Preparation method of fondaparinux sodium related substance C

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a fondaparinux sodium related substance C. The method comprises the following steps: reacting a compound C-1 with an acylation reagent under the action of alkali to obtain a compound C-2; the compound C-2 is subjected to a catalytic hydrogenation reaction, a compound C-3 is obtained, and the reaction route is shown in the specification. The invention provides the novel preparation method of the fondaparinux sodium related substance C, so that the yield of the fondaparinux sodium related substance C is 69.3-71.2%, the purity is 98.8-99.9%, and the preparation method has the advantages of mild reaction conditions, simplicity and convenience in operation, few three wastes, low cost and the like, makes up for the blank of no preparation method of the fondaparinux sodium related substance C, and is suitable for industrial production. And a good foundation is laid for quality research and control of the fondaparinux sodium. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for preparing a fondaparinux sodium-related substance C. Background Art

[0002] Fondaparinux, also known as Fondaparinux, is the first chemically synthesized heparin drug and the only synthetic heparin anticoagulant currently available. The drug was launched in 2001 under the trade name of Andrews. Compared with traditional heparin drugs, Fondaparinux has the advantages of fewer side effects, high bioavailability, controllable quality standards, and good target selectivity.

[0003] The Chinese chemical name of Fondaparinux sodium is: O-(2-deoxy-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-β-D-pyranoglucopyranosyl-(1→4)-O-(2-deoxy-2-sulfonylamino-3,6-di-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-(2-O-sulfonyl-α-L-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranoside decasodium salt, and its chemical structural formula is:

[0004]

[0005] Related substance C of fondaparinux sodium is included in the quality standard of fondaparinux sodium injection in the United States Pharmacopoeia. Its relative retention time under the related substance analysis method is 0.76. It is generally believed to be produced by degradation under acidic conditions and is a degradation impurity of fondaparinux sodium injection. The Chinese chemical name is: O-(2-deoxy-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-(β-D-pyranoglucopyranosyl)-(1→4)-O-(2-deoxy-2-amino-3,6-di-O-sulfonyl-α-D-pyranoglucopyranosyl)-(1→4)-O-(2-O-sulfonyl-α-L-iduronic acid)-(1→4)-2-deoxy-1-O-methyl-2-sulfonylamino-6-O-sulfonyl-α-D-pyranoglucopyranoside nonasodium salt, and its chemical structure is:

[0006]

[0007] Chinese invention patent application CN104910217A discloses a method for separating and purifying impurities generated by degradation of a finished product of fondaparinux sodium under acidic conditions. The compound can be used as a reference substance or standard substance for related substances in the quality control of fondaparinux sodium.

[0008] At present, there is no literature report on the preparation of fondaparinux sodium related substance C by chemical synthesis. This compound can be used as a reference substance for qualitative and quantitative analysis of fondaparinux sodium related substances, and for the impurity research of fondaparinux sodium raw materials and preparations to improve the safety of the product. Summary of the invention

[0009] The present invention aims at the problems existing in the prior art and provides a method for preparing a related substance C of fondaparinux sodium. The preparation method has mild reaction conditions and low operation difficulty, and can obtain the related substance C with high yield and high purity.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] A method for preparing a substance C related to fondaparinux sodium comprises the following steps:

[0012] (1) Compound C-1 reacts with an acylating agent under the action of a base to obtain compound C-2;

[0013] (2) Compound C-2 undergoes a catalytic hydrogenation reaction to obtain compound C-3;

[0014] (3) Compound C-3 is subjected to N-sulfonation and aminolysis reaction in the presence of a sulfonating agent, a sodium phosphate solution and a reaction solvent to obtain fondaparinux-related substance C.

[0015] The reaction route is as follows:

[0016]

[0017] Preferably, the acylating agent in step (1) is selected from one or more of methyl chloroformate, ethyl chloroformate, 2-(trimethylsilyl)ethyl chloroformate, 2-(trimethylsilyl)ethoxycarbonyloxysuccinimide, trimethylsilylethylbenzotriazolyl carbonate and 2-(trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate.

[0018] More preferably, the acylating agent is methyl chloroformate, 2-(trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate or 2-(trimethylsilyl)ethyl chloroformate.

[0019] Preferably, the base in step (1) is selected from one or more of triethylamine, sodium bicarbonate, N,N-diisopropylethylamine and 4-dimethylaminopyridine.

