Tazobactam synthesis

Penicillins and other /3-lactam antibiotics (see the Focus On in this chapter) typically develop a resistance to bacteria due to bacterial synthesis of /Mactamase enzymes. Tazobactam, however, is able to inhibit the activity of the /3-lactamase by trapping it, thereby preventing resistance from developing. 

Tautomer, 264, 842 Tautomerism, 842 Tazobactam, 836 Teflon, structure and uses of, 242 Template strand (DNA), 1108 Tercphthalic acid, synthesis of, 576-577... 

Mechanism of Action Piperacillin inhibits cell wall synthesis by binding to bacterial cell membranes. Tazobactam inactivates bacterial beta-lactamase. Therapeutic Effect Piperacillin is bactericidal in susceptible organisms. Tazobactam protects piperacillin from enzymatic degradation, extends its spectrum of activity, and prevents bacterial overgrowth. 

The synthesis of tazobactam from 6-APA (Scheme 6.15) proceeded via the 2- -(chloromethyl)penam ester (81 a), which was first prepared by Gottstein and co-workers [47] during the synthesis of 2-/S-(chloromethyl)-2-a-methylpenam-3a-carboxylic acid 1,1-dioxide (29). 6-APA (8) was converted to 6a-bromopenicillanic acid (77) by treatment with sodium nitrite and hydrobromic acid. Oxidation with peracetic acid in the presence of benzophenone hydrazone gave benzhydryl 6a-bromopenicillanate-l-oxide (78) and reduction with zinc and acetic acid gave benzhydryl penicillanate-1-oxide (79). The unsymmetrical azetidinone disulphide (80) was obtained by heating with 2-mercaptobenzothiazole reaction with copper (II) chloride... 

CH3) which has activity similar to that of davulanic acid and inhibits many of the type I Cephases. The synthesis (156), microbiological activity (152,156—162), and stability (152) of tazobactam have been reported... 

The synthesis of tazobactam was first reported by Taiho Pharmaceutical Company Ltd, Japan [130]. Starting with the benzhydryl ester of penicillanic acid 102 (Scheme 2.9), tazobactam has been synthesized [131a] in six steps in an overall yield of 40% as outlined in Scheme 2.10. The impurities that are formed in this synthesis are listed in (Figure 2.30). 

There are other reports available in the literature for the synthesis of tazobactam [131b, c, 132] (Figure 2.30). 

Figure 2.30 Impurities formed during the synthesis of tazobactam [131a].

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