376653-43-9

Basic information

• Product Name: Ceftobiprole medocaril
• Synonyms: Ceftobiprole medocaril;5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,7-[[(2Z)-2-(5-aMino-1,2,4-thiadiazol-3-yl)-2-(hydroxyiMino)acetyl]aMino]-3-[[(E,3'R)-1'-[[(5-Methyl-2-oxo-1,3-dioxol-4-yl)Methoxy]carbonyl]-2-oxo[1,3'-bipyrrolidin]-3-ylidene]Methyl]-8-oxo-,(6R,7R)-
• CAS NO: 376653-43-9
• Molecular Formula: C26H26N8O11S2
• Molecular Weight: 690.66
• Mol File: 376653-43-9.mol
• Article Data: 0

Chemical Properties

• Appearance: /
• Density: 1.95
• PKA: 2.46±0.50(Predicted)
• CAS DataBase Reference: Ceftobiprole medocaril(CAS DataBase Reference)
• NIST Chemistry Reference: Ceftobiprole medocaril(376653-43-9)
• EPA Substance Registry System: Ceftobiprole medocaril(376653-43-9)

Safety Data

• Hazardous Substances Data: 376653-43-9(Hazardous Substances Data)

Usage

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 hospitaland community-acquired infections, including MRSA. It is a water-soluble pro-drug of ceftobiprole, a pyrrolidinone-3-ylidenemethyl cephem with a 3-pyrrolidinyl side chain, derived by the attachment of a carbamoyl ester group on the pyrrolidine nitrogen of ceftobiprole.

Uses

Used in Pharmaceutical Industry:
Ceftobiprole medocaril is used as an antibiotic for the treatment of cSSSI, including diabetic foot infection, due to its broad-spectrum activity against both Gram-positive and Gram-negative bacteria. It inhibits cell wall synthesis by binding to and inhibiting penicillin-binding proteins (PBPs), resulting in weakened bacterial cell walls and susceptibility to osmotic pressure and cell lysis.
Ceftobiprole medocaril is used as a treatment for various Gram-positive pathogens such as coagulase-negative staphylococci (both methicillin-susceptible and methicillin-resistant strains), S. pneumoniae (including penicillin-resistant strains), and other streptococcal species, as well as Enterococcus faecalis.
Additionally, Ceftobiprole medocaril is used as a treatment for a broad range of aerobic Gram-negative bacilli, including P. aeruginosa, with activity similar to that of cefepime.

Originator

Roche (Switzerland)

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;">