CN112745372B

CN112745372B - Functional saccharide molecule based on TDG molecular skeleton and preparation method thereof

Info

Publication number: CN112745372B
Application number: CN201911051372.6A
Authority: CN
Inventors: 李伟; 王怀雨
Original assignee: Shenzhen Institute of Advanced Technology of CAS
Current assignee: Shenzhen Institute of Advanced Technology of CAS
Priority date: 2019-10-31
Filing date: 2019-10-31
Publication date: 2022-07-12
Anticipated expiration: 2039-10-31
Also published as: CN112745372A

Abstract

The invention designs a saccharide compound, the structure of which is shown as the formula X,

wherein R is₁、R₂Independently selected from substituted amido, substituted triazolyl, substituted amino; r is₃Selected from mercapto, azido, amino, carboxyl; a is

or-C_mH_2mR₃X is selected from oxygen atom; n is selected from 0, 1,2, 3,4,5, 6, 7; m is selected from 2,3, 4,5, 6,7, 8, 9, 10. The invention adopts a synthesis strategy of firstly side chain derivatization and then glycosylation coupling, realizes the side chain derivatization modification of the TDG molecular skeleton, and realizes the high-efficiency synthesis of the compound. The TDG sugar ligand molecule is used for identifying and combining target protein, plays a role of identifying and combining a target of the target protein, is used as the target molecule to further construct functional target molecules, and has wide application prospect in the fields of tumor detection, tumor immunity and the like.

Description

Functional saccharide molecule based on TDG molecular skeleton and preparation method thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a functional saccharide molecule based on a TDG molecular skeleton and a preparation method thereof.

Background

Galectins (galectins) are a class of lectin proteins, belong to sugar binding proteins, and can recognize and bind sugar ligand molecules having galactose and lactose residues through a Carbohydrate binding Domain (CRD) pocket, which is possessed by the Galectin, thereby playing an important role in various physiological and pathological processes (such as cancer, inflammation, and the like).

The recognition and binding mechanism of galectin protein and its carbohydrate ligand molecules is elucidated, and a series of carbohydrate ligand molecules with high specific recognition and high affinity binding to galectin are developed (WO 2005/113569A 1, WO 2016/113335A 1, WO 2017/019770A 1 and W O2017/080973A 1), wherein the carbohydrate ligand molecule with a Thiodigalactoside (TDG) molecular skeleton can better match and occupy CRD of the galectin protein, and further shows higher binding activity.

However, the currently available carbohydrate ligand molecules block recognition binding of galectin proteins to carbohydrate ligands or antibodies in vivo only by competitive binding, and the resulting biological effects are unclear and remain to be studied; however, the use of the recognition binding between these sugar ligand molecules and galectins is still a blank in the field of wider biological applications, such as tumor detection and tumor immunotherapy by the specific recognition binding between the sugar ligands and the tumor markers, galectins 1 and 3.

The research around TDG carbohydrate ligand molecules focuses on developing TDG carbohydrate ligand molecules with high specific recognition and high affinity binding, for example, by introducing different substituent groups (such as substituted triazole group, substituted aryl amide group, etc.) on the TDG carbohydrate ligand molecules, a series of carbohydrate ligand molecules with high binding force to galectin are developed, and the selectivity and specificity of TDG carbohydrate ligand molecules for recognizing and binding different galectin proteins can be adjusted through the change of the substituent groups.

At present, the utilization of TDG sugar ligand molecules is basically limited to the pharmaceutical chemical application of TDG sugar ligands as galectin protein inhibitors, and the TDG sugar ligand molecules are mainly used for competitive binding of the target galectin protein, blocking the binding of the target galectin protein and natural sugar ligands or antibodies in organisms, further blocking corresponding signal channels and exerting corresponding biological effects.

In addition to the medicinal chemical application of TDG carbohydrate ligands, studies using TDG carbohydrate ligand molecules in combination with recognition of galectin proteins and using TDG carbohydrate ligand molecules as functional molecules targeting galectin proteins have not been reported, and functional molecules capable of exerting the target effects of these carbohydrate ligand molecules have not been reported. The sugar ligand molecule with the TDG molecular skeleton can be used for high-specificity recognition and high-affinity binding of galectin protein, and the target function of the sugar ligand molecule with the TDG molecular skeleton on the recognition and binding of the galectin protein target can be fully exerted by designing and preparing a novel functional sugar molecule compound based on the TDG molecular skeleton, so that the ligand molecule has wider biological functions.

Compared with the existing synthesis methods of sugar ligands with TDG molecular frameworks (WO 2005/113569A 1, WO 2016/113335A 1, WO 2017/019770A 1 and WO 2017/080973A 1), the synthesis method adopts a synthesis strategy of firstly side chain derivatization and then glycosylation coupling, realizes the side chain derivatization modification of the TDG molecular framework, provides a new synthesis route, and realizes the high-efficiency synthesis of the compounds.

The invention aims to provide a novel compound of a functional carbohydrate molecule based on a TDG molecular skeleton and a synthesis preparation method thereof according to a recognition and combination mechanism of a TDG carbohydrate ligand molecule and a galectin protein. The functional side chain is derived from the non-binding site of the TDG molecular skeleton to design the molecular structure, so that the novel compound derives different active reaction groups on the functional side chain on the basis of keeping the high specific recognition and high affinity binding effect of the TDG molecular skeleton on galectin target protein, thereby having the reactivity for constructing various functional molecules, and efficiently preparing the novel compound of the functionalized TDG sugar ligand molecule by the practice of a new synthesis route.

The invention provides a new functional saccharide molecule compound based on TDG molecular skeleton and a synthesis preparation method of the new compound, wherein a new functional saccharide molecule is obtained by performing functional side chain derivative modification on a saccharide ligand with the TDG molecular skeleton, the new compound further extends out a functional side chain on the basis of keeping the high specific recognition and high affinity binding effect of the saccharide ligand molecule with the TDG molecular skeleton on galectin protein, and can be functionally constructed through an active reaction group on the functional side chain, and the new compound is used for constructing reagents and molecules for detecting tumors, targeting tumors, immunizing tumors, inhibiting inflammations and the like based on the galectin protein target.

