Automatic preparation method of fondaparinux sodium pentasaccharide intermediate

Abstract

The invention relates to an automatic preparation method of a fondaparinux sodium pentasaccharide intermediate. The method is based on an automatic preparation device. According to the method, automatic preparation of three components (D+EF+GH) is realized through automatic sample injection and automatic sampling and monitoring, the fully-protected fondaparinux sodium pentasaccharide intermediate(formula I) is obtained, and automatic synthesis of the fondaparinux sodium pentasaccharide intermediate is realized, so that the manpower can be saved, the efficiency and productivity are improved, and relatively high safety and reproducibility are achieved; direct online monitoring can be realized, the real-time state of a reaction is convenient to optimize and monitor, and meanwhile, the automatic temperature control can better meet the requirements of the reaction on heating and cooling; a pre-activation one-kettle mode is adopted, so that the separation frequency is reduced, and the operation is convenient; and a common ester protecting group is selected, relatively high stereoselectivity and yield are achieved, a universal deprotection method can be used, and the method has importantsignificance in reducing the production cost of fondaparinux sodium and achieving large-scale production. The definition of each substituent in the formula I is the same as the definition in the specification.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an automatic preparation method of fondaparinette sodium pentasaccharide intermediate. Background technique [0002] Heparin and sulfated heparin are a very important class of linear sulfated polysaccharides in glycosaminoglycans, which exist on the surface of most animal cells and play key roles in various physiological processes, such as anticoagulation, antiviral infection, Inflammatory response, cell adhesion, cell growth regulation, lipid metabolism and tumor metastasis, etc. Fondaparinux sodium (Arixtra, Fondaparinuxsodium) is the smallest pentasaccharide domain that can specifically bind to antithrombin III, and its structural formula is as follows: Figure 5 As shown, the five sugar rings are named D, E, F, G, and H rings according to customary conventions. [0003] Fondaparinux sodium is the first and currently the only synthetic heparin oligosaccharide anticoagulant d...

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Problems solved by technology

[0003] Fondaparinux sodium is the first and currently the only synthetic heparin oligosaccharide anticoagulant drug on the market. It was launched in 2002, and the product name is "Android". It is widely used in lower limb orthopedic surgery to prevent venous thrombosis In 2017, the global market sales were about 190 million US dollars; compared with other low molecular weight heparins, it has significant anticoagulant activity, fewer side effects and longer half-life, but the total yield of more than 50 steps is low The artificial synthesis of less than 0.1% makes it the most expensive heparin drug, which greatly limits its wide application

Since the patent expired in 2008, there are many (3+2) [ChemMedChem 2014,9,1071-1080; J.Org.Chem.2016,81,162-184.], (4+1 )[Angew.Chem.Int.Ed.2014,53,9876–9879.] convergent synthesis, one-pot three-component synthesis (Org.Chem.Front.2019,6,3116-3120; Org.Lett.2020 , 22, 4638-4642.) and enzymatic, chemoenzymatic extended synthesis and sulfation modification (Science 2011, 334, 498-501.), but all require highly specialized professionals trained in special sugar chemistry in special The completion of the glycochemical laboratory is time-consuming and laborious, which greatly increases the cost of obtaining fondaparinux, so there is still an urgent need for better strategies and technologies to improve the efficiency of obtaining fondaparinux sodium pentasaccharide

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