Fondaparinux sodium heparin pentasaccharide and preparation method for synthesizing Fondaparinux sodium heparin pentasaccharide by taking naphthyl methyl as temporary protecting group

Abstract

The invention discloses a fondaparinux sodium heparin pentasaccharide and a preparation method for synthesizing the fondaparinux sodium heparin pentasaccharide by taking naphthyl methyl as a temporary protecting group, and relates to the technical field of medicines. Naphthyl methyl is adopted as a new temporary protecting group of hydroxyl on each monosaccharide monomer, and compared with a traditional benzyl protecting group, monosaccharide intermediates can be separated out from a solvent more easily, so that a recrystallization purification mode can be used for replacing traditional column chromatography, the purification cost is greatly reduced, and the synthesis time is shortened; meanwhile, a plurality of brand-new monosaccharide monomers are prepared, a new synthesis route is designed to prepare the fondaparinux sodium heparin pentasaccharide, and the route has the advantages of mild reaction, high controllability and low operation difficulty, and is very beneficial to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a fondaparinux sodium heparin pentasaccharide and a preparation method for synthesizing fondaparinux sodium heparin pentasaccharide by using naphthylmethyl as a temporary protecting group. Background Art

[0002] Fondaparinux is an anticoagulant drug, which is mainly used in clinical practice for thromboembolic diseases, myocardial infarction and cardiovascular surgery. Fondaparinux has excellent efficacy, safety and good market potential.

[0003] Fondaparinux sodium is a pentasaccharide structure composed of five monosaccharide monomers and is a drug synthesized by a total synthetic chemical method. During the synthesis of Fondaparinux sodium, the protective groups on the hydroxyl groups on the monosaccharide monomers need to be temporarily protected.

[0004] At present, the traditional synthesis method for synthesizing fondaparinux sodium is to use benzyl as a protecting group for unsulfated sites. However, this compound with a benzyl protecting group is not easy to crystallize during the purification process. Column chromatography is required for purification in each step of the synthesis process. The purification process takes a lot of time and results in high costs.

[0005] In this regard, the inventors believe that how to re-select and design the temporary protecting group of the hydroxyl group so as to facilitate the use of recrystallization instead of column chromatography for purification during synthesis and reduce costs is a technical problem that the technicians in this field urgently need to solve.

[0006] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention

[0007] In view of the above technical problems, the embodiments of the present invention provide a fondaparinux sodium heparin pentasaccharide and a preparation method for synthesizing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group to solve the problems raised in the above background technology.

[0008] A fondaparinux sodium heparin pentasaccharide, the structural formula of which is shown below: ; It should be noted that, compared with the traditional fondaparinux sodium pentasaccharide structure, the synthesized fondaparinux sodium heparin pentasaccharide structure of the present invention has an amino group modified at position 1 of the A sugar.

[0009] A method for preparing fondaparinux sodium heparin pentasaccharide by using naphthylmethyl as a temporary protecting group comprises the following steps: A naphthylmethyl protecting group is introduced into the hydroxyl group of the monosaccharide monomer by reacting a naphthylmethyl halide with the monosaccharide monomer for synthesizing fondaparinux sodium heparin pentasaccharide in advance; Monosaccharide monomers with naphthylmethyl protective groups introduced were connected through glycosidation reaction to synthesize fully protected pentasaccharides; The fully protected pentasaccharide is subjected to palladium-carbon hydrogenolysis to remove the naphthylmethyl protecting group, thereby obtaining fondaparinux sodium heparin pentasaccharide.

[0010] Preferably, the structural formulas of the monosaccharide monomers for synthesizing fondaparinux sodium heparin pentasaccharide are shown below: In this preparation method, naphthylmethyl protecting groups are introduced into the hydroxyl groups of monosaccharide monomer A, monosaccharide monomer B, monosaccharide monomer D and monosaccharide monomer E; and no naphthylmethyl protecting group is introduced into monosaccharide monomer C; .

[0011] Preferably, the preparation methods of monosaccharide monomer A, monosaccharide monomer B, monosaccharide monomer C, monosaccharide monomer D and monosaccharide monomer E respectively include: The preparation method of the raw material A1 of monosaccharide A is prior art, and can be synthesized according to the method reported in the existing literature: Zhang L, Liu Y, Xu Z, Hao T, Wang PG, Zhao W, Li T. Design and Synthesis of Neutralizable Fondaparinux. JACS Au. 2022 Nov 14;2(12):2791-2799. Then, the 4 and 6 positions are protected with benzyl groups; the 3 position is protected with naphthylmethyl, and finally the 4 and 6 positions benzyl groups are removed and the 6 position is selectively protected with acetyl groups; the specific synthesis route is detailed in Figure 2 ; B monosaccharide monomer uses diacetone glucose as raw material. First, the exposed hydroxyl group at position 3 is protected with naphthylmethyl, then the propylidene protection at positions 4 and 6 is removed, and the hydroxyl group at position 4 is flipped through the Piv group; then the propylidene protection at positions 1 and 2 is removed, and the monosaccharide monomer is fully acetylated; position 1 is protected with ethylthio and the acetyl group is removed; then positions 4 and 6 are protected with benzyl, and position 3 is acetylated; the specific synthetic route is described in detail. Figure 3 ; The preparation method of C monosaccharide monomer is prior art, and the specific details are as follows: Arungundram, S. et al. Modular synthesis of heparan sulfate oligosaccharides for structure-activity relationship studies. J. Am. Chem. Soc. 131, 17394–17405 (2009) reported method for synthesis; The D monosaccharide monomer is prepared from glucose protected at position 1 by p-methylthiophenol. Positions 4 and 6 are protected by PMP forks, and positions 2 and 3 are protected by naphthylmethyl. The PMP fork is selectively opened to position 4, position 6 is protected by DPPA, and position 1 is converted into an imidoester donor. For the specific synthetic route, see Figure 4 ; E monosaccharide uses the anomeric p-toluenethio protected sugar block E1 as the raw material, and the 6th position is selectively protected with the Trt group; then the 3rd and 4th positions are protected by naphthylmethyl, the 6th position Trt is removed, the 6th position is acetylated, and the 1st position is converted into an imidate donor; the specific synthetic route is described in detail in Figure 5 .

[0012] Preferably, the step of connecting the monosaccharide monomers introduced with the naphthylmethyl protecting group through a glycosylation reaction to synthesize a fully protected pentasaccharide specifically comprises: A monosaccharide monomer and B monosaccharide monomer are synthesized into AB disaccharide intermediate through glycosylation; C monosaccharide monomer and D monosaccharide monomer are glycosylated to synthesize CD disaccharide, and then CD disaccharide is structurally modified and glycosylated with E monosaccharide monomer to synthesize CDE trisaccharide intermediate; The AB disaccharide intermediate and the CDE trisaccharide intermediate are synthesized into a fully protected pentasaccharide; The structural formulas of the CDE trisaccharide intermediate and the AB disaccharide intermediate are shown below: ; The structural formula of the fully protected pentasaccharide is shown below: .

[0013] Preferably, the step of synthesizing the AB disaccharide intermediate from the A monosaccharide monomer and the B monosaccharide monomer by glycosidation specifically comprises: Monosaccharide B monomer and monosaccharide A monomer are dissolved in dry dichloromethane, and coupled under the action of N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid to obtain disaccharide AB1; Disaccharide AB1 was dissolved in 80% acetic acid aqueous solution, and then heated to 70°C to remove the benzyl group, exposing the C6 carboxylation site to obtain disaccharide AB2; The disaccharide AB2 was oxidized by Tempo and iodophenyl diethyl ester to expose the primary alcohol, and the carboxyl group obtained after oxidation was methyl esterified with iodomethane to obtain the AB disaccharide intermediate; the specific synthetic route is detailed in Figure 6 .

[0014] Preferably, the steps of synthesizing the CD disaccharide by glycosylation of the C monosaccharide monomer and the D monosaccharide monomer, and then synthesizing the CDE trisaccharide intermediate by glycosylation of the CD disaccharide with the E monosaccharide monomer after structural modification, specifically include: Monosaccharide D and monosaccharide C were dissolved in acetonitrile, catalyzed by trimethylsilyl trifluoromethanesulfonate at -25°C, and the two were coupled, and then purified by column chromatography to obtain disaccharide CD1; Disaccharide CD1 was dissolved in a hot mixed solution of dichloromethane and methanol and treated with nickel trifluoromethanesulfonate to remove the DPPA group to obtain disaccharide CD2; Disaccharide CD2 was oxidized with Tempo and iodophenyl diethyl ester to expose the primary alcohol, and the carboxyl group obtained after oxidation was protected by methyl iodide to obtain disaccharide CD3; The disaccharide CD3 was dissolved in dichloromethane and the PMB group was removed using trifluoroacetic acid to obtain the CD disaccharide intermediate; The disaccharide intermediate CD and the monosaccharide E monomer were dissolved in dichloromethane and coupled under the catalysis of trifluoromethanesulfonic acid to obtain the trisaccharide CDE1; The obtained trisaccharide CDE1 was dissolved in tetrahydrofuran, and the trimethyl tert-hexyl protecting group at the anomeric position was removed under the action of hydrofluoric acid. The obtained intermediate was dissolved in acetone and reacted with 2,2,2-trifluoro-N-phenylacetylimidoyl chloride under alkaline conditions to obtain the CDE trisaccharide intermediate. The specific synthetic route is described in Figure 7 .