Disclosure of Invention

The invention provides a TDG molecular skeleton-based functional saccharide molecular novel compound and a synthesis preparation method thereof. The invention firstly designs a functional carbohydrate molecular new compound based on the TDG molecular skeleton on the basis of analyzing the identification combination of the TDG molecular skeleton and the galectin protein, and then develops a synthetic route through synthetic practice to realize the high-efficiency preparation of the functional carbohydrate molecular new compound based on the TDG molecular skeleton. Design of novel functional carbohydrate molecule compound based on TDG molecular skeleton

Currently, the binding mechanism of galectin protein to sugar ligand molecules has been elucidated (Nilsson et al, 2005; Nilsson et al,2008), the CRD pocket of galectin is mainly divided into A, B, C, D, E five regions (A in FIG. 1), and in binding to its natural lactose ligand, recognition binding is mainly performed by the action of 5 amino acid residues of His158, Asn160, Arg162, Asn174 and Glu184 in C, D region with hydroxyl groups at C-3, C-4 'and C-6' positions of lactose molecule (B in FIG. 1), while a molecule having TDG molecular skeleton is used as sugar ligand molecule, from which R extends₁、R₂The group may further interact with the Arg 186 in region E and the Arg144 residue in region A, B to further match the CRD pocket (C in fig. 1) occupying galectin. Based on the functional side chain (D in figure 1) with functional groups is extended from the C-6 position of the non-binding site of the sugar ligand molecule of the TDG molecular skeleton, and a new functional sugar molecular compound (E in figure 1) based on the TDG molecular skeleton is designed, wherein R is R₁、R₂Is selected from substituted triazole group, amide group, side chain functional group R₃Selected from mercapto (-SH), amino (-NH)₂) Azido (-N)₃) X is selected from oxygen atom (O) and carbon atom (C), n is selected from 0-7, etc.; the design principle and the corresponding compound structure are shown in figure 1.

Based on the design, the invention designs a saccharide compound, the structure of which is shown as the formula X,

wherein R is₁、R₂Independently selected from substituted amido, substituted triazolyl, substituted amino;

R₃selected from mercapto, azido, amino, carboxyl;

a is

or-C_mH_2mR₃

X is selected from oxygen atom;

n is selected from 0, 1,2, 3,4,5, 6, 7;

m is selected from 2,3, 4,5, 6,7, 8, 9, 10.

In the present invention, the amide group

Wherein R is₄Selected from alkyl, substituted alkyl, aryl, substituted aryl;

in the present invention, the substituted triazolyl group

Wherein R is₅Selected from aryl, substituted aryl, aromatic amide, substituted aromatic amide, alkyl amide and ester.

In the present invention, substituted amino group(s) ((

Wherein R is₆Selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylamido, substituted arylamido, alkylamido.

In the present invention, the aryl group in the aryl group or the substituted aryl group is selected from phenyl, naphthyl, pyrenyl, anthryl, phenanthryl, furan, thiophene.

In the present invention, the alkyl group in the alkyl group or the substituted alkyl group is selected from hydrocarbon groups of C1 to C6.

In the invention, the substituent on the substituted aryl is hydrogen, halogen, alkyl or alkoxy of C1-C6, haloalkyl or nitro of C1-C6, and hydroxyl; preferably, the halogen is selected from Cl, Br, I, F.

In the present invention, the substituents on the substituted aryl group are optionally independently substituted with 1 to 3 substituents.

In the present invention, R₅Is selected from

-COOR₁₂，-CONHR₁₃Wherein R is₇-R₁₁As set forth in the following table, wherein A is independently selected from F, Cl, Br, I: r is₁₂Selected from C1-6 alkyl, R₁₃Is selected from C1-6 alkyl, aryl or substituted aryl, wherein the aryl is selected from phenyl, naphthyl, pyrenyl, anthryl, phenanthryl, furan and thiophene;

in the present invention, the compound of formula X is further represented by,

a, R therein₁、R₂、R₃、R₄、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃And X is as defined above; preferably, R₄Selected from naphthyl, phenyl, substitutedOr substituted phenyl, the substituted phenyl being more preferably

In another aspect, the present invention provides a method for preparing the saccharide compound according to the present invention, which comprises the following steps:

1) the compound of formula IV and the compound of formula VII are glycosylated and coupled under the action of an accelerating agent to obtain a compound of formula VIII,

2) converting the compound shown in the formula VIII through a side chain group to obtain a compound shown in the formula IX;

3) subjecting the compound of formula IX to deacetylation to obtain a compound of formula X;

wherein R is₃Is selected from acetylpropionyloxy (LevO-), 4-methoxyphenoxy (4-MP-O-), A, R₁、R₂、R₃The definition is the same as that of the previous description.

The accelerant in the step 1) is selected from potassium carbonate and sodium carbonate,

the conversion of the side chain group in the step 2) comprises the following steps:

step 2-1) Selective deprotection group R₃Obtaining a key intermediate;

step 2-2) carrying out continuous acylation reaction on the key intermediate obtained in the step 2-1), and then carrying out substitution reaction to realize group conversion, so as to prepare the compound of the formula IX;

wherein, the reagent for removing the protective group in the step 2-1) is hydrazine acetate (N)₂H₄AcOH), Cerium Ammonium Nitrate (CAN). The protecting group removing agent is the same as R₃"the radicals correspond to each other when R₃When the molecular structure is LevO-, the protective group removing reagent is hydrazine acetate N₂H₄AcOH when R₃When the' is 4-MP-O-, the protecting group removing reagent selects ammonium ceric nitrate CAN.

Wherein, the acylation reagent in the acylation reaction condition in the step 2-2) is selected from trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride, preferably performed under basic conditions, and more preferably, the base is selected from triethylamine, pyridine, diisopropylethylamine and triisopropylamine;

wherein, in the step 2-2), the substituting reagent in the substituting reaction is selected from potassium thioacetate, sodium thioacetate, potassium thioacetate, thioacetic acid, sodium hydrosulfide, lithium azide, sodium azide, tetrabutylammonium azide, trimethylsilyl azide and a fluoride combined reagent, preferably, the fluoride is selected from lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, sodium hydrogen fluoride, potassium hydrogen fluoride, ammonium bifluoride, tetrabutylammonium fluoride and tetramethylammonium fluoride; when R is₃When the substituted reagent is sulfhydryl-SH, the substituted reagent is selected from potassium thioacetate, sodium thioacetate, potassium thioacetate, thioacetic acid and sodium hydrosulfide₃When the reagent is azide or amino, the substituting reagent is selected from lithium azide, sodium azide, tetrabutylammonium azide, azidotrimethylsilane and fluoride combined reagent.

The deacetylation reaction in step 3) is carried out under alkaline conditions, the pH value of the reaction is 8-12, and preferably, the alkaline conditions are obtained by adding one or more selected from sodium methoxide, triethylamine, trimethylamine and ammonia water.

