Practical Large-Scale Synthesis of Cefmatilen, A New Cephalosporin Antibiotic

Abstract

A practical large-scale process for the synthesis of cefmatilen hydrochloride hydrate (1), a new oral cephalosporin antibiotic, is described. Several impurities are isolated from a bulk drug and identified. Side reactions are discussed in order to prevent them. The conditions were optimized to control the formation of impurities. The process is amenable to a multikilogram-scale preparation. Several kilograms of compound 1 for clinical trials were successfully prepared by this process from the three starting materials (7-aminocephem hydrochloride 4, triethylammonium acetate 5, and triazole 7) on a pilot scale in overall yields of 61-65% (10-14% higher than those for the previous process).

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

“… General remarks: MsCl has seen very limited application in process chemistry despite the advantages previously mentioned. ,, The reagent is a liquid, which facilitates its handling in the plant, but its acute toxicity is a major drawback to its use and requires special worker safety protocols during large-scale operations. Table lists the molecules synthesized via MsCl-mediated amide bond formation, with each newly created bond indicated by an arrow. CAS number: 124-63-0 MW: 114.55 g/mol Atom economy: High. Cost per mole: Low. Acid activation mechanism: Upon deprotonation of the acid by the base, the resulting carboxylate displaces chloride to afford the mixed anhydride intermediate, which then reacts with the amine to provide the desired amide product (Scheme ). Anhydrous conditions are required during the acid activation step. Acid activation conditions: TEA was added to a solution of the acid ammonium salt and MsCl in DCM below −15 °C MsCl was added to a mixture of the acid, HOBt, and TEA in PhCl below 40 °C to form the HOBt ester, which was isolated …”

Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing

“…Table shows DSC data for peptide coupling reagents commonly used in the scale-up of amidation reactions . Methanesulfonyl chloride (MsCl, entry 1) and p -toluenesulfonyl chloride (TsCl, entry 2) generate the sulfonyl esters from the corresponding carboxylic acids. Both reagents have relatively high thermal onsets at 341 and 249 °C, respectively.…”

Synthesis of Novel N-Heterocyclic Compounds Containing 1,2,3-Triazole Ring System via Domino, “Click” and RDA Reactions

“…In the past few years, researchers have exploited heterocycles containing the 1,2,3-triazole ring to generate many medicinal scaffolds exhibiting anti-HIV [ 9 ], antibacterial [ 10 , 11 , 12 ] and anticancer activities [ 13 , 14 ]. Building a triazole ring into a compound can change or even improve the pharmacokinetic properties of a drug [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”