This contribution describes the operation of a pilot plant for the production of 3-exomethylene-7(R)-glutaroylaminocepham-4-carboxylic acid 1(S)-oxide (4a) by the electrochemical reduction of 3-acetoxymethyl-7(R)-glutaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide (3a). This conversion is a key step in a new process for the production of Ceftibuten (1). The scale-up of the electrochemical reduction was demonstrated using a commercial flow-cell. The use of a novel type of extended-area tin cathode, which had been shown on a laboratory scale to produce significant improvements in the process, was successfully implemented in an ICI FM21-SP commercial-scale electrochemical reactor. † Ceftibuten was discovered by Shionogi and Co. Ltd., Osaka, Japan, and licensed to Schering Plough Corporation, Kenilworth, New Jersey. The drug is manufactured by Shionogi.

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.

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Executive _vmma_The second phase of research performed at The Electrosynthesis C_il _Inc. has demonstrated the successful removal of nitrite and nitrate from a synthetic effluent stream via a direct electrochemical reductionat a cathode. We have shown that direct reduction occurs at good current efficiencies in 1000 hour studies. We also have determined that the membrane separation process is not readily achievable for the removal of nitrites and nitrates due to poor current efficiencies and membrane stability problems.A direct reduction process was studied at various cathode materialsin a flow cell.using the complete synthetic mix. We determined that lead was the cathode material of choice, displaying good current efficiencies and stability in both short and long term tests under conditions of high temperature and high current density. We investigated several anode materials in both undivided and divided cell configurations and concluded that a divided cell configurationwas preferable because it would prevent re-oxidation of nitrite by the anode. The membrane's electrical resistance was shown to be unaffected by radiation. Thus we achieved our technical objective of eliminating elect.rode fouling and solids formation. However, those anode materials (DSA_ platinized niobium, and platinum clad niobium) which had demonstratedgood stability_in short term divided cell tests corroded in 1000 hour experiments. The cause for corrosion is thought to be _!lons from the synthetic mix migrating across the cation exchange membrane and forming HF, a highly corrosive agent, in the acid anolyte. Preliminaryinvestigation of the use of an inexpensive stainless steel anode with a caustic anolyte demonstratedthat the concept was feasible but required furtheroptimization. Other possibilities for anode materials include _iilcoated Ebonex or the use of aluminum salts to compleX!! thereby avoiding corrosion of DSA anodes.A membrane separation process was also investigated. This process employs an anion and cation exchange membrane to remove nitrite and nitrate, recovering caustic and nitricacid. Initial Phase I results showed promise for this process providing a stable anion exchange , membranecould be identified. Present research has shown poor current efficiencies for nitrite and nitrate transport across the anion exchange membrane due to co-migration of hydroxide anions. Also, precipitates form within the anion exchange membraneswhich would eventually result in the failure of the membranes, In conclusion we believe that electrochemical processing offers a highly promising and viable method for the treatmentof nitrate waste solutions.