Wherein, the reaction solvent in the step 1) is selected from water-miscible solvents, preferably acetonitrile, tetrahydrofuran and N, N-dimethylformamide; in the acylation reaction condition of the step 2-2), the reaction solvent is selected from aprotic polar solvents, preferably dichloromethane, trichloromethane, acetonitrile and tetrahydrofuran; the reaction solvent of the substitution reaction in the step 2-2) is selected from water-miscible solvents, preferably N, N-dimethylformamide, acetonitrile and tetrahydrofuran; the reaction solvent in step 3) is selected from the group consisting of protic polar solvents, preferably water, alcohols or aqueous alcohol solutions, more preferably methanol, methanol/water mixtures, water, ethanol.

In the technical scheme of the invention, the compound of the formula IV is obtained by the following steps,

1-11) preparing a crude bromo-sugar product from the compound of formula III under the action of a bromination reagent, wherein the bromination reagent is selected from 33% hydrobromic acid in acetic acid solution HBr/AcOH, a methanol/acetyl bromide combined reagent, titanium tetrabromide and phosphorus tribromide;

1-12) preparing an intermediate by carrying out substitution reaction on the crude bromo-sugar product obtained in the step 1-11), wherein a substitution reagent is selected from potassium thioacetate, sodium hydrosulfide, thioacetic acid, sodium thioacetate and ammonium thioacetate;

1-13) carrying out end group selective deacetylation reaction on the intermediate obtained in 1-12) to prepare a compound shown in a formula IV,

wherein the terminal selective deacetylation reagent is selected from N, N-dimethylaminopropylamine, ethylenediamine/acetic acid combined reagent, benzylamine and aniline;

R₂as previously described.

Wherein, the solvent in the step 1-11) is selected from a mixed solution of an aprotic polar solvent and acetic acid, preferably a mixed solvent of dichloromethane and acetic acid; in the step 1-12), the reaction solvent is selected from acetonitrile MeCN, N, N-dimethylformamide DMF;

in the technical scheme of the invention, the compound of the formula VII is obtained by the following steps,

1-21) hydrolyzing the compound of the formula V at 1, 2-position propylidene for ring opening and acetylation to prepare an intermediate of the formula VI;

1-22) preparing an intermediate from the compound of formula VI by a protecting group conversion reaction;

1-23) carrying out bromination reaction on the intermediate obtained in the step 1-22) under the action of a bromination reagent to prepare a compound shown in a formula VII;

wherein R is₁、R₃"is as defined above, R₃' is 2-naphthylmethyl (Nap), benzyl (Bn-), allyl (All-).

In the step 1-21), the reaction reagent for the acid hydrolysis and ring opening of the 1, 2-propylidene is toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and trifluoroacetic acid, and the ring opening reaction is carried out by refluxing; the acetylation reaction conditions are a mixture of sodium acetate and acetic anhydride, a mixture of acetic anhydride and pyridine, a mixture of acetyl bromide and pyridine, a mixture of acetyl chloride and pyridine, and a mixture of perchloric acid and acetic anhydride.

In the step 1-22), R is removed by 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone or ceric ammonium nitrate through a deprotection agent₃' Nap protection, or by deprotection agents palladium on carbon (Pd/C), palladium hydroxide (Pd (OH)₂) Removal of R₃' Bn protecting group, or by deprotecting agent PdCl₂Removal of R₃' All-protection;

in steps 1-22), deprotection followed by reaction under levulinic acid or levulinic anhydride yields R3 "as Lev, or reaction under 4-methoxyphenol yields R3" as 4-MP-OH.

In steps 1-23), the brominating reagent is selected from 33% hydrobromic acid in acetic acid solution HBr/AcOH, methanol/acetyl bromide combined reagent, titanium tetrabromide, phosphorus tribromide.

In the technical scheme of the invention, the compound of the formula V is obtained by the following steps,

1-21-1) selective ring opening of the propylidene in the 5,6 position of the compound of formula II;

1-21-2) performing side chain derivatization;

before or after the step 1-21-1) or after the step 1-21-2), further comprising the step 1-21-3) of carrying out a group conversion reaction;

wherein

In the step 1-21-1), the conditions of the selective ring-opening reaction of the 5, 6-propylidene are that the reaction is carried out under acidic conditions and normal temperature, the acidic conditions are obtained by adding p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and trifluoroacetic acid, and the reaction is carried out under the condition that water exists;

step 1-21-2) LG-PEG_n+1-R₃' or LG-C_mH_2m-R₃' conducting the reaction under the condition of a catalyst, wherein the catalyst is selected from dibutyltin oxide and cesium fluoride, and LG is selected from chlorine atom, bromine atom and p-toluenesulfonyloxy;

the condition of the group conversion reaction in the step 1-21-3) is to react with R under the condition of a catalyst₁-C ≡ C reaction, said catalyst beingCuI and N, N-diisopropylethylamine DIPEA combination, CuSO₄And Vc-Na; or first of all the hydrogenation of the-N on the compound of the formula II₃is-NH₂At a position of and R₆-Cl.

In the technical scheme of the invention, the compound of the formula III is obtained by the following steps,

1-11-1) carrying out propylidene ring-opening reaction on the compound of the formula II;

1-11-2) carrying out acetylation on sugar ring hydroxyl;

before or after the step 1-11-1) or after the step 1-11-2), performing a group conversion reaction by further comprising the step 1-11-3);

wherein

The ring-opening reaction of propylidene in the step 1-11-1) is carried out under the reflux of acidic conditions, the acidic conditions are obtained by adding p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and trifluoroacetic acid, and the reaction is carried out in the presence of water;

the acetylation reaction conditions in the step 1-11-2) are a mixture of sodium acetate and acetic anhydride, a mixture of acetic anhydride and pyridine, a mixture of acetyl bromide and pyridine, a mixture of acetyl chloride and pyridine, and a mixture of perchloric acid and acetic anhydride;

the condition of the group conversion reaction of the step 1-11-3) is to react with R under the condition of a catalyst₂-C.ident.C reaction, the catalyst is a combination of CuI and N, N-diisopropylethylamine DIPEA, CuSO₄And Vc-Na; or first of all the hydrogenation of the-N on the compound of the formula II₃is-NH₂At a position of and R₆-Cl.

In the technical scheme of the invention, the compound of the formula II is obtained by the following steps,

i) preparation of the Compound of formula I diacetone gulose by Ring inversion of diacetone glucose through sugar

II) preparing a compound of a formula II by acylation and azide substitution reaction of the compound of the formula I;

wherein step i) comprises the following two steps:

i-1) oxidation to give the compound of formula I-1

With acetic anhydride Ac₂O and dimethyl sulfoxide DMSO composition are used as oxidant to carry out oxidation reaction,

i-2) catalytic hydrodeacetylation with a catalyst selected from Pd/C, Pd (OH)₂/C。

Wherein step ii) comprises the following two steps:

ii-1) adding an acylating agent selected from the group consisting of trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, preferably under basic conditions, more preferably a base selected from the group consisting of triethylamine, pyridine, diisopropylethylamine, triisopropylamine;

ii-2) adding an azide reagent selected from lithium azide, sodium azide, tetrabutylammonium azide or a combination of trimethylsilyl azide and a fluoride selected from lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, sodium hydrogen fluoride, potassium hydrogen fluoride, ammonium hydrogen fluoride, tetrabutylammonium fluoride, tetramethylammonium fluoride to carry out the reaction.

