Study On The Synthetic And Production Process Of Intermediates Of Fondaparinux Sodium

Objective: Fondaparinux sodium is a synthesized anticoagulant,reported methods require at least forty nine steps to get this compound so there is no production by domestic enterprises.On the basis of literature analysis and summarizing,this study designed a synthesis route for the fondaparinux sodium and optimized the process to improve the yield,reduce the cost and simplify the operation.Methods : Fondaparinux sodium contain five sugar rings named D,E,F,G and H ring accordingly.Through literature analyzing,we proposed a strategy: Splice D ring and EF ring to get DEF ring,splice H ring and G ring to get GH ring,then codifying the functional groups after splicing DEF ring and GH ring to synthesize fondaparinux sodium.Through literature analyzing,we proposed a strategy: 1.Use N-acetyl-Dglucosamine as starting material,followed by azidotion,methylation,benzyl protection,ester exchange,selective hydrolysis of acetyl groups and activate hydroxyl to get the activated D ring(D7).2.Use cellobiose as starting material,followed by epoxidation,benzylidene protection,selectives tosylation,epoxidation,benzyl protection,azidotion,benzoyl protection,deprotection,TEMPO oxidation and finally methylation to get the activated fragments of EF(EF10).3.Splicing D7 and EF10,followed by acetylation to get fragments DEF(DEF2).4.Use 1,2,5,6-oxygen-diisopropylidene-α-D-furan glucose as starting material,followed by benzyl protection,deprotection,methanesulfonylation,ester exchange,epoxidation,hydrolysis,rearrangement and acetylation to get G ring(G8).Results: Achieved the important fragments DEF ring and G ring of fondaparinux sodium.1.In the synthesis of D ring,acetylglucosamine was used to replace D-Glucal as starting materials to reduce cost.The D2,D4 and D5 was purified through column chromatography in the original literature was replaced by recrystallization to simplify the operation.The overall yield reached 37.4%.2.In the synthesis of EF ring,the reaction steps wasreduced to ten,three steps less than the original literature.The EF4,EF5,EF6 and EF7 was purified through column chromatography in the original literature was replaced by recrystallization to simplify the operation.The yield of EF ring was 9%.3.In the synthesis of DEF,the ratio of the α and β isomer of DEF2 improved from reported 10:1 to 29:1 and the synthetic yield was 48.8% for two steps.4.In the synthesis of G ring,G4,G5 and G6 was purified through column chromatography in the original literature was replaced by recrystallization to simplify the operation.The yield of G7 increased to 67.5%,20.6% higher than the original literature.Conclusion :Optimized the synthetic methods for the important fragments DFE and the G ring of the fondaparinux sodium with the advantage of shorter synthetic route,easier operation and finally laid a foundation for the subsequent synthesis of fondaparinux sodium.