Methoxy- and Other 3-Oxygen-Substituted Cephems

Concurrent research studies directed toward modification of the substituents at the 3-position of the cephem molecule occurred at the Lilly Research Laboratories and the Ciba-Geigy Corporation in 1972 and during the ensuing years. 

While Lilly scientists were working on the discoveries leading to cefaclor, scientists in Basel were searching for orally active cephalosporins. At that time it was well known that biological properties of cephalosporins were strongly influenced by the substituent at the 3-position of the cephem molecule, since this substituent is electronically linked via the 3,4-double bond with the p-lactam bond of the azetidinone ring (Murphy and Webber, 1973 Sweet and Dahl, 1970 Gorman and Ryan, 1973). 

Earlier modifications at the 3-position were mostly concentrated on indirect, formal displacement of the lO-acetoxy group or involved chemical manipulations of the carbon atom at the 10-position. When 3-meth-yienecephams became accessible, a new era in B-lactam antibiotics research was opened for the preparation of cephalosporins bearing a heteroatom directly attached at the 3-position. Several industrial insti- 

Apparently, the high antibiotic potency and oral activity of 3-meth-oxycephalosporins provided the impetus for collaboration between Ciba-Geigy and Woodward Research Institute chemists to find new chemical routes to these agents using an inexpensive penicillin as starting material (Gosteli, 1976 Pfaendler et al., 1976 Scartazzini, 1977 W. Ger. Patent 2,506,330). This joint venture culminated in a more practical synthesis of the 3-methoxy-3-cephem nucleus (149). The sequence of reactions is outlined below  

Bacterial infection Route 139c Cefaclor Cephalexin Cephalo- glycin 

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