[0015] Preferably, the step of synthesizing the fully protected pentasaccharide from the AB disaccharide intermediate and the CDE trisaccharide intermediate specifically comprises: The fully protected heparin pentasaccharide ABCDE 1 was obtained by glycosylation coupling of the AB disaccharide intermediate and the CDE trisaccharide intermediate in the presence of trifluoromethanesulfonic acid; The heparin pentasaccharide ABCDE 1 is hydrolyzed with an alkali solution to obtain the heparin pentasaccharide ABCDE 2; In the presence of an organic solvent, heparin pentasaccharide ABCDE 2 reacts with sulfur trioxide pyridine to obtain heparin pentasaccharide ABCDE 3; In the presence of an organic solvent, heparin pentasaccharide ABCDE 3 reacts with triphenylphosphine to reduce the azide group to an amino group, and then reacts with sulfur trioxide pyridine to obtain heparin pentasaccharide ABCDE 4; Subsequently, the heparin pentasaccharide ABCDE 4 was subjected to palladium-carbon hydrogenolysis to remove the 2-naphthylmethyl group and the benzyloxycarbonyl protecting group on the anomeric linker to obtain the target pentasaccharide ABCDE; the specific synthetic route is described in Figure 8 .

[0016] A use of the fondaparinux sodium heparin pentasaccharide as described above in the preparation of anticoagulant drugs.

[0017] The embodiments of the present invention provide a fondaparinux sodium heparin pentasaccharide and a preparation method for synthesizing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group, which have the following beneficial effects: 1. The present invention uses naphthylmethyl as a new temporary protecting group for the hydroxyl group on each monosaccharide monomer. Compared with the traditional benzyl protecting group, the monosaccharide intermediate is easier to precipitate from the solvent. Therefore, the purification method of recrystallization can replace the traditional column chromatography, which greatly reduces the purification cost and shortens the synthesis time. 2. The present invention prepares a plurality of new monosaccharide monomers and designs a new synthetic route to prepare fondaparinux sodium heparin pentasaccharide. This route has the advantages of mild reaction, strong controllability and low operation difficulty, and is very conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a schematic diagram of the synthesis strategy of fondaparinux sodium heparin pentasaccharide of the present invention; Figure 2 The specific synthesis route of monosaccharide monomer A is shown in FIG. Figure 3 The specific synthesis route of B monosaccharide monomer; Figure 4 The specific synthetic route for D monosaccharide monomers is shown below; Figure 5 The specific synthetic route for E monosaccharide monomer; Figure 6 The specific synthetic route for the AB disaccharide intermediate; Figure 7 The specific synthetic route for the CDE trisaccharide intermediate is shown; Figure 8 A detailed roadmap for the synthesis of fondaparinux sodium heparin pentasaccharide from the AB disaccharide intermediate and the CDE trisaccharide intermediate; Fig. 9 is the nuclear magnetic resonance spectrum of fondaparinux sodium heparin pentasaccharide of the present invention; Fig.10 These are the pharmacological activity test results of the fondaparinux sodium heparin pentasaccharide of the present invention. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0020] In view of the above technical problems, the embodiments of the present invention provide a fondaparinux sodium heparin pentasaccharide and a preparation method for synthesizing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group to solve the problems raised in the above background technology.

[0021] Example 1. Synthesis of fondaparinux sodium heparin pentasaccharide 1. Example of A monosaccharide monomer synthesis:

[0022] The raw material A1 (6 g, 1 eq) was dissolved in a dry acetonitrile solution (60 mL), and benzaldehyde dimethyl acetal (3.25 mL, 1.5 eq) was added. After stirring evenly, the catalyst camphorsulfonic acid (657 mg, 0.2 eq) was added. After stirring for 3 hours, thin layer chromatography showed that the reaction was completed; after adding a sufficient amount of triethylamine to quench the reaction, the acetonitrile was removed by concentration under reduced pressure, and the product was extracted with dichloromethane and purified by column chromatography to obtain a benzyl protected intermediate (5.43 g, 1 eq) with a yield of 74.9%, which was dissolved in 55 mL of dry NN dimethylamide solution, and 2-bromomethylnaphthalene (7.32 g, 3 eq) was added and stirred evenly; sodium hydride (1.27 g, 3 eq) was added under ice bath conditions, and the ice bath was removed after 30 molecules, and stirred at room temperature for 5 hours. After the reaction was confirmed to be complete by thin layer chromatography, saturated ammonium chloride solution was added to quench the reaction and the pH was adjusted to about 7; after extraction with ethyl acetate, an appropriate amount of hot ethyl acetate was used to dissolve the product, and a large amount of petroleum ether was added after the product naturally cooled to room temperature, and then the product was transferred to 4°C for further cooling and crystallization, and then filtered to obtain 8.38 g of product A2 with a yield of 99.8%; 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.24 (m, 24H, H-Ar), 5.23 (d, J= 15.0 Hz, 2H, CH2-Nap), 5.12 (d, J = 11.3 Hz, 1H, H-6), 4.99 (d, J = 11.3Hz, 1H, H-6), 4.85 (d, J = 15.4 Hz, 1H, H-1), 4.68 (d, J = 10.5 Hz, 2H, H-CH2-Nap), 4.30 (dd, J = 10.4, 4.6 Hz, 2H, CH2-CBz), 4.19 – 4.10 (m, 1H, H-3), 3.89 (d, J = 10.1 Hz, 1H, H-5), 3.82 – 3.67 (m, 2H, Linker-O-CH2), 3.37 (dt,J = 11.9, 5.8 Hz, 3H, H-2, Linker-N-CH2), 1.72 – 1.27 (m, 6H, Linker-CH2).

[0023] The raw material A2 (8.38 g, 1 eq) was dissolved in 80 mL of 80% acetic acid aqueous solution and stirred at 60 ° C overnight. After TLC confirmed that the reaction was completed, the product was evaporated to dryness. After extraction with dichloromethane, the product was evaporated to dryness. A small amount of dichloromethane was used to dissolve the product, and then 50 mL of saturated sodium carbonate solution with a pH of 9 was added and stirred for 6 hours. 100 mL of petroleum ether was added and the solution was transferred to 4 ° C and continued to stir and crystallize. After filtration, 5.26 g of product A3 was obtained with a yield of 70.6%; 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.34 (m,19H, H-Ar), δ 5.33 – 5.18 (m, 2H, CH2-Nap), 5.13 – 4.94 (m, 2H, CH2-CBz),4.88 – 4.77 (m, 1H, H-1), 4.68 (d, J = 14.1 Hz, 2H, CH2-Nap), 4.00 – 3.88 (m,1H, H-3), 3.86 – 3.77 (m, 2H, H-6), 3.76 – 3.58 (m, 3H, H-4, H-5, Linker O-CH2), 3.49 – 3.39 (m, 1H, Linker O-CH2), 3.39 – 3.20 (m, 3H, H-2, Linker N-CH2), 1.78 – 1.28 (m, 6H, Linker CH2).

[0024] The raw material A3 (5.26 g, 1 eq) was dissolved in acetic anhydride (107 mL, 150 eq), 4A molecular sieve 17 g was added, and the mixture was stirred at 0°C for 6 hours; the molecular sieve was removed by filtration after diatomaceous earth was padded in a suction funnel, and the mixture was extracted with ethyl acetate, washed with saturated sodium carbonate solution, dried, and purified by column chromatography to obtain 3.94 g of the target receptor A with a yield of 70.6%. 1H NMR (500 MHz, CDCl3)δ 7.88 – 7.12 (m, 19H, CH-Ar), 5.22 – 5.13 (m, 2H, CH2-Nap), 5.09 – 4.98 (m,2H, CH2-CBz), 4.88 (d, J = 9.7 Hz, 1H, H-1), 4.51 (d, J = 11.9 Hz, 3H, CH2-Nap, H-6), 4.23 (d, J = 12.2 Hz, 1H, H-6), 3.90 (p, J = 9.1 Hz, 1H, H-3), 3.84 – 3.72 (m, 1H, H-5), 3.71 – 3.58 (m, 1H, OCH2-Linker), 3.53 (d, J = 10.0Hz, 1H, H-4), 3.47 – 3.36 (m, 1H, O-CH2-Linker), 3.33 – 3.18 (m, 3H, H-2,NCH2-Linker), 2.14 – 2.03 (m, 3H, OAc-CH3), 1.77 – 1.48 (m, 6H, CH2-Linker). 2. Example of synthesis of monosaccharide B monomer:

[0025] The commercially available raw material diacetone-D-glucose B1 (50.0 g, 1 eq) was dissolved in a dry tetrahydrofuran solution (200 mL), and 2-bromomethylnaphthalene (51.0 g, 1.2 eq) was added. After stirring evenly, sodium hydride (15.4 g, 2 eq) was added in batches under ice bath conditions, and bubbles were seen in the solution; then the catalyst tetrabutylammonium iodide (7.1 g, 0.1 eq) was added and stirred overnight; after the thin layer chromatography indicated that the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, and the pH was adjusted to about 7; then ethyl acetate was used for extraction, and the obtained organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 76.9 g B2 (no purification was performed in this step);

[0026] The raw material B2 (76.9 g, 1.0 eq) was dissolved in 500 mL of 50% acetic acid aqueous solution, heated to 45°C in an oil bath and stirred overnight; after the reaction was completed by thin layer chromatography, a small amount of toluene was added and the mixture was concentrated under reduced pressure; ethyl acetate was then added to dissolve the mixture, and the residual acetic acid was washed away with a saturated sodium bicarbonate solution. The organic phase was dried with anhydrous sodium sulfate and then evaporated to dryness to obtain 70.0 g of B3 (no purification was performed in this step);