In a further aspect, the invention provides the use of the carbohydrate compounds of the invention in the preparation of a medicament or detection reagent for targeting, identifying or detecting galectin 1 protein.

In a further aspect, the present invention provides the use of the carbohydrate of the present invention as an active targeting ligand, which specifically recognizes galectin protein 1, and which is linked to an active ingredient or a detection reagent.

In the technical scheme of the invention, the active ingredient comprises an anti-tumor drug or an anti-inflammatory drug, and the detection reagent comprises a fluorescent label and a probe.

In the technical scheme of the invention, specifically, a commercial raw material diacetone glucose is used as an initial raw material, diacetone gulose II is obtained by sugar ring inversion, and then a key intermediate II is obtained by group conversion; synthesizing the intermediate II into a key intermediate III through group conversion, ring opening and acetylation, and obtaining a key intermediate IV through bromination, thio and selective deacetylation of the intermediate II; on the other hand, the intermediate I is subjected to group conversion, selective ring opening and side chain derivatization to react with a key intermediate V, and the intermediate V is subjected to ring opening, acetylation, side chain group conversion operation, bromination and other steps in sequence to obtain a key intermediate VII; the intermediate IV and the intermediate VII are prepared under the action of an accelerant to obtain an intermediate VIII, the intermediate VIII is subjected to selective deprotection, group conversion and other steps to obtain a functional saccharide molecule new compound X based on a TDG molecular skeleton, and the synthetic route is shown in the following flow.

The invention provides a functional molecule of a carbohydrate compound by designing and efficiently synthesizing a functional carbohydrate molecular compound based on a TDG molecular skeleton, and can be used for directly constructing various functional target molecules. When the targeting agent is used, the R3 group can be coupled with various detection reagents or active substances, so that the targeting purpose is realized.

Advantageous effects

1. A class of functional carbohydrate compounds is provided: the functional molecules of the novel carbohydrate compounds based on the TDG molecular skeleton are obtained by modifying the functional side chains of the TDG molecular skeleton.

2. The structural design of introducing functional side chains into non-binding sites of sugar ligand molecules leads the novel compound to have the reactivity of preparing various target molecules through efficient and simple chemical reaction by introducing side chain functional groups on the basis of keeping the recognition binding activity of the sugar ligands to target proteins.

3. By introducing functional side chain groups, reactive groups on the functional side chains can directly construct functional targeting molecules.

4. Different functional groups are introduced into the side chain, so that the method can be used for constructing various functional targeting molecules with different types, and has wide application range and obvious application value.

5. Different functional groups are introduced into the side chain, so that different types of functional molecules can be efficiently constructed by applying various different methods, and the method has wide application range and obvious application value

6. The synthesis route is provided for synthesizing and preparing the new compound, gram-scale mass synthesis is realized, the synthesis route degenerates reaction steps, simplifies post-treatment purification steps, each step of reaction is stable, economic and efficient, and does not involve anhydrous and anaerobic reaction, thereby being beneficial to mass and industrial production.

7. The synthetic route of the invention optimizes the conditions of each step of reaction, avoids the use of heavy metal oxidizing agents and other heavy pollution reagents, metal azide reagents and other strictly controlled reagents, and improves the reaction efficiency

The novel functional carbohydrate molecule compound based on the TDG molecular skeleton can utilize the identification and combination of TDG carbohydrate ligand molecules on target proteins, plays the role of identifying and combining target proteins, and further constructs functional target molecules by using the TDG carbohydrate ligand molecules as the target molecules, thereby having wide application prospect in the fields of tumor detection, tumor immunity and the like; and each step of reaction in the synthetic process is simple, stable and efficient, the reaction steps are degenerate, the post-treatment purification is simple, the cost is low, and the method is suitable for batch and industrial production.

Drawings

FIG. 1 shows the design of novel compounds of functionalized saccharide molecules based on TDG molecular skeleton.

Detailed Description

The feasibility of the invention is demonstrated by the following synthetic route of the novel compound XI as the functional sugar molecular compound based on TDG molecular skeleton.

Example 1

Diacetone glucose (40g,153.7mmol) dissolved in Ac₂Stirring overnight at room temperature in a mixed solution of O/DMSO (v/v ═ 1:2,150mL), detecting the reaction completion by TLC (PE: EA ═ 1:1), adding dichloromethane DCM into the reaction solution for dilution, washing for 3 times, combining organic phases, washing the organic phases with 30% hydrogen peroxide, drying with anhydrous sodium sulfate, and concentrating to obtain brown syrup intermediate which is directly used for the next reaction

The brown syrup intermediate was dissolved in pyridine (50mL), acetic anhydride (20mL) was added dropwise, the reaction was refluxed overnight in an oil bath at 90 ℃, TLC (PE: EA ═ 1:1) was checked for completion of the reaction, the reaction solution was cooled to room temperature, concentrated and purified by column chromatography (isocratic elution, PE: EA ═ 3:1) to give colorless syrup I-1(39.5g, 85% in 2 steps).¹H NMR(400M，CDCl₃)δ6.04(d,J＝5.5Hz,1H),5.40(d,J＝5.5Hz,1H), 4.71(t,J＝6.4Hz,1H),4.10-4.04(m,2H),2.22(s,3H),1.54(s,3H),1.48(s, 3H),1.45(s,3H),1.38(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.1,145.4, 129.2,113.6,110.6,104.2,81.0,68.8,66.1,28.1,28.0,25.9,25.8,20.7。

Example 2

Compound I-1(39.5g, 131.5mmol) was dissolved in ethyl acetate (100mL), Pd/C powder (2.0g) was added, after stirring, the mixture was stirred under hydrogen (40psi) atmosphere for 3 hours, TLC (PE: EA ═ 1:1) detected complete reaction, Pd/C powder was filtered off, the filtrate was concentrated to give a pale yellow syrup intermediate (36.6g, 92%),¹H NMR (400MHz,CDCl3)δ5.82(d,J＝4.1Hz,1H),5.10-5.06(m,1H),4.81(dd,J＝ 5.6,4.1Hz,1H),4.14-4.06(m,2H),3.57-3.51(m,1H),2.14(s,3H),1.59(s, 3H),1.45(s,3H),1.39(s,3H),1.36(s,3H).¹³C NMR(101MHz,CDCl3)δ 169.7,114.6,109.4,105.1,81.5,78.6,75.3,71.9,66.5,26.9,26.8,25.4,20.7.