[0020] More preferably, the base is sodium bicarbonate, 4-dimethylaminopyridine or N,N-diisopropylethylamine.

[0021] Preferably, the reaction in step (1) requires the addition of a solvent, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate and water, and the volume molar ratio of the solvent to compound C-1 is 15-20 ml:1 mmol.

[0022] More preferably, the solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran and water.

[0023] Preferably, in step (1), the molar ratio of compound C-1, acylating agent and base is 1:1-2:2-4.

[0024] Preferably, the reaction temperature in step (1) is 5-40° C., the reaction time is 2-10 h, and post-treatment is required after the reaction is completed. The post-treatment includes mixing the reaction solution with water and then extracting, concentrating the aqueous phase to dryness, pulping, filtering, concentrating the filtrate to dryness and purifying by column chromatography.

[0025] Preferably, the mobile phase medium of the column chromatography is a mixed solution of methanol and water in a volume ratio of 65-75:25-35.

[0026] More preferably, the reaction temperature is 20-30° C., and the reaction time is 6-10 h.

[0027] Preferably, the catalyst for the catalytic hydrogenation reaction in step (2) is selected from one or more of palladium hydroxide, palladium carbon and palladium alumina.

[0028] More preferably, the catalyst is 10% palladium hydroxide or 10% palladium on carbon.

[0029] Preferably, the solvent in step (2) is selected from one or more of dichloromethane, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water, and the volume molar ratio of the solvent to compound C-2 is 30-60ml:1mmol.

[0030] More preferably, the solvent is methanol, ethanol, isopropanol, N,N-dimethylacetamide or tert-butanol.

[0031] Preferably, in step (2), the molar ratio of the compound C-2 to the catalyst is 0.5-5:1.

[0032] Preferably, the reaction temperature of the catalytic hydrogenation in step (2) is 15-60° C., and the reaction time is 1-8 h. After the catalytic hydrogenation reaction is completed, suction filtration is required, and the filtrate is concentrated to dryness and purified by column chromatography.

[0033] Preferably, the mobile phase medium of the column chromatography is a mixed solution of methanol and water in a volume ratio of 10-20:85-95.

[0034] More preferably, the reaction temperature of the catalytic hydrogenation is 30-40°C, and the reaction time is 1-2h.

[0035] Preferably, the sulfonating agent in step (3) is selected from one or more of sulfur trioxide triethylamine complex, sulfur trioxide pyridine complex, trimethylammonium sulfur trioxide complex and N-ethyldiisopropylamine sulfur trioxide complex.

[0036] More preferably, the sulfonating agent is pyridine sulfur trioxide or trimethylammonium sulfur trioxide.

[0037] Preferably, the reaction solvent in step (3) is selected from one or more of acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water, and the volume molar ratio of the reaction solvent to compound C-3 is 8-10ml:1mmol.

[0038] More preferably, the reaction solvent is selected from one or more of N-methylpyrrolidone, methanol, ethanol and water.

[0039] Preferably, the pH of the sodium phosphate solution in step (3) is 9-11, and the volume molar ratio of the sodium phosphate solution to compound C-3 is 2-5 ml:1 mmol.

[0040] Preferably, in step (3), the molar ratio of compound C-3 to the sulfonating agent is 1:6-15.

[0041] Preferably, the reaction temperature of the N-sulfonation and ammonolysis reaction in step (3) is 10-65° C., and the reaction time is 10-24 h. After the N-sulfonation and ammonolysis reaction is completed, post-treatment is required, and the post-treatment includes concentrating under reduced pressure, dissolving the crude product in a tetrahydrofuran solution of N,N-dimethylformamide and tetrabutylammonium fluoride, stirring and filtering under nitrogen protection.

[0042] More preferably, the reaction temperature of the N-sulfonation and aminolysis reaction is 20-30° C., and the reaction time is 10-16 h.

[0043] Preferably, the preparation method of the compound C-1 comprises: reducing the compound C-0 with a tertiary phosphine to obtain the compound C-1,

[0044]

[0045] Preferably, the tertiary phosphine is a trialkyl phosphine or a triaryl phosphine, and the organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, isopropanol, tert-butanol and water.

[0046] More preferably, the tertiary phosphine is triphenylphosphine or triethylphosphine, and the organic solvent is tetrahydrofuran and water.

