Method for preparing glycoside compounds

Abstract

The present invention relates to a method for preparing glycoside compounds, which has a short synthesis process step, a single product structure, high selectivity and yield, simple production operation, low equipment requirements, and environmental friendliness, making it suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to a method for preparing glycoside compounds and belongs to the field of pharmaceutical chemical synthesis.

Background Art

[0002] Cerebrovascular diseases refer to a series of diseases in which cerebral arteries or carotid arteries that dominate the brain are damaged, interfering with intracranial blood circulation and causing damage to brain tissue. Clinically, the main symptoms include sudden lethargy, unconsciousness, or deviation of the eyes, poor speech, hemiplegia, etc. Ischemic cerebrovascular diseases mainly refer to cerebral thrombosis, cerebral embolism, multiple cerebral infarcts, etc. This disease is characterized by sudden onset, rapid progression, and critical condition. Also, since it mainly occurs in the elderly, damage to multiple organ functions is likely to occur, the prognosis is poor, and the mortality rate is high. Ischemic cerebrovascular diseases are also called cerebral infarcts because the blood flow in cerebral arteries is suddenly blocked and the brain tissue in the corresponding area undergoes ischemic necrosis.

[0003] Cerebral stroke, also known as "cerebral hemorrhage" or Cerebral Vascular Accident (CVA), is one of the most important fatal diseases in the world. It is a series of diseases in which sudden rupture of blood vessels in the brain or occlusion of blood vessels that prevent blood from flowing into the brain causes damage to brain tissue, including ischemic stroke and hemorrhagic stroke. The incidence of ischemic stroke is higher than that of hemorrhagic stroke. Ischemic stroke is caused by ischemic and hypoxic lesions due to blood supply disorders in local brain tissue areas caused by various reasons, leading to necrosis of brain tissue, and further causing clinical neurological deficits, which seriously affects the quality of life of patients.

[0004] The focus of research on pathological interventions for ischemic injury is mainly to improve cerebral blood circulation and neuroprotection. Among them, currently, the measures to improve cerebral blood circulation are mainly antithrombotic therapies. Antithrombotic drugs can be divided into thrombolytic drugs, antiplatelet aggregation drugs, and anticoagulants. Currently, neuroprotective drugs mainly include calcium ion antagonists, glutamate antagonists, glutamate release inhibitors, GABA receptor agonists, free radical scavengers, cell membrane stabilizers, and so on.

[0005] In recent years, the discovery of promoting angiogenesis has provided a new direction for the effective treatment of ischemic vascular diseases and has also become a hot spot in medical research. Angiogenesis can promote the survival of neurons after stroke and improve neurological deficits and quality of life after stroke. However, the influencing factors and regulatory mechanisms of angiogenesis after stroke are complex. In recent years, studies have shown that PAR1 is involved in processes such as microvascular angiogenesis and nerve repair after stroke. Angiogenesis refers to the formation of new capillaries by sprouting and / or non-sprouting from existing blood vessels. The main processes of angiogenesis include increasing vascular permeability, generating proteolytic enzymes, degrading the extracellular matrix to promote endothelial cell proliferation, separating endothelial cells from the basement membrane, moving them into the perivascular space, forming a three-dimensional lumen by adhesion-proliferation-remodeling, differentiating into new capillaries, allowing stromal cells to enter the vascular wall under the induction of intermediate molecules to stabilize and mature the blood vessels. Under normal physiological conditions, blood vessels in the body maintain a high degree of stability once formed and are regulated by many important molecules with positive or negative regulatory effects, namely, angiogenic factors and angiogenesis inhibitors. The initiation of angiogenesis is turned on only for a short time by the appearance of a stimulating signal and then turned off to maintain a dynamic balance between angiogenesis and regression. Factors affecting microvascular angiogenesis after stroke include the status of local blood supply and oxygen supply, changes in thrombin and its concentration, levels of angiogenic factors such as hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), etc. PAR1 usually plays a role in promoting angiogenesis by interacting with angiogenic factors. VEGF is currently recognized as a factor playing an important role in angiogenesis. Under normal circumstances, VEGF is expressed only in small amounts and maintains vascular density and permeability under physiological conditions. Some pathological processes such as inflammation, tumors, wound healing, ischemia, and hypoxia may promote the expression of VEGF.In stroke patients, the expression of VEGF in neurons and glial cells around the stroke lesion increases. By specifically binding to endothelial cell surface receptors, it promotes the proliferation and migration of vascular endothelial cells, increases vascular permeability, increases factors that degrade the extracellular matrix, thereby promoting angiogenesis.

[0006] Glycoside compounds are widely present in nature, and these compounds have various biological activities. Various glycoside compounds have attracted much attention due to their special medicinal effects. Currently, the main method for obtaining glycoside compounds is still biological extraction, and chemical synthesis methods still have significant limitations in terms of production scale, cost, and environmental protection.

[0007] The inventors unexpectedly discovered in previous studies that glycoside compounds with specific structures, their tautomers, optical isomers, solvates, polymorphs, pharmaceutically acceptable salts, esters, pharmaceutically acceptable prodrugs or derivatives can prevent and / or treat ischemic cerebrovascular diseases. Such glycoside compounds can be applied to all symptoms and / or pathological changes from the early to the late stages of brain tissue ischemia caused by vascular wall lesions, changes in blood components, and / or vascular lesions caused by hemodynamic changes.

[0008] The glycoside compound can be a glycoside compound represented by the following formula I, its tautomer, optical isomer, solvate, polymorph, pharmaceutically acceptable salt, ester, pharmaceutically acceptable prodrug or derivative.

[0009]

Chemical formula

[0010] It is used for the prevention and / or treatment of ischemic cerebrovascular diseases, R 1 , R 2 , R 3 , R 4 and R 5are each independently hydrogen, hydroxyl, sulfhydryl group, substituted or unsubstituted C1-C 20 alkoxy (e.g., substituted or unsubstituted C1-C 10 alkoxy, substituted or unsubstituted C1-C6 alkoxy), nitro or halogen, or R 1 , R 2 , R 3 , R 4 and R 5 any two adjacent groups in form a 5- to 7-membered heterocycle with the carbon atom to which they are attached to the benzene ring (e.g., said R 2 and R 3 form a 5- to 7-membered heterocycle), the heteroatom of the heterocycle is O or S (e.g., O), the number of heteroatoms is one or more (e.g., two), and when the number of heteroatoms is more than one, the heteroatoms are the same or different, the substituent in the substituted or unsubstituted C1-C 20 alkoxy is selected from C3-C 20 cycloalkyl (e.g., C3-C 10 cycloalkyl, C3-C6 cycloalkyl), C2-C 20 alkylene (e.g., C2-C6 alkylene, C2-C4 alkylene, or

Chemical formula

[0011] For example, substituted or unsubstituted C2-C 10heteroaryl, or substituted or unsubstituted C2-C6 heteroaryl), C3-C6 cycloalkoxy (e.g., (

Chemical Structure

Chemical Structure

[0012] When the inventors previously prepared glycoside compounds, they synthesized the glycoside compounds using a three-step method. Taking the preparation of glycoside compound IV-3 as an example:

[0013]

Chemical formula

[0014] In this reaction pathway, glucose ester I was used as the raw material, and intermediate V-3 and III-3 were reacted to finally obtain glycoside compound IV-3, with a total yield of about 12%. The bromination reaction in the first step required a large amount of hydrobromic acid, the conditions were harsh, a large amount of waste acid was generated, which was disadvantageous for environmental protection. The reaction in the second step required an expensive silver catalyst, resulting in high costs. In the last step of acetyl elimination, excessive triethylamine was used as the base, making separation and purification difficult, and the yield of the last step was only 64%.

[0015] Currently, the chemical synthesis methods of glycoside compounds mainly include the following methods. (1) In the Koenigs-Knorr glycosylation reaction method, an α-halogeno sugar is subjected to a substitution reaction with an alcohol under the action of silver carbonate to prepare a glycoside. First, a glycosyl halide is synthesized, and it is necessary to use an expensive silver reagent. This is the most common synthesis method. (2) In the Schmidt trichloroimidyl glycosylation reaction method, trichloroacetonitrile and glycosyl hemiacetal are added under alkaline conditions to obtain trichloroacetimidate ester, and then it reacts with an alcohol or phenol under the catalysis of a Lewis acid to generate a glycoside. This method generates trichloroacetonitrile, which is a Class 3 carcinogen, and trichloroacetamide, which is a genotoxic by-product during the reaction. (3) In the Kahne glycosylation reaction method, glycosyl sulfoxide is activated by trifluoromethanesulfonic anhydride, and then it reacts with an alcohol and phenol to obtain the corresponding glycoside compound. The temperature of this reaction is -30~-78°C, and the conditions are harsh. (4) Other glycoside synthesis methods, other glycosylation methods include the phase change catalyst method, the trifluoroacetate method, etc. All of them are improvements of the conventional methods, but there are also some problems and limitations.

Summary of the Invention

Problems to be Solved by the Invention

[0016] Therefore, in the prior art, there are still many difficulties and problems in the method for synthesizing and preparing glycosides with high selectivity, high efficiency, more economical and excellent environmental protection. The inventor carefully studied the synthetic process route of glycosides, and through a lot of experiments and creative work, shortened the process steps, improved the yield and stereoselectivity of the compounds, reduced the production cost, and discovered a method for preparing glycosides suitable for industrial large-scale production. And in a series of glycoside compounds constructed by this method, the compounds with a certain specific structure have the potential for drug application in cerebrovascular diseases.

Means for Solving the Problems

[0017] The present invention provides a method for preparing a glycoside compound, which is characterized by including the following two-step reaction steps.

[0018] (1) React an acetyl-protected glucose ester (I) with an alcohol compound represented by formula (II) under the catalysis of a Lewis acid to obtain an intermediate represented by formula (III).

[0019]

Chemical formula

[0020]

Chemical formula

[0021] Among them, in formulas II, III and IV, the substituents R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, hydroxyl, substituted or unsubstituted C1-C 20 alkoxy, substituted or unsubstituted C1-C 20 alkyl, substituted or unsubstituted C1-C 20 alkenyl, substituted or unsubstituted C1-C 20 alkynyl, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocyclyl, nitro or halogen, n is 4, 5, or 6.

[0022] Preferably, the reaction in step (1) is carried out in a first organic solvent, and the organic solvent is one or more of dichloromethane, chloroform, toluene, xylene, dimethylformamide, dioxane, methyl-t-butyl ether or tetrahydrofuran.