dissolving the light yellow syrup obtained in the previous step in methanol (100mL), adding sodium methoxide to adjust the pH of the reaction solution to 8-10, stirring at room temperature for 30min, indicating that the reaction is complete by TLC (PE: EA ═ 1:1), adding 732H⁺Adjusting reaction liquid to be neutral by resin, filtering resin, concentrating filtrate, separating by column chromatography (PE: EA is 3:1) to obtain light yellow syrup I, and solidifying after long-term storage (31.2g, 99%).¹H NMR(400MHz,CDCl₃)δ5.78(d,J＝4.1Hz, 1H),4.66(dd,J＝6.3,4.1Hz,1H),4.48(dt,J＝8.4,7.0Hz,1H),4.26-4.20(m, 2H),3.90(dd,J＝8.6,5.7Hz,1H),3.72(dd,J＝8.6,7.3Hz,1H),2.68(s,1H), 1.63(s,3H),1.45(s,3H),1.43(s,3H),1.38(s,3H).¹³C NMR(101MHz, CDCl₃)δ115.1,109.4,105.4,84.4,80.0,75.7,69.8,66.5,27.3,27.2,26.8, 25.3。

Example 3

Compound I (29.9g,114.88mmol) was dissolved in dichloromethane (100mL), pyridine (27.81mL, 344.6mmol) was added, cooled to ice bath temperature, trifluoromethanesulfonic anhydride (38.6mL, 229.7mmol) was added dropwise, stirred for 30min under ice bath, TLC (PE: EA ═ 1:1) showed completion of the reaction, and the reaction solution was then passed through 1N HCl_a.q.、sat. NaHCO_3a.q.Washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating to obtain brown syrup intermediate for the next reaction;

azidotrimethylsilane (52.9mL, 402.1mmol) and sodium fluoride (15.9g,379.1mmol) were mixed in DMF (150mL), refluxed for 1 hour in a 100 ℃ oil bath, cooled to room temperature, added with DMF solution of the brown syrup intermediate obtained in the previous step, the mixture was refluxed overnight in a 50 ℃ oil bath, TLC (PE: EA ═ 1:1) checked for completion of the reaction, the reaction solution was cooled to room temperature, poured into water, the mixture was extracted three times with dichloromethane (3 × 300mL), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated and stirred, and column chromatography (PE: EA ═ 6:1) was performed to obtain colorless syrup II, which was solidified after a long time (29.64g, 90.2%).¹H NMR(400MHz,CDCl₃)δ5.80(d,J＝3.9Hz,1H),4.60(dd,J＝3.9,1.8Hz, 1H),4.35(dd,J＝12.4,6.7Hz,1H),4.08(dd,J＝8.4,6.7Hz,1H),3.94(dd,J＝ 5.7,1.7Hz,1H),3.90-3.81(m,2H),1.57(s,3H),1.46(s,3H),1.39(s,3H), 1.37(s,3H).¹³C NMR(101MHz,CDCl₃)δ114.6,110.2,105.0,85.9,83.3, 74.7,65.7,65.7,27.7,27.0,26.5,25.3。

Example 4

The compound of formula II (29.2g, 89%) was isolated according to the same procedure as in example 3.

Example 5

The feeding proportion and the operation step 1) are the same as those in example 3;

azidotrimethylsilane (52.9mL, 402.1mmol) and tetrabutylammonium fluoride (15.9g,379.1mmol) were mixed in DMF (100mL), the mixture was refluxed for 30 minutes at 50 ℃ until no bubbles were produced, the DMF solution of the brown syrup intermediate obtained in step 1) was added, the mixture was refluxed overnight in a 50 ℃ oil bath, TLC (PE: EA: 1) was checked for completion of the reaction, the reaction was cooled to room temperature, dichloromethane was added to dilute the reaction solution (500mL), the mixture was washed three times with brine (3: 100mL), the aqueous phase was back-extracted 1 time with dichloromethane (100mL), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated and stirred, and column chromatography was performed to obtain the compound of formula II (30.2g, 92%).

Example 6

Compound II (8g,28.04mmol) was dissolved in tetrahydrofuran (40mL), CuI (1.07g, 5.61mmol) and DIPEA (5.86mL,33.65mmol) were added, and after vigorous stirring for 5min, 3,4, 5-trifluorophenylacetylene (4.11mL,33.65mmol) was added, stirred at room temperature for 1 hour, and detected by TLC (PE: EA ═ 4:1)The solvent was evaporated off, the residue dissolved in dichloromethane (50mL) and the organic phase washed with dilute ammonia, 1N HCl_a.q.、 sat.NaHCO_3a.q.Washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, mixing, purifying by column chromatography (PE: EA: 6:1) to obtain colorless solid compound XII (12.1g, 97.8%),¹H NMR(400M，CDCl₃) δ7.78(s,1H),7.39(dd,J＝8.1,6.5Hz,2H),5.99(d,J＝3.9Hz,1H),4.94(dd, J＝3.9,1.8Hz,1H),4.39(dd,J＝12.4,6.7Hz,1H),4.24(dd,J＝8.4,6.7Hz, 1H),4.03(dd,J＝5.7,1.7Hz,1H),3.99-3.91(m,2H),1.72(s,3H),1.60(s,3H), 1.52(s,3H),1.35(s,3H)；¹³C NMR(100M，CDCl₃)δ123.1,115.9,111.1,111.0, 110.9,110.8,106.5,86.2,81.6,73.6,65.5,27.8,27.2,26.2,25.2.

example 7

Compound II (8g,28.04mmol) was dissolved in tetrahydrofuran (40mL) and CuSO was added₄(0.9g, 5.6mmol) and sodium ascorbate (6.67g, mmol) were stirred vigorously for 5min, 3,4, 5-trifluorophenylacetylene (4.11mL,33.65mmol) was added, stirred at room temperature for 1h, the reaction was checked by TLC (PE: EA. RTM.4: 1) for completion, the solvent was evaporated, the residue was dissolved in dichloromethane (50mL), and the organic phase was washed with dilute ammonia, followed by 1N HCl_a.q.、 sat.NaHCO_3a.q.Washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, mixing, and purifying by column chromatography (PE: EA: 6:1) to obtain compound XII (11.8g, 95.3%)

Example 8

Compound XII (10g, mmol) was mixed with MeCN/H₂Adding a catalytic amount of TsOH into a mixed solvent of O (v/v ═ 1:3,60mL), placing the mixture in an oil bath for reflux reaction overnight, cooling the reaction liquid to room temperature, dropwise adding triethylamine to neutralize the reaction liquid, and concentrating to obtain a light yellow solid intermediate which is directly used for the next reaction;

dissolving the light yellow solid intermediate in pyridine (40mL), dripping acetic anhydride (20mL) into ice bath, stirring the mixture at room temperature for 12 hours, detecting the reaction completion by TLC (PE: EA is 1:1), dripping methanol into the ice bath to quench the reaction, concentrating the reaction solution, dissolving the residue in dichloromethane, and sequentially passing the organic phase through 1N HCl_a.q.、sat.NaHCO_3a.q.And saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound XIII (11.9g, 99%) as an anomeric mixture as a pale yellow solid.

