Study On The Synthetic Process Of New Type Of Antibacterial Agent: Linezolid And Its Analogs

Linezolid (Zyvox,U-100766,PNU-100766) is a new oxazolidinone antimicrobial agent.Linezolid is discovered by Pharmacia & Upjohn Co.Ltd of America and sanctioned by FDA on April 18th 2000.In recent years, the extensive use of antibiotics and even abuse, the growing resistance of bacteria to make new infectious diseases continue to emerge. Methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidennidis (MRSE). penicillin-resistant Streptococcus pneumoniae (PRSP), multidrug resistant-tubercule bacillus, particularly the appear of vancomycin resistant enterococci (VRE),make it difficult for clinical treatment.To solve the problem of resistant infections, many of the world's pharmaceutical companies and pharmaceutical chemists are striving to develop,design and screen a new antibacterial agents which has a new chemical structure, new mechanism or new target. Linezolid is a new class of antibiotics through 30 years of research and development.This class of drugs has novel structure and unique mechanism, it inhibit the synthesis of bacterial protein mainly in the early stages, role in the selection with the 50S ribosomal subunit of the 30S subunit point to prevent the formation of 70S initiation complex, thus inhibiting bacterial protein synthesis. This new mechanism makes the oxazolidinone and other antibacterial agents have no cross resistance that it has attracted attention from the medical profession at home and abroad. It displayed an excellent prospect in the treatment of multi-drug-resistant Gram-positive bacteria and Mycobacterium tuberculosis infection. It is expected to become another major new synthetic antibacterial agents after sulfonamides and quinolone. So in recent years, more foreign and domestic researchers have study on its analogues,in order to develop its activity analogues which have their own intellectual property.Linezolid((S)-N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-5-oxo-2-oxazolinealkyl)methyl)acetamide)has the oxazolidinone ring in its structure that is pharmacophore. This determines the key is cyclization reaction in the synthesis, and the necessary reagents is very expensive. The 5-S configuration of the oxazolidone is necessary for antibacterial activity, R configuration is ineffective. This researh have completely studied linezolid's synthetic route which have reported, and choose a possible total synthesis routes. On the basis of this improved route, we successfully synthesize 9 analogues for antibacterial screening.As for the synthesis of linezolid, we use morpholine and 3,4-difluoronitrobenz- ene as the starting material,via replacement,reduction,and acylation to gain the intermediate N-benzyloxycarbonyl-3-fluoro-4-anisidine.Then we have repeated the patent WO 02085849, and prefer other references to design a best route and improved it.Chemical structure of Linezolid and its intermediates has been confirmed by ~1H-NMR.