[0027] The raw material B3 (70.0 g, 1.0 eq) was dissolved in 300 mL of a mixed solution of dichloromethane / pyridine = 1 / 2 (v / v), stirred evenly, and trimethylacetyl chloride (35.7 mL, 1.5 eq) was added under ice bath conditions; after 3 hours of reaction, thin layer chromatography showed that the reaction was complete, and sufficient methanol was added to quench the reaction, followed by concentration under reduced pressure; the product was dissolved in dichloromethane, the organic phase was washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate, then concentrated under reduced pressure and drained overnight in a cold trap; an appropriate amount of hot ethyl acetate was added to dissolve it again, and a large amount of petroleum ether was added after cooling to room temperature, and then refrigerated at 4°C for crystallization; 70.61 g of intermediate B4 was obtained with a yield of 84.1% in three steps;

[0028] The raw material B4 (31.6 g, 1.0 eq) was dissolved in 300 mL of a mixed solution of dichloroethane / pyridine = 6 / 1 (v / v), trifluoromethanesulfonic anhydride (15.0 mL, 1.1 eq) was added dropwise at -15 °C and stirred for 4 hours; after the reaction was completed by thin layer chromatography, pure water (20.5 mL, 14 eq) was added, and the mixture was refluxed at 85 °C for 30 minutes. After the reaction was completed by thin layer chromatography, an appropriate amount of dichloromethane was added for dilution, and the organic phase was washed with pure water, saturated sodium bicarbonate, and saturated sodium chloride, respectively, and then dried with anhydrous sodium sulfate, filtered, and evaporated to obtain 31.6 g of B5 (no purification was performed in this step); 1H NMR (500 MHz, CDCl3) δ 7.90 – 7.80(m, 4H, H-Ar), 7.55 – 7.45 (m, 3H, H-Ar), 5.99 (d, J = 3.8 Hz, 1H, H-1), 4.90 (d, J = 11.9 Hz, 1H, H-3), 4.78 (d, J = 12.0 Hz, 1H, H-5), 4.69 (d, J = 3.7Hz, 1H, H-2), 4.47 – 4.39 (m, 1H, H-4), 4.29 – 4.23 (m, 2H, H-6), 4.22 – 4.17 (m, 2H, CH2-Nap), 1.53 – 1.22 (m, 15H, CH3).

[0029] The raw material B5 (31.6 g, 1 eq) was dissolved in an appropriate amount of methanol, and then the pH was adjusted to about 11 with sodium methoxide, and then the reaction was stirred overnight; after the reaction was completed, H-type ion exchange resin was added to the solution, the pH was adjusted to neutral, and then the solution was filtered and evaporated to dryness to obtain 25.1 g of product B6 (no purification was performed in this step); 1H NMR (500 MHz,CDCl3) δ 8.00 – 7.33 (m, 7H, H-Ar), 6.02 (d, J = 3.8 Hz, 1H, H-1), 4.88 (d, J= 11.9 Hz, 1H, H-3), 4.70 (d, J = 3.9 Hz, 1H, H-2), 4.63 (d, J = 11.9 Hz, 1H,H-4), 4.21 (dd, J = 5.4, 3.6 Hz, 1H, H-5), 4.12 – 4.05 (m, 2H, CH2-Nap), 3.68 – 3.58 (m, 2H, H-6), 1.53 – 1.28 (m, 6H, CH3).

[0030] The raw material B6 (25.1 g, 1 eq) was dissolved in 240 mL of dioxane solution, and 390 mL of 0.1 M sulfuric acid solution was added, and the mixture was reacted at 85 ° C in an oil bath for 4 hours. After the reaction was completed by thin layer chromatography, OH-type ion exchange resin was added, and the pH of the reaction solution was adjusted to neutral, and then filtered and evaporated to obtain 22.2 g of the intermediate; the intermediate was dissolved in 250 mL of pyridine, and acetic anhydride (39.1 mL, 6 eq) was added. 4-dimethylaminopyridine (1.69 g, 0.2 eq) was slowly added under ice bath conditions, and then stirred for 10 minutes, the ice bath was removed, and the mixture was left overnight; after the reaction was completed by thin layer chromatography, sufficient methanol was added The reaction was quenched; the reaction solution was evaporated to remove methanol, B was extracted with ethyl acetate and evaporated to dryness to obtain 21.44 g of the intermediate; the treated intermediate (21.44 g, 1 eq) was dissolved in 70 mL of dry dichloromethane, and then ethyl mercaptan (12.1 mL, 3.6 eq) was added, and boron trifluoride etherate (25.8 mL, 4.6 eq) was slowly added dropwise under ice bath conditions and stirred overnight; after thin layer chromatography showed that the reaction was complete, solid sodium bicarbonate was added to quench the reaction; an appropriate amount of dichloromethane was added to dilute the reaction solution, the organic phase was dried after washing with saturated sodium bicarbonate and saturated brine, evaporated to dryness, and purified by column chromatography to obtain 15.7 g of product B7 with a four-step yield of 73.2%;

[0031] The raw material B7 (15.7 g, 1 eq) was dissolved in an appropriate amount of methanol, and then the pH was adjusted to about 11 with sodium methoxide, and then stirred overnight for reaction; after the thin layer chromatography showed that the reaction was completed, H-type ion exchange resin was added to the solution, the pH was adjusted to neutral, and then suction filtered, and the filtrate was evaporated to dryness to obtain 11.7 g of product B8 (no purification was performed in this step);

[0032] The raw material B8 (11.7 g, 1 eq) was dissolved in 120 mL of anhydrous acetonitrile, and benzaldehyde dimethyl acetal (9.64 mL, 2 eq) was added under nitrogen protection, followed by the catalyst camphorsulfonic acid (1.49 g, 0.2 eq), and stirred overnight; after the reaction was detected by thin layer chromatography, sufficient triethylamine was added to quench the reaction, and the reaction was concentrated under reduced pressure and diluted with dichloromethane. The organic phase was evaporated after extraction and dried overnight in a cold trap; an appropriate amount of hot ethyl acetate was used to dissolve the product, and a large amount of petroleum ether was added and transferred to 4 ° C for crystallization, and 11.64 g of product B9 was obtained with a yield of 80.1%;

[0033] The raw material B9 (9.92 g, 1 eq) was dissolved in 100 mL of anhydrous pyridine, and the catalyst 4-dimethylaminopyridine (0.82 g, 0.3 eq) was added, and then acetic anhydride (6.3 mL, 3 eq) was slowly added under ice bath conditions, and the reaction was stirred overnight; after the reaction was completed by thin layer chromatography, sufficient methanol was added under ice bath conditions to quench the reaction, and the reaction was concentrated under reduced pressure; the reaction solution was diluted with ethyl acetate and washed, and 8.5 g of the target product B was obtained by column chromatography purification with a yield of 78.4%. 1H NMR (500 MHz, CDCl3) δ 7.83(p, J = 7.9 Hz, 5H, H-Ar), 7.49 (ddt, J = 12.8, 9.0, 6.4 Hz, 8H, H-Ar), 5.50(s, 1H, H-1), 5.46 (s, 1H, H-Bn), 5.14 (d, J = 2.6 Hz, 1H, H-2), 4.99 (d, J =12.0 Hz, 1H, CH2-Nap), 4.76 (d, J = 12.0 Hz, 1H, CH2-Nap), 4.34 (d, J = 4.0Hz, 1H, H-5), 4.28 (d, J = 12.6 Hz, 1H, H-6), 4.14 (dd, J = 12.7, 1.9 Hz, 1H,H-6), 4.00 (d, J = 2.4 Hz, 1H, H-4), 3.79 (s, 1H, H-3), 2.83 – 2.60 (m, 3H,S-CH3), 2.19 – 1.97 (m, 3H, CH3-OAc), 1.39 – 1.22 (m, 2H, S-CH2). 3. Example of D monosaccharide monomer synthesis:

[0034] The commercially available raw material D1 (15.0 g, 1 eq) was dissolved in 30 mL of a mixed solution of dichloromethane / methanol = 1 / 1 (v / v), sodium methoxide was added to adjust the pH to 11, and after reacting for 2.5 hours, the reaction solution was passed through a hydrogen ion exchange resin to adjust the pH to neutral, concentrated under reduced pressure, and then drained overnight; the obtained product was dissolved in 50 mL of acetonitrile solution, 4-methoxybenzaldehyde dimethyl acetal (20.812 mL, 3 eq) was added and stirred evenly, and camphorsulfonic acid (1.78 g, 0.2 eq) was added and reacted overnight; after the reaction was completed with thin layer chromatography, triethylamine was added to quench, and after extraction and column chromatography purification, 8.0 g of product D2 was obtained with a yield of 61.12%;

[0035] The raw material D2 (7.9 g, 1 eq) was dissolved in 50 mL of NN-dimethylamide solution, 2-bromomethylnaphthalene (20.4 g, 4 eq) was added, and sodium hydride (3.69 g, 4 eq) was added under ice bath conditions and stirred overnight. After the reaction was completed, saturated ammonium chloride was used to quench the reaction and the pH was adjusted to 7. After extraction with dichloromethane, the mixture was concentrated under reduced pressure. After being drained by cold trap overnight, the obtained solid was dissolved in hot ethyl acetate, a small amount of petroleum ether was added, and the mixture was cooled and crystallized to obtain the product D3 (14.37 g). 1H NMR (400 MHz, CDCl3)δ 7.90 – 7.72 (m, 18H, H-Ar), 7.57 – 7.35 (m, 18H, H-Ar), 5.57 (s, 1H, CH-PMB), 5.18 – 5.04 (m, 4H, CH2-Nap), 5.04 – 4.87 (m, 4H, CH2-Nap), 4.60 (dd, J= 16.4, 9.7 Hz, 2H, H-1-α, H-1-β), 4.36 (dd, J = 10.5, 5.0 Hz, 1H, H-6-α), 3.95 – 3.86 (m, 5H, CH3-PMB-α, H-6-β, H-3-α , 3.41 – 3.30 (m, 1H, H-4-α), 2.90 – 2.71 (m, 4H, SCH2), 1.35 (td, J = 7.5, 3.3 Hz, 6H, SCH3).

