Study On The Synthesis Of Novel Aminoglycoside Antibiotic Plazomicio

Bacteria are ubiquitous in our lives.There are usually 40 million bacteria in one gram of soil and 1 million bacteria in one milliliter of fresh water.It is closely related to people's lives.It benefits mankind,but at the same time,it also brings many diseases to humans.Antibiotics play an important role in the treatment of diseases caused by bacterial infections.Since the discovery of the first antibiotic in 1929,antibiotics have received more and more attention from countries.In the past more than half a century,nearly 10,000 antibiotics have been introduced.Currently,antibiotics are used in a variety of bacterial infections.However,due to the widespread use of broad-spectrum antibiotics,it has led to the emergence of multidrug-resistant(MDR)-negative bacteria,and the serious infection caused by multi-drug-resistant negative bacteria can not be effectively treated,which seriously threatens people's health.Therefore,people must face the threat of multi-drug-resistant negative bacteria,and it is urgent to find antibiotics against multi-drug resistant Gram-negative bacteria.In recent years,Achaogen Corporation of the United States has developed a novel aminoglycoside antibiotic,plazomicin(product name:zemdri),which is used to treat serious infections caused by multi-drug resistant enterobacteriaceae and carbapenem antibiotic-resistant enterobacteria.Plazomicin was awarded the FDA FastTrack Qualification in 2012.In 2014,it obtained the Qualified Infectious Disease Products(QIDP)certification from the FDA to treat complex urinary tract infections and blood infections as indications.In june 25,2018,the US FDA approved plazomicin to enter the market,for the treatment of adult patients with complex urinary tract infections(cUTI),as well as for the treatment of adult patients with limited or no alternative treatment options,including pyelonephritis caused by Escherichia coli,Klebsiella pneumoniae,Proters mirabilis,and Enterobacter cloacae.At the same time,plazomicin has a good effect on blood infections caused by carbapenem-resistant Enterobacteriaceae bacteria,but due to lack of evidence of efficacy in a clinical study for the treatment of blood infections,The FDA refused to approve the treatment of bloodstream infections.Plazomicin is chemically engineered on the basis of sisomicin.It is obtained by adding a hydroxy-aminobutyric acid(HABA)substituent at the 1 position of sisomicin and a hydroxyethyl substituent at the 6'position.By comparing and analyzing the existing synthetic routes,an optimal synthetic route was selected,which was based on sisomicin sulfate.In the first step,the sulfate group was removed by ion exchange resin.The second step is to protect the 6' amino group with p-nitrobenzyl chloroformate(PNZ-Cl).In the third step,the 2',3 amino group is protected with a tert-butoxycarbonyl group(Boc).In the fourth step,the amino group at the 1 position is protected with-9-fluorenylmethyl chloroformate(Fmoc-Cl),and then the 3' amino group is protected with Boc anhydride.In the fifth step,the protecting group Fmoc of the amino group is removed.In the sixth step,the amino group at the 1-position is amide-condensed with HABA.In the seventh step,remove the 6' PNZ protecting group.In the eighth step,Reductive amination at the 6'position.In the ninth step,removal of tert-butyldimethylsilyl chloride(TBSCl)and Boc protecting group gives plazomicin.The final structure was confirmed by MS,1H NMR and 13C NMR.Firstly,this paper carried out a small test optimization of the synthesis of plazomicin.By using different catalysts and reaction systems,a synthetic route with low cost,high yield and simple post-treatment was found.This research is mainly reflected in the following aspects.In the first step,the method of adding inorganic strong base to the methanol solution of sisomicin sulfate instead of using ion exchange resin not only reduces the cost but also simplifies the treatment method.In the second step,by adjusting the compounding ratio and post-treatment method,the reaction yield increased from 42.70%to 73.96%.In the fourth step,the ratio of the compounds is adjusted and a method of adding a protective group is used twice.After using this method,the generation of by-products are reduced,and the yield was increased from 50.0%to 70.90%.In the fifth step,the dioxane/ammonia/NaOH system was used to replace the dichloromethane/tris-(2-aminoethyl)amine in the original route,which greatly reduced the cost.The optimized synthesis route does not require microwave heating,which reduces the number of column purifications.The total yield increased from 0.83%to 5.07%.In addition,the improved synthetic route simplifies the synthesis step and reduces the cost of synthesis to 10%.It is more suitable for industrial production.In this paper,the original research route was targeted and optimized,and a small test was carried out to obtain a stable route of 65g.The optimized preparation process is simpler and the conditions are milder than the original research route,which Can be applied to industrial production.