[0023] Preferably, the Lewis acid in step (1) is one or more of tin tetrachloride, zinc chloride, aluminum trichloride, boron trifluoride complex, such as boron trifluoride diethyl ether complex, boron trifluoride butyl ether complex, boron trifluoride tetrahydrofuran complex, boron trifluoride acetonitrile complex or trimethylsilyl trifluoromethanesulfonate.

[0024] Preferably, step (1) is carried out under the protection of nitrogen or argon which is an inert gas.

[0025] Preferably, the reaction temperature of step (1) is -15 to 60 °C. A more preferable reaction temperature is -5 to 40 °C.

[0026] Preferably, the reaction of step (2) is carried out in a second organic solvent, and the second organic solvent is one or more of methanol, ethanol, isobutanol or tert-butanol.

[0027] Preferably, the alkaline condition in step (2) is a condition in which sodium hydroxide, potassium hydroxide or a sodium salt of C1-C4 alkanol is present, and more preferably a condition in which sodium methoxide, sodium ethoxide or sodium tert-butoxide is present.

[0028] The present invention specifically includes the following operation procedures.

[0029] 1) In step (1), first, the reaction flask is exchanged with an inert gas three times, the first solvent is added, and stirring is started. Then, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and alcohol II are sequentially added, and the temperature of the reaction flask is controlled to -15 to 60 °C, more preferably -5 to 40 °C. A Lewis acid is added, and then stirring is continued for 2 to 24 h, preferably 4 to 12 h.

[0030] 2) In step (1), after the reaction is completed, water is added dropwise to the reaction system for rapid cooling, the liquid is separated, the organic phase is washed with an aqueous Na2CO3 solution, the liquid is separated, and the organic phase is washed with water again. After separating the liquid, the organic phase is collected. The organic phase is concentrated until the distillate clearly disappears, and then column chromatography and separation are performed to obtain Compound III.

[0031] 3) In step (2), first, the reaction flask is purged with an inert gas three times, a second solvent is added, and stirring is started. Intermediate III is added to the reaction flask, the temperature is controlled at 25 ± 5 °C, sodium hydroxide, potassium hydroxide, or a sodium salt of C1-C4 alkanol is added to the reaction flask, more preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide sodium methoxide is added, and the mixture is stirred for 2 h to react.

[0032] 4) In step (2), after the reaction is completed, diatomaceous earth is filtered, rinsed with a second solvent, and then the filtrate is collected. + (H + ) type ion exchange resin is added and stirred for 10 h. The (H

[0033] The characteristics of the glycoside compound synthesized by the preparation method of the present invention are that Compound IV can be the following examples, but is not limited to the following structures.

[0034]

Chemical formula

[0035] This application has the following beneficial effects. Compared with the conventional glycoside synthesis technology, the method of the present invention uses peracetylated monosaccharides and alcohol hydroxyl ligands to directly condense under the catalytic action of Lewis acid to obtain tetraacetylated glycoside, which is an intermediate, and then deacetylate it by alcoholysis under alkaline conditions to directly obtain the target glycoside compound. The steps of this synthesis process are short, the composition of the product is single, the stereoselectivity is high, the total yield is high, the production operation is simple, the requirements for equipment are low, it is environmentally friendly and suitable for large-scale industrial production. And among a series of glycoside compounds constructed by this method, compounds with certain specific structures therein have the prospect of potential drug application for cerebrovascular diseases.

[0036] Definition of terms "Alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, generally having from 1 to about 12 carbon atoms. The term C1-C6 alkyl as used herein refers to an alkyl having from 1 to about 6 carbon atoms. When combined with another group herein to form C0-C n When using alkyl, taking (phenyl)C0-C4 alkyl as an example, for the specified group, in this case, phenyl is directly bonded via a single covalent bond (C0) or bonded via an alkyl chain having the specified number of carbon atoms (in this case, from 1 to about 4 carbon atoms). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, n-amyl, and sec-pentenyl.

[0037] "Alkenyl" or "alkylene" refers to straight-chain and branched hydrocarbon chains containing one or more unsaturated carbon-carbon bonds, and the carbon-carbon bonds can occur at any stable point along the chain. The alkenyl described herein usually has from 2 to about 12 carbon atoms. Preferred alkenyls are lower alkenyls, and those alkenyls have from 2 to about 8 carbon atoms, such as C2-C8, C2-C6, and C2-C4 alkenyls. Examples of alkenyl include vinyl, propenyl, and butenyl.

[0038] "Alkoxy" refers to the alkyl as defined above having a specified number of carbon atoms bonded through an oxygen bridge. Examples of alkoxy include methoxy, ethoxy, 3-ethoxy, and 3-methylpentyloxy.

[0039] The term "heterocycle" refers to a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring having from 1 to about 4 heteroatoms selected from N, O, and S and the remaining ring atoms being carbon, or a 7- to 11-membered saturated ring, a partially unsaturated ring, or an aromatic heterocyclic system and a 10- to 15-membered tricyclic system, the system having at least one heteroatom selected from N, O, and S in the polycyclic system and having up to about 4 heteroatoms independently selected from N, O, and S in each ring of the polycyclic system. Unless otherwise specified, the heterocycle can be bonded to a group that is substituted with any heteroatom and carbon atom to provide a stable structure. When specified, the heterocycle herein is substituted with a carbon or nitrogen atom as long as the resulting compound is stable. Optionally a nitrogen atom in the heterocycle is quaternized. Preferably, the total number of heteroatoms in the heterocyclic group is 4 or less, and the total number of S and O atoms in the heterocyclic group is 2 or less, more preferably 1 or less. Examples of heterocyclic groups include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetraazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinoline, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.

[0040] "Aryl" or "heteroaryl" means a stable 5- or 6-membered monocyclic or polycyclic ring having 1 to 4, preferably 1 to 3 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl is 2 or less. Particularly preferably, the total number of S and O atoms in the heteroaryl is 1 or less. Optionally, it is a nitrogen atom in a quaternized heterocycle. When specified, these heteroaryls may be substituted with carbon or non-carbon atoms or groups. Such substitutions include condensations with 5- to 7-membered saturated ring groups having 1 or 2 heteroatoms optionally independently selected from N, O and S, for example forming [1,3]dioxazolo[4,5-c]pyridyl. Examples of heteroaryls include, but are not limited to, pyridyl, indolyl, pyrimidinyl, pyridinidinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benz[b]thiophenyl, isoquinoline, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7,8-tetrahydroisoquinoline.

Mode for Carrying Out the Invention

[0041] Hereinafter, the present invention will be further described in detail in conjunction with specific embodiments, but such examples are used to explain the present invention and do not limit the scope of the present invention.

Examples

[0042] Example 1: Synthesis of 1-[4-(2-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-1

Chemical Formula

[0043] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 2-methoxyphenylbutanol II-1. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride tetrahydrofuran complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fraction disappears, and then perform column chromatography and separation to obtain compound III-1 with a yield of 30%. 1 H NMR (400 MHz, CDCl3): δ 6.32 (d, J = 2.2 hz, 2H), 6.29 (t, J = 2.2 hz, 1H), 5.20 (t, J = 9.5 hz, 1H), 5.08 (t, J = 9.7 hz, 1H), 4.98 (dd, J = 9.6, 8.0 hz, 1H), 4.48 (d, J = 8.0 hz, 1H), 4.26 (dd, J = 12.3, 4.7 hz, 1H), 4.13 (dd, J = 12.3, 2.3 hz, 1H), 3.89 (d, J = 9.5 hz, 1H), 3.78 (s, 6H), 3.68 (dd, J = 9.9, 2.2 hz, 1H), 3.49 (d, J = 9.4 hz, 1H), 2.55 (t, J = 6.6 hz, 2H), 2.08 (s, 3H), 2.05 - 1.97 (m, 9H), 1.63 (dd, J = 11.5, 4.3 hz, 4H). LRMS (ESI): [M+Na] + 533.5.

[0044] Synthesis of 1-(2-methoxy)benzyl-β-D-glucopyranoside IV-1

Chemical formula

[0045] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-1 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. By filtration, (H + )-type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain the final product IV-1, and the yield is 89%. 1 H NMR (400 MHz, CD3OD): δ 7.17 - 7.06 (m, 2H), 6.88 (d, J = 8.0 hz, 1H), 6.82 (td, J = 7.4, 0.9 hz, 1H), 4.23 (d, J = 7.8 hz, 1H), 3.91 (m, 1H), 3.85 (dd, J = 11.9, 2.0 hz, 1H), 3.80 (s, 3H), 3.66 (dd, J = 11.9, 5.3 hz, 1H), 3.55 (m, 1H), 3.37 - 3.21 (m, 3H), 3.19 - 3.12 (m, 1H), 2.61 (t, J = 7.0 hz, 2H), 1.64 (m, 4H). LRMS (ESI): [M+Na] + 365.1; LRMS (ESI): [M+H] + Calculated C 17 H 27 O7 + 343.1751, found 343.1748.

[0046] Example 2: Synthesis of 1-[4-(3-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-2

Chemical formula

[0047] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 3-methoxyphenylbutanol II-2. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride diethyl ether complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain the final product III-2, with a yield of 26%. 1 1H NMR (300 MHz, CDCl3): δ 7.19 (t, J = 8.1 hz, 1H), 6.81 - 6.65 (m, 3H), 5.28 - 4.88 (m, 3H), 4.48 (d, J = 8.0 hz, 1H), 4.32 - 4.06 (m, 2H), 3.88 (m, 1H), 3.80 (s, 3H), 3.68 (d, J = 8.2 hz, 1H), 3.51 (m, 1H), 2.59 (m, 2H), 2.03 (m, 12H), 1.64 (m, 4H). LRMS (ESI): [M+Na] + 533.5。

[0048] Synthesis of 1-(3-methoxy)benzyl-β-D-glucopyranoside IV-2

Chemical Structure

[0049] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-2 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Filter to obtain (H +) type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain the final product IV-2, and the yield is 92%. 1 H NMR (400 MHz, CD3OD): δ 7.15 (t, J = 7.8 hz, 1H), 6.79 - 6.67 (m, 3H), 4.24 (d, J = 7.8 hz, 1H), 3.92 (dt, J = 9.4, 6.4 hz, 1H), 3.85 (dd, J = 11.9, 1.8 hz, 1H), 3.76 (s, 3H), 3.66 (dd, J = 11.9, 5.2 hz, 1H), 3.60 - 3.51 (m, 1H), 3.39 - 3.21 (m, 3H), 3.19 - 3.12 (m, 1H), 2.60 (t, J = 7.3 hz, 2H), 1.78 - 1.56 (m, 4H). LRMS (ESI): [M + Na] + 365.1, HRMS (ESI): [M + NH4] + Calculated value C 17 H 30 O7N + 360.2017, found 360.2016.