[0036] The raw material D3 (14.37 g, 1 eq) was dissolved in 115.37 mL of 1 M borane tetrahydrofuran solution and stirred for 10 minutes under argon protection; then nickel trifluoromethanesulfonate (6.17 g, 0.8 eq) was added and the reaction was stirred overnight at room temperature; after the reaction was completed, triethylamine and methanol were added under ice bath conditions to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. After the cold trap was drained, the obtained solid was dissolved in hot ethyl acetate, and a small amount of petroleum ether was added and cooled for crystallization, and the product D4 was obtained in a two-step yield of 94.89%; 1H NMR (400 MHz, CDCl3) δ 7.93 – 6.64 (m, 18H, H-Ar), 5.17 –5.02 (m, 3H, CH2-Nap), 4.92 (d, J = 10.5 Hz, 1H, CH2-Nap), 4.74 (d, J = 10.5Hz, 1H, CH2-PMB), 4.48 (dd, J = 10.1, 8.7 Hz, 2H, CH2-PMB, H-1 ), 4.34 – 4.17(m, 2H, H-6), 3.76 (s, 3H, CH3-PMB), 3.70 (d, J = 8.5 Hz, 1H, H-3), 3.50 –3.37 (m, 3H, H-2, H-3, H-5), 2.87 – 2.65 (m, 2H, SCH2), 1.35 (t, J = 7.4 Hz,3H,SCH3).

[0037] The raw material D4 (13.68 g, 1 eq) and 2-diphenylphosphonoacetic acid (DPPA) (8.55 g, 1.5 eq) were dissolved in 50 mL of dry dichloromethane solution, 4-dimethylaminopyridine (0.53 g, 0.2 eq) was added, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (8.39 g, 2 eq) and the reaction was continued for 3.5 hours. After the reaction was completed by thin layer chromatography, ethyl acetate was extracted, EDC·HCl was washed off with water and concentrated under reduced pressure. After the cold trap was drained, the obtained solid was dissolved in hot ethyl acetate, a small amount of petroleum ether was added, and the product was cooled and crystallized to obtain 16.23 g of product D5 with a yield of 85.50%. 1H NMR (400 MHz, CDCl3) δ 8.06 – 7.20 (m, 28H, H-Ar), 5.14 – 4.98 (m, 3H, CH2-Nap), 4.89 (d, J = 10.5 Hz, 1H, CH2-Nap), 4.71 (d, J = 10.7 Hz, 1H, CH2-PMB), 4.50– 4.36 (m, 2H, CH2-PMB, H-1-A), 4.32 – 4.10 (m, 3H, H-6-A, H-5-A), 3.68 (t, J= 8.3 Hz, 4H, CH3-PMB, H-3-A), 3.57 – 3.32 (m, 4H, CH2-DPPA, H-4-A, H-2-A), 2.74 (dq, J = 14.9, 7.1 Hz, 2H, CH2-SCH2), 1.37 – 1.23 (m, 3H, CH3-SCH2CH3).

[0038] The raw material D5 (10 g, 1 eq) was dissolved in 100 mL of acetonitrile solution, and N-iodosuccinimide (NIS) (3.89 g, 1.5 eq) was added. Water (417.0 μL, 2 eq) and trifluoroacetic acid (88.3 μL, 0.1 eq) were added at -5 °C, and the reaction was stirred for 2.5 hours. The reaction was quenched with triethylamine, extracted with ethyl acetate, and concentrated under reduced pressure. After the cold trap was drained, the obtained solid was dissolved in hot ethyl acetate, and a small amount of petroleum ether was added and cooled for crystallization, and 6.8 g of the intermediate product without ethylthio group was obtained with a yield of 71.65%. A portion of the intermediate (4.27 g , 1eq) was dissolved in 100mL of dichloromethane solution, and 2,2,2-trifluoro-N-phenylacetylimidoyl chloride (1.26mL, 1.5eq) was added under argon protection. After stirring evenly, sodium hydride (0.42g, 2eq) was added under ice bath conditions. The ice bath was removed and the reaction was stirred at room temperature for 4.5 hours. The reaction was quenched with saturated ammonium chloride solution and the pH was adjusted to 7. After extraction with ethyl acetate, it was concentrated under reduced pressure, the cold trap was drained, and column chromatography was used for purification to obtain 4.28g of product D with a yield of 82.98%. After the cold trap was drained, it could be put into the next step of glycosidation reaction (imidoester is unstable and no nuclear magnetic resonance detection was performed).

[0039] 4. Example of synthesis of E monosaccharide monomer:

[0040] The raw material E1 (8.99 g, 1 eq) was dissolved in 200 mL of dry pyridine solution, and then triphenylmethane (22.04 g, 2.7 eq) was added under argon protection, followed by 4-dimethylaminopyridine (0.80 g, 0.2 eq), and the reaction was started at room temperature; after overnight, the reaction was detected by thin layer chromatography, and an appropriate amount of methanol was added to quench the reaction, and the reaction was concentrated under reduced pressure. The reaction solution was diluted with dichloromethane, and the organic phase was washed with 1 M hydrochloric acid solution, and then washed with saturated sodium bicarbonate to remove hydrochloric acid. The organic phase was dried and evaporated to dryness, and purified by column chromatography to obtain 15.48 g of E2 with a yield of 96.8%; 1H NMR (400 MHz, CDCl3) δ 7.60 –6.83 (m, 19H, H-Ar), 5.41 (dd, J = 3.4, 1.4 Hz, 1H, H-1), 4.22 (dd, J = 9.5,4.6 Hz, 1H, H-5), 3.69 (q, J = 3.6 Hz, 2H, H-3, H-2), 3.48 – 3.44 (m, 1H, H-4), 3.33 – 3.28 (m, 2H, H-6), 2.22 (d, J = 3.4 Hz, 3H, SCH3).

[0041] The raw material E2 (15.99 g, 1 eq) was dissolved in 160 mL of dry NN-dimethylamide solution, 2-bromomethylnaphthalene (19.95 g, 3 eq) was added, sodium hydride (4.62 g, 4 eq) was added under ice bath conditions, and the reaction was stirred for 2 hours. Thin layer chromatography showed that the reaction was complete; the reaction was quenched with saturated ammonium chloride solution and the pH was adjusted to 7. After multiple extractions with dichloromethane, the product was concentrated under reduced pressure. After being drained overnight in a cold trap, the obtained solid was dissolved in hot ethyl acetate and placed at 4°C for cooling and crystallization. The product 22.93 g E3 was obtained at 95.2%; 1H NMR (400 MHz, CDCl3) δ 8.02 – 6.45 (m, 33H, H-Ar), 5.63 – 5.58 (m, 1H,H-1-α ), 5.01 – 4.83 (m, 4H, CH2-Nap), 4.75 – 4.63 (m, 2H, H-6-α), 4.55 –4.46 (m, 2H, CH2), 4.45 – 4.30 (m, 5H, H-5-α, H-1-β, H-4-β, CH2), 4.25 (dq, J= 7.3, 4.6 Hz, 1H, H-4-β), 4.00 (td, J = 5.9, 2.7 Hz, 1H, H-2-α), 3.85 – 3.68 (m, 3H, H-3-α, H-3-β, H-5-β), 3.61 (d, J = 10.2 Hz, 1H, H-6-β), 3.50 (dt, J =10.2, 2.7 Hz, 1H, H-6-β), 3.38 (ddd, J = 9.5, 4.7, 2.3 Hz, 2H, H-2-β), 3.20 (ddt, J = 12.9, 10.2, 3.2 Hz, 3H, H-4-α), 2.30 – 2.05 (m, 9H, CH2-SPh), 1.46– 1.26 (m, 3H).

[0042] The raw material E3 (22.93 g, 1 eq) was dissolved in 200 mL of a mixed solution of dichloromethane / methanol = 1 / 1 (v / v), and p-toluenesulfonic acid (3.56 g, 0.7 eq) was added and reacted at room temperature overnight. After the reaction was completed by thin layer chromatography, dichloromethane was extracted, the organic phase was washed and evaporated to dryness under reduced pressure and then cold-trap dried overnight. The solid was dissolved in an appropriate amount of hot ethyl acetate, and after adding a large amount of petroleum ether, it was cooled and crystallized at 4°C to obtain 13.93 g of product E4 with a yield of 85.6%. 1H NMR (500 MHz, CDCl3) δ 7.86– 7.07 (m, 18H, H-Ar), 5.52 (d, J = 3.7 Hz, 1H, H-1-α), 5.13 – 5.05 (m, 4H,CH2-Nap), 4.89 – 4.77 (m, 2H, H-6-α), 4.42 (d, J = 10.4 Hz, 1H, H-1-β), 4.34 (dt, J = 10.1, 3.3 Hz, 1H, H-5-α), 3.96 – 3.93 (m, 2H, H-2-α, H-4-β), 3.86 –3.77 (m, 2H, H-6-β), 3.76 – 3.69 (m, 2H, H-3-α, H-5-β), 3.60 (p, J = 9.0 Hz, 1H, H-3-β), 3.46 – 3.39 (m, 1H, H-4-α), 3.34 (t, J = 9.4 Hz, 1H, H-2-β), 2.34(d, J = 7.5 Hz, 3H, CH3-SPh).

