Some Aspects in the Industrial Synthesis of β—Lactam Antibiotics

ABSTRACT

The recent discoveries of numerous significant new β—lactam antibiotics produced by fermentation, synthesis or semisynthesis have a fascinating and increasing role in antimicrobial chemotherapy. Cephalosporins and penicillins constitute about 63% of the total market in worldwide sales of antibiotics and will further predominate. The development in the field of β—lactam antibiotics is characterized by the fact that, despite the discovery and the structure elucidation of thousands of new antibiotics, only relatively few basic structures are to be found among the clinically important antibiotics. The variety of these β—lactam antibiotics includes penicillins, four generations of cephalosporins, especially aminothiazole cephalosporins, cephamycins and a number of nontraditional β—lactam antibiotics like 1-oxacephalosporins, penems, carbapenems, nocardicins, monobactams and irreversible inhibitors of β—lactamases.

Research and development work on the semisynthesis of β—lactam antibiotics is one of the most essential directions of KRKA's development. Industrial by important and known β—lactams were selected and synthesis and independent patents were elaborated. Own processes for synthesis of ampicillin, amoxycillin, talampicillin, flucloxacillin, piperacillin, cephalexin, cephamandole and cefotaxime were made in industrial scale. In this approach to the independent synthesis of acylation of 6-APA, 7-ACA and 7-ADCA by use of reactive intermediates of S-thiocarboxylic acid, 4-phenylthiazolidine-2, 5-dione, or mixed thioanhydrides, were introduced and developed mostly in semiindustrial and industrial scale.

In KRKA's fundamental research program, a variety of new β—lactam antibiotics have been prepared, more specifically the “thiazolidine type” semisynthetic penicillins and cephalosporins, thiazolidine acylaminopenicillins and substituted phenylcephalosporins. The new β—lactam antibiotics were tested for their antibacterial, antifungal and antiviral activities.