[0050] Example 3: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

Chemical Structure

[0051] Operating procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride diethyl ether complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until it is clearly free of fractions, and then perform column chromatography and separation to obtain compound III-3, with a yield of 37%. 1 H NMR(400 MHz,CDCl3): δ 7.0(d,J=8.6hz,2H),6.82(t,J=5.7hz,2H),5.20(t,J=9.5hz,1H),5.08(t,J=9.7hz,1H),4.98(t,J=9.6,8.0hz,1H),4.48(d,J=8.0hz,1H),4.26(dd,J=12.3,4.7hz,1H),4.16-4.07(m,1H),3.89(dd,J=5.8,3.7hz,1H),3.78(s,3H),3.68(m,J=9.9,4.6,2.4Hz,1H),3.49(dt,J=9.4,6.1hz,1H),2.55(t,J=6.6Hz,2H),2.08(s,3H),2.05-1.96(m,9H),1.68-1.52(m,4H). LRMS(ESI): [M+Na] + 533.2。

[0052] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical Structure

[0053] Operating procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + ) type ion exchange resin is added and stirred for 10 h. By filtration, (H + ) type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain the final product IV-3, and the yield is 91%. 1 H NMR (400 MHz, DMSO-d6): δ 7.10 (d, J = 8.5 hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.10 - 4.78 (m, 3H), 4.45 (t, J = 5.9 hz, 1H), 4.09 (d, J = 7.8 hz, 1H), 3.77 (m, J = 12.5, 6.4 hz, 1H), 3.71 (s, 3H), 3.65 (dd, J = 10.8, 6.0 hz, 1H), 3.49 - 3.37 (m, 2H), 3.17 - 2.98 (m, 3H), 2.92 (td, J = 8.3, 5.1 hz, 1H), 2.55 - 2.5 (m, 2H), 1.69 - 1.41 (m, 4H). LRMS (ESI): [M+Na] + 365.0, HRMS (ESI): [M+Na] + Calculated value C 17 H 26 O7Na + 365.1571, measured value 365.1569.

[0054] Example 4: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

Chemical Structure

[0055] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride diethyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fraction disappears, and then perform column chromatography and separation to obtain compound III-3 with a yield of 38%. 1 1H NMR and LRMS were consistent with Example 3.

[0056] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical formula

[0057] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 (1.0 eq) to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h for reaction. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3 with a yield of 89%. 1 1H NMR and LRMS were consistent with Example 3.

[0058] Example 5: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3 [Chemical formula]

[0059] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride tetrahydrofuran complex, and continue stirring for 12 h after the addition. After the reaction, dropwise add water to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-3, with a yield of 34%. 1 1H NMR and LRMS were consistent with those of Example 3.

[0060] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3 [Chemical formula]

[0061] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, with a yield of 85%. 1 1H NMR and LRMS were consistent with those of Example 3.

[0062] Example 6: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3 [Chemical formula]

[0063] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride tetrahydrofuran complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-3, with a yield of 32%. 1 1H NMR and LRMS were consistent with Example 3.

[0064] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3 [Chemical formula]

[0065] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-3 (1.0 eq) to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, with a yield of 84%. 11H NMR and LRMS were consistent with those of Example 3.

[0066] Example 7: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

[0067]

Chemical formula

[0068] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical formula

[0069] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. + Add (H +) The type ion-exchange resin is removed. After concentrating the organic phase, column chromatography and separation are performed to obtain the final product IV-3, with a yield of 91%. 1 1H NMR and LRMS were consistent with those in Example 3.

[0070] Example 8: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

Chemical formula

[0071] Operation procedure: The reaction flask is purged with nitrogen three times, dichloromethane is added as a solvent, and stirring is started. Then, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3 are added sequentially. The reaction flask is cooled to 0 ± 5 °C, boron trifluoride butyl ether complex is added dropwise, and stirring is continued for 12 h after the addition. After the reaction, water is added dropwise to the reaction system for rapid cooling, the liquid is separated, the organic phase is washed with an aqueous Na2CO3 solution, the liquid is separated, and the organic phase is washed with water again. After separating the liquid, the organic phase is collected. The organic phase is concentrated until no obvious fraction remains, and then column chromatography and separation are performed to obtain compound III-3, with a yield of 33%. 1 1H NMR and LRMS were consistent with those in Example 3.

[0072] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical formula

[0073] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to cause a reaction. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. (H + ) type ion exchange resin is added and stirred for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, and the yield was 95%. 1 1H NMR and LRMS were consistent with Example 3.

[0074] Example 9: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

Chemical formula

[0075] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride acetonitrile complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until there is no obvious fraction left, and then perform column chromatography and separation to obtain compound III-3, and the yield was 36%. 1 1H NMR and LRMS were consistent with Example 3.

[0076] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3 [Chemistry]

[0077] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, and the yield was 88%. 1 1H NMR and LRMS were consistent with Example 3.

[0078] Example 10: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3 [Chemistry]

[0079] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride acetonitrile complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until there is no obvious fraction left, and then perform column chromatography and separation to obtain compound III-3, and the yield was 30%. 1 1H NMR and LRMS were consistent with Example 3.

[0080] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3 [Chemical formula]

[0081] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. (H + ) type ion exchange resin is added and stirred for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, with a yield of 86%. 1 1H NMR and LRMS were consistent with Example 3.

[0082] Example 11: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3 [Chemical formula]

[0083] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, dropwise add trimethylsilyl trifluoromethanesulfonate, and continue stirring for 12 h after dropping. After the reaction, drop water into the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fraction disappears, and then perform column chromatography and separation to obtain compound III-3 with a yield of 28%. 1 1H NMR and LRMS were consistent with those in Example 3.

[0084] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical Structure

[0085] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3 with a yield of 84%. 1 1H NMR and LRMS were consistent with those in Example 3.

[0086] Example 12: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3 [Chemical formula]

[0087] Operating procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C, add trimethylsilyl trifluoromethanesulfonate dropwise, and continue stirring for 12 h after the addition. After the reaction, add water dropwise to the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fractions disappear, and then perform column chromatography and separation to obtain compound III-3 with a yield of 26%. 1 1H NMR and LRMS were consistent with those of Example 3.

[0088] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3 [Chemical formula]

[0089] Operating procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + [[ID=H]]) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3 with a yield of 89%. 1 1 1H NMR and LRMS were consistent with those of Example 3.

[0090] Example 13: Synthesis of 1-[4-(4-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-3

Chemical formula

[0091] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I, tin tetrachloride, and 4-methoxyphenylbutanol II-3. Cool the reaction flask to 0 ± 5 °C and stir for 12 h to allow the reaction to proceed. After the reaction, add water dropwise to the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-3, with a yield of 25%. 1 1H NMR and LRMS were consistent with those in Example 3.

[0092] Synthesis of 1-(4-methoxy)benzyl-β-D-glucopyranoside IV-3

Chemical formula

[0093] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-3 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-3, with a yield of 92%. 11H NMR and LRMS were consistent with Example 3.

[0094] Example 14: Synthesis of 1-[4-(3,4-dimethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-4

Chemical Structure

[0095] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 3,4-dimethoxyphenylbutanol II-4. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride diethyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-4, with a yield of 33%. 1 1H NMR (300 MHz, CDCl3): δ 6.82 - 6.59 (m, 3H), 5.27 - 4.83 (m, 3H), 4.46 (d, J = 7.9 hz, 1H), 4.32 - 3.99 (m, 2H), n 3.83 (m, 7H), 3.74 - 3.35 (m, 2H), 2.53 (m, 2H), 1.99 (m, 12H), 1.59 (m, 4H). LRMS (ESI): [M+Na] + 563.5.

[0096] Synthesis of 1-(3,4-dimethoxy)benzyl-β-D-glucopyranoside IV-4

Chemical Structure

[0097] Operating procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-4 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. By filtration, (H + )-type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain the final product IV-4, and the yield is 85%. 1 H NMR (400 MHz, CD3OD): δ 6.84 (d, J = 8.2 hz, 1H), 6.79 (d, J = 1.9 hz, 1H), 6.72 (dd, J = 8.1, 1.9 hz, 1H), 4.24 (d, J = 7.8 hz, 1H), 3.98 - 3.88 (m, 1H), 3.86 (dd, J = 11.9, 1.9 hz, 1H), 3.81 (s, 3H), 3.79 (s, 1H), 3.66 (dd, J = 11.9, 5.3 hz, 1H), 3.61 - 3.51 (m, 1H), 3.38 - 3.21 (m, 3H), 3.20 - 3.12 (m, 1H), 2.58 (t, J = 7.2 hz, 2H), 1.75 - 1.56 (m, 4H). LRMS (ESI): [M+Na] + 395.1; hRMS (ESI): [M+NH4] + Calculated value C 18 H 32 O8N + 390.2122, measured value 390.2118.

[0098] Example 15: Synthesis of 1-[4-(3,5-dimethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-5

Chemical Structure

[0099] Operating procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 3,5-dimethoxyphenylbutanol II-5. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride acetonitrile complex dropwise, and continue stirring for 12 h after the addition. After the reaction, add water dropwise to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until there is no obvious fraction, and then perform column chromatography and separation to obtain compound III-5 with a yield of 26%. 1 H NMR(400 MHz,CDCl3): δ 6.34 - 6.28(m,3H),5.20(t,J = 9.5hz,1H),5.08(t,J = 9.7hz,1H),4.98(dd,J = 9.6,8.0hz,1H),4.48(d,J = 8.0hz,1H),4.26(dd,J = 12.3,4.7hz,1H),4.13(dd,J = 12.3,2.3hz,1H),3.89(d,J = 9.5hz,1H),3.78(s,6H),3.68(dd,J = 9.9,2.2hz,1H),3.49(d,J = 9.4hz,1H),2.55(t,J = 6.6hz,2H),2.10 - 2.07(s,3H),2.03(s,3H),2.00(m,6H),1.63(dd,J = 11.5,4.3hz,4H). LRMS(ESI): [M+Na] + 563.5。

[0100] Synthesis of 1-(3,5-dimethoxy)benzyl-β-D-glucopyranoside IV-5

Chemical formula

[0101] Operation procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-5 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + ) type ion exchange resin is added and stirred for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-5, with a yield of 85%. 1 H NMR (400 MHz, CD3OD): δ 6.35 (d, J = 2.2 hz, 2H), 6.28 (t, J = 2.2 hz, 1H), 4.24 (d, J = 7.8 hz, 1H), 3.96 - 3.91 (m, 1H), 3.85 (dd, J = 11.8, 1.7 hz, 1H), 3.74 (s, 6H), 3.66 (dd, J = 11.9, 5.2 hz, 1H), 3.58 - 3.53 (m, 1H), 3.38 - 3.21 (m, 3H), 3.19 - 3.11 (m, 1H), 2.57 (t, J = 7.3 hz, 2H), 1.75 - 1.58 (m, 4H). LRMS (ESI): [M+Na] + 395.1, HRMS (ESI): [M+NH4] + Calculated value C 18 H 32 O8N + 390.2122, measured value 390.2122.