[0047] Preferably, R1, R2, R3, R4, R5 and R6 are each independently selected from benzyl or substituted benzyl, and R7 is selected from alkoxycarbonyl or alkylsilaneoxycarbonyl.

[0048] The present invention also provides the use of the fondaparinux sodium related substance C prepared by the above preparation method as a reference substance or standard substance of related substances in the quality control of fondaparinux sodium.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] The invention provides a novel preparation method of fondaparinux sodium related substance C, so that the yield of fondaparinux sodium related substance C is 69.3-72.1%, the purity is 98.8-99.9%, the method has the advantages of mild reaction conditions, simple operation, less three wastes and low cost, etc., fills the gap of no preparation method of fondaparinux sodium related substance C, and lays a good foundation for the quality research and control of fondaparinux sodium. DETAILED DESCRIPTION

[0051] It is worth noting that the raw materials used in the present invention are all common commercially available products.

[0052] Example 1

[0053] A method for preparing a substance C related to fondaparinux sodium, comprising the following steps:

[0054] (1) Compound C-0 (10.00 g, 4.16 mmol) was weighed and dissolved in tetrahydrofuran (100 ml) and water (100 ml), and triphenylphosphine (2.51 g, 9.57 mmol) was added, and the mixture was reacted at 25°C for 10 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (mobile phase: a mixed solution of acetonitrile and water in a volume ratio of 43:57) to obtain 8.82 g of solid C-1 with a purity of 97.1%.

[0055] The process route is as follows:

[0056]

[0057] (2) Weigh compound C-1 (10.00 g, 4.20 mmol) and sodium bicarbonate (1.06 g, 12.6 mmol) and dissolve in water (30 ml), stir and dissolve. Slowly add 2-(trimethylsilyl)ethyl chloroformate (0.91 g, 5.04 mmol) in 1,4-dioxane solution (60 ml), react at 25°C for 10 h. Pour the reaction solution into water (100 ml), extract with ethyl acetate, and discard the organic phase. Concentrate the aqueous phase to dryness, beat with isopropanol, filter, and concentrate the filtrate to dryness. The crude product is purified by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 69:31) to obtain 10.29 g of compound C-2 with a purity of 98.6%.

[0058] The process route is as follows:

[0059]

[0060] (3) Weigh compound C-2 (10.00 g, 3.96 mmol) and dissolve it in methanol (200 ml). After the reaction solution becomes clear, add 10% palladium hydroxide (30 g), replace the atmosphere with nitrogen, introduce hydrogen, heat to 30°C, and react for 2 h at 2.5 atmospheres. Filter with suction, concentrate the filtrate to dryness under reduced pressure, and purify the crude product by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 13:87) to obtain 5.96 g of compound C-3 with a purity of 98.4%.

[0061] The process route is as follows:

[0062]

[0063] (4) Compound C-3 (10.00 g, 6.38 mmol) was weighed and dissolved in methanol (25 ml) and water (25 ml), sulfur trioxide pyridine complex (1.02 g, 38.28 mmol) and sodium phosphate aqueous solution (15 ml) at pH = 10.0 were added, and the mixture was reacted at 25°C for 12 h. The mixture was concentrated to dryness under reduced pressure, and the crude product was dissolved in N,N-dimethylformamide (50 ml), and a tetrabutylammonium fluoride tetrahydrofuran solution (10.65 ml, 1 M) was slowly added under stirring, and the mixture was stirred for 40 h under nitrogen protection. After suction filtration, 9.03 g of the solid target fondaparinux sodium related substance C was obtained.

[0064] The process route is as follows:

[0065]

[0066] The total yield of fondaparinux sodium related substance C was 71.2% and the purity was 99.9%.

[0067] The fondaparinux sodium related substance C prepared in this example was characterized by H NMR and C NMR, and the characterization results were as follows:

[0068] 1 H-NMR(D2O,ppm)δ5.59-5.52(1H,d,J=3.6Hz),5.51-5.46(1H,d,J=3.6Hz),5.32-5.24(1H,m),5.19-5.10(1 H,m),5.04-4.97(1H,d,J=3.6Hz),4.65-4.61(1H,d,J=9.6Hz),4.60-4.55(1H,m),4.51-4.43(1H,m),4.41-4 .27(5H,m),4.26-4.19(2H,m),4.18-4.11(1H,m),4.07-3.95(4H,m),3.94-3.87(1H,m),3.86-3.81(1H,m), 3.80-3.73(2H,m),3.72-3.66(2H,m),3.62-3.53(2H,m),3.48-3.43(1H,m),3.41(3H,s),3.32-3.21(2H,m).

