A method for preparing mannuronic acid oligosaccharides and its intermediates

Abstract

This invention discloses a method for preparing mannuronic acid oligosaccharides and its intermediates. The invention provides a method for preparing a compound as shown in Formula A, comprising the following steps: in an organic solvent, under the action of NBS, a compound as shown in Formula II and water undergo a hydroxyl substitution reaction as shown below to obtain the compound as shown in Formula A. The preparation method of this invention has a short synthetic route, mild conditions, high yield, and low production cost. It can prepare mannuronic acid oligosaccharide compounds with arbitrary sugar chains and is suitable for industrial-scale production.

Description

Technical Field

[0001] This invention relates to a method for preparing mannouronic acid oligosaccharides and its intermediates. Background Technology

[0002] GV-971 is a mixture of mannuronic acid oligosaccharides isolated and extracted from marine alginate and modified through degradation. It was jointly developed by Ocean University of China, Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, and Shanghai Green Valley Pharmaceutical Co., Ltd. In 2005, Kong Lingna, Geng Meiyu, and others published in the *Acta Pharmaceutica Sinica* that the improvement of learning and memory function in Alzheimer's disease (AD) model mice by acidic oligosaccharide 971 may be related to changes in the expression of genes related to DNA damage repair, nerve growth, synaptic plasticity, and immune response (Acta Pharm. Sin., 2005, 40, 1105-1109). In 2017, Geng Meiyu et al. reported the results of a phase II clinical study of GV-971 in the *Chinese Journal of Pharmacology and Toxicology*, showing good safety and significant improvement in cognitive impairment in patients with mild to moderate AD (Chin. J. Pharmacol. Toxicol., 2017, 31, 459-460). In July 2018, GV-971 successfully completed its Phase III clinical trial, achieving the expected results in the primary efficacy endpoint of cognitive function improvement, demonstrating significant statistical and clinical significance. Furthermore, the incidence of adverse events was comparable to the placebo group, indicating good safety and suitability for long-term use. In November 2018, the National Medical Products Administration accepted the new drug application for GV-971, and officially approved it on November 2, 2019. In September 2019, Geng Meiyu et al., using an AD mouse model, discovered that during the development of AD, gut microbiota imbalance leads to abnormal accumulation of phenylalanine and isoleucine in peripheral blood, inducing differentiation and proliferation of peripheral pro-inflammatory T helper 1 (Th1) cells and promoting their infiltration into the brain. The infiltrating Th1 cells and the pre-existing M1 microglia in the brain are jointly activated, leading to AD-related neuroinflammation. The research team believes that the mechanism of action of GV-971 in treating AD is: by reshaping the balance of gut microbiota, reducing the accumulation of peripheral metabolites phenylalanine and isoleucine, alleviating neuroinflammation in the brain, and thus improving cognitive impairment, thereby achieving the effect of treating AD (Cell Res., 2019, 29, 787-803).

[0003]

[0004] GV-971 is a mixture of mannouronic acid oligosaccharides with a carboxyl group at the reducing end of 1. Its structural characteristic is that these oligosaccharides are linked by β-D-mannuronic acid via a 1,4-beta glycosidic bond, and the reducing end is a product of the oxidative cleavage of manno-oligosaccharide diacid. In the initial GV-971 preparation patent, Fehling's reagent was used for oxidation, and the reducing end sugar ring of the produced GV-971 did not undergo oxidative cleavage. In 2017, a new GV-971 synthesis patent changed the production process, using ozone as the oxidant. This process resulted in the oxidative cleavage of the reducing end sugar ring in GV-971, leading to a more complex structure (Chinese patent applications: 201711482873.0 and 201711467596.6, structural formulas shown below).

[0005]

[0006] In the synthetic chemistry of glycans, constructing the β-glycosidic bond of mannose is a challenge because anodic effects and steric hindrance tend to generate α-glycosidic bonds (Acc. Chem. Res., 2010, 43, 1144-1153). Van der Marel and Codée et al. found that glycosylation using mannuronic acid donors yields excellent β-selectivity (J. Am. Chem. Soc., 2006, 128, 13066-13067; J. Org. Chem., 2009, 74, 38-47; J. Carbohydr. Chem., 2011, 30, 438-457). However, there are currently no reports on the synthesis of GV-971-like oligosaccharides. Synthesizing structurally well-defined mannuronic acid oligosaccharides would allow for better research and understanding of the specific mechanism of action of GV-971 in Alzheimer's disease. Similar to the heparin-like drug fondaparinux, GV-971-type compounds with a single structure may be used as Alzheimer's disease drugs in the future. Summary of the Invention

[0007] The technical problem this invention aims to solve is to overcome the shortcomings of a single method for preparing mannuronic acid oligosaccharides, and to provide a method for preparing mannuronic acid oligosaccharides and their intermediates. The preparation method of this invention features a short synthetic route, mild conditions, high yield, and low production cost. It can prepare mannuronic acid oligosaccharide compounds of any sugar chain and is suitable for industrial-scale production.

[0008] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0009] The present invention provides a method for preparing a compound as shown in Formula A, comprising the following steps: in an organic solvent, under the action of NBS, a compound as shown in Formula II and water are subjected to a hydroxyl substitution reaction as shown below to obtain a compound as shown in Formula A;

[0010]

[0011] Where n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0012] R 1 and R 2 Independently R 1-1 It can be hydrogen, methoxy, methyl, nitro, or halogen independently;

[0013] R 3 Independently R 3-1 R 3-2 and R 3-3 Independently, it is a C1-C4 alkyl group;

[0014] LG independently R 5 For one or more R 5-1 Substituted phenyl; R 5-1 It is independently a C1-C4 alkyl group.

[0015] In some implementations, R 1 and R 2 Independently

[0016] In some implementations, R 1-1 It is hydrogen independently.

[0017] In some implementations, when R 1-1 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine.

[0018] In some implementations, R 1-1 It can be hydrogen, 4-methoxy, 4-methyl, 4-nitro or 4-halogen independently.

[0019] In some implementations, R 3-1 R 3-2 and R 3-3 It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or tert-butyl.

[0020] In some implementations, R 5-1 It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0021] In some implementations, LG is positioned as an upright key.

[0022] In some embodiments, the compound shown in Formula II is

[0023] In the hydroxyl substitution reaction, the organic solvent can be a conventional organic solvent used in this type of reaction in the art, and the present invention particularly prefers a ketone solvent. The ketone solvent can be acetone.

[0024] In the hydroxyl substitution reaction, the molar concentration of the compound as shown in Formula II in the organic solvent can be the conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.05 mol / L-0.2 mol / L, for example 0.1 mol / L-0.15 mol / L, for example 0.124 mol / L.

[0025] In the hydroxyl substitution reaction, the molar ratio of the NBS to the compound shown in Formula II can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-10:1, for example 2:1-6:1, for example 4:1.

[0026] In the hydroxyl substitution reaction, the volume molar ratio of water to the compound shown in Formula II can be a conventional volume molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-10:1 L / mol, for example 1:1-2:1 L / mol, for example 1.24:1 L / mol.

[0027] In the hydroxyl substitution reaction, the reaction temperature can be from 0 to -40°C, for example from -10°C to -30°C, for example -20°C.

[0028] In the hydroxyl substitution reaction, the reaction time can be 0.5h-3h, for example 0.5h-1.5h, for example 1h.

[0029] In the hydroxyl substitution reaction described above, a post-treatment step may be further included after the reaction is completed. The post-treatment step includes quenching the reaction, extraction, washing, drying, filtration, concentration, and purification to obtain the compound shown in Formula A. The reagent used for the quenching reaction can be Na₂S₂O₃ solution or NaHCO₃ solution. The reagent used for extraction can be dichloromethane. The reagent used for washing can be a saturated NaCl solution. The reagent used for drying can be anhydrous Na₂SO₄. The purification method can be rapid column chromatography.

[0030] In some embodiments, the hydroxyl substitution reaction includes the following steps: mixing the compound as shown in Formula II, the organic solvent, and the water, and then mixing it with the NBS to carry out the hydroxyl substitution reaction.

[0031] The present invention provides a method for preparing a compound as shown in Formula B, comprising the following steps: in an organic solvent, under the action of an alkali, the compound as shown in Formula A and N-phenyltrifluoroacetylimine chloride are subjected to an imidization reaction as shown below to obtain the compound as shown in Formula B.

[0032]

[0033] Where, n, R 1 R 2 and R 3 As mentioned above.

[0034] In some embodiments, the compound shown in Formula A is

[0035]

[0036] In some embodiments, the method for preparing the compound shown in Formula B further includes the step of preparing the compound shown in Formula A according to the method for preparing the compound shown in Formula A described above.

[0037] In the iminolation reaction, the organic solvent can be a conventional organic solvent used in this type of reaction in the art, and the present invention particularly prefers a ketone solvent. The ketone solvent can be acetone.

[0038] In the imidization reaction, the molar concentration of the compound as shown in Formula A in the organic solvent can be a conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.05 mol / L-0.2 mol / L, for example 0.1 mol / L-0.15 mol / L, for example 0.124 mol / L.

[0039] In the iminolation reaction, the base can be a base conventional for this type of reaction in the art, but the present invention particularly prefers a carbonate. The carbonate can be potassium carbonate.

[0040] In the iminolation reaction, the molar ratio of the base to the compound as shown in Formula A can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-2:1, for example 1:1-1.5:1, for example 1.3:1.

[0041] In the iminolation reaction, the molar ratio of the N-phenyltrifluoroacetylimine chloride to the compound shown in Formula A can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-2:1, for example 1:1-1.3:1, for example 1.1:1.

[0042] In the imine reaction described above, the reaction temperature can be room temperature.

[0043] In the imidization reaction, the reaction time can be 1h-10h, for example 3h-7h, for example 5h.

[0044] In the imidization reaction, a post-processing step may be further included after the reaction is completed. The post-processing step includes filtration and concentration to obtain the compound as shown in Formula B. Preferably, the post-processing step includes a purification step.

[0045] In some embodiments, the imidization reaction comprises the following steps: mixing the organic solvent, the base, the compound of formula A, and the N-phenyltrifluoroacetylimine chloride to carry out the imidization reaction.

[0046] The present invention provides a method for preparing a compound as shown in Formula I, comprising the following steps: in a protective gas and an organic solvent, under the action of a Lewis acid, performing a condensation reaction as shown below to obtain a compound as shown in Formula I.

[0047]

[0048] Where, n, R 1 R 2 and R 3 As mentioned above;

[0049] m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0050] R 4 Independently for -SR 4-1 ;R 4-1 Independently phenyl, or, R 4-1-1 Substituted phenyl; R 4-1-1 It is independently a C1-C4 alkyl group.

[0051] In some implementations, R 4-1-1 It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0052] In some embodiments, the compound shown in Formula B is

[0053]

[0054] In some embodiments, the compound shown in Formula III is

[0055] In some embodiments, the method for preparing the compound of formula I further includes the step of preparing the compound of formula B according to the method for preparing the compound of formula B described above.

[0056] In the condensation reaction described above, the protective gas can be any conventional protective gas used in this type of reaction in the art, but argon is particularly preferred in this invention.

[0057] In the condensation reaction described herein, the organic solvent can be a conventional organic solvent for this type of reaction in the art. The present invention particularly prefers a haloalkanes solvent, such as a dry haloalkanes solvent. The haloalkanes solvent can be dichloromethane, for example, dry dichloromethane.

[0058] In the condensation reaction, the molar concentration of the compound of formula B in the organic solvent can be a conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.05 mol / L-0.2 mol / L, for example 0.1 mol / L-0.15 mol / L, for example 0.124 mol / L.

[0059] In the condensation reaction described herein, the Lewis acid can be a Lewis acid conventional for this type of reaction in the art. The present invention particularly prefers one or more of trifluoromethanesulfonic acid, TMSOTf, TESOTf, TBSOTf, Au-L-OTf, Au-L-NTf2, and NIS, wherein L is triphenylphosphine, tributylphosphine, triethylphosphine, or triadamantylphosphine. The Lewis acid is further preferably TBSOTf.

[0060] In the condensation reaction, the molar ratio of the Lewis acid to the compound shown in Formula B can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 0.001:1-2:1, for example 0.1:1-0.5:1, for example 0.2:1.

[0061] In the condensation reaction, the molar ratio of the compound shown in Formula III to the compound shown in Formula B can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 0.5:1-10:1, for example 1:1-1.3:1, for example 1.06:1.

[0062] In the condensation reaction, the reaction temperature can be from -78°C to -30°C, for example from -30°C to -50°C, for example -40°C.

