Study On Synthesis Process Of Novel Oxazolidinone Antibacterial Agent Delpazolid

Because of bacterial resistance,people are facing a shortage of effective antibiotics.In the past 40 years,only four new antibiotics have been launched to the market,and people have entered the "post-antibiotic era".However,nowadays,more and more bacteria are becoming resistant to antibiotics,which seriously threatens the quality of life and health of human beings.From a grobal point,human beings will face the predicament of no effective antibiotics,just like returning to the era without any antibiotics.However,the trend of bacterial resistance has become more and more serious due to the popularization and abuse of antibiotics.In response to this grim situation,scientists have developed a series of oxazolidinone antibacterial agents,such as Linezolid,the first oxazolidinone antibacterial agent approved by FDA in 2000,Sutezolid is developed by Pfizer and is currently in the phase ? clinical trials;Contezolid is developed by MicuRx Pharmaceuticals,which is currently in the phase? clinical trials;and Delpazolid,developed by Lego Company,which is currently in the phase ? clinical trials.Although there are many oxazolidinone antibacterial agent in clinical trials,there are no new oxazolidinone antibacterial agents on the market except Linezolid.Therefore,it is particularly important to develop a new antibiotic to combat the growing bacterial resistance.Delpazolid ((R)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1H)-yl)phenyl)-5-(hydroxy methyl)oxazolidin-2-one,CAS No.1219707-39-7)is currently in the phase II clinical trials,its germicidal efficacy is approximately the same as that of linezolid,but its structure is simpler than linezolid.The MIC90 of Delpazolid against MRSA(methicillin-resistant Staphylococcus aureus)and MSSA(methicillin-sensitive Staphylococcus aureus)are all 2 ug/mL,and its efficacies against vancomycin-resistant Enterococcus and Haemophilus influenzae are better than that of linezolid.Based on these above characteristics,Delpazolid has very bright prospects in the treatment of bacterial infection.Once launched into the market in the future,it may replace the Linezolid as a novel oxazolidinone antibacterial agent.Therefore,the study of its synthesis method is particularly important.It is particularly important to study the synthetic methods of Delpazolid.In recent years,as the increasingly serious environmental problems,the state has set higher standards for the pharmaceutical and chemical industry in green chemistry and safety in production,a green,environmental friendly,economic synthesis route which meet the national policy has become the general trend.In this paper,we have conducted a systematical investigation into a large number of literatures.Two Delpazolid synthesis routes have been compared,considering the yield,environmental friendliness,step length,reaction conditions and the difficulty of post-treatment,one of them has been selected for in-depth study and optimization.Using the 3,4-difluoronitrobenzene as the starting material,by three-step substituted reactions,cyclized with triethyl orthoformate,nitro group was reduced by hydrogenation,then the amino group was activated by CDI and replaced by ethanol,and then reacted with glycidyl R-butyrate to obtain the final product Delpazolid.In.the optimization of Delpazolid synthetic route,on the premise of yield,we reduced the equivalent ratio of ethanolamine from 2.5 times to 1.7,which greatly reduced the cost of raw materials.In the optimization of the synthesis of intermediate 3,we optimized the post-treatment,avoiding the cumbersome problems caused by column chromatography;in the optimization of the synthesis of intermediate 4,The reaction of triethyl orthoformate with intermediate 3 was replaced by formic acid.Compared with the original route,it not only reduced the cost of raw materials,shortened the reaction time and improved the yield,but also skipped the purification process.Through the above research,we finally obtained a Delpazolid synthesis route with the following characteristics:mild reaction conditions,low cost of raw materials,simple operation,high yield,short reaction time.It provides reliable data for Delpazolid production in the future.