[0069] 13 C-NMR(D2O,ppm)δ176.75,175.31,104.94,101.84,101.27,101.15,94.29,80.76,80.50,78.46,77.75,76.11,75.7 0,75.50,74.00,73.69,73.11,72.86,72.29,71.87,71.44,69.85,69.22,68.42,65.69,60.85,60.81,58.38,56.15.

[0070] Example 2

[0071] A method for preparing a substance C related to fondaparinux sodium, comprising the following steps:

[0072] (1) Compound C-0 (10.00 g, 4.16 mmol) was weighed and dissolved in tetrahydrofuran (100 ml) and water (100 ml), and triethylphosphine (1.97 g, 16.64 mmol) was added. The mixture was reacted at 35°C for 11 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (mobile phase: a mixed solution of acetonitrile and water in a volume ratio of 43:57) to obtain 8.91 g of solid C-1 with a purity of 97.6%.

[0073] (2) Weigh compound C-1 (10.00 g, 4.20 mmol) and N,N-diisopropylethylamine (1.09 g, 8.40 mmol) and dissolve in water (40 ml), stir and dissolve. Slowly add methyl chloroformate (0.40 g, 4.20 mmol) in 1,4-dioxane solution (40 ml), react at 30°C for 6 h. Pour the reaction solution into water (100 ml), extract with ethyl acetate, and discard the organic phase. Concentrate the aqueous phase to dryness, beat with isopropanol, filter, and concentrate the filtrate to dryness. The crude product is purified by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 69:31) to obtain 9.76 g of compound C-2 with a purity of 98.2%.

[0074] (3) Weigh compound C-2 (10.00 g, 3.96 mmol) and dissolve it in isopropanol (120 ml). Stir until it becomes clear, add 10% palladium carbon (30 g), replace the nitrogen atmosphere with hydrogen, heat to 40°C, and keep the temperature at 2.5 atmospheres for 1 hour. Filter with suction, concentrate the filtrate to dryness under reduced pressure, and purify the crude product by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 13:87) to obtain 5.83 g of compound C-3 with a purity of 97.6%.

[0075] (4) Weigh compound C-3 (10.00 g, 6.38 mmol) and dissolve it in ethanol (30 ml) and water (30 ml), add trimethylammonium sulfur trioxide (7.10 g, 51.04 mmol) and sodium phosphate aqueous solution (30 ml) with pH = 10.0, and react at 20°C for 16 h. Concentrate to dryness under reduced pressure, dissolve the crude product in N,N-dimethylformamide (80 ml), slowly add tetrabutylammonium fluoride tetrahydrofuran solution (20.5 ml) under stirring, and stir for 40 h under nitrogen protection. Filter by suction to obtain 9.34 g of solid target fondaparinux sodium related substance C.

[0076] The total yield of fondaparinux sodium related substance C was 70.0% and the purity was 99.4%.

[0077] Example 3

[0078] A method for preparing a substance C related to fondaparinux sodium, comprising the following steps:

[0079] (1) Compound C-0 (10.00 g, 4.16 mmol) was weighed and dissolved in N,N-dimethylacetamide (100 ml) and water (100 ml), and triphenylphosphine (2.51 g, 9.57 mmol) was added. The mixture was reacted at 60°C for 12 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (mobile phase: a mixed solution of acetonitrile and water in a volume ratio of 43:57) to obtain 9.01 g of solid C-1 with a purity of 97.3%.

[0080] (2) Weigh compound C-1 (10.00 g, 4.20 mmol) and 4-dimethylaminopyridine (2.05 g, 16.8 mmol) and dissolve in water (50 ml) and stir to dissolve. Slowly add 3-nitro-1H-1,2,4-triazole-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (2.17 g, 8.40 mmol) in 1,4-dioxane (70 ml) and react at 5°C for 10 h. Pour the reaction solution into water (150 ml), extract with ethyl acetate, and discard the organic phase. Concentrate the aqueous phase to dryness, beat with isopropanol, filter, and concentrate the filtrate to dryness. The crude product is purified by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 69:31) to obtain 9.97 g of compound C-2 with a purity of 97.8%.

