Synthesis, Separation And Purification Of A New Antibacterial Drug, Tamarind

Retapamulin is an new mutilin-antibaclerials developed by GSK, and was approved by US FDA in 2007. It is indicated for use in adults and pcdiatric patients aged 9 months and older for the topical treatment of impetigo due to Staplaylococcus aureus or Streptococcus pyogenes. It has unique mechanism. strong antibacterial activity and small little toxic effects.After literature review on synthesis of Retapamulin, the scheme in patent W02006092334 was chosen for optimization. The optimized process was follows:On the one hand, ?-tropine was starting material, followed by mesylati-onto give endo-8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl methanesulfonate(5),Co-mpound 5 reacted with Potassium ethyl xanthogen te to give exo-8-methyl-8-a-za-bicyclo[3.2.1]octan-3-eth-yl xantlogenate(6),6 was hydrolyze to give oxo-8-me-thyl-8-a-za-bicyclo[3.2.1]octa-ne-3-thiol hydrochloride(7·HCI);On the other hand,pleuromutilin was starting material of matrix-cycle,followed by mesylati-on to give(3aS,4R,S,6S,8R,9R,9aR,10R)-2-mesyl-acetate-1-oxo-4.6.9.10-tetrameth y1-5-hydroxy-6-vinyl-3a,9-propyl-cyclopentane-cyclooctane-8-ester(3).compound 3 reacted with compound 7·HC1 in an alkalescent condition to give Retapamu-lin(1).(1)In the literature,compound 6 was contain some impurities,it was in stable in solution and difficult to be purified;and therefore it was subjected to subsequent reactions without purification,resulting in quality uncontrolled pro-ducts.In order to control the quality of the intermediate products,Potassium ethyl xanthogenate was used to replace Sodium ethyl xanthogenate to react wi-th compound 5 in water,compound 6 was synthesized and separated out from the solution,and it has a high purity and could be stored conveniently.Besi-des,there is hardly any stink in the whole process.(2)Retapamulin was synthesized via a strong base in multiphases system,the product was an oily amine compound that was difficult to be purified.We replaced Sodium hydroxide with Potassium carbonate,at the same time,Retap-amulin was synthesized in singlephase rather than in multiphases.In our way,Retapamnulin was achieved by higher yield and higher purity.(3)Some impurity compounds could not be removed in literature's way.We salified and crystalized retapamulin with Succinic acid,and got pure prod-uct with high yield.In conclusion,We have found,on a development scale,the new process method gives a yield of final compound(99.8%)of about 75%from pleuromu-tilin and 32%from ?-tropine.We believe that the new process method is very competetive on the market due to its high yield,lowcost of materials and ex-cellent adaptability towards mass production.