[0063] In the condensation reaction, the reaction time can be 1h-10h, for example 3h-7h, for example 5h.

[0064] In some embodiments, the reaction system in the condensation reaction is an anhydrous system.

[0065] In the condensation reaction described herein, the compounds shown in Formula B and Formula III may be dried compounds shown in Formula B and Formula III. The drying process may involve mixing the compounds shown in Formula B and Formula III, adding water to toluene three times, and then drying under vacuum.

[0066] In the condensation reaction described above, the reaction system may further include a desiccant. The desiccant is preferably... Molecular sieves (e.g., acid-washed) Molecular sieves) Molecular sieves (e.g., acid-washed) Molecular sieves) Molecular sieves (e.g., acid-washed) Molecular sieves, anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous copper sulfate, and anhydrous magnesium sulfate, or one or more of these, more preferably activated ones. Molecular sieve. The mass ratio of the desiccant to the compound shown in Formula B can be 1:1 to 3:1, for example, 5:3.

[0067] In some embodiments, the condensation reaction includes the following steps: under the protective gas, mixing the organic solvent, the compound of formula B, the desiccant, and the compound of formula III, and then mixing them with the Lewis acid to carry out the condensation reaction.

[0068] The condensation reaction may further include a post-processing step after the reaction is complete. The post-processing step includes quenching, filtration, concentration, and purification to obtain the compound shown in Formula I. The reagent used in the quenching reaction may be triethylamine. The purification method may be rapid column chromatography.

[0069] The present invention provides a method for preparing a compound as shown in formula C, comprising the following steps: reacting a compound as shown in formula I with water in an organic solvent under the action of NBS to obtain a compound as shown in formula C;

[0070]

[0071] Where, n, m, R 1 R 2 R 3 and R 4 As mentioned above.

[0072] In some embodiments, the compound shown in Formula I is

[0073] In some embodiments, the method for preparing the compound shown in Formula C further includes the step of preparing the compound shown in Formula I according to the method for preparing the compound shown in Formula I described above.

[0074] In the method for preparing the compound as shown in Formula C, the organic solvent can be a conventional organic solvent for this type of reaction in the art, and the present invention particularly prefers a ketone solvent. The ketone solvent can be acetone.

[0075] In the preparation method of the compound shown in Formula C, the molar concentration of the compound shown in Formula I in the organic solvent can be the conventional molar concentration for this type of reaction in the art. In particular, the present invention prefers 0.05 mol / L-0.2 mol / L, for example 0.05 mol / L-0.12 mol / L, for example 0.095 mol / L.

[0076] In the preparation method of the compound shown in Formula C, the molar ratio of NBS to the compound shown in Formula I can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-10:1, for example 2:1-6:1, for example 4:1.

[0077] In the preparation method of the compound shown in Formula C, the volume molar ratio of water to the compound shown in Formula I can be a conventional volume molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 0.1:1-10:1, for example 0.6:1-2:1, for example 1.05:1 L / mol.

[0078] In the method for preparing the compound as shown in Formula C, the reaction temperature can be from 0 to -40°C, for example from -10°C to -30°C, for example -20°C.

[0079] In the method for preparing the compound as shown in Formula C, the reaction time can be 0.5h-3h, for example 0.5h-1.5h, for example 1h.

[0080] In the method for preparing the compound as shown in Formula C, a post-processing step may be further included after the reaction is completed. The post-processing step includes quenching the reaction, extraction, washing, drying, filtration, concentration, and purification to obtain the compound as shown in Formula C. The reagent used for the quenching reaction can be Na₂S₂O₃ solution or NaHCO₃ solution. The reagent used for extraction can be ethyl acetate. The reagent used for washing can be saturated NaCl solution. The reagent used for drying can be anhydrous Na₂SO₄. The purification method can be rapid column chromatography.

[0081] In some embodiments, the preparation method of the compound shown in Formula C includes the following steps: mixing the compound shown in Formula I, the organic solvent, and the water, and then mixing it with the NBS to carry out the reaction.

[0082] The present invention provides a method for preparing a compound as shown in Formula IV, comprising the following steps: under a protective gas, in an organic solvent, and in the presence of an oxidant, an oxidation reaction is carried out on a compound as shown below to obtain a compound as shown in Formula IV.

[0083]

[0084] Where, n, m, R 1 R 2 and R 3 As mentioned above.

[0085] In some embodiments, the compound shown in Formula C is

[0086]

[0087] In some embodiments, the method for preparing the compound shown in Formula IV further includes the step of preparing the compound shown in Formula C according to the method for preparing the compound shown in Formula C described above.

[0088] In the oxidation reaction described herein, the protective gas can be any conventional protective gas for this type of reaction in the art, but argon is particularly preferred in this invention.

[0089] In the oxidation reaction described herein, the organic solvent may be a conventional organic solvent for this type of reaction in the art, and the present invention particularly prefers a sulfone solvent, such as dimethyl sulfoxide.

[0090] In the oxidation reaction, the molar concentration of the compound as shown in Formula C in the organic solvent can be the conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.05 mol / L-0.5 mol / L, for example 0.1 mol / L-0.25 mol / L, for example 0.173 mol / L.

[0091] In the oxidation reaction described herein, the oxidant may be a conventional oxidant for this type of reaction in the art, and the present invention particularly prefers a mixture of dimethyl sulfoxide and acetic anhydride; the volume ratio of dimethyl sulfoxide to acetic anhydride in the mixture may be 10:1-2:1 (e.g., 11:3.6). When the oxidant is a mixture of dimethyl sulfoxide and acetic anhydride, the dimethyl sulfoxide may be the solvent described herein.

[0092] In the oxidation reaction, the molar ratio of the oxidant to the compound shown in Formula C can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 1:1-40:1, for example 15:1-25:1, for example 20:1.

[0093] In the oxidation reaction described above, the reaction temperature can be room temperature.

[0094] In the oxidation reaction, the reaction time can be 10h-48h, for example 20h-30h, for example 24h.

[0095] In the oxidation reaction described above, a post-processing step may be further included after the reaction is completed. The post-processing step includes quenching the reaction, extraction, washing with water, drying, filtration, concentration, and purification to obtain the compound shown in Formula IV. The reagent used for the quenching reaction can be water. The reagent used for extraction can be ethyl acetate. The reagent used for washing can be a saturated NaHCO3 solution and a saturated NaCl solution. The reagent used for drying can be anhydrous Na2SO4. The purification method can be rapid column chromatography.

[0096] In some embodiments, the oxidation reaction includes the following steps: mixing the solvent, the oxidant, and the compound as shown in Formula C to carry out the reaction.

[0097] This invention provides a method for preparing a compound as shown in Formula V, comprising the following steps: in a solvent, under the action of a pyridine hydrogen fluoride complex, a deprotecting reaction is carried out on a compound as shown below to obtain a compound as shown in Formula V.

[0098]

[0099] Where, n, m, R 1 R 2 and R 3 As mentioned above.

[0100] In some embodiments, the compound shown in Formula IV is

[0101] In some embodiments, the method for preparing the compound of formula V further includes the step of preparing the compound of formula IV according to the method described above.

[0102] In the deprotection reaction, the solvent can be a conventional solvent for this type of reaction in the art, but the present invention particularly prefers an ether solvent. The ether solvent can be tetrahydrofuran.

[0103] In the deprotection reaction, the molar concentration of the compound shown in Formula IV in the solvent can be the conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.01 mol / L-1 mol / L, for example 0.05 mol / L-0.2 mol / L, for example 0.1 mol / L.

[0104] In the deprotection reaction, the molar ratio of the pyridine hydrogen fluoride complex to the compound shown in Formula IV can be a conventional molar ratio for this type of reaction in the art, and is particularly preferred in the present invention to be 2:1-20:1, for example 7:1-12:1, for example 9:1.

[0105] In the deprotection reaction, the reaction temperature can be from 10°C to 80°C, for example from 20°C to 60°C, for example 40°C.

[0106] In the deprotection reaction, the reaction time can be 10h-36h, for example 15h-25h, for example 20h.

[0107] In the deprotection reaction, a post-processing step may be further included after the reaction is completed. The post-processing step includes quenching, extraction, washing, drying, filtration, concentration, and purification. The reagent used for the quenching reaction can be a saturated NaHCO3 solution. The reagent used for extraction can be dichloromethane. The reagent used for washing can be a saturated NaCl solution. The reagent used for drying can be anhydrous Na2SO4. The purification method can be rapid column chromatography.

[0108] In some embodiments, the deprotection reaction includes the following steps: mixing the compound as shown in Formula IV with the solvent, and then mixing it with the pyridine hydrogen fluoride complex to carry out the reaction.

[0109] The present invention provides a method for preparing a compound as shown in formula D, comprising the following steps: in a solvent, under the action of a catalyst and a hydrogen source, a compound as shown in formula V is subjected to a hydrogenation reaction to obtain a compound as shown in formula D;

[0110]

[0111] Where, n, m, R 1 and R 2 As mentioned above.

[0112] In some embodiments, the compound shown in Formula V is

[0113] In some embodiments, the method for preparing the compound of formula D further includes the step of preparing the compound of formula V according to the method described above for preparing the compound of formula V.

[0114] In the hydrogenation reaction, the solvent can be a conventional solvent for this type of reaction in the art, and the present invention particularly prefers ether solvents, water, alcohol solvents, and organic acid solvents. The ether solvent can be tetrahydrofuran. The alcohol solvent can be tert-butanol. The organic acid solvent can be acetic acid. The volume ratio of the ether solvent, water, alcohol solvent, and organic acid solvent can be 5:5:1:0.1.

[0115] In the hydrogenation reaction, the molar concentration of the compound as shown in Formula V in the solvent can be the conventional molar concentration for this type of reaction in the art, and is particularly preferred in this invention to be 0.01 mol / L-0.2 mol / L, for example 0.03 mol / L-0.07 mol / L, for example 0.047 mol / L.

[0116] In the hydrogenation reaction, the catalyst can be a conventional catalyst for this type of reaction in the art; however, palladium on carbon and palladium hydroxide on carbon are particularly preferred in this invention. The palladium on carbon can be 10% palladium on carbon with a water content of 55%. The palladium hydroxide on carbon can be 10% palladium hydroxide on carbon with a water content of 50%.

[0117] In the hydrogenation reaction, the mass molar ratio of the catalyst to the compound shown in Formula V can be a conventional mass molar ratio for this type of reaction in the art. The present invention particularly prefers a ratio of 100:1 g / mol to 400:1 g / mol, for example 230:1 g / mol to 290:1 g / mol, for example 256:1 g / mol.

[0118] In the hydrogenation reaction, the hydrogen source can be any conventional hydrogen source for this type of reaction in the art, but hydrogen gas is particularly preferred in this invention. The reaction can be carried out in a hydrogen atmosphere, and the reaction pressure can be 1 atm.

[0119] In the hydrogenation reaction, the reaction temperature can be room temperature.

[0120] In the hydrogenation reaction, the reaction time can be 10h-48h, for example 20h-30h, for example 24h.

[0121] In the hydrogenation reaction, a post-processing step may be further included after the reaction is completed. The post-processing step includes filtration and concentration.

[0122] In some embodiments, the hydrogenation reaction includes the following steps: mixing the compound as shown in Formula V, the solvent, and the catalyst, and reacting them under a hydrogen source.

[0123] The present invention provides a method for preparing a compound as shown in Formula VI, comprising the following steps: in a solvent, under the action of an alkali, a compound as shown in Formula D is subjected to a hydrolysis reaction as shown below to obtain a compound as shown in Formula VI;

[0124]

[0125] Where n and m are as described above, M + It can be a hydrogen ion or a metal cation.

[0126] In some embodiments, the compound shown in Formula D is

[0127]

[0128] In some embodiments, the method for preparing the compound of formula VI further includes the step of preparing the compound of formula D according to the method described above for preparing the compound of formula D.

[0129] In some implementations, when M + When the metal cation is a metal cation, the metal cation is a sodium ion, a potassium ion, or a calcium ion.

[0130] In the hydrolysis reaction, the solvent can be a conventional solvent for this type of reaction in the art, but water is particularly preferred in this invention.

[0131] In the hydrolysis reaction, the molar concentration of the compound shown in Formula D in the solvent can be the conventional molar concentration for this type of reaction in the art. In particular, the present invention prefers 0.01 mol / L-0.2 mol / L, for example 0.03 mol / L-0.07 mol / L, for example 0.062 mol / L.

[0132] In the hydrolysis reaction, the base can be a conventional base for this type of reaction in the art, and M is particularly preferred in this invention. + OH - M + The metal cation is described above. The M... + OH - It can be sodium hydroxide, such as 1M sodium hydroxide.