Example 9

Compound I (5g,17.53mmol) is mixed with MeCN/H₂Adding a catalytic amount of TsOH into a mixed solvent of O (v/v ═ 1:3,30mL), placing the mixture in an oil bath for reflux reaction overnight, cooling the reaction liquid to room temperature, dropwise adding triethylamine to neutralize the reaction liquid, and concentrating to obtain a white solid intermediate which is directly used for the next reaction;

dissolving the white solid intermediate in pyridine (10mL), adding acetic anhydride (5mL) dropwise in ice bath, stirring at room temperature for 12 hours, detecting the reaction completion by TLC (PE: EA is 1:1), adding methanol dropwise in ice bath to quench the reaction, concentrating the reaction solution, dissolving the residue in dichloromethane, and sequentially adding 1N HCl into an organic phase_a.q.、sat.NaHCO_3a.q.Washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating to obtain yellowish syrup intermediate, standing, and solidifying

Dissolving the syrup intermediate in tetrahydrofuran, adding CuI (667mg,3.51mmol) and DIPEA (3.66mL,21.03mmol), stirring vigorously for 5min, adding 3,4, 5-trifluoro-phenylacetylene (2.41mL, 21.03mmol), stirring at room temperature for 1 hr, detecting reaction completion by TLC (PE: EA ═ 2:1), evaporating to remove solvent, dissolving the residue in dichloromethane, and subjecting the organic phase to dilute ammonia water and 1N HCl_a.q.、sat.NaHCO_3a.q.And brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to purify compound XIII (8.8g, 94.8%).

Example 10

Dissolving compound XIII (5g, mmol) in dichloromethane/acetic anhydride (v/v 10:1,16.5mL) mixed solvent, dropping 33% HBr/AcOH solution (5mL) under ice bath, stirring for 8 hours, detecting reaction completion by TLC (PE: EA 2:1), pouring reaction liquid into ice water mixture, stirring for 30min, extracting mixture with dichloromethane (3X 50mL), combining organic phases, and then sat_3a.q.Washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give foamy compound XIV (4.3g, 82.7%) which was used directly in the next reaction.¹H NMR(400MHz,CDCl₃)δ7.80(s,1H),7.44(dd,J＝8.0,6.5Hz,2H),6.89 (d,J＝3.8Hz,1H),5.82(dd,J＝11.3,3.8Hz,1H),5.62(d,J＝1.8Hz,1H), 5.32(dd,J＝11.4,2.9Hz,1H),4.64(t,J＝6.6Hz,1H),4.24(dd,J＝11.5,6.4 Hz,1H),4.14(dd,J＝11.5,6.7Hz,1H),2.07(s,6H),1.96(s,3H).¹³C NMR (101MHz,CDCl₃)δ170.5,169.7,169.3,120.5,110.3,110.2,110.1,110.0, 88.7,71.4,67.8,67.0,61.0,59.2,20.8,20.7,20.6。

Example 11

Compound XIV (5g,9.09mmol) was dissolved in N, N-dimethylformamide (20mL), potassium thioacetate KSAc (2.08g,18.17mmol) was added, stirred at room temperature for 2 hours, TLC (PE: EA ═ 2:1) checked for completion of the reaction, the reaction solution was diluted with dichloromethane (100mL), the organic phase was washed with water (3 × 100mL), dried over anhydrous sodium sulfate, and concentrated to give yellow syrup XV (4.7g, 94.8%), which was solidified after a long time.¹H NMR(400MHz, CDCl₃)δ7.77(s,1H),7.40(dd,J＝7.9,6.6Hz,2H),5.85(t,J＝10.5Hz,1H), 5.61(d,J＝2.8Hz,1H),5.41(d,J＝10.0Hz,1H),5.21(dd,J＝11.0,3.2Hz, 1H),4.25(t,J＝6.4Hz,1H),4.15(dd,J＝11.5,6.4Hz,1H),4.08(dd,J＝11.5, 6.7Hz,1H),2.43(s,3H),2.05(d,J＝7.1Hz,6H),1.88(s,3H)；¹³C NMR(101 MHz,CDCl₃)δ191.9,170.5,169.6,169.0,119.1,110.1,110.1,110.0,109.9, 81.5,76.1,68.7,65.5,63.5,61.3,31.1,20.8,20.6,20.5；

Example 12

Dissolving compound XV (1g,1.83mmol) in tetrahydrofuran (10mL), adding N, N-dimethylaminopropylamine (0.35mL,2.75mmol) dropwise, stirring at room temperature for 30 minutes, detecting completion of reaction by TLC (PE: EA ═ 1:1), adding acetic acid dropwise to neutralize the reaction solution, evaporating the reaction solvent, dissolving the residue in dichloromethane, and subjecting the organic phase to 1N HCl successively_a.q.、sat.NaHCO_3a.q.And washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give yellow syrup XVI, which is immediately used in the next reaction.

Example 13

Compound II (5g,17.53mmol) was mixed with MeCN/H₂O (v/v ═ 3:1,40mL) mixed solvent, adding catalytic amount of TsOH, stirring at room temperature for 24 hours, detecting by TLC (PE: EA ═ 2:1) that the reaction is complete, dropping triethylamine to neutralize the reaction solution, evaporating to remove solvent to obtain pale yellow oily intermediate, directly using in the next reaction,¹H NMR (400MHz,CDCl₃)δ5.88(d,J＝4.1Hz,1H),4.65(dd,J＝4.1,1.3Hz,1H), 4.13-4.09(m,1H),4.00(dd,J＝6.1,4.2Hz,1H),3.89-3.84(m,1H),3.78(dd,J ＝11.7,4.1Hz,1H),3.70(dd,J＝11.7,4.7Hz,1H),1.55(s,3H),1.35(s,3H)；¹³C NMR(101MHz,CDCl₃)δ113.8,105.4,85.5,85.1,70.1,65.9,63.8,27.1, 26.5.