[0102] Example 16: Synthesis of 1-[4-(3,4,5-trimethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-6

Chemical formula

[0103] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 3,4,5-trimethoxyphenylbutanol II-6. Cool the reaction flask to 0 ± 5 °C, dropwise add trimethylsilyl trifluoromethanesulfonate, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography purification to obtain compound III-6, and the yield was 24%. LRMS(ESI): [M+Na] + 593.5。

[0104] Synthesis of 1-(3,4,5-trimethoxy)benzyl-β-D-glucopyranoside IV-6

Chemical formula

[0105] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-6 (1.0 eq) to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-6, and the yield was 88%. 11H NMR (400 MHz, CD3OD): δ 6.49 (s, 2H), 4.24 (d, J = 7.8 hz, 1H), 3.97 - 3.83 (m, 2H), 3.81 (s, 6H), 3.72 (s, 3H), 3.69 - 3.52 (m, 2H), 3.37 - 3.21 (m, 3H), 3.20 - 3.13 (m, 1H), 2.59 (t, J = 7.3 hz, 2H), 1.79 - 1.55 (m, 4H). LRMS (ESI): [M+Na] + 425.1, HRMS (ESI): [M+NH4] + Calculated value C 19 H 34 O9N + 420.2228, found 420.2226.

[0106] Example 17: Synthesis of 1-[5-(4-methoxyphenyl)pentyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-7

Chemical Structure

[0107] Procedure: The reaction flask was flushed with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-methoxyphenyl amyl alcohol II-7 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride butyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated again, and the organic phase was washed with water again. After separating the liquids, the organic phase was collected. The organic phase was concentrated until no obvious fraction remained, and then column chromatography and separation were performed to obtain compound III-7, with a yield of 22%. 11H NMR (300 MHz, CDCl3): δ 7.08 (d, J = 6.9 Hz, 2H), 6.82 (d, J = 6.8 Hz, 2H), 5.69 (d, J = 4.2 Hz, 1H), 5.19 (m, 1H), 4.91 (d, J = 9.3 Hz, 1H), 4.30 (m, 1H), 4.20 (m, 2H), 3.96 (m, 1H), 3.79 (s, 3H), 3.46 (t, J = 5.7 Hz, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.09 (m, 9H), 1.71 (s, 3H), 1.66 - 1.48 (m, 4H), 1.36 (d, J = 6.7 Hz, 2H). LRMS (ESI): [M+Na] + 547.5

[0108] Synthesis of 1-(4 - methoxy)phenylpentyl-β-D-glucopyranoside IV-7

Chemical Structure

[0109] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-7 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. Concentrate the organic phase, and then perform column chromatography and separation to obtain the final product IV-7 with a yield of 95%. 11H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.75 (s, 3H), 3.66 (dd, J = 11.9, 5.3 Hz, 1H), 3.52 (dt, J = 9.5, 6.7 Hz, 1H), 3.38 - 3.22 (m, 3H), 3.20 - 3.12 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 1.68 - 1.61 (m, 4H), 1.47 - 1.31 (m, 2H). LRMS (ESI): [M + Na] + 375.1, HRMS (ESI): [M + H] + Calculated value C 18 H 29 O7 + 357.1908, found 357.1906.

[0110] Example 18: Synthesis of 1 - [6 - (4 - methoxyphenyl)hexyl] - 2,3,4,6 - O - tetraacetyl - β - D - glucopyranoside III - 8

Chemical Structure

[0111] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then, 1,2,3,4,6 - penta - O - acetyl - β - D - glucopyranose I, tin(IV) chloride, and 4 - methoxyphenylhexanol II - 8 were added sequentially. The reaction flask was cooled to 0 ± 5 °C and stirred for 10 h to allow the reaction to proceed. After the reaction, water was added dropwise to the reaction system to quench it rapidly. The layers were separated, the organic phase was washed with an aqueous Na2CO3 solution, the layers were separated again, and the organic phase was washed with water once more. After separating the layers, the organic phase was collected. After concentrating the organic phase, column chromatography was performed to obtain compound III - 8, with a yield of 18%. 11H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 5.7 Hz, 2H), 5.20 (t, J = 9.5 Hz, 1H), 5.08 (t, J = 9.7 Hz, 1H), 4.98 (dd, J = 9.6, 8.0 Hz, 1H), 4.48 (d, J = 8.0 Hz, 1H), 4.26 (dd, J = 12.3, 4.7 Hz, 1H), 4.12 (m, 1H), 3.86 (dt, J = 9.6, 6.3 Hz, 1H), 3.79 (s, 3H), 3.68 (ddd, J = 9.9, 4.6, 2.4 Hz, 1H), 3.46 (dt, J = 9.5, 6.8 Hz, 1H), 2.58 - 2.49 (m, 2H), 2.08 (s, 3H), 2.02 (m, 9H), 1.62 - 1.49 (m, 4H), 1.36 - 1.28 (m, 4H). LRMS (ESI): [M+Na] + 561.5。

[0112] Synthesis of 1-(4 - methoxy)phenylhexyl-β-D-glucopyranoside IV-8

Chemical Structure

[0113] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-8 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-8 with a yield of 84%. 11H NMR (400 MHz, CD3OD): δ 7.06 (d, J = 8.6 Hz, 2H), 6.84 - 6.80 (d, J = 8.6 Hz, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.93 - 3.82 (m, 2H), 3.75 (s, 3H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.52 (dt, J = 9.5, 6.7 Hz, 1H), 3.38 - 3.21 (m, 3H), 3.20 - 3.11 (m, 1H), 2.53 (t, J = 7.6 Hz, 2H), 1.68 - 1.50 (m, 4H), 1.47 - 1.25 (m, 4H). LRMS (ESI): [M+Na] + 393.1, HRMS (ESI): [M+NH4] + Calculated value C 19 H 34 O7N + 388.2330, found 388.2327.

[0114] Example 19: Synthesis of 1-[4-(4-Fluorophenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-9

Chemical formula

[0115] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-fluorophenylbutanol II-9 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid cooling, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated, and the organic phase was washed again with water. After separating the liquid, the organic phase was collected. The organic phase was concentrated until no obvious fraction remained, and then column chromatography and separation were performed to obtain compound III-9, with a yield of 22%. LRMS (ESI): [M+Na] + 521.5.

[0116] Synthesis of 1-(4-Fluoro)benzyl-β-D-glucopyranoside IV-9

Chemical Structure

[0117] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-9 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with ethanol, and collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-9, with a yield of 93%. 1 H NMR (400 MHz, CD3OD): δ 7.18 (dd, J = 8.5, 5.6 hz, 2H), 7.00 - 6.91 (m, 2H), 4.24 (d, J = 7.8 hz, 1H), 3.92 (dt, J = 9.6, 6.3 hz, 1H), 3.87 - 3.82 (m, 1H), 3.66 (dd, J = 11.8, 5.2 hz, 1H), 3.56 (dt, J = 9.5, 6.3 hz, 1H), 3.37, 3.22 (m, 3H), 3.20 - 3.11 (m, 1H), 2.62 (t, J = 7.3 hz, 2H), 1.78 - 1.54 (m, 4H). LRMS (ESI): [M+COOH] - 375.0, HRMS (ESI): [M+Cl] - Calculated value for C 16 H 23 O6FCl - 365.1173, Measured value 365.1173.

[0118] Example 20: Synthesis of 1-[4-(4-Bromophenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-10

Chemical Structure

[0119] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-bromophenylbutanol II-10. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride diethyl ether complex, and continue stirring for 12 h after the addition. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fractions disappear, and then perform column chromatography and separation to obtain compound III-10, with a yield of 18%. LRMS(ESI): [M+Na] + 582.4。

[0120] Synthesis of 1-(4-bromo)benzyl-β-D-glucopyranoside IV-10

Chemical Structure

[0121] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-10 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-10, with a yield of 83%. 11H NMR (400 MHz, CD3OD): δ 7.38 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 4.24 (d, J = 7.8 Hz, 1H), 3.92 (dt, J = 9.5, 6.4 Hz, 1H), 3.85 (dd, J = 11.9, 1.6 Hz, 1H), 3.66 (dd, J = 11.8, 5.2 Hz, 1H), 3.56 (dt, J = 9.6, 6.3 Hz, 1H), 3.31 (m, 3H), 3.19 - 3.11 (m, 1H), 2.61 (t, J = 7.4 Hz, 2H), 1.77 - 1.55 (m, 4H). LRMS (ESI): [M+Na] + 414.9, HRMS (ESI): [M+Na] + Calculated value C 16 H 23 O6BrNa + 413.0570, found 413.0568.

[0122] Example 21: Synthesis of 1-[4-(4-Nitrophenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-11

Chemical Structure

[0123] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-nitrophenylbutanol II-11 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride butyl ether complex was added dropwise, and after the addition, stirring was continued for 12 h. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated, and the organic phase was washed again with water. After separating the liquid, the organic phase was collected. After concentrating the organic phase, purification by column chromatography was carried out to obtain compound III-11, with a yield of 27%. LRMS (ESI): [M+Na] + 548.5.

[0124] Synthesis of 1-(4-nitro)benzyl-β-D-glucopyranoside IV-11

Chemical Structure

[0125] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-11 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with methanol, and collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-11, with a yield of 89%. 1 H NMR (400 MHz, CD3OD): δ 8.14 (d, J = 8.7 hz, 2H), 7.45 (d, J = 8.7 hz, 2H), 4.25 (d, J = 7.8 hz, 1H), 4.00 - 3.82 (m, 2H), 3.70 - 3.50 (m, 2H), 3.37 - 3.22 (m, 3H), 3.21 - 3.12 (m, 1H), 2.78 (t, J = 7.6 hz, 2H), 1.85 - 1.57 (m, 4H). LRMS (ESI): [M+Na] + 380.0, HRMS (ESI): [M+Na] + Calculated value for C 16 H 23 O8NNa + 380.1327, measured value 380.1314.

