Research On Preparation Of Formic Acid Thio-S-p-tolyl Ester And Its Use In Synthesis Of Isepamicin

Aminoglycoside antibiotics, as one important member of antibiotics family, widely used because of its fine curative effect and its unique indications, was briefly reviewed in this paper.Isepamicin, as one kind of important aminoglycoside antibiotics, with advantages (including less adverse reactions, less drug risistance, and strong antibacterial acivity)over other aminoglycoside antibiotics, is occupying more and more market share.The synthesis method of Isepamicin in literature was classified into two kinds.The first kind of method is as following:starting from Gentamicin B, through protection of aminogroups, condensation, and deprotection;thus Isepamicin is synthesized, in total yield 38-81%. The second kind of method is as following:starting from Sisomicin through chelation, protection of aminogroups, condensation with aminoprotected (s)-isoserine,hydrolysis,condensationwith6-azide-2,3,4-O-benzyl-6-deoxy-a-D-glucop yranosyl chloride, deprotection;thus Isepamicin is synthesized, in total yield 8.8%.In order to increase the yield and make it easy to scale-up, through comparing the advantages and disadvantages of above references, the method with highest yield was improved, in which the process of preparing 2-formylmercaptobenzothiazole and N,O-Diformyl-(S)-Isoserine, is difficult to operate, hard to scale up.A new formation reagent, formic acid thio-S-p-tolyl ester,was prepared to take place of 2-formylmercaptobenzothiazole; and the method to prepare N-formyl-(S)-isoserine was improved by use of formic acid thio-S-p-tolyl ester;It takes 2-4hrs of reaction time to prepare formic acid thio-S-p-tolyl ester in yield 93.1%,with DCC recovered in yield 60.1%;takes 24hrs of reaction time to prepare N-formyl-(S)-isoserine in yield 78%,with formic acid thio-S-p-tolyl ester and p-methyl thiolphenol recovered in total yield 89.3%;takes 4-6hrs of reaction time to prepare 3,6'-Di-N-formylgentamicin B in yield 90.5%;and takes 24-30hrs of reaction time to prepare Isepamicin in yield 82.6% by condesation and hydrolysis.The total yield is 72.6%.And structures of intermediates and finish compound were approved by NMR or MS. The improved process for preparing Isepamicin is easy to operate and easy to scale-up,with relatively higher yield.