[0133] In the hydrolysis reaction, the pH of the reaction system can be 12 to 13.

[0134] In the hydrolysis reaction described above, the reaction temperature can be room temperature.

[0135] In the hydrolysis reaction, the reaction time can be 10h-48h, for example 20h-30h, or for example 24h.

[0136] The hydrolysis reaction may further include a post-treatment step after the reaction is complete. The post-treatment step includes adjusting the reaction system to neutral, filtering, concentrating, recrystallizing, centrifuging, washing, and drying. The reagent used to adjust the reaction system to neutral can be H₂O. + Ion exchange resin (e.g., model number) 50W x 4, 200-400 mesh H + (Ion exchange resin). The reagent used for recrystallization can be water and methanol. The reagent used for washing can be methanol. The drying method can be air drying.

[0137] In some embodiments, the hydrolysis reaction includes the following steps: mixing and reacting the compound as shown in Formula D, the solvent, and the base.

[0138] The present invention also provides a method for preparing a compound as shown in Formula VI, comprising the following steps:

[0139]

[0140] Among them, n, LG, R 1 R 2 R 3 m, R 4 M + As mentioned above.

[0141] In some embodiments, the preparation conditions of the compounds shown in Formula A, Formula B, Formula I, Formula C, Formula IV, Formula V, Formula D, and Formula VI are the same as described above.

[0142] This invention provides compounds as shown in Formula VI.

[0143]

[0144] Where n and m are as described above; M + It is a metal cation.

[0145] In some embodiments, the compound shown in Formula VI is

[0146] This invention provides compounds as shown in Formula V.

[0147]

[0148] Where, n, m, R 1 and R 2 As mentioned above.

[0149] In some embodiments, the compound shown in Formula V is

[0150] This invention provides compounds as shown in Formula IV.

[0151]

[0152] Where, n, m, R 1 R 2 and R 3 As mentioned above.

[0153] In some embodiments, the compound shown in Formula IV is

[0154] This invention provides compounds as shown in Formula III.

[0155]

[0156] m、R 1 R 2 and R 4 As mentioned above.

[0157] In some embodiments, the compound shown in Formula III is

[0158]

[0159] This invention provides compounds as shown in Formula II.

[0160]

[0161] n, LG, R 1 R 2 and R 3 As mentioned above.

[0162] In some embodiments, the compound shown in Formula II is

[0163]

[0164] This invention provides compounds as shown in Formula I.

[0165]

[0166] Where, n, m, R 1 R2 R 3 and R 4 As mentioned above.

[0167] In some embodiments, the compound shown in Formula I is

[0168] This invention provides compounds as shown in Formula A.

[0169]

[0170] Where, n, R 1 R 2 and R 3 As mentioned above.

[0171] In some embodiments, the compound shown in Formula A is

[0172]

[0173] This invention provides compounds as shown in Formula B.

[0174]

[0175] Where, n, R 1 R 2 and R 3 As mentioned above.

[0176] In some embodiments, the compound shown in Formula B is

[0177]

[0178] This invention provides compounds as shown in Formula C.

[0179]

[0180] Where, n, m, R 1 R 2 and R 3 As mentioned above.

[0181] In some embodiments, the compound shown in Formula C is

[0182]

[0183] This invention provides compounds as shown in Formula D.

[0184]

[0185] Where n and m are as described above.

[0186] In some embodiments, the compound shown in Formula D is

[0187]

[0188] In this invention, when M + The "+" in M ​​should be understood as having the same valence state as M. For example, when M is Ca, "+" should be understood as "2+", that is, M... + It should be understood as M 2+ .

[0189] In this invention, the room temperature is between 10°C and 30°C.

[0190] In this invention, the glycosyl donor is obtained by derivatizing the anodic position (1 position) of the sugar ring to obtain the glycosylation donor, which facilitates the glycosylation reaction and the splicing of the sugar chain.

[0191] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0192] The reagents and raw materials used in this invention are all commercially available.

[0193] The positive and progressive effects of this invention are as follows: the preparation method of this invention has a short synthetic route, mild conditions, high yield, low production cost, can prepare mannouronic acid oligosaccharide compounds of any sugar chain, and is suitable for industrial-scale production. Detailed Implementation

[0194] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0195] Example 1: Synthesis of Compounds 1-2

[0196]

[0197] Compound 1-1 was prepared using D-mannose as a raw material. For details, please refer to the literature (Org. Lett. 2011, 13, 16, 4360-4363).

[0198] Dissolve 1-1 (14.7 g, 31.5 mmol) in dichloromethane (160 mL) and add water (80 mL). After cooling in an ice bath, add TEMPO (984 mg, 6.3 mmol) and diacetic acid iodobenzene (25.4 g, 78.8 mmol) sequentially, and react at room temperature for 2 h. Quench the reaction with Na₂S₂O₃ solution slowly in an ice bath, separate the organic phase, acidify the aqueous phase to pH 3 with 1 M hydrochloric acid, and extract three times with dichloromethane. Combine the organic phases, wash with saturated NaCl solution, dry to anhydrous Na₂SO₄, filter, and concentrate to obtain a yellow syrup (66% yield), which is used directly in the next reaction. ESI-HRMS theoretical value C 27 H 28 O6SNa[M+Na] + 503.1499, measured value 503.1500.

[0199] The yellow syrup obtained in the previous step was dissolved in dry DMF (150 mL), and potassium bicarbonate (7.9 g, 78.8 mmol) and benzyl bromide (5.6 mL, 47.3 mmol) were added. The reaction was allowed to proceed overnight at room temperature. The reaction was quenched by slow dropwise addition of acetic acid, washed with water, and extracted several times with ethyl acetate. The combined organic phases were washed successively with saturated NaHCO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain yellow syrup 1-2 (11.5 g, 97% concentration in one step).

[0200] Compounds 1-2: [α] D 25 =46.3 (c 0.9, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.40–7.27(m,16H),7.05–7.01(m,2H),5.57(d,J=2.3Hz,1H),5.22(q,J=12.4Hz,2H) ,4.73–4.55(m,5H),4.44(t,J=9.0Hz,1H),3.96(t,J=2.7Hz,1H),3.74(dd,J=9.0,3.0Hz,1H),2.33(s,3H); 13 C NMR (125MHz, CDCl3) δ 169.79, 138.05, 138.03, 137.81, 135.33, 132.43, 129.93, 129.80, 128.68, 128.58, 128.50, 128.44, 128.23, 128.06, 127.98, 127.95, 127.89, 86.50, 78.35, 75.75, 72.60, 72.40, 68.67, 67.29, 21.24; ESI-HRMS theoretical value C 34 H34 O6SNa[M+Na] + 593.1968, measured value 593.1971.

[0201] Example 2 Synthesis of compounds 1-3

[0202]

[0203] Under argon protection, compounds 1-2 (8.7 g, 15.2 mmol) were dissolved in 100 mL of dry dichloromethane. 2,6-Dimethylpyridine (3.5 mL, 30.5 mmol) and TBSOTf (4.6 mL, 19.8 mmol) were added dropwise in an ice bath, and the reaction was carried out at room temperature for 3 h. The reaction was quenched with methanol, washed with saturated NaHCO3 and NaCl solutions, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain colorless syrup 1-3 (10.2 g, 98%).

[0204] Compounds 1-3: [α] D 25 =35.2 (c 1.1, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.47(d,J=7.9Hz,2H),7.35–7.24(m,15H),7.03–6.99(m,2H),5.68(d,J=7.6Hz,1H),5.05(m,2H),4.61(d,J=11.9H z,1H),4.53–4.42(m,5H),3.81(dd,J=7.7,2.7Hz,1H),3.58(dd,J=5.7,2.7Hz,1H),2.32(s,3H),0.82(s,9H),0.02(s,3H),-0.05(s,3H); 13 C NMR (125MHz, CDCl3) δ 169.39, 138.12, 138.00, 137.13, 135.50, 132.06, 129.97, 129.63, 128.58, 128.45, 128.39, 128.35, 128.28, 128.17, 128.04, 127.82, 127.80, 76.62, 73.84, 72.49, 69.87, 66.96, 25.82, 21.22, 18.06, -4.71, -5.10; ESI-HRMS theoretical value C 40 H 48 O6SSiNa[M+Na] + 707.2833, measured value 707.2834.

[0205] Example 3 Synthesis of compounds 1-4

[0206]

[0207] Compounds 1-3 (10.2 g, 14.9 mmol) were dissolved in acetone (120 mL), water (12 mL) was added, and the temperature was lowered to -20 °C. N-bromosuccinimide (10.6 g, 59.6 mmol) was added in portions, and the reaction was maintained at -20 °C for 1 h. The reaction was quenched with Na₂S₂O₃ and NaHCO₃ solutions, extracted three times with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by rapid column chromatography to obtain a white solid hemiacetal (yield 99%, ESI-HRMS theoretical value C). 33 H 42 O7SiNa[M+Na] + 601.2592 (measured value 601.2594), used for the next step of donor preparation.

[0208] Under argon protection, the above hemiacetal was dissolved in acetone (120 mL), and potassium carbonate (2.68 g, 19.4 mmol) and N-phenyltrifluoroacetylimine chloride (2.4 mL, 16.4 mmol) were added. The reaction was carried out at room temperature for 5 h. The solid was filtered off, and the mixture was concentrated to obtain the donor as a colorless syrup (yield 98%, ESI-HRMS theoretical value C). 41 H 46 NO7F3SiNa[M+Na] + 772.2888 (measured value 772.2891), directly used in glycosylation reaction.

[0209] The donor and acceptor 1-2 (9.0 g, 15.8 mmol) were mixed, diluted three times with water in toluene, and dried under vacuum. Under argon protection, the mixture was dissolved in dry dichloromethane (120 mL), and activated [the solution] was added. MS (15 g) was heated to -40 °C and stirred for 20 min. TBSOTf (0.68 mL, 2.98 mmol) was added, and the reaction was maintained at -40 °C for 4 h. The mixture was quenched with triethylamine, the solid was filtered off, the mixture was concentrated, and the solids were separated by rapid column chromatography to obtain colorless syrup 1-4 (14.7 g, 90% yield) and α-isomer 1-4-α (1.1 g, 6.7% yield).

[0210] Compounds 1-4: [α] D 25 =2.8 (c 1.1, CHCl3); 1H NMR (500MHz, CDCl3) δ7.42–7.38(m,2H),7.37–7.34(m,2H),7.33–7.15(m,28H),6.91(d,J=8.0Hz,2H),5.68(d,J=8 .3Hz,1H),5.17(d,J=12.4Hz,1H),5.09(d,J=12.4Hz,1H),4.98–4.86(m,2H),4.73(d,J=12.2Hz,1H),4.62(s,1H),4 .56(d,J=12.3Hz,1H),4.54–4.48(m,3H),4.47–4.29(m,6H),4.07(s,1H),3.85(dd,J=2.9,0.9Hz,1H),3.82(d,J=8. 7Hz,1H),3.67(dd,J=8.4,2.7Hz,1H),3.26(dd,J=9.0,2.8Hz,1H),2.23(s,3H),0.81(s,9H),0.01(d,J=6.6Hz,6H); 13 C NMR (150MHz, CDCl3) δ169.13,168.24,138.85,138.14,137.99,137.97,137.06,135.29,135.25,131. 92,129.89,129.58,128.66,128.63,128.60,128.47,128.43,128.38,128.35,128.23,128.13,127.9 8,127.85,127.73,127.67,127.65,127.62,127.42,101.33,82.81,81.33,77.56,76.15,74.80,74.17,73.77,73.11,71.94,71.16,69.07,67.23,67.15,25.93,21.18,18.18,-3.85,-5.10; ESI-HRMS theoretical value C 67 H 74 O 12 SSiNa[M+Na] + 1153.4562, measured value 1153.4566.