[0126] Example 22: Synthesis of 1-[4-(4-hydroxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-12

Chemical Structure

[0127] Synthesis of 1-(4-hydroxy)benzyl-β-D-glucopyranoside IV-12

Chemical formula

[0128] Operation procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-12 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-12, and the yield was 79%. 11H NMR (400 MHz, CD3OD): δ 6.99 (d, J = 8.5 Hz, 2H), 6.70 - 6.63 (m, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.54 (dt, J = 9.5, 6.1 Hz, 1H), 3.38 - 3.21 (m, 3H), 3.16 (dd, 1H), 2.53 (t, J = 7.0 Hz, 2H), 1.70 - 1.56 (m, 4H). LRMS (ESI): [M+Na] + 351.1; HRMS (ESI): [M+NH4] + Calculated value C 16 H 28 O7N + 346.1860, found 346.1857.

[0129] Example 23: Synthesis of 1-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-13

Chemical Structure

[0130] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-hydroxy-3-methoxyphenylbutanol II-13 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated, and the organic phase was washed with water again. After separating the liquids, the organic phase was collected. After concentrating the organic phase, purification by column chromatography was performed to obtain compound III-13, and the yield was 19%. LRMS (ESI): [M-H] - 525.2.

[0131] Synthesis of 1-(4-Hydroxy-3-methoxy)benzyl-β-D-glucopyranoside IV-13

Chemical Structure

[0132] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-13 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-13, with a yield of 80%. 1 H NMR (400 MHz, CDCl3): δ 6.83 (d, J = 7.6 Hz, 1H), 6.70 - 6.64 (m, 2H), 6.26 (br, 1H), 4.83 (br, 8H), 4.00 (s, 1H), 3.88 (s, 3H), 3.74 (t, J = 6.4 hz, 2H), 3.55 (s, 2H), 2.58 (t, J = 7.2 hz, 2H), 1.69 - 1.62 (m, 4H). LRMS (ESI): [M+Na] + 381.2

[0133] Example 24: Synthesis of 1-[4-(3,4-Methylenedioxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-14

Chemical Structure

[0134] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 3,4-methylenedioxyphenylbutanol II-14. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride ethyltetrahydrofuran complex dropwise, and continue stirring for 12 h after the addition. After the reaction, add water dropwise to the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until there is no obvious fraction left, and then perform column chromatography and separation to obtain compound III-14, with a yield of 27%. LRMS(ESI): [M+Na] + 547.5.

[0135] Synthesis of 1-(3,4-methylenedioxy)benzyl-β-D-glucopyranoside IV-14

Chemical Structure

[0136] Operation procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-14 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-14, with a yield of 82%. 11H NMR (400 MHz, CD3OD): δ 6.71 - 6.67 (m, 2H), 6.65 - 6.61 (m, 1H), 5.87 (s, 2H), 4.23 (d, J = 7.8 hz, 1H), 3.95 - 3.88 (m, 1H), 3.85 (m, 1H), 3.66 (dd, J = 11.8, 5.2 hz, 1H), 3.60 - 3.48 (m, 1H), 3.38 - 3.20 (m, 3H), 3.19 - 3.12 (m, 1H), 2.55 (t, J = 7.1 hz, 2H), 1.73 - 1.53 (m, 4H). LRMS (ESI): [M+Na] + 379.0, HRMS (ESI): [M+Na] + Calculated value C 17 H 24 O8Na + 379.1374, found 379.1362.

[0137] Example 25: Synthesis of 1-[4-(4-Ethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-15

Chemical Structure

[0138] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-ethoxyphenylbutanol II-15 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride acetonitrile complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid quenching, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated, and the organic phase was washed again with water. After separating the liquids, the organic phase was collected. The organic phase was concentrated until no obvious fractions remained, and then column chromatography and separation were performed to obtain compound III-15, with a yield of 26%. LRMS (ESI): [M+Na] + 547.2.

[0139] Synthesis of 1-(4-ethoxy)benzyl-β-D-glucopyranoside IV-15

Chemical Structure

[0140] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-15 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, wash with methanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-15, and the yield was 92%. 1 H NMR (400 MHz, CD3OD): δ 7.10 (d, J = 8.5 hz, 2H), 6.82 (d, J = 8.6 hz, 2H), 4.27 (d, J = 7.8 hz, 1H), 4.02 (q, J = 7.0 hz, 2H), 3.98 - 3.92 (m, 1H), 3.89 (dd, J = 11.8, 1.6 hz, 1H), 3.69 (dd, J = 11.8, 5.2 hz, 1H), 3.58 (dt, J = 9.5, 6.2 hz, 1H), 3.41 - 3.29 (m, 3H), 3.23 - 3.13 (m, 1H), 2.59 (t, J = 7.1 hz, 2H), 1.78 - 1.56 (m, 4H), 1.39 (t, J = 7.0 hz, 3H). LRMS (ESI): [M+Na] + 379.1

[0141] Example 26: Synthesis of 1-[4-(4-propoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-16

Chemical Structure

[0142] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-propoxyphenylbutanol II-16. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride acetonitrile complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until it is clearly free of fractions, and then perform column chromatography and separation to obtain compound III-16, with a yield of 33%. LRMS(ESI): [M+Na] + 561.5.

[0143] Synthesis of 1-(4-propoxy)benzyl-β-D-glucopyranoside IV-16

Chemical formula

[0144] Operation procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-16 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h for reaction. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin, and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-16, with a yield of 94%. 11H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.96 - 3.80 (m, 4H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.38 - 3.21 (m, 3H), 3.20 - 3.11 (m, 1H), 2.56 (t, J = 7.1 Hz, 2H), 1.75 (m, 2H), 1.70 - 1.57 (m, 4H), 1.02 (t, J = 7.4 Hz, 3H). LRMS (ESI): [M+Na] + 393.1, HRMS (ESI): [M+Na] + Calculated value C 19 H 30 O7Na + 393.1884, found 393.1880.

[0145] Example 27: Synthesis of 1-[4-(4-isopropoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-17

Chemical Structure

[0146] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-isopropoxyphenylbutanol II-17 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride acetonitrile complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid cooling, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated again, and the organic phase was washed with water again. After separating the liquid, the organic phase was collected. The organic phase was concentrated until no obvious fraction remained, and then column chromatography and separation were performed to obtain compound III-17 with a yield of 35%. LRMS (ESI): [M+Na] + 561.2.

[0147] Synthesis of 1-(4-isopropoxy)benzyl-β-D-glucopyranoside IV-17 [Chemical formula]

[0148] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-17 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. By filtration, the (H + )-type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are performed to obtain the final product IV-17, and the yield is 88%. 1 H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8.6 hz, 2H), 6.89 - 6.70 (m, 2H), 4.52 (dt, J = 12.1, 6.1 hz, 1H), 4.23 (d, J = 7.8 hz, 1H), 3.95 - 3.88 (m, 1H), 3.85 (dd, J = 11.9, 1.9 hz, 1H), 3.66 (dd, J = 11.8, 5.3 hz, 1H), 3.62 - 3.51 (m, 1H), 3.36 - 3.33 (m, 1H), 3.28 - 3.20 (m, 2H), 3.17 (dd, J = 15.1, 7.2 hz, 1H), 2.56 (t, J = 7.1 hz, 2H), 1.75 - 1.54 (m, 4H), 1.27 (d, J = 6.0 hz, 6H). LRMS (ESI): [M+Na] + 393.0, HRMS (ESI): [M+Na] + Calculated value C 19 H 30 O7Na + 393.1884, measured value 393.1880.

[0149] Example 28: Synthesis of 1-[4-(4-allylphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-18 [Chemical formula]

[0150] Procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-allylphenylbutanol II-18. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride butyl ether complex, and continue stirring for 12 h after dropping. After the reaction, drop water into the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase until the obvious fractions disappear, and then perform column chromatography and separation to obtain compound III-18, with a yield of 18%. LRMS(ESI): [M+Na] + 559.5.

[0151] Synthesis of 1-(4-allyl)benzyl-β-D-glucopyranoside IV-18 [Chemical formula]

[0152] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-18 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-18, with a yield of 81%. 1 1H NMR (400 MHz, CD3OD): δ 7.08 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.12 - 5.96 (m, 1H), 5.37 (dd, J = 17.3, 1.6 Hz, 1H), 5.22 (dd, J = 10.6, 1.4 Hz, 1H), 4.55 - 4.44 (m, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.97 - 3.80 (m, 2H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.60 - 3.50 (m, 1H), 3.38 - 3.21 (m, 3H), 3.20 - 3.12 (m, 1H), 2.56 (t, J = 7.1 Hz, 2H), 1.73 - 1.55 (m, 4H). LRMS (ESI): [M+Na] + 391.0, HRMS (ESI): [M+Na] + Calculated value C 19 H 28 O7Na + 391.1727, Measured value 391.1726.

[0153] Example 29: Synthesis of 1-[4-(4-Cyclopropylmethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-19

Chemical Structure

[0154] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-cyclopropylmethoxyphenylbutanol II-19 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated again, and the organic phase was washed with water again. After separating the liquid, the organic phase was collected. After concentrating the organic phase, compound III-19 was obtained by column chromatography, and the yield was 18%. LRMS (ESI): [M+Na]+ 573.2。

[0155] Synthesis of 1-(4-Cyclopropylmethoxy)benzyl-β-D-glucopyranoside IV-19

Chemical Structure

[0156] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-19 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-19, with a yield of 78%. 1 H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8.6 hz, 2H), 6.79 (d, J = 8.6 hz, 2H), 4.23 (d, J = 7.8 hz, 1H), 3.91 (m, 1H), 3.88 - 3.82 (m, 1H), 3.77 (d, J = 6.8 hz, 2H), 3.67 (dd, J = 12.0, 5.3 hz, 1H), 3.55 (m, 1H), 3.33 - 3.17 (m, 4H), 2.56 (t, J = 7.1 hz, 2H), 1.76 - 1.54 (m, 4H), 1.27 - 1.16 (m, 1H), 0.59 (dd, J = 8.1, 1.4 hz, 2H), 0.38 - 0.24 (m, 2H). LRMS (ESI): [M+Na] + 405.0, HRMS (ESI): [M+Na] + Calculated value C 20 H 30 O7Na + 405.1884, Measured value 405.1883.

