U.S. Pat. No. 4,634,697 describes cephalosporin compounds including Ceftibuten, a commercially important third generation cephalosporin type antibiotic having the chemical formula (I) ##STR3##
The synthesis of ceftibuten starting from penicillin G is described in Yoshioka, Pure Appl. Chem., 59, 1041 (1987). However, this process is costly and inefficient leaving a current need for a more cost effective and efficient process for the commercial scale preparation of ceftibuten.
The electrochemical transformation of derivatives of cephalosporin C is known. See, Jones, et al., J. Pharm. Pharmac., 20, (Suppl.) 45S-47S (1968), and Hall, J. Pharm. Sci., 62, (6) 980-983 (1973). The formation of 3-exomethylene cephalosporins via eletrochemical reduction is described in Ochiai, et al., J. Chem. Soc., Perkin Trans. I, 258-262 (1974) and U.S. Pat. Nos. 3,792,995 and 4,042,472. Baldwin, et al., Tetrahedron, 49, (22) 4907-4922 (1993), also describes the electrochemical reduction of cephalosporin C to form an 3-exomethylene compound of the formula ##STR4## In addition, EP 082,656 describes the electrochemical reduction of acetoxymethyl compounds of the formula ##STR5## wherein n is 0 or 1, and R is H or an acyl group, to form the corresponding 3-exomethylene compounds.
The eletrochemical processes described above are chemically inefficient, providing low yields and producing significant levels of the 3-methyl tautomer of the desired 3-exomethylene compounds. These 3-methyl compounds are essentially useless for the synthesis of cephalosporin type antibiotics and are difficult to remove from the desired 3-exomethylene product. As a result, 3-exomethylene compounds prepared via the prior art the prior art electrochemical processes are unsuitable for use in the manufacture of cephalosporin drugs. Consequently, in spite of the potential advantages of these electrochemical processes, such as environmental cleanliness and safety, not one has been developed into a commercial scale process. There is therefore a need for an electrochemical process which will produce 3-exomethylene cephalosporins in high yield and with low levels (i.e., less than 10%) of 3-methyl tautomers.
USPTO Backgrounds
USPTO Backgrounds