[0211] Compound 1-4-α: [α] D 25 =32.1 (c 1.4, CHCl3); 1H NMR (500MHz, CDCl3) δ7.49 (d, J=7.6Hz, 2H), 7.37–7.15 (m, 30H), 7.02 (d, J=7.9Hz, 2H), 5. 71(d,J=7.3Hz,1H),5.43(d,J=5.7Hz,1H),5.13(d,J=12.2Hz,1H),5.05–4.96(m,2H),4.9 4–4.84(m,2H),4.71(m,1H),4.56–4.30(m,9H),4.25(d,J=4.5Hz,1H),3.91–3.78(m,2H), 3.61(ddd,J=13.0,5.8,2.7Hz,2H),2.28(s,3H),0.81(s,9H),-0.01(s,3H),-0.05(s,3H); 13 C NMR (125MHz, CDCl3) δ169.28,168.83,138.54,138.10,138.03,137.87,137.04,135.54, 135.50,132.00,129.95,129.59,128.52,128.42,128.33,128.24,128.19,128.06,127.8 2,127.69,127.65,127.57,127.54,99.13,78.44,76.04,75.26,74.86,74.36,72.93,72.39,72.15,72.08,69.75,66.90,66.87,25.83,21.15,18.08,-4.64,-5.11; ESI-HRMS theoretical value C 67 H 74 O 12 SSiNa[M+Na] + 1153.4562, measured value 1153.4567.

[0212] Example 4 Synthesis of compounds 1-5

[0213]

[0214] Compounds 1-4 (2.15 g, 1.9 mmol) were dissolved in acetone (20 mL), water (2 mL) was added, and the temperature was lowered to -20 °C. N-bromosuccinimide (1.35 g, 7.6 mmol) was added in portions, and the reaction was maintained at -20 °C for 1 h. The reaction was quenched with Na₂S₂O₃ and NaHCO₃ solutions, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by rapid column chromatography to obtain a white, foamy solid hemiacetal (yield 99%, ESI-HRMS theoretical value C). 60 H 68 O 13 SiNa[M+Na] + 1047.4321 (measured value 1047.4324), used for the next oxidation step.

[0215] Under argon protection, the above hemiacetal was dissolved in DMSO (11 mL), and acetic anhydride (3.6 mL) was added dropwise. The mixture was reacted overnight at room temperature. The solution was diluted with ethyl acetate, washed three times with water, washed with saturated NaHCO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to give a white solid 1-5 (1.88 g, yield 97%).

[0216] Compounds 1-5: [α] D 25 = -29.3 (c 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.37–7.15(m,30H),5.15(d,J=12.3Hz,1H),5.05(d,J= 12.3Hz,1H),4.96(d,J=12.3Hz,1H),4.89–4.78(m,3H),4.69(d,J=1.6Hz,1H) ,4.62–4.53(m,5H),4.50–4.30(m,6H),3.88(d,J=7.6Hz,1H),3.85(dd,J=2.7 ,1.5Hz,1H),3.35(dd,J=8.2,2.7Hz,1H),0.85(s,9H),0.05(d,J=8.7Hz,6H); 13C NMR (125MHz, CDCl3) δ168.76,168.04,167.48,138.34,137.89,137.63,137.54,135.21,134.98 ,128.67,128.59,128.51,128.44,128.41,128.37,128.36,128.32,128.28,128.14,127.82,12 7.79, 127.78, 127.76, 127.74, 127.73, 127.47, 100.91, 80.55, 78.49, 77.33, 76.52, 74.51, 73.94, 73.58, 73.52, 73.26, 71.75, 69.20, 67.63, 67.16, 25.89, 18.13, -4.02, -5.07; ESI-HRMS theoretical value C 60 H 66 O 13 SiNa[M+Na] + 1045.4165, measured value 1045.4169.

[0217] Example 5: Synthesis of Compounds 1-6

[0218]

[0219] Compounds 1-5 (1.88 g, 1.84 mmol) were dissolved in tetrahydrofuran (18 mL), cooled in an ice bath, and a pyridine hydrogen fluoride complex (1.5 mL) was added dropwise. After the addition was complete, the mixture was heated to 40 °C and reacted for 20 h. The reaction was quenched by slowly adding the mixture to a saturated NaHCO3 solution in an ice bath. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain colorless syrup 1-6 (1.56 g, 93%).

[0220] Compounds 1-6: [α] D 25 = -43.0 (c 1.0, CHCl3); 1H NMR (500MHz, CDCl3) δ7.39–7.17(m,28H),7.14(m,2H),5.24(d,J=12.1Hz,1H),5. 14(d,J=12.1Hz,1H),4.93(m,2H),4.77–4.72(m,2H),4.68–4.59(m,4H),4.57–4. 47(m,4H),4.42–4.37(m,2H),4.31(t,J=9.5Hz,1H),4.22(d,J=11.5Hz,1H),3.81 (d,J=2.9Hz,1H),3.77(d,J=9.6Hz,1H),3.34(dd,J=9.4,2.9Hz,1H),3.07(s,1H); 13 C NMR (125MHz, CDCl3) δ168.87,168.64,167.35,138.11,137.85,137.52,137.42,134.88, 134.80,128.81,128.80,128.68,128.64,128.58,128.50,128.46,128.33,128.32,128. 31,128.25,128.12,128.04,127.91,127.86,127.82,101.90,80.17,78.89,77.48,77.20,75.03,74.68,74.27,74.21,73.72,73.25,72.45,68.27,67.76,67.68; ESI-HRMS theoretical value C 54 H 52 O 13 Na[M+Na] + 931.3300, measured value 931.3303.

[0221] Example 6 Synthesis of compounds 1-7

[0222]

[0223] Compounds 1-6 (1.42 g, 1.56 mmol) were dissolved in a mixed solvent of tetrahydrofuran / water / tert-butanol / acetic acid (15 / 15 / 3 / 0.3 mL), and 10% palladium on carbon (containing 55% water, 200 mg) and 10% palladium hydroxide on carbon (containing 50% water, 200 mg) were added. The system was purged with hydrogen three times, and the reaction was carried out at room temperature for 24 h under a hydrogen atmosphere of 1 atm. The solid was filtered off, concentrated, and used directly in the next reaction, with a yield of 97%. The theoretical value of the product according to ESI-HRMS is C. 12 H 14 O 13 [M-2H] 2-183.0223, measured value 183.0217.

[0224] Dissolve compound 1-7-1 from the previous step in water (25 mL), and adjust the pH of the system to 12-13 by adding 1M sodium hydroxide aqueous solution dropwise. React overnight at room temperature. Add H... + Ion exchange resin ( Neutralize with 50W x 4, 200-400 mesh, filter, evaporate to dryness, dissolve in water (5 mL), add methanol to precipitate the solid, centrifuge, wash with methanol, and air dry to give white solid 1-7 (670 mg, yield 98%).

[0225] Compounds 1-7: [α] D 25 = -51.3 (c 1.0, H2O); 1 H NMR(500MHz,D2O)δ4.27(d,J=6.3Hz,1H),4.18(d,J=8.5Hz,1H),4.14(dd,J=6.3, 1.8Hz,1H),4.03(d,J=3.1Hz,1H),3.90(dd,J=8.6,1.8Hz,1H),3.78–3.65(m,3H); 13 C NMR (125MHz, D2O) δ 179.77, 178.60, 176.28, 98.89, 77.44, 75.43, 72.65, 72.39, 71.82, 71.47, 70.62, 68.59; ESI-HRMS theoretical value C 12 H 16 O 14 [M-3Na+H] 2- 192.0276, measured value 192.0269.

[0226] Example 7 Synthesis of compounds 1-8

[0227]

[0228] Compounds 1-4 (3.0 g, 2.65 mmol) were dissolved in tetrahydrofuran (25 mL), cooled in an ice bath, and a pyridine hydrogen fluoride complex (2.2 mL) was added dropwise. After the addition was complete, the mixture was heated to 40 °C and reacted for 32 h. The reaction was quenched by slowly adding the mixture to a saturated NaHCO3 solution in an ice bath. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain colorless syrup 1-8 (2.65 g, 98%).

[0229] Compounds 1-8: [α] D 25= -13.2 (c 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.45–7.38(m,4H),7.37–7.14(m,28H),6.92(d,J=7.9Hz,2H),5.7 2(d,J=8.3Hz,1H),5.24(d,J=12.2Hz,1H),5.15(d,J=12.2Hz,1H),4.97–4.86(m,2H),4 .75(d,J=12.2Hz,1H),4.66–4.42(m,10H),4.31(t,J=9.5Hz,1H),4.17(s,1H),3.86(d, J=2.9Hz,1H),3.81–3.72(m,2H),3.32(dd,J=9.5,3.0Hz,1H),2.97(s,1H),2.23(s,3H); 13 C NMR (125MHz, CDCl3) δ169.07,168.98,138.46,138.12,137.89,137.89,137.09,135.1 7,135.04,131.96,129.77,129.56,128.70,128.61,128.58,128.48,128.45,128.40,1 28.37, 128.30, 128.06, 128.04, 127.94, 127.81, 127.72, 127.65, 101.76, 80.10, 76.65, 75.20, 74.49, 74.00, 73.14, 71.93, 71.85, 68.18, 67.47, 67.25, 21.14; ESI-HRMS theoretical value C 61 H 60 O 12 SNa[M+Na] + 1039.3698, measured value 1039.3703.

[0230] Example 8 Synthesis of compounds 1-9

[0231]

[0232] Following the preparation method of compounds 1-4, compounds 1-9 (8.4 g) and α isomer 1-9-α (1 g) were prepared from disaccharide donors and disaccharide acceptors 1-8.

[0233] The first step yielded 97%, with an ESI-HRMS theoretical value of C. 60 H 68 O 13 SiNa[M+Na] +1047.4321 (measured value 1047.4325). Second-step yield 99%, ESI-HRMS theoretical value C. 68 H 72 NO 13 F3SiNa[M+Na] + 1218.4617, measured value 1218.4622. The yield of compounds 1-9 in step three was 82%, and the α isomer 1-9-α was 9%.

[0234] Compounds 1-9: [α] D 25 = -26.5 (c 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.43(d,J=8.0Hz,2H),7.41–7.13(m,55H),6.94(d,J=7.9Hz,2H),5.71(d,J=8.0Hz,1H),5.13–5.05(m,3H),5.03(d ,J=12.5Hz,1H),4.96(d,J=12.3Hz,1H),4.90(d,J=12.1Hz,1H),4.86(d,J=12.1Hz,1H),4.82–4.64(m,8H),4.63–4.24(m,17H),4.11(s, 1H),3.81(d,J=8.8Hz,1H),3.77(d,J=3.0Hz,1H),3.76–3.72(m,2H),3.64(d,J=3.0Hz,1H),3.62(d,J=9.4Hz,1H),3.51(d,J=9.2Hz,1H) ,3.44(dd,J=9.1,2.9Hz,1H),3.21(dd,J=9.1,2.9Hz,1H),2.97(dd,J=9.2,2.8Hz,1H),2.25(s,3H),0.83(s,9H),-0.01(d,J=1.9Hz,6H); 13C NMR (125MHz, CDCl3) δ169.05,168.26,168.17,167.83,139.34,139.16,139.08,138. 91,138.52,138.18,138.06,137.96,137.04,135.43,135.36,135.18,135.15,131.91 ,129.85,129.54,128.76,128.71,128.62,128.59,128.54,128.44,128.42,128.36,128.30,128.28,128.26,128.23,128.19,128.13,128.11,128.08,128.00,127.92,127 .66,127.60,127.58,127.50,127.48,127.47,127.36,127.27,127.22,127.14,102.48,102.00,101.08,81.40,79.32,79.10,77.51,77.27,77.24,76.49,76.31,75.30,75 .11,75.01,74.57,74.52,74.36,74.17,73.54,73.05,73.03,72.76,72.00,70.72,68.79,67.19,67.10,66.87,66.85,25.88,21.14,18.11,-3.90,-5.18;MALDI-HRMS theoretical value C 121 H 126 O 24 SSiNa[M+Na] + 2045.8021, measured value 2045.8057.