[0043] The raw material E4 (13.93 g, 1 eq) was dissolved in 200 mL of anhydrous pyridine, and the catalyst 4-dimethylaminopyridine (1.32 g, 0.5 eq) was added, followed by the slow addition of acetic anhydride (8.31 mL, 3.7 eq) under ice bath conditions, and the reaction was stirred overnight; after the reaction was completed by thin layer chromatography, sufficient methanol was added under ice bath conditions to quench the reaction, and the mixture was concentrated under reduced pressure; the reaction solution was diluted with ethyl acetate and washed, the organic phase was evaporated to dryness and dissolved in an appropriate amount of hot ethyl acetate, a large amount of petroleum ether was added, and the mixture was cooled and crystallized at 4 ° C to obtain 11.75 g of the target product E5 with a yield of 78.73%. 1H NMR (500 MHz, CDCl3) δ 7.95 – 6.86 (m,18H, H-Ar), 5.53 (d, J = 5.0 Hz, 1H, H-1- α), 5.10 – 4.95 (m, 4H, CH2-Nap),4.52 (ddd, J = 12.6, 7.3, 4.1 Hz, 1H, H-5-α), 4.46 – 4.42 (m, 1H, H-6-α), 4.38 (d, J = 10.1 Hz, 1H, H-1-β), 4.28 (dd, J = 6.4, 3.6 Hz, 2H, H-6-β), 4.22– 4.16 (m, 1H, H-6-α), 4.01 – 3.92 (m, 2H, H-2-α, H-3-α), 3.69 – 3.56 (m, 3H,H-4-α, H-3-β. H-4-β), 3.53 (d, J = 7.9 Hz, 1H, H-5-β), 3.35 (t, J = 9.7 Hz, 1H, H-2-β), 2.34 (d, J = 9.4 Hz, 3H, CH3-SPh), 1.96 (d, J = 14.8 Hz, 3H, CH3-OAc).

[0044] The raw material E5 (7.17 g, 1 eq) was dissolved in 88 mL of a mixed solution of acetone / water = 10 / 1 (v / v), and N-bromosuccinimide (NBS) (4.11 g, 2 eq) was added. The mixture was stirred for 2 hours. Thin layer chromatography showed that the reaction was complete. The mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated sodium thiosulfate solution and concentrated under reduced pressure. After the cold trap was drained, the obtained solid was dissolved in hot ethyl acetate, and a small amount of petroleum ether was added and cooled to crystallize. Thus, 3.58 g of the intermediate without p-toluenethioyl was obtained with a yield of 60.02%. Product; Take a part of the intermediate (2.23g, 1eq) and dissolve it in 30mL acetone solution, add potassium carbonate (2.34g, 4eq) and stir, add 2,2,2-trifluoro-N-phenylacetylimidoyl chloride (1.37mL, 2eq) under argon protection, and stir and react overnight at room temperature; use diatomaceous earth to filter out solid impurities, evaporate the filtrate and purify it by column chromatography to obtain 2.35g product E with a yield of 79.53%. After the cold trap is drained, it can be put into the next glycosidation reaction (imidoester is unstable and nuclear magnetic resonance detection is not performed).

[0045] 6. Example of synthesis of CDE trisaccharide intermediate:

[0046] The reagents and equipment required for glycosylation were prepared according to the anhydrous operation. The acceptor C (4.63 g, 1 eq) and the donor D7 (16 g, 1.5 eq) were dissolved and mixed with dichloromethane, evaporated and then cold-trap dried for 2 h. After argon ventilation, an appropriate amount of molecular sieves were added, and 120 mL of anhydrous acetonitrile was added, and the mixture was stirred for 60 minutes after ultrasonic dissolution. The reaction bottle was transferred to a low-temperature reactor, stirred at -25 °C for 20 minutes, and then trimethylsilyl trifluoromethanesulfonate (1.867 mL, 1 eq) was added dropwise, stirred overnight, and detected by thin layer chromatography. After the reaction was completed, triethylamine was added to quench the reaction. The reaction solution was filtered through a diatomaceous earth pad on a suction funnel, concentrated under reduced pressure, and purified by column chromatography to obtain 7.4 g of the target β-configuration disaccharide intermediate CD1 with a yield of 55.79%; 1H NMR (400 MHz, CDCl3) δ 7.89 – 6.74 (m, 28H, H-Ar),5.03 (d, J = 11.4 Hz, 1H, CH2-Nap), 4.97 – 4.85 (m, 4H, CH2-Nap, H-3-C), 4.66(d, J = 10.4 Hz, 1H, H-6-D), 4.47 – 4.32 (m, 3H, H-1-C, H-6-D, H-6-C), 4.28 –4.13 (m, 4H, H-6-C, H-1-D, CH2-PMB), 3.75 (s, 3H, CH3-PMB), 3.56 – 3.41 (m,2H, H-3-D, H-4-C), 3.38 – 3.21 (m, 5H, H-5-D, H-2-D, H-4-D, H-2-C, H-5-C), 2.03 (s, 3H, CH3-OAc), 1.80 (s, 3H, CH3-OAc), 1.61 (t, J = 6.7 Hz, 9H, CH3-TDS), 1.26 (s, 3H, CH3-TDS), 0.98 – 0.75 (m, 13H, CH3-TDS,).

[0047] The raw material CD1 (1.08 g, 1 eq) was dissolved in 30 mL of a mixed solution of dichloromethane / methanol = 3 / 7 (v / v), and nickel trifluoromethanesulfonate (0.32 g, 1 eq) was added, and the mixture was refluxed at 80°C for 4.5 hours; after extraction, the mixture was concentrated under reduced pressure, dissolved in hot ethyl acetate, and cooled and crystallized at 4°C after adding a large amount of petroleum ether to obtain 834 mg of the product CD2 with a yield of 96.04%;

[0048] The raw material CD2 (0.83 g, 1 eq) was dissolved in 15 mL of a mixed solution of dichloromethane / water = 2 / 1 (v / v), and diethyl iodobenzene (0.82 g, 3 eq) was added. After stirring, tetramethylpiperidinium oxide (Tempo) (0.03 g, 0.3 eq) was added and reacted at room temperature for 5.5 hours. After the reaction was detected by thin layer chromatography, saturated sodium thiosulfate solution was quenched, and the mixture was extracted with dichloromethane and concentrated under reduced pressure and dried by cold trap. Then, the intermediate was dissolved in 10 mL of NN-dimethylamide solution, and potassium bicarbonate (0.17 g, 2 eq) and iodomethane (340.5 μL, 5 eq) were added under ice bath conditions. After the reaction was detected by thin layer chromatography, the mixture was extracted with ethyl acetate and evaporated to dryness, and then dissolved with an appropriate amount of hot ethyl acetate. After adding a large amount of petroleum ether, the mixture was cooled and crystallized at 4 °C to obtain 673 mg of product CD3 with a yield of 78.47%. 1H NMR (400 MHz, CDCl3) δ 8.14 – 6.42 (m, 18H, H-Ar), 5.12 –4.90 (m, 5H, CH2-Nap, H-3-C), 4.74 (d, J = 10.5 Hz, 1H, H-6-D), 4.59 – 4.52(m, 1H, H-6-D), 4.46 (d, J = 7.6 Hz, 1H, H-1-C), 4.41 – 4.32 (m, 2H, H-1-D,H-6-C), 4.19 (dd, J = 11.8, 6.5 Hz, 1H, H-6-C), 3.92 – 3.69 (m, 10H, H-4-D,H-5-D, H-3-D, CH3-PMB), 3.64 (dd, J = 10.5, 8.7 Hz, 1H, H-4-C), 3.58 – 3.47(m, 1H, H-2-D), 3.39 – 3.23 (m, 2H, H-2-C, H-5-C), 2.31 – 0.66 (m, 27H, CH3-TDS, CH3-OAc, CH-TDS, CH3-COOMe).

[0049] The raw material CD3 (673 mg, 1 eq) was dissolved in 5 mL of dichloromethane solution, trifluoroacetic acid (1 mL, 20 eq) was added, and the reaction was stirred for 4 hours; the reaction was quenched with saturated sodium bicarbonate, extracted and concentrated under reduced pressure, dissolved in hot ethyl acetate, added with a small amount of petroleum ether and cooled and crystallized at 4 ° C to obtain 466.7 mg of the target product CD with a yield of 78.58%; 1H NMR (400 MHz, CDCl3) δ8.05 – 6.92 (m, 14H, H-Ar), 5.07 – 4.81 (m, 5H, CH2-Nap, H-3-C), 4.42 (d, J =7.7 Hz, 1H, H-1-C), 4.37 – 4.26 (m, 2H, H-2-D, H-6-D), 4.14 (dd, J = 11.7,6.6 Hz, 1H, H-6-C), 3.90 – 3.70 (m, 5H, H-4-D, H-5-D, CH3), 3.66 – 3.52 (m,2H, H-3-D, H-4-C), 3.45 (dd, J = 9.2, 7.7 Hz, 1H, H-2-D), 3.36 – 3.18 (m, 2H,H-2-C, H-5-C), 2.24 – 0.73 (m, 25H, CH3-TDS, CH3-OAc, CH-TDS).

