BMS-247243

Methicillin-resistant Staphylococcus aureus (MRSA) is now one of the commonest causes of nosocomial infection worldwide. The mainstay of treatment until now has been the glycopeptides (vancomycin and teicoplanin). They are not without toxicity and need parenteral administration and monitoring of levels. The increasing frequency of MRSA infections, coupled with the emergence of glycopeptide resistance in S. aureus has made the introduction of new drugs active against Gram-positive organisms essential. New agents active against Gram-positive organisms represent either genuinely novel classes of antimicrobials (e.g., oxazolidinones and lipoproteins) or those derived from existing classes (e.g., tetracyclines, glycopeptides, streptogramins and cephalosporins). Some of these newer antibiotics appear to be effective against multi-resistant organisms including MRSA.

A practical synthesis of the anti-methicillin resistant Staphylococcus aureus cephem (6R-trans)-E-7-[[[[2,5-dichloro-4-[3-[(carboxymethyl)amino]-3-oxo-1-propenyl]phenyl]thio]acetyl]amino]-4-[[(2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]thio]-2,6-dimethyl-1-[3-(4-methylmorpholino-4-yl)propyl]-1-pyridinium, hydroxide, inner salt (BMS-247243) was developed.A process was developed for the interchange of the iodide counterion in 4-(3-aminopropyl)-4-methylmorpholinium HCl to chloride that was essential for an efficient synthesis of the C-3 4-mercaptopyridone sidechain.Use of catalytic Bu₄NCl in the reaction of a chlorocinnamide with the lithium salt of methylthioglycolate formed the Me ester of the C-7 side chain of I in high yield.Reaction with the dianion of thioglycolic acid gave an increased level of the corresponding Michael addition byproduct that led to lower quality thermodn. product I by the reverse reaction.Cephem nucleus ACLH HCl was acylated with the acid chloride of acid I in a biphasic system to circumvent the cumbersome workup involved in reactions mediated by carbodiimdes DCC or EDAC for the synthesis of the cephem diester.An unusual degradation product diacid was obtained during the deprotection of the cephem diester with TFA to amorphous diacid II.Reaction of II with the 4-mercaptopyridone methylmorpholinium reactant formed BMS 247243 in moderate yield.Alternately, an efficient coupling of the cephem diester with the 4-mercaptopyridone methylmorpholinium reactant gave crystalline diester III with minimal (<1%) contamination of the double bond isomer.Double deprotection of diester III followed by crystallization furnished the double zwitterion BMS 247243 in high yield.