[0235] Compound 1-9-α: [α] D 25 = -4.1(c 1.1, CHCl3); 11H NMR (500 MHz, CDCl3) δ 7.41–7.05 (m, 57H), 6.88 (d, J = 7.9 Hz, 2H), 5.69 (d, J = 8.4 Hz, 1H), 5.50 (s, 1H), 5.14–4.99 (m, 4H), 4.96–4.84 (m, 4H), 4.79 (d, J = 12.2 Hz, 1H), 4.69–4.48 (m, 8H), 4.47–4.24 (m, 14H), 4.14 (d, J = 6.4 Hz, 1H), 4.10 (s, 1H), 3.99 (s, 1H), 3.87 (s, 1H), 3.80 (d, J = 2.8 Hz, 1H), 3.76 (d, J = 2.8 Hz, 1H), 3.67 (dd, J = 8.4, 2.7 Hz, 1H), 3.61 (d, J = 9.0 Hz, 1H), 3.56 (dd, J = 4.7, 2.8 Hz, 1H), 3.37 (d, J = 6.7 Hz, 2H), 3.06 (d, J = 8.0 Hz, 1H), 2.20 (s, 3H), 0.79 (s, 9H), -0.03 (d, J = 2.6 Hz, 6H); 13 13C NMR (125 MHz, CDCl3) δ 169.10, 169.07, 168.20, 167.65, 139.12, 138.92, 138.57, 138.54, 138.15, 137.96, 137.92, 136.92, 135.55, 135.48, 135.29, 135.21, 131.81, 129.92, 129.51, 128.67, 128.60,128.57, 128.50, 128.43, 128.41, 128.38, 128.31, \128.28, 128.25, 128.20, 128.18, 128.17, 128.11, 128.00, 127.94, 127.80, 127.68, 127.65, 127.60, 127.56, 127.52, 127.48, 127.41, 127.32, 127.17, 101.94, 100.68, 99.24, 81.35, 80.43, 77.38, 76.67, 76.34, 76.11, 75.82, 74.83, 74.59, 74.25, 74.11, 73.80, 73.27, 73.01, 72.99, 72.36, 71.76, 71.64, 70.83, 68.90, 67.16, 66.97, 66.92, 25.89, 21.13, 18.12, -3.88, -5.17; MALDI-HRMS calculated for C 121 H 126 O 24 It should be noted that there seems to be an incorrect "0000186" in the original text which is likely a typo and should probably be "0000186". The translation has been done as accurately as possible based on the provided text.SSiNa[M+Na] + 2045.8021, measured value 2045.8097.

[0236] Example 9: Synthesis of Compounds 1-10

[0237]

[0238] Following the preparation method for compounds 1-5, compounds 1-10 (1.76 g) were prepared. The first step yield was 95%, and the theoretical MALDI-HRMS value was [value missing]. 114 H 120 O 25 SiNa[M+Na] + 1939.7780, measured value 1939.7811. Second step yield 98%.

[0239] Compounds 1-10: [α] D 25 = -39.7 (c 0.9, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.42–7.15(m,61H),5.13–5.01(m,4H),4.96(d,J=12.3Hz,1H),4.90(d,J =11.7Hz,1H),4.85–4.26(m,28H),3.90(d,J=7.2Hz,1H),3.77(t,J=2.2Hz,1H),3.75(d,J=2.8 Hz,1H),3.70(d,J=9.1Hz,1H),3.67(d,J=2.9Hz,1H),3.61(dd,J=7.9,2.7Hz,1H),3.55(d,J=9 .2Hz,1H),3.30(dd,J=9.0,2.8Hz,1H),3.01(dd,J=9.2,2.8Hz,1H),0.82(s,9H),-0.01(s,6H); 13CNMR (126MHz, CDCl3) δ168.85,168.31,168.14,167.79,167.56,139.30,139.08,1 38.92,138.78,138.08,138.07,137.76,137.59,135.36,135.34,135.08,134.99, 128.81, 128.80, 128.78, 128.64, 128.57, 128.49, 128.41, 128.41, 128.34, 128.33, 128.31, 128.30, 128.26, 128.20, 128.16, 128.15, 128.13, 127.99, 127.84, 127.82 ,127.76,127.72,127.68,127.60,127.54,127.42,127.34,127.21,102.47,101.87,100.50,81.49,79.20,78.49,77.99,77.47,77.31,77.21,76.67,76.17,75.31,7 4.69, 74.67, 74.61, 74.44, 74.41, 74.38, 73.71, 73.47, 73.41, 73.16, 73.08, 70.88, 68.84, 67.62, 67.25, 67.01, 66.96, 25.90, 18.14, -3.87, -5.14; MALDI-HRMS theoretical value C 114 H 118 O 25 SiNa[M+Na] + 1937.7624, measured value 1937.7659.

[0240] Example 10 Synthesis of compounds 1-11

[0241]

[0242] Compounds 1-11 (1.53 g, 94%) were prepared using the same method as compounds 1-6.

[0243] Compounds 1-11: [α] D 25 = -55.1 (c 1.1, CHCl3); 1H NMR (500MHz, CDCl3) δ7.43–7.13(m,55H),5.16–5.01(m,4H),4.99–4.30(m,29H),4.20(t,J=9.6Hz,1H),3.92(d,J=7.2Hz,1H),3.8 1–3.70(m,4H),3.63(d,J=6.0Hz,1H),3.50(d,J=9.6Hz,1H),3.39(dd,J=9.0,2.9Hz,1H),3.13(dd,J=9.5,2.9Hz,1H),2.81(s,1H); 13 C NMR (125MHz, CDCl3) δ169.17,168.83,168.09,167.80,167.55,138.99,138.89, 138.74,138.15,138.08,137.76,137.59,135.24,135.24,135.07,134.99,128. 81,128.79,128.74,128.72,128.61,128.59,128.58,128.56,128.54,128.41,128.39,128.38,128.34,128.32,128.31,128.26,128.21,128.16,128.12,128.10 ,127.93,127.83,127.75,127.70,127.69,127.55,127.46,127.44,127.43,127.41,127.38,102.33,101.95,100.50,80.35,79.30,78.48,78.03,77.27,77.18 ,76.67,75.74,75.14,75.10,75.03,74.70,74.67,74.39,74.34,73.70,73.47,73.40,73.06,72.68,71.70,68.17,67.61,67.26,67.17,67.10; MALDI-HRMS theoretical value C 108 H 104 O 25 Na[M+Na] + 1823.6759, measured value 1823.6782.

[0244] Example 11 Synthesis of compounds 1-12

[0245]

[0246] Following the preparation method for compounds 1-7, compounds 1-12 (586 mg) were prepared. The yield of the first step was 86%, and the theoretical value of C from ESI-HRMS was [missing value]. 24 H 30 O 25 [M-2H] 2- 359.0544, measured value 359.0535. Second step yield 97%.

[0247] Compounds 1-12: [α] D 25 = -107.4 (c 0.6, H2O); 1 H NMR(500MHz,D2O)δ4.83(s,1H),4.68(s,1H),4.64(s,1H),4.28(d,J=5.8Hz,1H),4.17(d,J=8.2Hz,1H),4.13(dd,J=5.8,1.8Hz,1 H),4.09(d,J=3.3Hz,1H),4.07(d,J=3.3Hz,1H),4.00(d,J=3.6Hz,1H),3.95–3.87(m,3H),3.82–3.75(m,4H),3.74–3.64(m,3H); 13 C NMR (150MHz, D2O) δ 179.54, 178.46, 176.04, 175.36, 175.28, 100.04, 99.98, 98.82, 78.02, 77.88, 77.68, 75.87, 75.85, 75.68, 72.63, 72.54, 71.94, 71.86, 71.42, 71.33, 70.37, 70.22, 69.92, 68.47; ESI-HRMS theoretical value C 24 H 31 O 26 [M-5Na+2H] 3- 245.0373, measured value 245.0377.

[0248] Example 12 Synthesis of compounds 1-13

[0249]

[0250] Compounds 1-13 (2.12 g, 96%) were prepared using the same method as compounds 1-8.

[0251] Compounds 1-13: [α] D 25 = -36.2 (c 1.0, CHCl3); 1H NMR(500MHz, CDCl3)δ7.48–7.13(m,57H),6.94(d,J=7.9Hz,2H),5.71(d,J=8.0Hz, 1H),5.16–4.29(m,31H),4.20(t,J=9.6Hz,1H),4.11(s,1H),3.83(d,J=8.8Hz,1H) ,3.78(d,J=2.9Hz,1H),3.76–3.72(m,2H),3.71–3.67(m,2H),3.50–3.44(m,2H),3 .30(dd,J=9.1,2.9Hz,1H),3.10(dd,J=9.5,2.9Hz,1H),2.82(s,1H),2.26(s,3H); 13 C NMR (125MHz, CDCl3) δ169.19,169.08,168.16,167.88,139.07,139.03,139.01 ,138.86,138.51,138.19,138.15,137.97,137.08,135.32,135.27,135.19,135 .15,131.92,129.86,129.56,128.74,128.70,128.65,128.60,128.59,128.56,128.52,128.43,128.37,128.36,128.34,128.33,128.30,128.27,128.20,128 .11,128.01,127.94,127.90,127.82,127.80,127.68,127.51,127.41,127.39,127.32,127.29,102.33,102.10,101.10,80.29,79.41,79.13,77.31,77.26,7 6.32, 76.08, 75.11, 75.05, 74.99, 74.68, 74.56, 74.19, 73.57, 73.05, 72.76, 72.57, 72.02, 71.58, 68.12, 67.21, 67.15, 67.12, 66.99, 21.15; MALDI-HRMS theoretical value C 115 H 112 O 24 SNa[M+Na] + 1931.7156, measured value 1931.7105.

[0252] Example 13 Synthesis of compounds 1-14

[0253]

[0254] Following the preparation method of compounds 1-4, compounds 1-14 (865 mg) and the α-isomer 1-14-α (70 mg) were prepared from a disaccharide donor and a tetrasaccharide acceptor 1-13. The yield of the first step was 97%, and the theoretical ESI-HRMS value was [value missing]. 60 H 68 O 13 SiNa[M+Na] + 1047.4321 (Measured value 1047.4325). Second step yield 99%, ESI-HRMS theoretical value C. 68 H 72 NO 13 F3SiNa[M+Na] + 1218.4617, measured value 1218.4622. The yield of compound 1-14 in step three was 89%, and the yield of the α isomer 1-14-α was 7%.

[0255] Compounds 1-14: [α] D 25 = -43.0 (c 1.0, CHCl3); 1 H NMR(500MHz,Chloroform-d)δ7.52–7.09(m,85H),6.97(d,J=7.9Hz,2H),5.74(d,J=7.9Hz,1H),5.17–4.19(m, 48H),4.14(s,1H),3.86(d,J=8.8Hz,1H),3.80(d,J=2.9Hz,1H),3.79–3.74(m,2H),3.70(d,J=2.9Hz,1H),3.6 8–3.64(m,2H),3.62(d,J=3.0Hz,1H),3.59–3.46(m,4H),3.28(dd,J=9.2,2.9Hz,1H),3.18(dd,J=9.2,2.9Hz, 1H),3.13(dd,J=9.3,2.9Hz,1H),2.97(dd,J=9.2,2.8Hz,1H),2.29(s,3H),0.86(s,9H),0.02(d,J=2.4Hz,6H); 13C NMR (126MHz, cdcl3) δ169.06,168.28,168.19,168.08,168.04,167.88,139.36,139.31,139.23,139.17,139.15, 139.14,139.06,138.87,138.52,138.19,138.08,137.98,137.06,135.51,135.37,135.35,135.29,135.20,135. 16,131.93,129.87,129.55,128.73,128.72,128.65,128.63,128.62,128.59,128.57,128.55,128.53,128.44,128.42,128.35,128.31,128.28,128.25,128.22,128.20,128.18,128.11,128.09,128.00,127.91,127.89,127.83 ,127.82,127.66,127.59,127.58,127.51,127.46,127.39,127.34,127.30,127.27,127.26,127.21,127.17,127.13,102.50,102.15,102.10,102.07,101.10,81.38,79.59,79.48,79.19,79.13,77.51,77.37,77.28,77.22,76. 51,76.43,76.36,75.24,75.07,74.63,74.60,74.55,74.36,74.19,73.55,73.06,72.88,72.86,72.78,72.74,72.03,70.68,68.78,67.18,67.13,66.96,66.86,66.83,66.73,25.88,21.13,18.11,-3.90,-5.18; MALDI-HRMS theoretical value C 175 H 178 O 36 SSiNa[M+Na] + 2938.1480, measured value 2938.1445.

[0256] Compound 1-14-α: [α] D 25 = -24.9 (c 1.1, CHCl3); 1H NMR(500MHz,CDCl3)δ7.50–7.03(m,83H),6.93(d,J=7.8Hz,2H),5.70(d,J=8.1Hz,1H),5.46(s,1H),5.14–4.18(m,47H),4.12–4.06(m,2H),3.86–3.77(m,3H),3.76(d,J=2.9Hz,1H),3.72(dd,J=8.1,2.5Hz,1H),3.69(d,J=2.6Hz,1H),3.64–3.54(m,5H),3.45–3.40(m,1H),3.18(dd,J=9.0,2.3Hz,1H),3.08–3.01(m,2H),2.25(s,3H),0.82(s,9H),-0.01(s,6H); 13C NMR (125MHz, CDCl3) δ169.18,169.11,168.25,168.21,167.89,167.63,139.26,139.17,139.12,139.09,1 38.96,138.71,138.59,138.25,138.04,138.04,137.10,135.68,135.61,135.46,135.37,135.25,135.21, 131.96,129.94,129.58,128.75,128.70,128.67,128.63,128.61,128.58,128.51,128.45,128.42,128.39,128.34,128.34,128.32,128.29,128.27,128.23,128.21,128.19,128.17,128.13,128.04,128.00,127. 96,127.90,127.77,127.69,127.63,127.58,127.52,127.39,127.33,127.29,127.25,127.24,127.23,127.14,102.25,102.16,102.04,101.12,99.25,81.40,81.22,79.30,79.15,77.67,77.32,76.59,76.44,76. 39,75.69,75.24,75.17,74.77,74.63,74.34,74.32,74.23,73.36,73.10,72.99,72.82,72.37,72.08,71.32,70.77,68.92,67.22,67.14,66.97,66.89,66.86,25.93,21.17,18.16,-3.85,-5.13; MALDI-HRMS theoretical value C 175 H 178 O 36 SSiNa[M+Na] + 2938.1480, measured value 2938.1521.