[0050] The reagents and equipment required for glycosylation were prepared according to the anhydrous operation. The acceptor CD (405 mg, 1 eq) and the donor E (627.4 mg, 2 eq) were dissolved and mixed with dichloroethane, evaporated and then cold-trap dried for 2 h. After argon ventilation, an appropriate amount of molecular sieves were added, and 10 mL of anhydrous dichloromethane was added and stirred for 60 min. The reaction bottle was transferred to a low-temperature reactor, stirred at 0 °C for 20 min, and trifluoromethanesulfonic acid (39.72 μL, 1 eq) was added dropwise and stirred for 4.5 h. Thin layer chromatography was performed for detection. After the reaction was completed, sufficient triethylamine was added to quench the reaction. The reaction solution was filtered through a diatomaceous earth pad on a suction funnel, concentrated under reduced pressure, and purified by column chromatography to obtain 390 mg of the target intermediate CDE1 with a yield of 61.54%; 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.13 (m, 38H, H-Ar), 5.54 (d, J =3.7 Hz, 1H, H-1-E), 5.16 – 4.66 (m, 11H, CH2-Nap, H-3-C, H-6-D), 4.39 (d, J =7.6 Hz, 1H, H-6-D), 4.36 – 4.26 (m, 3H, H-1-C, H-1-D, H-6-E), 4.24 – 4.07 (m,4H, H-6-E, H-6-C, H-3-E), 3.96 (dt, J = 10.3, 4.2 Hz, 1H, H-4-D), 3.90 (d, J= 9.7 Hz, 1H, H-4-E), 3.82 (d, J = 9.1 Hz, 1H, H-3-D), 3.64 – 3.45 (m, 4H, H-2-D, H-4-C, H-5-D, H-5-E), 3.36 – 3.26 (m, 2H, H-2-C, H-5-C), 3.21 (ddd, J =9.0, 6.4, 2.1 Hz, 1H, H-2-E), 2.11 – 0.64 (m, 46H, CH3-TDS, CH-TDS, CH3-OAc).

[0051] The raw material CDE1 (736.88 mg, 1 eq) was placed in a plastic centrifuge tube, 10 mL of dry tetrahydrofuran solution was added, and then hydrogen fluoride pyridine (6.72 mL, 100 eq) was added. The reaction was stirred overnight, and thin layer chromatography showed that the reaction was complete; the reaction solution was diluted with dichloromethane, and a saturated sodium bicarbonate solution was added to slowly quench the reaction until no bubbles were generated. After extraction, the solution was concentrated under reduced pressure, and after the cold trap was drained, the obtained solid was dissolved in hot ethyl acetate, and a large amount of petroleum ether was added and cooled to crystallize, and 480.0 mg of the intermediate without the TDS group was obtained with a yield of 72.44%. Intermediate product; take a part of the intermediate (300.0 mg, 1 eq) and dissolve it in 5 mL of acetone solution, add potassium carbonate (130.65 mg, 4 eq) and stir, add 2,2,2-trifluoro-N-phenylacetylimidoyl chloride (76.66 μL, 2 eq) under argon protection, and stir at room temperature for 5.5 hours; use diatomaceous earth to filter out solid impurities, evaporate the filtrate and purify it by column chromatography to obtain 323.6 mg of the target product CDE with a yield of 95.05%. After the cold trap is drained, it can be put into the next glycosidation reaction (imidoester is unstable and no NMR detection is performed).

[0052] 7. Synthesis example of AB disaccharide intermediate:

[0053] Dissolve donor B (2.68 g, 1 eq) and acceptor A (2.13 g, 1.2 eq) in 20 mL of dry dichloromethane solution, add N-iodosuccinimide (1.65 g, 2 eq) and an appropriate amount of molecular sieves, stir for 1 hour and then cool to -0 °C, add trifluoromethanesulfonic acid (64.8 μL, 0.2 eq) dropwise under argon protection, turn off the low-temperature stirrer, allow to return to room temperature naturally, and react overnight; after thin-layer chromatography shows that the reaction is complete, add enough triethylamine to quench the reaction, then filter with diatomaceous earth in a suction funnel, concentrate under reduced pressure, and obtain a total of 4.05 g of a mixture containing AB1 after simple purification. 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.25(m, 31H, H-Ar), 5.21 (d, J = 12.2 Hz, 2H, CH2-CBz), 5.12 (s, 1H, H-1-B), 5.03(d, J = 2.5 Hz, 1H, OCHO-Bn), 4.98 – 4.81 (m, 5H, CH2-Nap, H-1-A), 4.66 (d, J= 9.0 Hz, 2H, CH2-Nap), 4.49 (d, J = 12.3 Hz, 1H, H-6-B), 4.17 (d, J = 12.4Hz, 1H, H-6-B), 4.01 – 3.88 (m, 4H, H-3-B, H-5-B, H-3-A, H-5-A), 3.84 – 3.59 (m, 5H, H-2-B, HA-4, HA-6, OCH2-Linker), 3.52 – 3.37 (m, 3H, H-4-B, H-2-A, O-CH2-Linker), 3.34 – 3.21 (m, 2H, N-CH2-Linker), 2.06 (d, J = 7.5 Hz, 6H,CH3-OAc), 1.62 (d, J = 13.9 Hz, 6H, CH2-Linker).

[0054] The raw material obtained in the previous step (4.05 g, 1 eq) was dissolved in 40 mL of 80% acetic acid aqueous solution, heated to 60 ° C in an oil bath, stirred for reaction, and refluxed overnight; after the reaction was completed by thin layer chromatography, acetic acid was removed by rotary evaporation; the product was dissolved in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and then rotary dried. After column chromatography, 2.47 g of AB2 was obtained in two steps with 65.87%; 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.15 (m, 26H, H-Ar), 5.13 (d, J= 12.8 Hz, 2H, CH2-CBz), 4.95 (s, 1H, OCHO-Bn), 4.88 – 4.69 (m, 6H, H-1-B, H-1-A, CH2-Nap ), 4.58 (d, J = 9.3 Hz, 2H, CH2-Nap), 4.35 (d, J = 12.3 Hz, 1H,H-6-B), 4.27 – 4.14 (m, 2H, H-6-B, H-4-A), 3.86 (d, J = 9.4 Hz, 4H, H-4-A, H-3-B, H-4-B, H-5-B), 3.69 – 3.44 (m, 3H, H-2-B, H-6-A, H-5-A), 3.40 – 3.11 (m,5H, H-6-A, H-2-A, N-CH2-Linker, O-CH2-Linker), 3.01 (dt, J = 12.1, 3.3 Hz,1H, O-CH2-Linker), 2.07 – 1.93 (m, 6H, CH3-OAc), 1.66 – 1.08 (m, 6H, CH2-Linker).

[0055] The raw material AB2 (2.51 g, 1 eq) was dissolved in 60 mL of a mixed solution of dichloromethane / water = 2 / 1 (v / v), and diethyl iodobenzene (2.24 g, 3 eq) was added. After stirring, tetramethylpiperidinium oxide (Tempo) (0.09 g, 0.3 eq) was added and reacted at room temperature for 2 hours. After the reaction was completed by thin layer chromatography, saturated sodium thiosulfate solution was used to quench the reaction. After separation, the organic phase was diluted with ethyl acetate, extracted and concentrated under reduced pressure, and then dried by cold trap. The intermediate was then dissolved in 40 mL of NN-dimethylamide solution, potassium bicarbonate (0.72 g, 3 eq) and iodomethane (882.9 μL, 5.5 eq) were added under ice bath conditions, and the reaction was allowed to proceed overnight. After the reaction was completed by thin layer chromatography, the product was extracted with ethyl acetate and evaporated to dryness, and then dissolved with an appropriate amount of hot ethyl acetate. After adding a large amount of petroleum ether, it was cooled and crystallized at 4 °C to obtain 1.6 g of product AB with a yield of 60.7%. 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.09(m, 26H, H-Ar), 5.13 (d, J = 11.2 Hz, 2H, CH2-CBz), 5.01 (s, 1H, H-1-B), 4.93(s, 1H, H-5-B), 4.90 – 4.70 (m, 6H, H-1-A, H-2-B, CH2-Nap), 4.37 (d, J = 12.3Hz, 1H, CH2-Nap), 4.18 (d, J = 12.5 Hz, 1H, CH2-Nap), 4.04 (d, J = 7.1, 1.1Hz, 1H, HA-6), 3.91 – 3.78 (m, 4H, H-3-A, H-3-B, H-4-B, H-5-A), 3.69 (d, J =3.2 Hz, 1H, H-4-A), 3.65 – 3.49 (m, 1H, OCH2-Linker), 3.42 – 3.12 (m, 4H,OCH2-Linker, H-2-A, N-CH2-Linker), 2.07 – 1.93 (m, 6H, CH2-OAc), 1.70 – 1.23(m, 6H, CH2-Linker). 8. Example of synthesis of heparin pentasaccharide ABCDE:

[0056] Disaccharide AB (261.59 mg, 1 eq) and trisaccharide CDE (404.0 mg, 1.2 eq) were dissolved in 5 mL of dry dichloromethane solution, and an appropriate amount of molecular sieves were added. After stirring, the temperature was cooled to -20 °C, and trifluoromethanesulfonic acid (20.68 μL, 1 eq) was added dropwise under argon protection. The reaction was allowed to proceed for 5 hours. After TLC showed that the reaction was completed, the filtration funnel was padded with diatomaceous earth for filtration, and the mixture was concentrated under reduced pressure. 365.0 mg of pentasaccharide ABCDE1 was obtained by column chromatography purification with a yield of 65.88%. 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.00(m, 54H, H-Ar), 5.44 (d, J = 3.7 Hz, 1H, H-1-E), 5.31 (dd, J = 10.8, 9.1 Hz,1H, H-3-B), 5.19 (d, J = 3.4 Hz, 1H, H-1-C), 5.16 – 5.02 (m, 3H, CH2-Linker-OCH2), 5.00 – 4.81 (m, 9H, CH2-Nap, H-2-C, H-1-B), 4.80 – 4.62 (m, 6H, H-6-B,H-1-A, CH2-Nap, CH2-CBz), 4.56 (s, 2H, CH2-Linker-NCH2), 4.41 – 4.27 (m, 3H,H-6-C, H-1-D), 4.27 – 4.14 (m, 3H, H-6-A, H-6-D), 4.14 – 3.96 (m, 8H, H-6-D,H-6-E, H-5-A, H-2-A, H-5-B, H-3-C, H-4-D), 3.93 (t, J = 4.6 Hz, 1H, H-4-E), 3.82 (td, J = 9.5, 3.3 Hz, 4H, H-3-A, H-3-E, H-4-C, H-5-D), 3.73 – 3.64 (m,1H, H-5-E), 3.51 – 3.42 (m, 3H, H-5-C, H-4-A, H-2-D), 3.22 (q, J = 5.1 Hz, 6H, H-2-E, CH3-COOCH3), 3.09 (dd, J = 10.8, 3.4 Hz, 1H, H-2-B), 2.09 – 1.71(m, 15H, CH3-OAc), 1.18 (t, J = 7.1 Hz, 8H, CH2-Linker).

[0057] ABCDE1 (181.0 mg, 1 eq) was dissolved in 5 mL of tetrahydrofuran, and a mixed solution of 30% hydrogen peroxide (1.3 mL) and 1.25 M LiOH (5.2 mL) was added. After reacting at room temperature for 24 h, 0.65 mL of 4 M NaOH solution was added and stirring was continued for 18 h. After adjusting the pH with acetic acid, the product was concentrated under reduced pressure and purified by reverse column to obtain 143.5 mg of product ABCDE2 with a yield of 88.14%; 1H NMR (400 MHz, DMSO) δ 8.22 – 7.08 (m, 54H, H-Ar), 5.42 (d, J = 3.7 Hz, 2H, H-1-B,H-1-E), 5.23 – 5.05 (m, 6H, CH2-Nap), 5.04 – 4.86 (m, 8H, H-1-C, H-6-C, H-6-D, CH2-Nap), 4.87 – 4.76 (m, 4H, CH2-Nap, H-6-D, H-1-A,), 4.72 (d, J = 6.8Hz, H-1-D), 4.68 – 4.52 (m, 4H, H-6-B, CH2-CBz), 4.44 (t, J = 7.1 Hz, 2H, H-3-C, H-3-B), 4.17 (d, J = 7.1 Hz, 1H, H-2-B), 4.02 – 3.66 (m, 15H, H-6-A, H-6-E, H-2-B, H-5-E, H-4-E, H-3-E, H-3-D, H-3-A, H-5-A, H-5-B, H-4-B, H-4-C, H-5-D, H-5-C, H-2-D, H-5-D, H-4-A, H-2-C, H-2-A, H-2-E, H-5-D, H-5-A), 1.83 –0.61 (m, 35H, CH2-Linker).

[0058] ABCDE2 (20.0 mg, 1 eq) was dissolved in 2 mL N,N-dimethylformamide, and sulfur trioxide pyridine (112 mg, 64 eq) was added. The mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure, and purified by reverse column chromatography to obtain 18.9 mg of product ABCDE3 with a yield of 75.06%; 1H NMR (400 MHz, MeOD) δ 7.91 – 7.04 (m, 54H, H-Ar), 5.59 (dd, J =7.8, 3.9 Hz, H-1-E), 5.50 (s, 1H, H-1-B), 5.31 (d, J = 3.9 Hz, 1H, H-1-C),5.20 – 5.08 (m, 5H, CH2-Nap, CH2-CBz, H-6-C), 5.08 – 4.91 (m, 10H, CH2-Nap,H-6-C, H-6-D, H-1-D, H-1-A), 4.75 – 4.54 (m, 7H, H-3-C, HCB, H-6-B), 4.46 –4.19 (m, 10H, H-6-A, H-6-E, H-2-B, H-5-E, H-4-E), 4.18 – 3.81 (m, 12H, H-3-E,H-3-D, H-3-A, H-5-A, H-5-B, H-4-B, H-4-C, H-5-D), 3.79 – 3.44 (m, 6H, H-5-C,H-2-D, H-5-D, H-4-A, H-2-C, H-2-A), 3.36 (dd, J = 10.2, 3.8 Hz, 3H, H-2-E, H-5-D, H-5-A), 3.24 (s, 3H, CH2-Linker), 1.77 – 1.04 (m, 16H, CH2-Linker).

[0059] ABCDE3 (100 mg, 1 eq) was dissolved in 10 mL tetrahydrofuran, and 22.5 mL 0.1 M NaOH solution was added. After stirring, trimethylphosphine (146.25 μL, 45 eq) was added and stirred at room temperature for 4 hours. The pH was adjusted to 8.5 with acetic acid, and the mixture was concentrated under reduced pressure and purified by reverse column. 87.4 mg of the intermediate pentasaccharide was obtained with a yield of 95.66%. 17.0 mg of the intermediate product was dissolved in 3.2 mL of a mixed solution of methanol and triethylamine, and sulfur trioxide pyridine (66.14 mg, 60 eq) was added. The pH was adjusted to 11 with 0.1 M NaOH solution, and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, the mixture was purified by reverse column and 10.6 mg of pentasaccharide ABCDE4 was obtained with a yield of 56.84%. 1HNMR (400 MHz, MeOD) δ 8.06 – 6.86 (m, 54H, H-Ar), 5.66 (d, J = 3.4 Hz, 1H, H-1-E), 5.49 (s, 1H, H-1-B), 5.39 (d, J = 3.9 Hz, 1H, H-1-C), 5.26 – 5.12 (m,7H, CH2-Nap, H-1-A), 5.12 – 5.03 (m, 3H, H-1-D, H-6-D), 5.02-4,93(m, 7H, H-6-D, CH2-Nap), 4.79 (m, 5H, H-6-C, CH2-Nap), 4.76 – 4.59 (m, 10H, H-6-B, H-5-E,H-3-C, CH2-Linker-NCH2), 4.48 – 4.23 (m, 11H, H-6-E, H-6-A, H-2-B, H-4-E, H-2-A, CH2-CBz), 4.15 – 3.82 (m, 11H, H-3-E, H-3-B, H-2-D, H-4-C, H-5-C, H-3-A,H-5-A, H-3-D, H-4-D), 3.78 – 3.43 (m, 8H, H-4-B, H-5-B, H-4-A, H-5-D, H-2-E,H-2-C, CH2-Linker-NCH2), 1.70 – 1.12 (m, 6H, CH2-Linker). ABCDE4 (10.6 mg, 1 eq) was dissolved in 2 mL of a mixed solution of tetrahydrofuran / water = 1 / 1 (v / v), 15 mg of palladium carbon was added under argon protection, and the argon was replaced with hydrogen. The mixture was stirred overnight, filtered, and concentrated under reduced pressure. After purification using a reverse column, the target pentasaccharide ABCDE was obtained with a yield of 96.77%.

[0060] 1H NMR (500 MHz, D2O): δ 5.62 (d, J = 3.7 Hz, 1H, H-1-GlcN3), 5.57(d, J= 3.5 Hz, 1H, H-1-GlcN2), 5.28 (d, J = 3.6 Hz, 1H, H-1-IdoA), 5.18 (d, J= 3.7 Hz, 1H, H-1-GlcN1), 4.98 (d, J = 3.0 Hz, 1H, H-5-IdoA), 4.69 (d, J =7.9 Hz, 1H, H-1-GlcA), 4.52-4.49 (m, 1H, H-6-GlcN), 4.42-4.31 (m, 6H, H-3-GlcN2, H-2-IdoA, 4 x H-6-GlcN), 4.25-4.19 (m, 3H, including H-6-GlcN, H-4-IdoA), 4.12-3.98 (m, 4H), 3.94-3.84 (m, 3H), 3.81-3.71 (m, 3H, including H-3-GlcN1, OCH2CH2CH2CH2CH2NH2), 3.67-3.59 (m, 3H, including H-3-GlcN3,OCH2CH2CH2CH2CH2NH2), 3.51-3.45 (m, 2H, H-2-GlcN2, H-2-GlcA), 3.34-3.29 (m,2H, H-2-S21GlcN3, H-2-GlcN1), 3.09-3.06 (m, 2H, OCH2CH2CH2CH2CH2NH2), 1.82-1.66 (m, 4H, OCH2CH2CH2CH2CH2NH2), 1.57-1.49 (m, 2H, OCH2CH2CH2CH2CH2NH2).13C NMR (125 MHz, D2O): δ 173.33 (C=O), 172.92 (C=O), 101.36 (C-1-GlcA),98.87 (C-1-IdoA), 98.08 (C-1-GlcN3), 97.09 (C-1-GlcN1), 96.43 (C-1-GlcN2),77.35, 76.92, 76.46, 75.96, 75.73, 75.56, 73.55, 72.68, 71.09, 70.08, 69.87,69.74, 69.45, 69.40, 69.01, 68.74, 68.57, 68.05, 66.80, 66.32, 65.92, 57.92,57.85, 56.75, 39.57 (OCH2CH2CH2CH2CH2NH2), 28.04 (OCH2CH2CH2CH2CH2NH2), 26.39(OCH2CH2CH2CH2CH2NH2), 22.42 (OCH2CH2CH2CH2CH2NH2). For details of the NMR spectrum, see. Fig. 9 .