dissolving the oily intermediate in methanol (40mL), adding dibutyltin oxide (5.24g,21.03mmol), placing in an oil bath for reflux reaction for 3 hours until the solution is clear, cooling the reaction solution to room temperature, and evaporating the solvent to obtain a yellow syrup intermediate; syrup intermediate was dissolved in DMF (40mL) and Ts-PEG was added₄-ONap (12.84g,26.29mmol) and cesium fluoride (3.99g,26.29mmol) were put in an oil bath at 70 ℃ and refluxed overnight, TLC (PE: EA ═ 1:1) was used to detect completion of the reaction, and the reaction solution was cooled to a temperature where the reaction solution was cooledThe solvent is evaporated off at room temperature, the residue is dissolved in dichloromethane, the organic phase is washed three times with water, dried over anhydrous sodium sulfate, concentrated, stirred and purified by column chromatography (PE: acetone ═ 3:1) to give yellow syrup XVII (9.3g, 94.5% in 2steps),¹H NMR(400MHz,CDCl₃)δ7.86-7.78 (m,4H),7.51-7.45(m,3H),5.83(d,J＝4.1Hz,1H),4.74(s,2H),4.59(dd,J＝ 4.1,1.4Hz,1H),4.22(dd,J＝4.1,1.2Hz,1H),4.00-3.91(m,2H),3.72-3.61(m, 16H),3.55(dd,J＝10.0,5.2Hz,1H),2.18(s,1H),1.55(s,3H),1.34(s,3H). ¹³C NMR(101MHz,CDCl₃)δ135.8,133.3,133.0,128.2,127.9,127.7,126.5, 126.1,125.9,125.9,113.7,105.2,85.6,85.2,73.4,72.6,70.9,70.7,70.7,70.6, 70.5,69.4,68.8,65.8,27.1,26.5。

example 14

Compound XVII (9.3g,16.65mmol) is dissolved in tetrahydrofuran (40mL), CuI (0.63g, 3.31mmol) and DIPEA (3.47mL,19.87mmol) are added, after vigorous stirring for 5min, 3,4, 5-trifluorophenylacetylene (2.14mL, 19.87mmol) is added and the reaction is carried out at room temperature for 1h, TLC (PE: acetone ═ 3:1) is checked for completion, the solvent is evaporated off, the residue is taken up in dichloromethane and the organic phase is passed over dilute aqueous ammonia, 1N HCl, etc_a.q.、sat.NaHCO_3a.q.And washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, stirred, and purified by column chromatography to give compound XVIII (11.2g, 94.2%) as a pale yellow syrup.¹H NMR(400MHz,CDCl₃) δ8.17(s,1H),7.84-7.76(m,3H),7.73(s,1H),7.54-7.40(m,5H),6.11(d,J＝ 3.9Hz,1H),5.30(d,J＝3.2Hz,1H),5.08-5.04(m,1H),4.67(s,2H),4.30(dd, J＝6.6,4.3Hz,1H),4.04(dd,J＝12.4,6.6Hz,1H),3.74(dd,J＝9.7,5.5Hz, 1H),3.70-3.55(m,16H),3.49(dd,J＝9.7,6.7Hz,1H),1.63(s,3H),1.34(s, 3H).¹³C NMR(101MHz,CDCl₃)δ135.6,133.2,133.0,128.2,127.9,127.7, 126.6,126.1,125.9,125.8,121.7,114.1,110.0,109.8,105.7,86.6,85.5,77.3, 73.4,72.7,70.7,70.7,70.6,70.6,70.5,70.5,70.4,69.5,68.6,65.5,31.0,27.3, 26.5.

Example 15

Compound XII (5g,11.33mmol) suspended in MeCN/H₂O (v/v ═ 3:2,40mL) in a mixed solvent, a catalytic amount of p-toluenesulfonic acid was added, the mixture was stirred at room temperature for 24 hours, TLC (PE: EA ═ 3:1) detected completion of the reaction, triethylamine was added dropwise to neutralize the reaction mixture, the solvent was distilled off, the residue was dissolved in dichloromethane, washed with brine, the organic phases were combined and concentrated to give compound XIX (4.3g, 94.6%) as a white solid,¹H NMR(400MHz,MeOD) δ8.54(s,1H),7.64(dd,J＝8.8,6.6Hz,2H),6.07(d,J＝4.2Hz,1H),5.36(dd, J＝6.7,2.5Hz,1H),5.11(dd,J＝4.1,2.6Hz,1H),4.36(dd,J＝6.7,4.3Hz, 1H),3.75-3.59(m,3H),1.66(s,3H),1.39(s,3H).¹³C NMR(101MHz,MeOD) δ123.1,115.9,111.1,110.8,106.5,87.7,84.5,71.1,66.9,64.1,28.0,27.4.

example 16

Dissolving a compound XIX (4.3g,10.71mmol) in methanol (30mL), adding dibutyltin oxide (3.2g, 12.86mmol), placing in an oil bath for reflux reaction for 3 hours until the solution is clear, cooling the reaction solution to room temperature, and evaporating the solvent to obtain a yellow syrup intermediate; syrup intermediate was dissolved in DMF (20mL) and Ts-PEG was added₄-ONap (7.85g,16.07mmol) and cesium fluoride (2.44g,16.07mmol) were put in a 70 ℃ oil bath for reflux reaction overnight, TLC (PE: EA ═ 1:1) was checked for completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off, the residue was dissolved in dichloromethane, the organic phase was washed with water three times, dried over anhydrous sodium sulfate, concentrated and sample-stirred, purified by column chromatography (PE: acetone ═ 3:1), and isolated as yellow syrup XVIII (7.4g, 96.2%).

Example 17

The feeding operation was the same as in example 13, step 1;

the resulting intermediate was dissolved in tetrahydrofuran (40mL), CuI (667mg,3.51mmol) and DIPEA (3.67mL,21.03mmol) were added, after vigorous stirring for 5min, 3,4, 5-trifluorophenylacetylene (2.25mL,21.03mmol) was added, the reaction was allowed to proceed at room temperature for 1h, TLC (PE: acetone ═ 3:1) checked for completion, the solvent was evaporated, the residue was dissolved in dichloromethane, and the organic phase was washed with dilute aqueous ammonia, followed by 1N HCl_a.q.、sat. NaHCO_3a.q.And brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound XIX (6.5g, 92.4%).