[0257] Example 14 Synthesis of compounds 1-15

[0258]

[0259] Following the preparation method for compounds 1-5, compounds 1-15 (726 mg) were prepared. The first step yield was 96%, and the theoretical MALDI-HRMS value was [value missing]. 168 H 172 O37 SiNa[M+Na] + 2832.1239, measured value 2832.1233. Second step yield 99%.

[0260] Compounds 1-15: [α] D 25 = -58.6 (c 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.45–7.13(m,90H),5.12–4.71(m,25H),4.69(s,1H),4.67–4.40(m,15H),4.39–4.33(m,4H) ,4.32–4.20(m,5H),3.94(d,J=7.2Hz,1H),3.80(t,J=2.2Hz,1H),3.77–3.71(m,3H),3.68(d,J=2.9Hz,1H),3.67– 3.63(m,1H),3.63–3.58(m,2H),3.54(d,J=9.5Hz,1H),3.50(d,J=9.2Hz,1H),3.37(dd,J=9.0,2.6Hz,1H),3.21(d d,J=9.2,2.8Hz,1H),3.13(dd,J=9.2,2.9Hz,1H),2.96(dd,J=9.2,2.8Hz,1H),0.85(s,9H),0.01(d,J=2.1Hz,6H); 13C NMR (126MHz, cdcl3) δ168.82,168.29,168.16,168.01,167.99,167.76,167.51,139.31,139.25,139.14,139.09 ,139.07,139.05,138.83,138.68,138.04,138.01,137.70,137.53,135.46,135.32,135.27,135.15,135.01,13 4.93, 128.77, 128.75, 128.73, 128.67, 128.63, 128.59, 128.53, 128.43, 128.38, 128.31, 128.29, 128.28, 128.25, 128.24, 128.23, 128.22, 128.13, 128.12, 128.09, 127.92, 127.84, 127.83, 127.82, 127.79, 127.73, 127.67, 12 7.56, 127.53, 127.46, 127.41, 127.36, 127.33, 127.30, 127.26, 127.24, 127.18, 127.16, 127.13, 102.47, 102.11, 102.05, 101.93, 100.48, 81.31, 79.47, 79.43, 79.14, 78.44, 77.98, 77.48, 77.34, 77.29, 77.09, 76.63, 76.44 ,76.35,75.92,75.21,75.04,75.02,74.60,74.58,74.49,74.41,74.34,74.28,73.67,73.42,73.36,73.03,72.91,72.88,72.79,70.64,68.74,67.59,67.24,67.06,66.87,66.73,25.86,18.09,-3.91,-5.20;MALDI-HRMS theoretical value C 168 H 170 O 37 SiNa[M+Na] + 2830.1082, measured value 2830.1078.

[0261] Example 15 Synthesis of compounds 1-16

[0262]

[0263] Compounds 1-16 (592 mg, 95%) were prepared using the same method as compounds 1-6.

[0264] Compound 1-16: [α] D 25 = -67.9 (c 1.1, CHCl3); 1 1H NMR (500 MHz, CDCl3) δ 7.46–7.15 (m, 82H), 5.17–4.27 (m, 49H), 4.22 (t, J = 9.5 Hz, 1H), 3.95 (d, J = 7.2 Hz, 1H), 3.82 (t, J = 2.3 Hz, 1H), 3.78–3.72 (m, 3H), 3.71–3.60 (m, 5H), 3.49 (d, J = 9.6 Hz, 1H), 3.38 (dd, J = 9.0, 2.6 Hz, 1H), 3.24 (dt, J = 9.2, 2.7 Hz, 2H), 3.11 (dd, J = 9.5, 2.9 Hz, 1H); 13C NMR (125MHz, CDCl3) δ169.15,168.77,168.11,168.02,167.97,167.75,167.48,139.16,139.06,139 .04,139.02,138.98,138.82,138.67,138.11,138.01,137.69,137.52,135.33,135.25,135.22,135. 14,135.00,134.92,128.74,128.72,128.65,128.63,128.58,128.55,128.50,128.46,128.35,128.30,128.28,128.26,128.22,128.20,128.15,128.11,128.07,128.06,127.89,127.80,127.78,127.7 6,127.73,127.70,127.65,127.62,127.50,127.39,127.34,127.32,127.28,127.26,127.21,127.18,102.27,102.12,102.10,101.89,100.45,80.21,79.45,79.39,79.23,78.41,77.96,77.29,77.23, 77.09, 76.60, 76.27, 76.02, 75.93, 75.01, 74.92, 74.60, 74.57, 74.54, 74.39, 74.31, 73.67, 73.40, 73.33, 73.01, 72.89, 72.74, 72.36, 71.47, 68.05, 67.55, 67.21, 67.04, 66.87, 66.83; MALDI-HRMS theoretical value C 162 H 156 O 37 Na[M+Na] + 2716.0218, measured value 2716.0201.

[0265] Example 16 Synthesis of compounds 1-17

[0266]

[0267] Following the preparation method for compounds 1-7, compounds 1-17 (196 mg) were prepared. The yield of the first step was 79%, and the theoretical value of ESI-HRMS was [value missing]. 36 H 45 O 37 [M-3H] 3-356.3885, measured value 356.3871. Second step yield 97%.

[0268] Compounds 1-17: [α] D 25 = -73.7 (c 1.0, H2O); 1 H NMR(500MHz,D2O)δ4.82(s,1H),4.68(s,1H),4.66(s,2H),4.64(s,1H),4.28(d,J=5.9Hz,1H),4.16(d,J=8.3Hz,1H),4. 14–4.11(m,1H),4.09(d,J=3.3Hz,1H),4.07–4.03(m,3H),3.99(d,J=3.2Hz,1H),3.95–3.85(m,5H),3.82–3.63(m,11H); 13 C NMR (150MHz, D2O) δ 179.58, 178.47, 176.04, 175.36, 175.27, 175.23, 100.04, 99.97, 99.90, 98.83, 78.05, 77.88, 77.76, 77.68, 75.87, 75.85, 75.77, 75.69, 72.61, 72.54, 71.96, 71.78, 71.43, 71.34, 71.28, 70.37, 70.23, 69.92, 69.90, 68.47; ESI-HRMS theoretical value C 36 H 46 O 38 [M-7Na+3H] 4- 271.5422, measured value 271.5392.

[0269] Example 17 Synthesis of compounds 1-18

[0270]

[0271] Following the preparation method of compounds 1-4, compound 1-18 (3.84 g) was prepared from a tetrasaccharide donor and a tetrasaccharide acceptor 1-13. The first step yield was 96%, and the theoretical MALDI-HRMS value was [value missing]. 114 H 120 O 25 SiNa[M+Na] + 1939.7780, measured value 1939.7747. Second step yield 99%, MALDI-HRMS theoretical value C 122 H 124 NO 25 F3SiNa[M+Na] +2110.8076, measured value 2110.8024. Third step yield: 95%.

[0272] Compounds 1-18: [α] D 25 = -52.4 (c 1.1, CHCl3); 1 H NMR(500MHz, CDCl3)δ7.49–7.08(m,111H),6.96(d,J=8.1Hz,2H),5.73(d,J=8.0Hz,1H), 5.15–4.17(m,64H),4.13(s,1H),3.85(d,J=8.7Hz,1H),3.79(d,J=2.8Hz,1H),3.78–3.7 3(m,2H),3.69(d,J=2.9Hz,1H),3.68–3.44(m,11H),3.27(dd,J=9.1,2.5Hz,1H),3.20–3 .08(m,4H),2.96(dd,J=9.2,2.9Hz,1H),2.28(s,3H),0.84(s,9H),0.00(d,J=2.2Hz,6H); 13C NMR (125MHz, CDCl3) δ169.06,168.30,168.20,168.08,168.05,167.88,139.35,139.31,139.24,139.22,139.21,13 9.17,139.14,139.13,139.11,139.04,138.85,138.50,138.17,138.08,137.96,137.07,135.50,135.36,135.34,13 5.33,135.27,135.18,135.15,131.92,129.84,129.55,128.73,128.72,128.66,128.63,128.59,128.57,128.55,128.44,128.36,128.32,128.29,128.25,128.22,128.11,128.10,128.00,127.92,127.89,127.83,127.82,127.79,1 27.68,127.59,127.57,127.51,127.46,127.41,127.34,127.31,127.30,127.24,127.17,127.13,127.12,102.50,102.17,102.11,102.08,101.10,81.34,79.57,79.46,79.44,79.16,79.13,77.51,77.37,77.27,76.47,76.41,76.3 3,75.22,75.05,75.01,74.62,74.59,74.52,74.36,74.19,73.52,73.04,72.86,72.84,72.77,72.69,72.68,72.66,72.02,70.65,68.77,67.20,67.14,66.97,66.87,66.81,66.72,25.88,21.15,18.11,-3.90,-5.19; MALDI-HRMS theoretical value C 229 H 230 O 48 SSiNa[M+Na] + 3830.4939, measured value 3830.4919.

[0273] Example 18 Synthesis of compounds 1-19

[0274]

[0275] Following the preparation method for compounds 1-5, compounds 1-19 (1.42 g) were prepared. The first step yield was 78%, and the theoretical MALDI-HRMS value was [value missing]. 222 H 224 O 49 SiNa[M+Na] + 3724.4698, measured value 3724.4502. Second step yield 96%.

[0276] Compounds 1-19: [α] D 25 = -66.3 (c 1.1, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.46–7.07(m,111H),5.11–4.14(m,66H),3.92(d,J=7.2Hz,1H),3.78(s,1H),3.74–3.44(m,13H),3.34(dd,J =9.0,2.8Hz,1H),3.20(dd,J=9.2,2.9Hz,1H),3.17–3.06(m,3H),2.93(dd,J=9.2,2.9Hz,1H),0.82(s,9H),-0.02(d,J=1.8Hz,6H); 13C NMR (125MHz, CDCl3) δ168.84,168.32,168.20,168.08,168.07,168.05,168.01,167.78,167.54,139.34,139.31,139.23,139.2 0,139.17,139.13,139.10,139.09,139.06,138.85,138.70,138.08,138.02,137.73,137.55,135.50,135.35,135.33,135.29, 135.17,135.03,134.95,128.80,128.77,128.75,128.70,128.68,128.64,128.62,128.60,128.55,128.45,128.41,128.33,128.32,128.31,128.28,128.26,128.25,128.23,128.16,128.14,128.12,127.94,127.85,127.81,127.80,127.75,127.70,127.5 9,127.57,127.47,127.44,127.39,127.36,127.33,127.30,127.29,127.27,127.24,127.19,127.15,127.13,102.50,102.16,102.08,101.96,100.51,81.33,79.50,79.47,79.44,79.15,78.48,78.00,77.51,77.36,77.34,77.12,76.66,76.45,76.40,76. 33,76.30,75.94,75.21,75.04,75.02,74.99,74.63,74.60,74.51,74.43,74.37,74.31,73.70,73.46,73.39,73.07,72.93,72.87,72.78,72.69,70.65,68.76,67.62,67.27,67.09,66.93,66.89,66.83,66.74,25.88,18.12,-3.90,-5.19;MALDI-HRMS theoretical value C 222 H 222 O 49 SiNa[M+Na] + 3722.4541, measured value 3722.4368.

[0277] Example 19 Synthesis of compounds 1-20

[0278]

[0279] Compounds 1-20 (1.11 g, 92%) were prepared using the same method as compounds 1-6.

