Ceftobiprole medocaril

Description

Ceftobiprole medocaril is a new injectable cephalosporin antibiotic with broad-spectrum activity against a wide range of difficult-to-treat Gram-positive and Gram-negative hospital- and community-acquired infections including MRSA. It was launched in Canada for the treatment of cSSSI, including diabetic foot infection. Ceftobiprole medocaril is a water-soluble pro-drug of ceftobiprole, which is a pyrrolidinone-3-ylidenemethyl cephem with a 3-pyrrolidinyl side chain. The pro-drug is derived by the attachment of a carbamoyl ester group on the pyrrolidine nitrogen of ceftobiprole. Like all beta-lactam antibiotics, ceftobiprole produces its bactericidal effects by inhibiting cell wall synthesis through the prevention of the cross-linking of peptides on the mucosaccharide chains that make up the cell wall. This is accomplished by binding to and inhibiting the penicillin-binding proteins (PBPs). As a result, bacterial cell walls are weakened and susceptible to osmotic pressure and cell lysis. The broad-spectrum activity of ceftobiprole is due to the inhibition of PBPs in both Gram-positive and Gram-negative bacteria. In addition, ceftobiprole inhibits PBP2x in penicillin-resistant Streptococcus pneumoniae as well as PBP3 and other PBPs in certain Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa.Among Gram-positive pathogens, it has excellent activity against coagulase-negative staphylococci (both methicillin-susceptible and methicillin-resistant strains), S. pneumoniae (including penicillinresistant strains) and other streptococcal species, and Enterococcus faecalis (MIC90 4 mg/mL).Ceftobiprole is also active in vitro against a broad range of aerobic Gram-negative bacilli, including P. aeruginosa, against which its activity is similar to that of cefepime.

Originator

Roche (Switzerland)

Uses

Broad spectrum antibiotic.

Definition

ChEBI: Ceftobiprole medocaril is a cephalosporin. It has a role as a prodrug.

brand name

Zeftera

Synthesis

The synthesis of ceftobiprole and ceftobiprole medocaril have been reported in several patents and the synthesis of the prodrug will be highlighted as shown in Schemes 4.1-4.3. Activation of the amino dithiazole acid salt 26 with benzothiazole disulfide 27 via diethyl phosphite gave thioester 28 in 82% yield. Condensation of 28 with aminocephalosporin 29 using tetramethyl guanidine (30) as the base in DMF at 0 °C provided intermediate acid 31, which was then immediately esterified by reaction with diphenyl diazomethane at 0 °C to give diphenylemethyl ester 33 in 91% yield. Alcohol 33 was then oxidized with sodium hypochlorite in the presence of TEMPO to give the desired aldehyde 34 in 74% yield, which was ready to be coupled to the phosphonium salt 41. The preparation of phosphonate 41 is described in Scheme 4.2 and was initiated by the reaction of amino pyrrolidine 35 with acid chloride 36 with 50% sodium hydroxide in DCM to provide the amidopyrrolidine 37 in quantitative yield. Bromide 37 was then treated with triphenylphosphine to give phosphonate 38 in 78% yield. Removal of the allyl carbonate protecting group was accomplished through reaction with tributyltin hydride with palladium catalysis to afford bipyrrolidine 39, which was then treated with the carbonate 40 to give phosphonium salt 41 in 26% yield, which was now activated for Wittig condensation with aldehyde 34. The completion of the preparation of ceftobiprole medocaril is described in the scheme. Phosphonate 41 was deprotonated with potassium t-butoxide to generate the corresponding ylide that was subsequently reacted with the cephalosporin aldehyde 34 to produce the olefinic betalactam ester 42 in 29% yield. Removal of the diphenylmethyl ester and trityl groups were accomplished by reaction with triethylsilane in the presence of TFA completing the synthesis of ceftobiprole medocaril (IV) in 92% yield.< style="text-align: center;">

Raw materials

Preparation Products