[0061] Example 2: Pharmacological Activity Test of Fondaparinux Sodium Heparin Pentasaccharide The synthetic heparin pentasaccharide ABCDE (heparin pentasaccharide with fondaparinux sodium) and the reference substance fondaparinux sodium were diluted into a series of concentration gradients (0–1000 ng / mL) using Tris-EDTA-NaCl-BSA (pH 8.4) buffer. 40 μL of each of the above compound solutions was added to a 96-well plate, antithrombin ATIII (40 μL, 1 IU / mL) was added, mixed and incubated at 37°C for 2 minutes. Coagulation factor Xa (FXa, 40 μL, 1 IU / mL) was then added and incubated at 37°C for 2 minutes.

[0062] Then, the colorimetric substrate CS-11 (65) (BIOPHENTM) (40 μL, 1.2 μmol / mL) of factor Xa was added, and after incubation at 37°C for 2 minutes, the stop solution (80 μL, 30% acetic acid solution) was added, and the absorbance was measured at a wavelength of 405 nm on an ELISA reader, and the resulting curve was plotted and analyzed using Origin.

[0063] Pharmacological activity test results Fig.10 As shown, the heparin pentasaccharide ABCDE (heparin pentasaccharide with fondaparinux sodium) synthesized by the present invention has a similar inhibitory activity on factor Xa as fondaparinux sodium.

[0064] The embodiments described above are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the claims of the present invention.

Claims

1. A fondaparinux sodium heparin pentasaccharide, characterized in that: The structural formula is shown below: 。 2. A method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group, characterized in that: The following steps are involved: A naphthylmethyl protecting group is introduced into the hydroxyl group of the monosaccharide monomer by reacting a naphthylmethyl halide with the monosaccharide monomer for synthesizing fondaparinux sodium heparin pentasaccharide in advance; Monosaccharide monomers with naphthylmethyl protective groups introduced were connected through glycosidation reaction to synthesize fully protected pentasaccharides; The fully protected pentasaccharide is subjected to palladium-carbon hydrogenolysis to remove the naphthylmethyl protecting group, thereby obtaining fondaparinux sodium heparin pentasaccharide.

3. A method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group as claimed in claim 2, characterized in that: The structural formulas of the monosaccharide monomers for synthesizing fondaparinux sodium heparin pentasaccharide are shown in the following formulas; wherein, naphthylmethyl protecting groups are introduced into the hydroxyl groups of monosaccharide monomer A, monosaccharide monomer B, monosaccharide monomer D and monosaccharide monomer E; 。 4. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 3, characterized in that: The preparation methods of monosaccharide monomer A, monosaccharide monomer B, monosaccharide monomer C, monosaccharide monomer D and monosaccharide monomer E respectively include: A monosaccharide monomer uses glucosamine as raw material, first converts the amino group into an azide group for protection, then performs full acetylation and protects position 1 with a linker; removes the acetyl group, protects positions 4 and 6 with benzyl groups; protects position 3 with naphthylmethyl, and finally removes the benzyl groups at positions 4 and 6 and selectively protects position 6 with an acetyl group; Monosaccharide monomer B uses diacetone glucose as raw material, firstly protects the exposed hydroxyl group at position 3 with naphthylmethyl, then removes the propylidene protection at positions 4 and 6, and flips the hydroxyl group at position 4 through the TfO group; then removes the propylidene protection at positions 1 and 2, and fully acetylates the monosaccharide monomer; protects position 1 with ethylthio and removes the acetyl group; then protects positions 4 and 6 with benzyl, and acetylates position 3; Monosaccharide C monomer uses azido glucose synthesized from monosaccharide A monomer as raw material, and the 1st position is protected with TDS, the acetyl group is removed, the 4th and 6th positions are protected with benzyl groups, and the 3rd position is acetylated; the benzyl groups are then removed, and the 6th position is selectively acetylated; D monosaccharide monomers are prepared from glucose protected by ethylthio group at position 1, and positions 4 and 6 are protected by PMP fork, and positions 2 and 3 are protected by naphthylmethyl; the PMP fork is selectively opened to position 4, position 6 is protected by DPPA, and position 1 is converted into an imidoester donor; The E monosaccharide uses a fully hydroxylated azidosugar with a p-methylphenylthio group at position 1 as a raw material, and selectively protects position 6 with a Trt group; then positions 3 and 4 are protected by naphthylmethyl, Trt at position 6 is removed, position 6 is acetylated, and position 1 is converted into an imidate donor.

5. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 3, characterized in that: The step of connecting the monosaccharide monomers introduced with the naphthylmethyl protecting group through a glycosylation reaction to synthesize a fully protected pentasaccharide specifically comprises: A monosaccharide monomer and B monosaccharide monomer are synthesized into AB disaccharide intermediate through glycosylation; C monosaccharide monomer and D monosaccharide monomer are glycosylated to synthesize CD disaccharide, and then CD disaccharide is structurally modified and glycosylated with E monosaccharide monomer to synthesize CDE trisaccharide intermediate; The AB disaccharide intermediate and the CDE trisaccharide intermediate are synthesized into a fully protected pentasaccharide; The structural formulas of the CDE trisaccharide intermediate and the AB disaccharide intermediate are shown below: ； The structural formula of the fully protected pentasaccharide is shown below: 。 6. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 5, characterized in that: The step of synthesizing the AB disaccharide intermediate by glycosidation of the A monosaccharide monomer and the B monosaccharide monomer specifically comprises: Monosaccharide B monomer and monosaccharide A monomer are dissolved in dry dichloromethane, and coupled under the action of N-iodosuccinimide and trifluoromethanesulfonic acid to obtain disaccharide AB1; Disaccharide AB1 was dissolved in 80% acetic acid aqueous solution, and then heated to 70°C to remove the benzyl group, exposing the C6 carboxylation site to obtain disaccharide AB2; The disaccharide AB2 was oxidized by Tempo and diethyl iodophenyl to obtain the exposed primary alcohol, and the carboxyl group obtained after oxidation was protected by methyl iodide to obtain the AB disaccharide intermediate.

7. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 5, characterized in that: The steps of synthesizing the CD disaccharide by glycosidation of the C monosaccharide monomer and the D monosaccharide monomer, and then synthesizing the CDE trisaccharide intermediate by glycosidation of the CD disaccharide with the E monosaccharide monomer after structural modification include: Monosaccharide D and monosaccharide C were dissolved in acetonitrile, catalyzed by trimethylsilyl trifluoromethanesulfonate at -25°C, and the two were coupled, and then purified by column chromatography to obtain disaccharide CD1; Disaccharide CD1 was dissolved in a hot mixed solution of dichloromethane and methanol and treated with nickel trifluoromethanesulfonate to remove the DPPA group to obtain disaccharide CD2; Disaccharide CD2 was oxidized with Tempo and iodophenyl diethyl ester to expose the primary alcohol, and the carboxyl group obtained after oxidation was protected by methyl iodide to obtain disaccharide CD3; The disaccharide CD3 was dissolved in dichloromethane and the PMB group was removed using trifluoroacetic acid to obtain the CD disaccharide intermediate; The disaccharide intermediate CD and the monosaccharide E monomer were dissolved in dichloromethane and coupled under the catalysis of trifluoromethanesulfonic acid to obtain the trisaccharide CDE1; The obtained trisaccharide CDE1 is dissolved in tetrahydrofuran, and the trimethyl tert-hexyl protecting group at the anomeric position is removed under the action of hydrofluoric acid to obtain trisaccharide CDE2; The trisaccharide CDE2 is dissolved in acetone and reacted with 2,2,2-trifluoro-N-phenylacetimidyl chloride under alkaline conditions to obtain the CDE trisaccharide intermediate.

8. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 5, characterized in that: The step of synthesizing the fully protected pentasaccharide from the AB disaccharide intermediate and the CDE trisaccharide intermediate specifically comprises: The fully protected heparin pentasaccharide ABCDE 1 was obtained by glycosylation coupling of the AB disaccharide intermediate and the CDE trisaccharide intermediate in the presence of trifluoromethanesulfonic acid; The heparin pentasaccharide ABCDE 1 is hydrolyzed with an alkali solution to obtain the heparin pentasaccharide ABCDE 2; In the presence of an organic solvent, heparin pentasaccharide ABCDE 2 reacts with sulfur trioxide pyridine to obtain heparin pentasaccharide ABCDE 3; In the presence of an organic solvent, heparin pentasaccharide ABCDE 3 reacts with triphenylphosphine to reduce the azide group to an amino group, and then reacts with sulfur trioxide pyridine to obtain heparin pentasaccharide ABCDE 4.

9. The method for preparing fondaparinux sodium heparin pentasaccharide using naphthylmethyl as a temporary protecting group according to claim 5, characterized in that: The step of subjecting the fully protected pentasaccharide to palladium-carbon hydrogenolysis to remove the naphthylmethyl protecting group to obtain fondaparinux sodium heparin pentasaccharide specifically comprises: In the presence of an organic solvent, heparin pentasaccharide ABCDE 4 is subjected to palladium-carbon hydrogenolysis to obtain heparin pentasaccharide ABCDE; the heparin pentasaccharide ABCDE is fondaparinux sodium heparin pentasaccharide.

10. Use of the fondaparinux sodium heparin pentasaccharide according to claim 1 in the preparation of anticoagulant drugs.

Images