[0280] Compounds 1-20: [α] D 25 = -70.3 (c 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.49–7.14(m,107H),5.18–4.19(m,66H),3.96(d,J=7.1Hz,1H),3.83(s,1H),3.79–3.5 4(m,12H),3.49(d,J=9.6Hz,1H),3.39(dd,J=9.0,2.8Hz,1H),3.28–3.15(m,4H),3.12(dd,J=9.5,2.9Hz,1H); 13C NMR (125MHz, CDCl3) δ169.16,168.76,168.12,168.04,168.02,167.97,167.74,167.47,139.19,139.16,139.08,139 .06,139.06,139.05,139.03,139.02,138.98,138.82,138.67,138.10,138.00,137.68,137.51,135.34,135.29,135 .25,135.22,135.13,135.00,134.91,128.73,128.72,128.65,128.61,128.59,128.58,128.56,128.55,128.49,128.45,128.35,128.29,128.27,128.25,128.21,128.19,128.14,128.10,128.06,127.88,127.79,127.78,127.76,127 .74,127.73,127.69,127.64,127.62,127.50,127.38,127.34,127.33,127.31,127.28,127.25,127.23,127.19,127.17,127.14,127.13,102.27,102.12,101.89,100.46,80.20,79.45,79.41,79.39,79.20,78.41,77.95,77.36,77.3 0,77.23,77.09,76.61,76.29,76.01,75.91,74.99,74.97,74.91,74.59,74.58,74.53,74.38,74.31,73.66,73.39,73.33,73.01,72.88,72.73,72.64,72.61,72.31,71.44,68.04,67.55,67.20,67.03,66.87,66.81; MALDI-HRMS theoretical value C 216 H 208 O 49 Na[M+Na] + 3608.3676, measured value 3608.3700.

[0281] Example 20 Synthesis of compounds 1-21

[0282]

[0283] Following the preparation method for compounds 1-7, compounds 1-21 (296 mg) were prepared. The yield of the first step was 67%, and the theoretical value from ESI-HRMS was [value missing]. 48 H 59 O 49 [M-5H] 5- 283.8430, measured value 283.8401. Second step yield 91%.

[0284] Compounds 1-21: [α] D 25 =-94.7(c 1.0,H2O); H NMR(500MHz,D2O)δ4.83(s,1H),4.68(s,1H),4.66(s,4H),4.64(s,1H),4.28(d,J=5.7Hz,1H),4.17(d,J=8.1Hz,1H),4. 15–4.12(m,1H),4.09(d,J=3.4Hz,1H),4.08–4.03(m,5H),4.00(d,J=3.2Hz,1H),3.96–3.87(m,7H),3.82–3.65(m,15H); 13 C NMR (150MHz, D2O) δ 179.54, 178.45, 176.04, 175.37, 175.27, 175.24, 100.02, 99.95, 99.87, 98.81, 77.98, 77.83, 77.71, 75.88, 75.84, 75.76, 75.68, 72.64, 72.55, 71.93, 71.87, 71.41, 71.32, 71.27, 70.36, 70.23, 69.91, 68.47; ESI-HRMS theoretical value C 48 H 57 O 50 Na3[M-6Na] 6- 250.3607, measured value 250.3558.

[0285] Comparative Example 1

[0286]

[0287] The starting material (122 mg, 0.125 mmol) was dissolved in tetrahydrofuran (2 mL), and TBAF (1 M, 0.25 mL, 0.25 mmol) was added. The reaction was carried out at room temperature for 5 h. The solution was diluted with dichloromethane, washed with saturated NaHCO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain a colorless syrup (45 mg, 76%). ESI-HRMS theoretical value C 28 H 28O5SNa[M+Na] + 499.1550, measured value 499.1555.

[0288] Comparative Example 2

[0289]

[0290] Under argon protection, hydrazine hydrate (24 μL, 0.5 mmol) was mixed thoroughly with pyridine (0.15 mL) and acetic acid (0.1 mL), and added dropwise to a pyridine (2 mL) solution of the starting material (150 mg, 0.175 mmol) under ice bath conditions. The reaction was carried out at room temperature for 3 h. The mixture was quenched with acetone, diluted with dichloromethane, washed with water, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and separated by rapid column chromatography to obtain the product (48 mg, 35%). ESI-HRMS theoretical value C 42 H 48 N2O 13 Na[M+Na] + 811.3049, measured value 811.3052.

[0291] Comparative Example 3

[0292]

[0293] Raw material A' (20 mg, 0.026 mmol) was dissolved in tetrahydrofuran (1 mL), and then slowly mixed with 30% hydrogen peroxide (0.5 mL) and 1 M LiOH (2 mL). The mixture was stirred at room temperature for 12 h. Acidic resin was added for neutralization. The mixture was filtered, concentrated, and product B' (8%) was separated by HPLC. The theoretical value of C from ESI-HRMS was... 40 H 41 O 14 [MH] - 745.2502, measured value 745.2495; product C' (26%), ESI-HRMS theoretical value C 20 H 21 O7[MH] - 373.1293, measured value 373.1289; product D' (21%), ESI-HRMS theoretical value C 20 H 19 O7[MH] - 371.1136, measured value 371.1131.

[0294] Comparative Example 4

[0295]

[0296] The starting material (53 mg, 0.061 mmol) was dissolved in tetrahydrofuran (3 mL), cooled in an ice bath, and a pyridine hydrogen fluoride complex (0.2 mL) was added dropwise. After the addition was complete, the reaction was maintained at 0 °C for 12 h, and then increased to room temperature for 36 h. The reaction was quenched by slowly adding the solution to a saturated NaHCO3 solution while in an ice bath. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and separated by rapid column chromatography to obtain a white solid (6 mg, 12%). ESI-HRMS theoretical value: C42H44O13Na[M+Na] + 779.2674, measured value 779.2674.

Claims

1. A method for preparing a compound as shown in Formula VI, characterized in that, It includes the following steps: (1) In an organic solvent, under the action of NBS, the compound shown in Formula II and water undergo a hydroxyl substitution reaction as shown below to obtain the compound shown in Formula A. (2) In an organic solvent, under the action of a base, the compound shown in Formula A and N-phenyltrifluoroacetylimine chloride are subjected to an imidization reaction as shown below to obtain the compound shown in Formula B. (3) In a protective gas and an organic solvent, under the action of a Lewis acid, the compound shown in Formula B and the compound shown in Formula III are subjected to the following condensation reaction to obtain the compound shown in Formula I. (4) In an organic solvent, under the action of NBS, the compound shown in Formula I is reacted with water to obtain the compound shown in Formula C; (5) Under a protective gas and in an organic solvent, the compound shown in formula C is subjected to the following oxidation reaction to obtain the compound shown in formula IV. (6) In a solvent, under the action of a pyridine hydrogen fluoride complex, the compound shown in Formula IV undergoes the following deprotection reaction to obtain the compound shown in Formula V. (7) In a solvent, under the action of a catalyst and a hydrogen source, the compound shown in formula V is hydrogenated to obtain the compound shown in formula D. (8) In a solvent, under the action of a base, the compound shown in formula D is subjected to the following hydrolysis reaction to obtain the compound shown in formula VI. ； Among them, R 1 and R 2 Independently , or ;R 1-1 It can be hydrogen, methoxy, methyl, nitro, or halogen independently; R 3 Independently ;R 3-1 R 3-2 and R 3-3 Independently C1-C4 alkyl; R 4 Independently for -SR 4-1 ;R 4-1 Independently phenyl, or, R 4-1-1 Substituted phenyl; R 4-1-1 Independently C1-C4 alkyl; LG independently ;R 5 For one or more R 5-1 Substituted phenyl; R 5-1 Independently C1-C4 alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8, M + It can be a hydrogen ion or a metal cation; In step (8), the alkali is M. + OH - M + It is the metal cation mentioned above.

2. The method for preparing the compound as shown in Formula VI according to claim 1, characterized in that, The compound shown in formula D is , , or ; And / or, when M + When the metal cation is a metal cation, the metal cation is a sodium ion, a potassium ion, or a calcium ion; And / or, the solvent is water; And / or, the molar concentration of the compound of formula D in the solvent is 0.01 mol / L to 0.2 mol / L; And / or, the pH of the system in which the reaction is carried out is 12 to 13; And / or, the reaction temperature is room temperature; And / or, the reaction time of the said reaction is 10 h-48 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes adjusting the reaction system to neutral, filtering, concentrating, recrystallizing, centrifuging, washing and drying; And / or, the hydrolysis reaction includes the following steps: mixing and reacting the compound as shown in Formula D, the solvent, and the base.

3. The method for preparing the compound as shown in Formula VI according to claim 2, characterized in that, The molar concentration of the compound as shown in Formula D in the solvent is 0.03 mol / L-0.07 mol / L; And / or, the M + OH - It is sodium hydroxide; And / or, the reaction time of the reaction is 20 h-30 h; And / or, the reagent used to adjust the reaction system to neutrality is H + Ion exchange resin; And / or, the reagents used for the recrystallization are water and methanol; And / or, the reagent used for the washing is methanol; And / or, the drying method is air drying.

4. The method for preparing the compound as shown in Formula VI according to claim 3, characterized in that, And / or, the molar concentration of the compound of formula D in the solvent is 0.062 mol / L; And / or, the base is 1 M sodium hydroxide; And / or, the reaction time of the reaction is 24 h; And / or, the reagent used to adjust the reaction system to neutrality is DOWEX® 50WX4, 200-400 mesh H2O. + Ion exchange resin.

5. The method for preparing the compound of formula VI as described in claim 1, characterized in that, When R 1-1 When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine; And / or, R 1-1 It can be hydrogen, 4-methoxy, 4-methyl, 4-nitro, or 4-halogen independently; And / or, R 3-1 R 3-2 and R 3-3 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl independently; And / or, R 5-1 It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

6. The method for preparing the compound as shown in Formula VI according to claim 5, characterized in that, R 3-1 R 3-2 and R 3-3 It can be methyl or tert-butyl independently; And / or, R 5-1 It is methyl on its own.

7. The method for preparing the compound of formula VI as described in any one of claims 5-6, characterized in that, R 1 and R 2 Independently ; And / or, R 1-1 Independently hydrogen; And / or, LG is in the upright position.

8. The method for preparing the compound as shown in Formula VI according to claim 7, characterized in that, The compound shown in Formula II is , or ; And / or, the organic solvent is a ketone solvent; And / or, the molar concentration of the compound of formula II in the organic solvent is 0.05 mol / L to 0.2 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula II is 1:1 to 10:1; And / or, the volume molar ratio of the water to the compound shown in Formula II is 1:1-10:1 L / mol; And / or, the reaction temperature is 0 to -40°C. o C; And / or, the reaction time of the reaction is 0.5 h-3 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes quenching the reaction, extraction, washing, drying, filtration, concentration and purification to obtain a compound as shown in Formula A; And / or, the hydroxyl substitution reaction comprises the following steps: mixing the compound as shown in Formula II, the organic solvent, and the water, and then mixing it with the NBS to carry out the hydroxyl substitution reaction.

9. The method for preparing the compound of formula VI as described in claim 8, characterized in that, The ketone solvent mentioned is acetone; And / or, the molar concentration of the compound of formula II in the organic solvent is 0.1 mol / L to 0.15 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula II is 2:1 to 6:1; And / or, the volume molar ratio of the water to the compound shown in Formula II is 1:1-2:1 L / mol; And / or, the reaction temperature is -10°C. o C to -30 o C; And / or, the reaction time of the reaction is 0.5 h to 1.5 h; And / or, the reagents used in the quenching reaction are Na2S2O3 solution and NaHCO3 solution; And / or, the reagent used for the extraction is dichloromethane; And / or, the reagent used for the washing is a saturated NaCl solution; And / or, the reagent used for the drying is anhydrous Na2SO4; And / or, the purification method is rapid column chromatography.

10. The method for preparing the compound of formula VI as described in claim 9, characterized in that, The molar concentration of the compound as shown in Formula II in the organic solvent is 0.124 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula II is 4:1; And / or, the volume molar ratio of the water to the compound shown in Formula II is 1.24:1 L / mol; And / or, the reaction temperature is -20°C. o C; And / or, the reaction time of the reaction is 1 h.

11. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in Formula A is , or ; And / or, the organic solvent is a ketone solvent; And / or, the molar concentration of the compound of formula A in the organic solvent is 0.05 mol / L to 0.2 mol / L; And / or, the base is a carbonate; And / or, the molar ratio of the base to the compound shown in Formula A is 1:1 to 2:1; And / or, the molar ratio of the N-phenyltrifluoroacetylimine chloride to the compound shown in Formula A is 1:1-2:1; And / or, the reaction temperature is room temperature; And / or, the reaction time of the reaction is 1 h to 10 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes filtration and concentration to obtain the compound shown in Formula B. And / or, the iminolation reaction includes the following steps: The imidization reaction can be carried out by mixing the organic solvent, the base, the compound as shown in Formula A, and the N-phenyltrifluoroacetylimine chloride.

