A New Method for the Oxazolidinone Key Intermediate of Linezolid and its Formal Synthesis

Abstract

In recent years, the incidence of increase in bacterial resistance to a number of available antimicrobial agent, such as β-lactam (penicillin) antibiotics, macrolides, quinolones and vancomycin, has become a critical issue. For instance, vancomycin, an antibiotic generally considered as the ultimate solution against serious gram-positive infections, has been found ineffective on the vancomycin-resistant enterococci (VRE). Therefore, there has been an increased need for totally new agents for effective therapy of grampositive infections by antimicrobial-resistant species. In the search for a new antimicrobial agent, several kinds of synthetic organic compounds have been focused. Among these new compounds, an oxazolidinone was first suggested as a candidate for use as a new antimicrobial agent by Du Pont scientists in 1978. With several biological assay tests, it was claimed that oxazolidinone compounds represent a new class of antimicrobial agents having a unique structure and activity against gram-positive pathogenic bacteria. After early discoveries of the new oxazolidinone antibacterial compounds demonstrated weak in vitro antimicrobial activity, further studies have been encouraged to develop the lead compound DuP-721 (Figure 1) as a drug candidate. Even though DuP-721 showed promising activity, advanced clinical testing was discontinued due to its toxicity. As a result, instead of the early lead compound, two new oxazolidinone compounds, eperezolid and linezolid (Figure 1), have been developed, both of which are active in vitro and in vivo against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumonise and vancomycin-resistant Enterococcus faecium. A New Drug Application has been filed with the Food and Drug Administration (FDA, USA) for linezolid, presently being sold in the US under the brand name of “Zyvox”. It is known that the mechanism of action of this oxazolidinone antimicrobial agent is based on the inhibition of bacterial protein synthesis. Since the first synthesis of the oxazolidinone antimicrobial agent DuP-721 was reported in the 1980’s, numerous new oxazolidinone compounds have been synthesized and several new synthetic methods have been reported. Several synthetic methods have been studied and developed; however, in response to increasing concern about its antimicrobial activity, comparatively fewer studies on the development of the new synthetic method to provide the oxazolidinone compound have been performed. Hence, there is a clear need for the development of a new synthetic method for an oxazolidinone; in order to study this method of oxazolidinone antimicrobial agents, especially linezolid, we have utilized the epoxide intermediate, which has been developed in our research group. In this paper, a new pathway to the key intermediate oxazolidinone antibiotics is described, and the formal synthesis of linezolid is demonstrated. From a review of the previous syntheses it was determined that most methods for preparing an oxazolidinone ring were closely related to the intermolecular reaction. During the study of epoxide chemistry, it was discovered that an acidmediated epoxide ring opening of an epoxy carbamate yielded the oxazolidinone compound through an intramolecular reaction. Our synthetic strategy for linezolid, including the formation of the oxazolidinone ring, is outlined briefly in Scheme 1. According to Baldwin’s Rule, the formation of the smaller ring over the larger ring from this intramolecular cyclization could be properly explained. One of the detailed mechanisms of this reaction could be proposed in Scheme 2. First, CF3COOH, that is the best reagent for an intramolecular cyclization of an epoxy carbamate compound, might act as a Lewis acid liberating a proton to be coordinated on the epoxide oxygen atom. Now it is probable that the protoncoordinated epoxide could be easily attacked by a neighboring group, another oxygen atom of the carbamate group.