Synthesis Of The Anticoagulant Drug Fondaparinux Sodium Building Block C And E

Heparin(2)is widely used as anticoagulant drugs for major cardiovascular and orthopedic surgeries such as hip fractures,knee surgery or hip replacement,preventing the occurrence of venous thrombosis.Despite its widespread use,current heparin therapies present challenges in product quality control and material supply safety,due to the many diverse sources and nonuniformity of the organs used to produce the drug,so to find a more safe and effective new anticoagulant drug is very necessary.It was found that the pentasaccharide structural units in heparin could effectively prevent thrombosis.Two pharmaceutical companies,Sanofi and Organon,synthesized an analogue of this pentasaccharide,which was developed into a novel antithrombotic drug,Fondaparinux Sodium(7)in 2001.As a novel selective inhibitor of coagulation factor Xa,Fondaparinux Sodium has great potentiality in the development of antithrombotic drugs,and chemists have been working on its synthetic research in recent decades.In this study,with the objective to find a synthesis route involving new common intermediate to shorten the total synthetic route of Fondaparinux and to provide guarantee for industrial production,we focused on the synthesis and industrialization of the building block C and E.Commercial D-glucosamine hydrochloride 80 was chosen as the initial material for preparing the common intermediate 89 through the azidation,acetylation,selective deprotection,TBS protection and deacetylation.Notably,this route was conducted in 5 steps with 65% overall yield.Subsequently,The building block C 68a/68 b and the building block E 65 were prepared respectively by using the common intermediate 89 as a substrate according to their structural homology and correlation.PMB or Bz protection of hydroxyl groups at the C4,C6 position of the common intermediate 89 delivered the building block C 68 a or 68 b.In the synthetic studies of building block E,to synthesize the monosaccharide intermediate 90,we designed two synthetic routes depending on the different operation ways of the protecting groups at C3,C4 and C6 position.In the route I,compound 90 was successfully prepared in 40% overall yield through the PMB selective protection at C6 position,followed by the Bn protection at C3,C4 position and selective deprotection at C6 position.Next,employing the strategy of route II,compound 90 was also successfully achieved in 57% overall yield by a 3-step sequence of acetal protection at C4,C6-position,Bn protection at C3 position and the regioselective reductive ring opening of the resulting benzylidene acetals.Then,the compound 90 was chosen as substrate for preparing the building block E 65 through the Bz selective protection at C6 position,selective deprotection at C1 position and the introduction of activated group.In brief,this route was conducted in 3 steps with 54% overall yield.In conclusion,we sythesized the building block C of anticoagulant Fondaparinux Sodium in 6 steps with 46%(68a)and 33%(68b)overall yield,and the building block E of in 11 steps with 13%(route I)and 21% overall yield(route II)from the common intermediate 89,respectively.In this study,scalable preparation reached hundred gram scale,which could be beneficial for industrial production.Simultaneously,the efficiency and yield were both significantly improved through the use of a common intermediate and a series of one-pot operation.