12. The method for preparing the compound of formula VI as described in claim 11, characterized in that, The ketone solvent mentioned is acetone; And / or, the molar concentration of the compound of formula A in the organic solvent is 0.1 mol / L to 0.15 mol / L; And / or, the carbonate is potassium carbonate; And / or, the molar ratio of the base to the compound as shown in Formula A is 1:1 to 1.5:1; And / or, the molar ratio of the N-phenyltrifluoroacetylimine chloride to the compound shown in Formula A is 1:1 to 1.3:1; And / or, the reaction time of the said reaction is 3 h-7 h; And / or, the post-processing steps include a purification step.

13. The method for preparing the compound of formula VI as described in claim 12, characterized in that, The molar concentration of the compound as shown in Formula A in the organic solvent is 0.124 mol / L; And / or, the molar ratio of the base to the compound as shown in Formula A is 1.3:1; And / or, the molar ratio of the N-phenyltrifluoroacetylimine chloride to the compound shown in Formula A is 1.1:1; And / or, the reaction time is 5 h.

14. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in Formula B is , or ; And / or, the compound shown in Formula III is , or ; And / or, the protective gas is argon; And / or, the organic solvent is a halocarbon solvent; And / or, the molar concentration of the compound of formula B in the organic solvent is 0.05 mol / L to 0.2 mol / L; And / or, the Lewis acid is one or more of trifluoromethanesulfonic acid, TMSOTf, TESOTf, TBSOTf, Au-L-OTf, Au-L-NTf2, and NIS, wherein L is triphenylphosphine, tributylphosphine, triethylphosphine, or triadamantylphosphine. And / or, the molar ratio of the Lewis acid to the compound shown in Formula B is 0.001:1-2:1; And / or, the molar ratio of the compound of formula III to the compound of formula B is 0.5:1 to 10:1; And / or, the reaction temperature is -78°C. o C to -30 o C; And / or, the reaction time of the reaction is 1 h to 10 h; And / or, the reaction system is an anhydrous system; And / or, the compounds shown in Formula B and Formula III are dried compounds shown in Formula B and Formula III. And / or, the reaction system further includes a desiccant; And / or, the condensation reaction includes the following steps: under the protective gas, mixing the organic solvent, the compound of formula B, the desiccant and the compound of formula III, and then mixing with the Lewis acid to carry out the condensation reaction; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes quenching the reaction, filtering, concentrating and purifying to obtain a compound as shown in Formula I.

15. The method for preparing the compound of formula VI as described in claim 14, characterized in that, The organic solvent is a dry halogenated hydrocarbon solvent; And / or, the molar concentration of the compound of formula B in the organic solvent is 0.1 mol / L to 0.15 mol / L; And / or, the Lewis acid is TBSOTf; And / or, the molar ratio of the Lewis acid to the compound shown in Formula B is 0.1:1 to 0.5:1; And / or, the molar ratio of the compound of formula III to the compound of formula B is 1:1 to 1.3:1; And / or, the reaction temperature is -30°C. o C to -50 o C; And / or, the reaction time of the said reaction is 3 h-7 h; And / or, the drying method is to mix the compound shown in Formula B and the compound shown in Formula III, remove water from toluene three times, and then dry under vacuum; And / or, the desiccant is one or more of 3Å molecular sieve, 4Å molecular sieve, 5Å molecular sieve, anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous copper sulfate and anhydrous magnesium sulfate; And / or, the reagent used in the quenching reaction is triethylamine; And / or, the purification method is rapid column chromatography.

16. The method for preparing the compound of formula VI as described in claim 15, characterized in that, The halocarbon solvent mentioned is dichloromethane; And / or, the molar concentration of the compound of formula B in the organic solvent is 0.124 mol / L; And / or, the molar ratio of the Lewis acid to the compound shown in Formula B is 0.2:1; And / or, the molar ratio of the compound of formula III to the compound of formula B is 1.06:1; And / or, the reaction temperature is -40°C. o C; And / or, the reaction time of the reaction is 5 h; And / or, the desiccant is an activated 4Å molecular sieve.

17. The method for preparing the compound of formula VI as described in claim 16, characterized in that, The mass ratio of the desiccant to the compound shown in Formula B is 1:1 to 3:

1.

18. The method for preparing the compound of formula VI as described in claim 17, characterized in that, The mass ratio of the desiccant to the compound shown in Formula B is 5:

3.

19. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in Formula I is , , or ; And / or, the organic solvent is a ketone solvent; And / or, the molar concentration of the compound of Formula I in the organic solvent is 0.05 mol / L to 0.2 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula I is 1:1 to 10:1; And / or, the volume molar ratio of the water to the compound shown in Formula I is 0.1:1 to 10:1; And / or, the reaction temperature is 0 to -40°C. o C; And / or, the reaction time of the reaction is 0.5 h-3 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes quenching the reaction, extraction, washing, drying, filtration, concentration and purification to obtain a compound as shown in Formula C; And / or, the preparation method of the compound shown in Formula C includes the following steps: mixing the compound shown in Formula I, the organic solvent and the water, and then mixing it with the NBS to carry out the reaction.

20. The method for preparing the compound of formula VI as described in claim 19, characterized in that, The ketone solvent mentioned is acetone; And / or, the molar concentration of the compound of Formula I in the organic solvent is 0.05 mol / L to 0.12 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula I is 2:1 to 6:1; And / or, the volume molar ratio of the water to the compound shown in Formula I is 0.6:1-2:1; And / or, the reaction temperature is -10°C. o C to -30 o C; And / or, the reaction time of the reaction is 0.5 h to 1.5 h; And / or, the reagents used in the quenching reaction are Na2S2O3 solution and NaHCO3 solution; And / or, the reagent used for the extraction is ethyl acetate; And / or, the reagent used for the washing is a saturated NaCl solution; And / or, the reagent used for the drying is anhydrous Na2SO4; And / or, the purification method is rapid column chromatography.

21. The method for preparing the compound of formula VI as described in claim 20, characterized in that, And / or, the molar concentration of the compound of Formula I in the organic solvent is 0.095 mol / L; And / or, the molar ratio of the NBS to the compound shown in Formula I is 4:1; And / or, the volume molar ratio of the water to the compound shown in Formula I is 1.05:1 L / mol; And / or, the reaction temperature is -20°C. o C; And / or, the reaction time of the reaction is 1 h.

22. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in formula C is , , or ; And / or, the protective gas is argon; And / or, the organic solvent is a sulfone solvent; And / or, the molar concentration of the compound of formula C in the organic solvent is 0.05 mol / L to 0.5 mol / L; And / or, the oxidant is a mixture of dimethyl sulfoxide and acetic anhydride; And / or, the molar ratio of the oxidant to the compound shown in Formula C is 1:1 to 40:1; And / or, the reaction temperature is room temperature; And / or, the reaction time of the said reaction is 10 h-48 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes quenching the reaction, extraction, washing with water, washing, drying, filtering, concentration and purification to obtain the compound shown in Formula IV; And / or, the oxidation reaction includes the following steps: mixing the solvent, the oxidant and the compound as shown in Formula C to carry out the reaction.

23. The method for preparing the compound of formula VI as described in claim 22, characterized in that, The organic solvent is dimethyl sulfoxide; And / or, the molar concentration of the compound of formula C in the organic solvent is 0.1 mol / L to 0.25 mol / L; And / or, the volume ratio of dimethyl sulfoxide to acetic anhydride in the mixture is 10:1-2:1; And / or, the molar ratio of the oxidant to the compound shown in Formula C is 15:1 to 25:1; And / or, the reaction time of the reaction is 20 h-30 h; And / or, the reagent used in the quenching reaction is water; And / or, the reagent used for the extraction is ethyl acetate; And / or, the reagents used for the washing are saturated NaHCO3 solution and saturated NaCl solution; And / or, the reagent used for the drying is anhydrous Na2SO4; And / or, the purification method is rapid column chromatography.

24. The method for preparing the compound of formula VI as described in claim 23, characterized in that, The molar concentration of the compound shown in Formula C in the organic solvent is 0.173 mol / L; And / or, the volume ratio of dimethyl sulfoxide to acetic anhydride in the mixture is 11:3.6; And / or, the molar ratio of the oxidant to the compound shown in Formula C is 20:1; And / or, the reaction time is 24 h.

25. The method for preparing the compound of formula VI as described in claim 24, characterized in that, When the oxidant is a mixture of dimethyl sulfoxide and acetic anhydride, the dimethyl sulfoxide is the solvent.

26. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in Formula IV is , , or ; And / or, the solvent is an ether solvent; And / or, the molar concentration of the compound of formula IV in the solvent is 0.01 mol / L to 1 mol / L; And / or, the molar ratio of the hydrogen fluoride pyridine complex to the compound shown in Formula IV is 2:1 to 20:1; And / or, the reaction temperature is 10°C. o C to 80 o C; And / or, the reaction time of the reaction is 10 h-36 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes quenching the reaction, extraction, washing, drying, filtration, concentration and purification; And / or, the deprotection reaction comprises the following steps: mixing the compound as shown in Formula IV with the solvent, and then mixing it with the pyridine hydrogen fluoride complex to carry out the reaction.

27. The method for preparing the compound of formula VI as described in claim 26, characterized in that, The ether solvent is tetrahydrofuran; And / or, the molar concentration of the compound of formula IV in the solvent is 0.05 mol / L to 0.2 mol / L; And / or, the molar ratio of the pyridine hydrogen fluoride complex to the compound shown in Formula IV is 7:1 to 12:1; And / or, the reaction temperature is 20°C. o C to 60 o C; And / or, the reaction time of the reaction is 15 h-25 h; And / or, the reagent used in the quenching reaction is a saturated NaHCO3 solution; And / or, the reagent used for the extraction is dichloromethane; And / or, the reagent used for the washing is a saturated NaCl solution; And / or, the reagent used for the drying is anhydrous Na2SO4; And / or, the purification method is rapid column chromatography.

28. The method for preparing the compound of formula VI as described in claim 27, characterized in that, The molar concentration of the compound as shown in Formula IV in the solvent is 0.1 mol / L; And / or, the molar ratio of the hydrogen fluoride pyridine complex to the compound shown in Formula IV is 9:1; And / or, the reaction temperature is 40°C. o C; And / or, the reaction time is 20 h.

29. The method for preparing the compound of formula VI as described in claim 1, characterized in that, The compound shown in formula V is , , or ; And / or, the solvent is an ether solvent, water, an alcohol solvent, or an organic acid solvent; And / or, the molar concentration of the compound of formula V in the solvent is 0.01 mol / L to 0.2 mol / L; And / or, the catalyst is palladium on carbon and palladium hydroxide on carbon; And / or, the mass molar ratio of the catalyst to the compound shown in Formula V is 100:1 g / mol - 400:1 g / mol; And / or, the hydrogen source is hydrogen gas; And / or, the reaction temperature is room temperature; And / or, the reaction time of the said reaction is 10 h-48 h; And / or, the reaction further includes a post-processing step after completion; the post-processing step includes filtration and concentration; And / or, the hydrogenation reaction includes the following steps: mixing the compound as shown in Formula V, the solvent, and the catalyst, and reacting them under a hydrogen source.

30. The method for preparing the compound of formula VI as described in claim 29, characterized in that, The ether solvent is tetrahydrofuran; And / or, the alcohol solvent is tert-butanol; And / or, the organic acid solvent is acetic acid; And / or, the molar concentration of the compound of formula V in the solvent is 0.03 mol / L to 0.07 mol / L; And / or, the palladium on carbon is 10% palladium on carbon with a water content of 55%; And / or, the palladium hydroxide on carbon is 10% palladium hydroxide on carbon with a water content of 50%; And / or, the mass molar ratio of the catalyst to the compound shown in Formula V is 230:1 g / mol to 290:1 g / mol; And / or, the reaction is carried out in a hydrogen atmosphere; And / or, the reaction time is 20 h-30 h.

31. The method for preparing the compound of formula VI as described in claim 30, characterized in that, The volume ratio of the ether solvent, water, alcohol solvent, and organic acid solvent is 5:5:1:0.1; And / or, the molar concentration of the compound of formula V in the solvent is 0.047 mol / L; And / or, the mass molar ratio of the catalyst to the compound shown in Formula V is 256:1 g / mol; And / or, the pressure of the reaction is 1 atm; And / or, the reaction time is 24 h.

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