with workingi no xygen-containing atmospherese mployed in aerobic oxidationp rotocols. The methodi s, indeed, increasingly used in industry,w ith examples including the synthesis of betulinic acid.…”

“…Though being “innately sustainable”, synthetic organic electrochemistry in fine and medicinal chemistry is still applied to a few industrial productions, most notably for pharmaceuticals such as cephalosporin antibiotic Ceftibuten or the direct synthesis of the free base of cysteine…”

“…Thea ldehydea nd ketone reaction products therebyo btained are widely used as valued drug precursors, fragrances, and aromas, namely in commercial products, in which contamination with organic solventa nd transition metals generallye mployed as reactioncatalysts is subject to stringent limits. [8] Though being "innately sustainable", [9] synthetic organic electrochemistry [10] in fine and medicinal chemistry is still applied to afew industrial productions, most notably for pharma-ceuticals such as cephalosporin antibiotic Ceftibuten [11] or the direct synthesis of the free base of cysteine. [12] Some of us have recently provided arguments for which solgel electrodes functionalized with TEMPO are likely to soon find practical application in the oxidation of alcohols.…”