[0081] (3) Weigh compound C-2 (10.00 g, 3.96 mmol) and dissolve it in N,N-dimethylacetamide (240 ml). Stir until dissolved. Add 10% palladium hydroxide (30 g). After nitrogen replacement, introduce hydrogen. Control the temperature to 15°C and keep the reaction at 2.5 atmospheres for 8 hours. Filter with suction, concentrate the filtrate to dryness under reduced pressure, and purify the crude product by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 13:87) to obtain 5.71 g of compound C-3 with a purity of 97.5%.

[0082] (4) Compound C-3 (10.00 g, 6.38 mmol) was weighed and dissolved in N-methylpyrrolidone (65 ml), sulfur trioxide pyridine complex (15.23 g, 95.7 mmol) and sodium phosphate aqueous solution (30 ml) with pH = 10.0 were added, and the mixture was reacted at 10°C for 24 h. The mixture was concentrated to dryness under reduced pressure, and the crude product was dissolved in N,N-dimethylformamide (80 ml), and tetrabutylammonium fluoride tetrahydrofuran solution (30 ml) was slowly added under stirring, and the mixture was stirred for 40 h under nitrogen protection. After suction filtration, 9.13 g of the solid target fondaparinux sodium related substance C was obtained.

[0083] The total yield of fondaparinux sodium related substance C was 69.3% and the purity was 98.8%.

[0084] Comparative Example 1

[0085] The same as Example 1, the only difference is that the acylating agent in step (2) is acetic anhydride. Specifically, step (2) is as follows: Weigh compound C-1 (10.00g, 4.20mmol) and sodium bicarbonate (1.06g, 12.6mmol) and dissolve in water (30ml), stir and dissolve. Slowly add acetic anhydride (0.51g, 5.04mmol) in 1,4-dioxane solution (60ml), react at 25°C for 10h. Pour the reaction solution into water (100ml), extract with ethyl acetate, and discard the organic phase. The aqueous phase is concentrated to dryness, slurried with isopropanol, filtered, and the filtrate is concentrated to dryness. The crude product is purified by column chromatography (mobile phase medium: a mixed solution of methanol and water with a volume ratio of 69:31) to obtain 1.31g of compound C-2 with a purity of 99.1%.

[0086] The final total yield of fondaparinux sodium related substance C was 9.4% and the purity was 92.4%.

[0087] Comparative Example 2

[0088] The same as Example 1, the only difference is that the reaction temperature in step (2) is 60°C. Specifically, step (2) is as follows: Weigh compound C-1 (10.00g, 4.20mmol) and sodium bicarbonate (1.06g, 12.6mmol) and dissolve in water (30ml), stir and dissolve. Slowly add 2-(trimethylsilyl)ethyl chloroformate (0.91g, 5.04mmol) in 1,4-dioxane solution (60ml), and react at 60°C for 10h. The reaction solution is poured into water (100ml), extracted with ethyl acetate, and the organic phase is discarded. The aqueous phase is concentrated to dryness, slurried with isopropanol, filtered, and the filtrate is concentrated to dryness. The crude product is purified by column chromatography (mobile phase medium: a mixed solution of methanol and water with a volume ratio of 69:31) to obtain 5.22g of compound C-2 with a purity of 98.8%.

[0089] The final total yield of fondaparinux sodium related substance C was 36.1% and the purity was 87.2%.

[0090] Comparative Example 3

[0091] The same as Example 1, the only difference is that the catalyst in step (3) is platinum dioxide. Specifically, step (3) is as follows: weigh compound C-2 (10.00g, 3.96mmol) and dissolve it in methanol (200ml), stir to dissolve, add platinum dioxide (30g), replace with nitrogen and then introduce hydrogen, heat to 30°C, and keep the reaction at 2.5 atmospheres for 2h. Filter with suction, concentrate the filtrate to dryness under reduced pressure, and purify the crude product by column chromatography (mobile phase medium: a mixed solution of methanol and water in a volume ratio of 13:87) to obtain 3.40g of compound C-3 with a purity of 88.5%.

[0092] The final total yield of fondaparinux sodium related substance C was 40.6% and the purity was 83.4%.