[0157] Example 30: Synthesis of 1-[4-(4-Cyclobutylmethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-20

Chemical formula

[0158] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-cyclobutylmethoxyphenylbutanol II-20. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride diethyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench it rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-20, with a yield of 25%. LRMS(ESI): [M+Na] + 587.6。

[0159] Synthesis of 1-(4-Cyclobutylmethoxy)benzyl-β-D-glucopyranoside IV-20

Chemical formula

[0160] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-20 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-20, with a yield of 77%. 1 1H NMR (400 MHz, CD3OD): δ 7.10 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.27 (d, J = 7.8 Hz, 1H), 3.99 - 3.85 (m, 4H), 3.69 (dd, J = 11.8, 5.2 Hz, 1H), 3.58 (dt, J = 9.4, 6.2 Hz, 1H), 3.41 - 3.24 (m, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.85 - 2.71 (m, 1H), 2.59 (t, J = 7.1 Hz, 2H), 2.24 - 2.08 (m, 2H), 2.08 - 1.85 (m, 4H), 1.70 (m, 4H). LRMS (ESI): [M+Na] + 419.2

[0161] Example 31: Synthesis of 1-[4-(4-Cyclopentylmethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-21

Chemical Structure

[0162] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-cyclopentylmethoxyphenylbutanol II-21 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride tetrahydrofuran complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated again, and the organic phase was washed with water again. After separating the liquids, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were performed to obtain compound III-21, and the yield was 19%. LRMS (ESI): [M+Na] + 601.6

[0163] Synthesis of 1-(4-Cyclopentylmethoxy)benzyl-β-D-glucopyranoside IV-21 [Chemical formula]

[0164] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add Intermediate III-21 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, wash with methanol, and then collect the filtrate. (H + ) type ion exchange resin is added and stirred for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-21, and the yield was 87%. 1 H NMR (400 MHz, CD3OD): δ 7.10 (d, J = 8.5 hz, 2H), 6.82 (d, J = 8.6 hz, 2H), 4.27 (d, J = 7.8 hz, 1H), 3.99 - 3.86 (m, 2H), 3.83 (d, J = 6.9 hz, 2H), 3.69 (dd, J = 11.8, 5.2 hz, 1H), 3.62 - 3.54 (m, 1H), 3.41 - 3.24 (m, 3H), 3.21 - 3.17 (m, 1H), 2.59 (t, J = 7.0 hz, 2H), 2.40 - 2.30 (m, 1H), 1.93 - 1.78 (m, 2H), 1.76 - 1.57 (m, 8H), 1.47 - 1.35 (m, 2H). LRMS (ESI): [M+Na] + 433.2, HRMS (ESI): [M+Na] + Calculated value C 22 H 34 O7Na + 433.2197, Measured value 433.2192.

[0165] Example 32: Synthesis of 1-[4-(4-Cyclohexylmethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-22 [Chemical formula]

[0166] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-cyclohexylmethoxyphenylbutanol II-22. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride tetrahydrofuran complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-22, with a yield of 25%. LRMS(ESI): [M+Na] + 615.6。

[0167] Synthesis of 1-(4-cyclohexylmethoxy)benzyl-β-D-glucopyranoside IV-22

Chemical formula

[0168] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-22 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-22, with a yield of 88%. 11H NMR (400 MHz, CD3OD): δ 7.06 (d, J = 8. Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.95 - 3.82 (m, 2H), 3.72 (d, J = 6.4 Hz, 2H), 3.66 (dd, J = 11.9, 5.2 Hz, 1H), 3.59 - 3.50 (m, 1H), 3.37 - 3.20 (m, 3H), 3.19 - 3.12 (m, 1H), 2.56 (t, J = 7.1 Hz, 2H), 1.86 (d, J = 13.1 Hz, 2H), 1.81 - 1.57 (m, 8H), 1.38 - 1.16 (m, 3H), 1.09 (m, 2H). LRMS (ESI): [M+Na] + 447.2, HRMS (ESI): [M+Na] + Calculated value C 23 H 36 O7Na + 447.2353, found 447.2352.

[0169] Example 33: Synthesis of 1-[4-(4-tert-butylmethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-23 [Chemical formula]

[0170] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-tert-butylmethoxyphenylbutanol II-23 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride butyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated, and the organic phase was washed again with water. After separating the liquids, the organic phase was collected. The organic phase was concentrated until no obvious fraction remained, and then column chromatography and separation were performed to obtain compound III-23, with a yield of 15%. LRMS (ESI): [M+Na]+ 589.2。

[0171] Synthesis of 1-(4-tert-butylmethoxy)benzyl-β-D-glucopyranoside IV-23

Chemical formula

[0172] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-23 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-23, with a yield of 90%. 1 H NMR (400 MHz, CD3OD): δ 7.10 (d, J = 8.5 hz, 2H), 6.82 (d, J = 8.5 hz, 2H), 4.27 (d, J = 7.8 hz, 1H), 4.01 - 3.82 (m, 2H), 3.71 (d, J = 5.2 hz, 1H), 3.60 (m, 3H), 3.42 - 3.24 (m, 4H), 3.20 (t, J = 8.4 hz, 1H), 2.59 (t, J = 7.0 hz, 2H), 1.78 - 1.53 (m, 4H), 1.06 (s, 9H). LRMS (ESI): [M+Na] + 421.1; hRMS (ESI): [M+Na] + Calculated C 21 H 34 O7Na + 421.2197, found 421.2194.

[0173] Example 34: Synthesis of 1-[4-(4-tert-butylethoxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-24 [Chemical]

[0174] Operating procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-tert-butylethoxyphenylbutanol II-24. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride butyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-24, with a yield of 18%. LRMS(ESI): [M+Na] + 603.2.

[0175] Synthesis of 1-(4-tert-butylethoxy)benzyl-β-D-glucopyranoside IV-24 [Chemical]

[0176] Operating procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-24 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-24, with a yield of 80%. 11H NMR (400 MHz, CD3OD): δ 7.07 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.23 (d, J = 7.8 Hz, 1H), 3.99 (t, J = 7.1 Hz, 2H), 3.91 (dt, J = 9.3, 6.3 Hz, 1H), 3.85 (dd, J = 11.9, 1.9 Hz, 1H), 3.67 (dd, J = 11.9, 5.3 Hz, 1H), 3.57 - 3.52 (m, 1H), 3.26 - 3.11 (m, 4H), 2.56 (t, J = 7.1 Hz, 2H), 1.75 - 1.53 (m, 6H), 0.99 (s, 9H). LRMS (ESI): [M+Na] + 435.1, HRMS (ESI): [M+Na] + Calculated value C 22 H 36 O7Na + 435.2353, found 435.2352.

[0177] Example 35: Synthesis of 1-[4-(4-benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-25

Chemical Structure

[0178] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-benzyloxyphenylbutanol II-25 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid cooling, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated, and the organic phase was washed again with water. After separating the liquid, the organic phase was collected. The organic phase was concentrated until no obvious fraction remained, and then column chromatography and separation were performed to obtain compound III-25 with a yield of 35%. LRMS (ESI): [M+Na] + 609.6.

[0179] Synthesis of 1-(4-benzyloxy)benzyl-β-D-glucopyranoside IV-25

Chemical Structure

[0180] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-25 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, wash with ethanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-25, with a yield of 91%. 1 H NMR (400 MHz, CD3OD): δ 7.34 (m, 5H), 7.09 (d, J = 8.3 hz, 2H), 6.88 (d, J = 8.4 hz, 2H), 5.03 (s, 2H), 4.23 (d, J = 7.8 hz, 1H), 4.01 - 3.82 (m, 2H), 3.66 (dd, J = 11.8, 5.0 hz, 1H), 3.59 - 3.47 (m, 1H), 3.39 - 3.22 (m, 3H), 3.16 (t, J = 8.3 hz, 1H), 2.56 (t, J = 6.9 hz, 2H), 1.65 (d, J = 4.1 hz, 4H). LRMS (ESI): [M+Na] + 441.1, HRMS (ESI): [M+Na] + Calculated value for C 23 H 30 O7Na + 441.1884, measured value 441.1880.

[0181] Example 36: Synthesis of 1-[4-(4-(2-fluoro)benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-26

Chemical Structure

[0182] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(2-fluorobenzyloxy)phenylbutanol II-26. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride diethyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-26 with a yield of 37%. LRMS(ESI): [M+Na] + 654.23。

[0183] Synthesis of 1-[4-(2-fluoro)benzyloxy]benzyl-β-D-glucopyranoside IV-26

Chemical Structure

[0184] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-26 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-26 with a yield of 88%. 11H NMR (400 MHz, CD3OD): δ 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.42 - 7.34 (m, 1H), 7.21 (td, J = 7.5, 1.0 Hz, 1H), 7.18 - 7.10 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.12 (s, 2H), 4.27 (d, J = 7.8 Hz, 1H), 3.95 (dt, J = 9.4, 6.3 Hz, 1H), 3.89 (dd, J = 11.9, 1.8 Hz, 1H), 3.69 (dd, J = 11.9, 5.2 Hz, 1H), 3.58 (dt, J = 9.5, 6.3 Hz, 1H), 3.39 - 3.25 (m, 3H), 3.24 - 3.16 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 1.78 - 1.59 (m, 4H). LRMS (ESI): [M+Na] + 459.20。

[0185] Example 37: Synthesis of 1-[4-(4-(3-Fluoro)benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-27

Chemical Structure

[0186] Procedure: The reaction flask was flushed with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(3-fluorobenzyloxy)phenylbutanol II-27 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated again, and the organic phase was washed with water again. After separating the liquid, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were performed to obtain compound III-27 with a yield of 40%. LRMS (ESI): [M+Na] + 627.2。

[0187] Synthesis of 1-[4-(3-Fluoro)benzyloxy]benzyl-β-D-glucopyranoside IV-27

Chemical Structure

[0188] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-27 to the reaction flask, control the temperature at 25 ± 5 °C, add methanol to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-27, with a yield of 84%. 1 H NMR (400 MHz, CD3OD): δ 7.40 (dt, J = 7.9, 5.9 hz, 1H), 7.26 (d, J = 7.7 hz, 1H), 7.20 (d, J = 9.9 hz, 1H), 7.13 (d, J = 8.6 hz, 2H), 7.05 (td, J = 8.5, 2.3 hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 5.09 (s, 2H), 4.27 (d, J = 7.8 hz, 1H), 3.95 (dt, J = 9.4, 6.3 hz, 1H), 3.89 (dd, J = 11.9, 1.8 hz, 1H), 3.69 (dd, J = 11.9, 5.2 hz, 1H), 3.62 - 3.54 (m, 1H), 3.41 - 3.24 (m, 3H), 3.23 - 3.15 (m, 1H), 2.60 (t, J = 7.1 hz, 2H), 1.90 - 1.55 (m, 4H). LRMS (ESI): [M+Na] + 459.2