[0093] Comparative Example 4

[0094] The same as Example 1, the only difference is that the reaction solvent in step (4) is ethyl acetate. Specifically, step (4) is as follows: weigh compound C-3 (10.00 g, 6.38 mmol) and dissolve it in ethyl acetate (50 ml), add sulfur trioxide pyridine complex (1.02 g, 38.28 mmol) and sodium phosphate aqueous solution (15 ml) with pH = 10.0, and react at 25°C for 12 hours. Concentrate to dryness under reduced pressure, dissolve the crude product in N,N-dimethylformamide (50 ml), slowly add tetrabutylammonium fluoride tetrahydrofuran solution (10.65 ml, 1 M) under stirring, and stir for 40 hours under nitrogen protection. Filter by suction to obtain 3.26 g of solid target fondaparinux sodium related substance C.

[0095] The final total yield of fondaparinux sodium related substance C was 25.7% and the purity was 91.6%.

[0096] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a related substance C of fondaparinux sodium, characterized in that: The steps include: (1) Compound C-1 reacts with an acylating agent under the action of a base to obtain compound C-2; (2) Compound C-2 undergoes a catalytic hydrogenation reaction to obtain compound C-3; (3) Compound C-3 is subjected to N-sulfonation and aminolysis reaction in the presence of a sulfonating agent, a sodium phosphate solution and a reaction solvent to obtain fondaparinux-related substance C. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that: In step (1), the acylating agent is selected from one or more of methyl chloroformate, ethyl chloroformate, 2-(trimethylsilyl)ethyl chloroformate, 2-(trimethylsilyl)ethoxycarbonyloxysuccinimide, trimethylsilylethylbenzotriazolyl carbonate and 2-(trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate, the base is selected from one or more of sodium bicarbonate, triethylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine, and the molar ratio of the compound C-1, the acylating agent and the base is 1:1-2:2-4.

3. The preparation method according to claim 1, characterized in that: The reaction in step (1) requires the addition of a solvent, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate and water, the reaction temperature is 5-40°C, the reaction time is 2-10h, and after the reaction is completed, post-treatment is required, the post-treatment includes mixing the reaction solution with water and then extracting, concentrating the aqueous phase to dryness, pulping, suction filtering, concentrating the filtrate to dryness and column chromatography purification.

4. The preparation method according to claim 1, characterized in that: The catalyst for the catalytic hydrogenation reaction in step (2) is selected from one or more of palladium hydroxide, palladium carbon and palladium aluminum oxide.

5. The preparation method according to claim 4, characterized in that: The catalytic hydrogenation reaction in step (2) requires the addition of a solvent, the solvent is selected from one or more of dichloromethane, acetonitrile, ethyl acetate, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water, the molar ratio of the compound C-2 to the catalyst is 0.5-5:1, the reaction temperature of the catalytic hydrogenation is 15-60°C, the reaction time is 1-8h, and after the catalytic hydrogenation reaction is completed, suction filtration is performed, and the filtrate is concentrated to dryness and purified by column chromatography.

6. The preparation method according to claim 1, characterized in that: In step (3), the sulfonating agent is selected from one or more of sulfur trioxide triethylamine complex, sulfur trioxide pyridine complex, trimethylammonium sulfur trioxide complex and N-ethyldiisopropylamine sulfur trioxide complex; the reaction solvent is selected from one or more of acetonitrile, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water; and the pH of the sodium phosphate solution is 9-11.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the compound C-3 to the sulfonating agent in step (3) is 1:2-5, the reaction temperature of the N-sulfonation and aminolysis reaction is 10-65°C, and the reaction time is 10-24h. After the N-sulfonation and aminolysis reaction are completed, post-treatment is required, and the post-treatment includes concentrating under reduced pressure, dissolving the crude product in a tetrahydrofuran solution of N,N-dimethylformamide and tetrabutylammonium fluoride, stirring and filtering under nitrogen protection.

8. The preparation method according to claim 1, characterized in that: The preparation method of the compound C-1 comprises: reducing the compound C-0 with a tertiary phosphine to obtain the compound C-1, 9. The preparation method according to claim 8, characterized in that: The tertiary phosphine is a trialkyl phosphine or a triaryl phosphine, and the organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, isopropanol, tert-butanol and water.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The R1, R2, R3, R4, R5 and R6 are each independently selected from benzyl or substituted benzyl, and R7 is an alkoxycarbonyl or alkylsilyloxycarbonyl group.

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