[0189] Example 38: Synthesis of 1-[4-(4-(4-Fluoro)benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-28

Chemical Structure

[0190] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(4-fluorobenzyloxy)phenylbutanol II-28. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride tetrahydrofuran complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system for rapid cooling, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-28 with a yield of 44%. LRMS(ESI): [M+Na] + 654.23。

[0191] Synthesis of 1-[4-(4-fluoro)benzyloxy]benzyl-β-D-glucopyranoside IV-28

Chemical formula

[0192] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-28 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h for reaction. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-28 with a yield of 83%. 11H NMR (400 MHz, CD3OD): δ 7.47 (dd, J = 8.5, 5.5 Hz, 2H), 7.13 (d, J = 8.6 Hz, 4H), 7.14 - 7.09 (m, 1H), 6.91 (d, J = 8.6 Hz, 2H), 5.04 (s, 2H), 4.27 (d, J = 7.8 Hz, 1H), 3.95 (dt, J = 9.3, 6.2 Hz, 1H), 3.89 (dd, J = 11.8, 1.7 Hz, 1H), 3.69 (dd, J = 11.8, 5.2 Hz, 1H), 3.58 (dt, J = 9.4, 6.2 Hz, 1H), 3.33 - 3.24 (m, 3H), 3.23 - 3.14 (m, 1H), 2.60 (t, J = 7.1 Hz, 2H), 1.91 - 1.56 (m, 4H). LRMS (ESI): [M+Na] + 459.2

[0193] Example 39: Synthesis of 1-[4-(4-(3-Trifluoromethyl)benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-29

Chemical Structure

[0194] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(3-trifluoromethylbenzyloxy)phenylbutanol II-29 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, trimethylsilyl trifluoromethanesulfonate was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated, and the organic phase was washed with water again. After separating the liquid, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were performed to obtain compound III-29 with a yield of 34%. LRMS (ESI): [M+Na] + 677.23

[0195] Synthesis of 1-[4-(3-Trifluoromethyl)benzyloxy]benzyl-β-D-glucopyranoside IV-29

Chemical Structure

[0196] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-29 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-29 with a yield of 81%. 1 H NMR (400 MHz, CD3OD): δ 7.74 (s, 1H), 7.69 (d, J = 7.4 hz, 1H), 7.62 - 7.53 (m, 2H), 7.11 (d, J = 8.6 hz, 2H), 6.91 (d, J = 8.6 hz, 2H), 5.13 (s, 2H), 4.23 (d, J = 7.8 hz, 1H), 3.92 (dt, J = 9.4, 6.3 hz, 1H), 3.85 (dd, J = 11.9, 1.7 hz, 1H), 3.66 (dd, J = 11.8, 5.2 hz, 1H), 3.55 (dt, J = 9.6, 6.2 hz, 1H), 3.37 - 3.32 (m, 1H), 3.26 (t, J = 5.9 hz, 2H), 3.20 - 3.11 (m, 1H), 2.57 (t, J = 7.1 hz, 2H), 1.80 - 1.49 (m, 4H). LRMS (ESI): [M+Na] + 509.20

[0197] Example 40: Synthesis of 1-[4-(4-(4-Trifluoromethyl)benzyloxyphenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-30

Chemical Structure

[0198] Operation procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(4-trifluoromethylbenzyloxy)phenylbutanol II-30. Cool the reaction flask to 0 ± 5 °C, dropwise add trimethylsilyl trifluoromethanesulfonate, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-30 with a yield of 40%. LRMS(ESI): [M+Na] + 677.2。

[0199] Synthesis of 1-[4-(4-trifluoromethyl)benzyloxy]benzyl-β-D-glucopyranoside IV-30

Chemical formula

[0200] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-30 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and then collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-30 with a yield of 85%. 11H NMR (400 MHz, CD3OD): δ 7.68 (dd, J = 18.9, 8.3 Hz, 4H), 7.14 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 4.27 (d, J = 7.8 Hz, 1H), 3.95 (dt, J = 6.3, 3.3 Hz, 1H), 3.89 (dd, J = 11.8, 1.7 Hz, 1H), 3.69 (dd, J = 11.8, 5.2 Hz, 1H), 3.62 - 3.54 (m, 1H), 3.42 - 3.24 (m, 3H), 3.23 - 3.15 (m, 1H), 2.61 (t, J = 7.1 Hz, 2H), 1.83 - 1.52 (m, 4H). LRMS (ESI): [M+Na] + 509.2

[0201] Example 41: Synthesis of 1-[4-(4-(Oxetan-3-yl-methoxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-31

Chemical Structure

[0202] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(oxetan-3-yl-methoxy)phenylbutanol II-31. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride butyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-31, with a yield of 42%. LRMS (ESI): [M+Na] + 589.2

[0203] Synthesis of 1-[4-(Oxetan-3-yl-methoxy)]benzyl-β-D-glucopyranoside IV-31 [Chemical formula]

[0204] Operating procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-31 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, wash with methanol, and then collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-31, with a yield of 81%. 1 H NMR (400 MHz, CD3OD): δ 7.13 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.6 hz, 2H), 4.97 - 4.83 (m, 2H), 4.62 (t, J = 6.0 hz, 2H), 4.27 (d, J = 7.8 hz, 1H), 4.19 (d, J = 6.4 hz, 2H), 3.95 (dt, J = 6.3, 3.3 hz, 1H), 3.89 (dd, J = 11.8, 1.7 Hz, 1H), 3.69 (dd, J = 11.8, 5.2 hz, 1H), 3.63 - 3.54 (m, 1H), 3.52 - 3.41 (m, 1H), 3.41 - 3.24 (m, 3H), 3.23 - 3.15 (m, 1H), 2.61 (t, J = 7.1 hz, 2H), 1.81 - 1.57 (m, 4H). LRMS (ESI): [M+Na] + 421.1.

[0205] Example 42: Synthesis of 1-[4-(4-(tetrahydrofuran-4-yl-methoxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-32 [Chemical formula]

[0206] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(tetrahydrofuran-4-yl-methoxy)phenylbutanol II-32. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride butyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-32, with a yield of 34%. LRMS(ESI): [M+Na] + 617.6。

[0207] Synthesis of 1-[4-(tetrahydrofuran-4-yl-methoxy)]benzyl-β-D-glucopyranoside IV-32

Chemical formula

[0208] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-32 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, wash with methanol, and collect the filtrate. Add (H + ) type ion exchange resin, and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-32, with a yield of 80%. 11H NMR (400 MHz, CD3OD): δ 7.11 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.27 (d, J = 7.8 Hz, 1H), 4.05 - 3.86 (m, 4H), 3.82 (d, J = 6.3 Hz, 2H), 3.69 (dd, J = 11.8, 5.2 Hz, 1H), 3.58 (dt, J = 9.5, 6.2 Hz, 1H), 3.49 (td, J = 12.0, 1.7 Hz, 2H), 3.40 - 3.24 (m, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.60 (t, J = 7.1 Hz, 2H), 2.14 - 1.98 (m, 1H), 1.85 - 1.60 (m, 6H), 1.47 (qd, J = 12.3, 4.5 Hz, 2H). LRMS (ESI): [M+Na] + 449.2, HRMS (ESI): [M+H] + Calculated value C 22 H 35 O8 + 427.2326, found 427.2323.

[0209] Example 43: Synthesis of 1-[4-(4-(Pyridin-2-yl-methoxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-33

Chemical Structure

[0210] Procedure: The reaction flask was evacuated and backfilled with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(pyridin-2-yl-methoxy)phenylbutanol II-33 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system to quench it rapidly, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated, and the organic phase was washed again with water. After separating the liquids, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were performed to obtain compound III-33, with a yield of 28%. LRMS(ESI): [M+Na] + 610.2。

[0211] Synthesis of 1-[4-(pyridin-2-yl-methoxy)]benzyl-β-D-glucopyranoside IV-33

Chemical Structure

[0212] Procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-33 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with methanol, and collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. Concentrate the organic phase and then perform column chromatography and separation to obtain the final product IV-33, with a yield of 79%. 1 H NMR(400 MHz,CD3OD): δ 8.53(d,J=4.4hz,1H),7.86(td,J=7.8,1.6hz,1H),7.59(d,J=7.9hz,1H),7.36(dd,J=7.0,5.4hz,1H),7.10(d,J=8.6hz,2H),6.90(d,J=8.6hz,2H),5.13(s,2H),4.23(d,J=7.8hz,1H),3.95-3.88(m,1H),3.85(dd,J=11.9,1.7hz,1H),3.66(dd,J=11.9,5.2hz,1H),3.59-3.51(m,1H),3.35-3.12(m,4H),2.57(t,J=7.1hz,2H),1.81-1.52(m,4H). LRMS(ESI): [M+Na] + 442.0, HRMS(ESI): [M+Na] + Calculated value C 22 H 29 O7NNa + 442.1836, measured value 442.1834。

[0213] Example 44: Synthesis of 1-[4-(4-(Pyridin-3-yl-methoxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-34

Chemical formula

[0214] Procedure: The reaction flask was purged with nitrogen three times, toluene was added as a solvent, and stirring was started. Then 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(pyridin-3-yl-methoxy)phenylbutanol II-34 were sequentially added. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride diethyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid cooling, the liquid was separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquid was separated, and the organic phase was washed again with water. After separating the liquid, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were carried out to obtain compound III-34, and the yield was 31%. LRMS(ESI): [M+Na] + 610.6。

[0215] Synthesis of 1-[4-(Pyridin-3-yl-methoxy)]benzyl-β-D-glucopyranoside IV-34

Chemical formula

[0216] Procedure: The reaction flask was purged with nitrogen three times, methanol was added as a solvent, and stirring was started. Intermediate III-34 was added to the reaction flask, the temperature was controlled at 25 ± 5 °C, sodium methoxide was added to the reaction flask, and the mixture was stirred for 2 h for reaction. After the reaction, diatomaceous earth was filtered, rinsed with methanol, and the filtrate was collected. (H + ) type ion exchange resin was added and stirred for 10 h. Filtration was carried out to obtain (H +) type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain the final product IV-34, and the yield is 85%. 1 H NMR(400 MHz,CD3OD): δ 8.65(d,J=1.2hz,1H),8.52(dd,J=4.9,1.2hz,1H),7.96(d,J=7.9hz,1H),7.48(dd,J=7.8,5.0hz,1H),7.14(d,J=8.5hz,2H),6.94(d,J=8.6hz,2H),5.14(s,2H),4.27(d,J=7.8hz,1H),3.99-3.85(m,2H),3.69(dd,J=11.9,5.2hz,1H),3.58(dt,J=9.4,6.2hz,1H),3.43-3.24(m,3H),3.23-3.16(m,1H),2.60(t,J=7.1hz,2H),1.76-1.60(m,4H). LRMS(ESI): [M+Na] + 442.1, HRMS(ESI): [M+Na] + Calculated value C 22 H 29 O7NNa + 442.1836, found 442.1834.

[0217] Example 45: Synthesis of 1-[4-(4-(pyridin-4-yl-methoxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-35

Chemical Structure

[0218] Operation procedure: Replace the reaction flask with nitrogen three times, add toluene as the solvent, and start stirring. Then, sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(pyridin-4-yl-methoxy)phenylbutanol II-35. Cool the reaction flask to 0 ± 5 °C, dropwise add boron trifluoride diethyl ether complex, and continue stirring for 12 h after dropping. After the reaction, dropwise add water to the reaction system to rapidly cool it, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. After concentrating the organic phase, perform column chromatography and separation to obtain compound III-35, with a yield of 36%. LRMS(ESI): [M+Na] + 610.6。

[0219] Synthesis of 1-[4-(pyridin-4-yl-methoxy)]benzyl-β-D-glucopyranoside IV-35

Chemical formula

[0220] Operation procedure: Replace the reaction flask with nitrogen three times, add methanol as the solvent, and start stirring. Add intermediate III-35 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium methoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with methanol, and collect the filtrate. Add (H + ) type ion exchange resin, and stir for 10 h. Remove the (H + ) type ion exchange resin by filtration. After concentrating the organic phase, perform column chromatography and separation to obtain the final product IV-35, with a yield of 90%. 11H NMR (400 MHz, CD3OD): δ 8.66 - 8.44 (m, 2H), 7.54 (d, J = 5.9 hz, 2H), 7.15 (d, J = 8.6 hz, 2H), 6.93 (d, J = 8.6 hz, 2H), 5.18 (s, 2H), 4.26 (d, J = 7.8 hz, 1H), 3.95 (dt, J = 9.5, 6.3 hz, 1H), 3.89 (dd, J = 11.9, 1.9 hz, 1H), 3.69 (dd, J = 11.8, 5.2 hz, 1H), 3.62 - 3.54 (m, 1H), 3.41 - 3.24 (m, 3H), 3.23 - 3.16 (m, 1H), 2.61 (t, J = 7.1 hz, 2H), 1.77 - 1.58 (m, 4H). LRMS (ESI): [M+H] + 420.2, HRMS (ESI): [M+H] + Calculated value C 22 H 30 O7N + 420.2017, found 420.2014.

[0221] Example 46: Synthesis of 1 - [4 - (4 - hexadecyloxyphenyl)butyl] - 2,3,4,6 - O - tetraacetyl - β - D - glucopyranoside III - 36 [Chemical Structure Diagram]

[0222] Procedure: The reaction flask was purged with nitrogen three times, dichloromethane was added as a solvent, and stirring was started. Then 1,2,3,4,6 - penta - O - acetyl - β - D - glucopyranose I and 4 - hexadecyloxyphenylbutanol II - 36 were added sequentially. The reaction flask was cooled to 0 ± 5 °C, boron trifluoride butyl ether complex was added dropwise, and stirring was continued for 12 h after the addition. After the reaction, water was added dropwise to the reaction system for rapid cooling, the liquids were separated, the organic phase was washed with an aqueous Na2CO3 solution, the liquids were separated, and the organic phase was washed with water again. After separating the liquids, the organic phase was collected. After concentrating the organic phase, column chromatography and separation were performed to obtain compound III - 36 with a yield of 37%. LRMS (ESI): [M+Na] + 743.4.

[0223] Synthesis of 1-(4-Hexadecyloxy)benzyl-β-D-glucopyranoside IV-36

Chemical Structure

[0224] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-36 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to allow the reaction to proceed. After the reaction, filter through diatomaceous earth, rinse with ethanol, and collect the filtrate. (H + )-type ion exchange resin is added and stirred for 10 h. Remove the (H + )-type ion exchange resin by filtration. Concentrate the organic phase and then perform column chromatography and separation to obtain compound IV-36, with a yield of 78%. 1 H NMR (400 MHz, CD3OD) δ 7.07 (d, J = 8.6 hz, 2H), 6.79 (d, J = 8.6 hz, 2H), 4.23 (d, J = 7.8 hz, 1H), 3.92 (dd, J = 7.9, 5.1 hz, 2H), 3.85 (dd, J = 11.9, 1.9 hz, 1H), 3.66 (dd, J = 11.9, 5.2 hz, 1H), 3.55 (m, 1H), 3.34 - 3.21 (m, 4H), 2.56 (t, J = 7.1 hz, 2H), 1.70 (m, 6H), 1.45 (m, 2H), 1.41 - 1.20 (m, 24H), 0.99 (s, 1H), 0.89 (t, J = 6.8 hz, 3H). LRMS (ESI): [M+Na] + 575.3, HRMS (ESI): [M+Na] + Calculated value C 32 H 56 O7Na + 575.3918, Measured value 575.3917.

[0225] Example 47: Synthesis of 1-[4-(4-(2,5,8,11-Tetraoxatridecyloxy)phenyl)butyl]-2,3,4,6-O-tetraacetyl-β-D-glucopyranoside III-37

Chemical Structure

[0226] Procedure: Replace the reaction flask with nitrogen three times, add dichloromethane as the solvent, and start stirring. Then sequentially add 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose I and 4-(2,5,8,11-tetraoxatridecyloxy)phenylbutanol II-37. Cool the reaction flask to 0 ± 5 °C, add boron trifluoride butyl ether complex dropwise, and continue stirring for 12 h after dropping. After the reaction, add water dropwise to the reaction system to quench rapidly, separate the liquid, wash the organic phase with an aqueous Na2CO3 solution, separate the liquid, and wash the organic phase with water again. After separating the liquid, collect the organic phase. Concentrate the organic phase and then perform column chromatography and separation to obtain compound III-37, with a yield of 30%. LRMS(ESI): [M+Na] + 709.3。

[0227] Synthesis of 1-[4-(2,5,8,11-Tetraoxatridecyloxy)]benzyl-β-D-glucopyranoside IV-37

Chemical Structure

[0228] Procedure: Replace the reaction flask with nitrogen three times, add ethanol as the solvent, and start stirring. Add intermediate III-37 to the reaction flask, control the temperature at 25 ± 5 °C, add sodium ethoxide to the reaction flask, and stir for 2 h to react. After the reaction, filter through diatomaceous earth, rinse with ethanol, and collect the filtrate. Add (H + ) type ion exchange resin and stir for 10 h. Filter to obtain (H +) The type ion exchange resin is removed. After concentrating the organic phase, column chromatography and separation are carried out to obtain Compound IV-37 with a yield of 81%. 1 H NMR (400 MHz, CD3OD) δ 7.08 (d, J = 8.5 hz, 2H), 6.83 (d, J = 8.6 hz, 2H), 4.23 (d, J = 7.8 hz, 1H), 4.15 - 4.02 (m, 2H), 3.91 (m, 1H), 3.85 (dd, J = 11.8, 1.7 hz, 1H), 3.83 - 3.78 (m, 2H), 3.71 - 3.47 (m, 14H), 3.36 - 3.17 (m, 7H), 2.56 (t, J = 7.0 hz, 2H), 1.66 (m, 4H). LRMS (ESI): [M+Na] + 541.2, HRMS (ESI): [M+Na] + Calculated C 25 H 42 O 11 Na + 541.2619, found 541.2618.

Industrial Applicability

[0229] The above description is a general description of the present invention. Depending on the circumstances and actual requirements, changes in form and equivalent substitutions can be made. Although specific terms are used in this specification, these terms are used for the purpose of explanation and are not restrictive. Those skilled in the art can make various changes and modifications to the present invention, and these equivalent forms should also be included within the scope defined by the appended claims of this application.

Claims

1. (1) reacting an acetyl-protected glucose ester (I) with an alcohol compound represented by formula (II) under the catalysis of a Lewis acid to obtain an intermediate represented by formula (III); 【Chemical 1】 (2) removing the acetyl-protecting group from the intermediate represented by formula (III) in the presence of a base to obtain a glycoside compound represented by formula (IV); and [Chemical Formula 2] Among them, in Formulas II, III and IV, the substituents R １ , R ２ , R ３ , R ４ and R ５ are each independently selected from hydrogen, hydroxyl, substituted or unsubstituted C １ to C ２０ alkoxy, substituted or unsubstituted C １ to C ２０ alkyl, substituted or unsubstituted C １ to C ２０ alkenyl, substituted or unsubstituted C １ to C ２０ alkynyl, substituted or unsubstituted aryl, heteroaryl, cycloalkyl, heterocyclyl, nitro or halogen, n is 4, 5, or 6, A method for preparing a glycoside compound, characterized in that.

2. The reaction of step (1) is carried out in a first organic solvent, and the first organic solvent is one or more of dichloromethane, chloroform, toluene, xylene, dimethylformamide, dioxane, methyl-t-butyl ether or tetrahydrofuran. The preparation method according to claim 1, characterized in that.

3. The Lewis acid in step (1) is one or more of tin tetrachloride, zinc chloride, aluminum trichloride, boron trifluoride diethyl ether complex, boron trifluoride butyl ether complex, boron trifluoride tetrahydrofuran complex, and boron trifluoride acetonitrile complex. The preparation method according to claim 1, characterized in that it is one or more of the selected boron trifluoride complexes and trimethylsilyl trifluoromethanesulfonate.

4. Step (1) is carried out under the protection of an inert gas, nitrogen or argon. The preparation method according to claim 1, characterized in that.

5. The reaction temperature of step (1) is -15 to 60 °C. The preparation method according to claim 1, characterized in that.

6. The reaction temperature of step (1) is -5 to 40 °C. The preparation method according to claim 5, characterized in that.

7. The reaction of step (2) is carried out in a second organic solvent, and the second organic solvent is one or more of methanol, ethanol, isobutanol or tert-butanol. The preparation method according to claim 1, characterized in that.

8. The alkaline condition in step (2) is a condition in which a sodium salt of sodium hydroxide, potassium hydroxide or C １ -C ４ alkanol is present, and the preparation method according to claim 1 is characterized in that.

9. The alkaline condition in step (2) is a condition in which sodium methoxide, sodium ethoxide or sodium tert-butoxide is present. The preparation method according to claim 8, characterized in that.

10. Compound IV is selected from the following compounds. The preparation method according to claim 1, characterized in that. [Chemical Formula 3]

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