Example 18

Compound XVIII (7.4g,10.31mmol) is mixed with MeCN/H₂Adding a catalytic amount of TsOH into a mixed solvent O (v/v ═ 3:1,40mL), placing the mixed solvent in an oil bath for reflux reaction overnight, detecting the reaction completion by TLC (PE: acetone ═ 2:1), dropping triethylamine to neutralize the reaction solution, and distilling off the solvent to obtain a light yellow syrup intermediate;

dissolving the yellowish syrup intermediate in pyridine (15mL), adding acetic anhydride (5mL), stirring at room temperature for 12 hr, detecting by TLC (PE: acetone 2:1), adding methanol in ice bath to quench reaction, evaporating to remove solvent, dissolving the residue in dichloromethane, and sequentially adding 1N HCl to organic phase_a.q.、sat.NaHCO_3a.q.Washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, mixing with sample, and purifying by column chromatography to obtain compound XX (6.9g, 83.3%), light yellow syrup

XX-α-anomer ¹H NMR(400MHz,CDCl₃)δ7.80(m,6H),7.50-7.38 (m,6H),6.50(d,J＝3.5Hz,1H),6.00(dd,J＝11.7,3.6Hz,1H),5.66(d,J＝ 2.0Hz,1H),5.33(dd,J＝11.8,2.9Hz,1H),4.72(s,2H),4.43(t,J＝6.2Hz, 1H),3.73-3.45(m,18H),2.20(s,3H),2.06(s,3H),1.87(s,3H).¹³C NMR(101 MHz,CDCl₃)δ169.6,169.0,168.8,135.7,133.3,133.0,128.2,127.9,127.7, 126.5,126.1,125.9,125.8,119.5,110.0,109.8,89.3,77.3,73.4,71.1,70.7, 70.7,70.6,70.6,70.5,70.3,69.4,69.0,68.8,65.6,60.4,58.4,36.5,21.0,20.5, 20.4,14.2。

XX-β-anomer ¹H NMR(400MHz,CDCl₃)δ7.85-7.77(m,6H), 7.50-7.38(m,6H),5.91-5.82(m,2H),5.61(d,J＝1.8Hz,1H),5.13(d,J＝8.5 Hz,1H),4.73(s,2H),4.15(dd,J＝10.0,4.3Hz,1H),3.75-3.48(m,18H),2.14 (s,3H),2.05(s,3H),1.87(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.3,168.9, 168.8,135.8,133.3,133.0,128.2,127.9,127.7,126.5,126.1,125.9,125.8, 119.4,110.0,109.8,92.7,77.3,73.9,73.3,71.2,70.7,70.6,70.5,69.5,68.7, 68.6,67.0,62.3,31.0,20.9,20.5,20.4。

Example 19

Compound XX (6.9g,8.58mmol) was dissolved in a dichloromethane/methanol (v/v ═ 10:1,44mL) mixed solvent, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (4.87g,21.46mmol) was added, the mixture was stirred at room temperature for 30 minutes, TLC (PE: acetone ═ 2:1) was checked for completion of the reaction, the reaction mixture was diluted with dichloromethane and then 1N HCl was added_a.q.、sat.NaHCO_3a.q.Washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating to obtain yellowish syrup intermediate;

the intermediate from the previous step was dissolved in dichloromethane (30mL), levulinic acid (1.99g,17.17mmol), EDC (4.94g,25.57mmol) and a catalytic amount of DMAP were added and stirred at room temperature for 2 hours, TLC (PE: acetone ═ 2:1) was used to detect completion of the reaction, and the reaction solution was then 1N HCl_a.q.、sat.NaHCO_3a.q.And saturated brine, dried over anhydrous sodium sulfate, concentrated, and sample-stirred, and purified by column chromatography to give compound XXI (5.6g, 85.6%), pale yellow syrup, and an anomer mixture.

Example 20

Compound XXI (5.6g,7.35mmol) was dissolved in a dichloromethane/acetic anhydride (v/v ═ 10:1,11mL) mixed solvent, and 33% HB was added dropwise in ice bathr/AcOH solution (3mL), stirring for 4 hours, detecting complete reaction by TLC (PE: acetone ═ 2:1), pouring the reaction solution into ice-water mixture, stirring for 30min, extracting the mixture with dichloromethane for three times, combining organic phases, and then carrying out sat_3a.q.Washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give foamy compound XXII (5.3g, 91.2%) as a pale yellow syrup which was used directly in the next reaction.¹H NMR(400MHz,CDCl3)δ7.89(s,1H),7.45(dd,J＝8.0, 6.6Hz,2H),6.90(d,J＝3.8Hz,1H),5.82(dd,J＝11.3,3.8Hz,1H),5.67(d,J ＝1.8Hz,1H),5.33(dd,J＝11.2,2.9Hz,1H),4.57(t,J＝6.3Hz,1H), 4.25-4.21(m,2H),3.72-3.55(m,17H),2.75(t,J＝6.5Hz,2H),2.60(t,J＝6.5 Hz,2H),2.19(s,3H),2.05(s,3H),1.95(s,3H).¹³C NMR(101MHz,CDCl₃)δ 206.79,172.84,169.55,169.12,120.77,110.04,109.98,109.81,89.28,72.23, 71.16,70.66,70.60,70.54,69.10,68.24,68.09,67.10,63.84,59.14,53.48, 37.94,29.93,27.96,20.54,20.44.

Example 21

Compound XVI (3.4g,6.75mmol) and compound XXII (5.3g,6.76mmol) were mixed in MeCN (50mL), potassium carbonate (1.87g,13.51mmol) was added, the reaction was stirred at room temperature for 12 hours, the reaction was checked by TLC for completion (PE: acetone ═ 2:1), the solvent was evaporated, and the residue was directly purified by column chromatography (PE: acetone ═ 5:2) to give compound XXIII (5.7g, 70%) as a pale yellow syrup.¹H NMR(400MHz,CDCl3) δ7.85(s,1H),7.83(s,1H),7.42(dd,J＝14.0,6.6Hz,4H),5.76(t,J＝10.2Hz, 1H),5.76(t,J＝10.2Hz,1H),5.62(s,2H),5.26(dd,J＝11.1,2.5Hz,1H),5.22 (dd,J＝11.0,2.3Hz,1H),5.16(d,J＝9.8Hz,1H),5.06(d,J＝9.8Hz,1H), 4.23(dd,J＝9.4,4.9Hz,3H),4.18(d,J＝4.8Hz,2H),4.11(t,J＝6.0Hz,1H), 3.74-3.53(m,16H),2.77(t,J＝6.4Hz,2H),2.60(t,J＝6.4Hz,2H),2.19(s, 3H),2.08(s,3H),2.06(s,6H),1.93(s,6H),1.93(s,6H)；¹³C NMR(101MHz, CDCl3)δ207.1,173.0,170.5,169.7,169.0,169.0,119.4,119.3,110.1,110.0, 109.9,109.9,82.3,82.2,75.5,71.1,70.7,70.6,70.6,69.5,69.4,69.1,68.9, 66.7,66.6,63.9,63.5,63.2,61.5,38.02 30.0,28.0,20.9,20.7,20.6,20.6。

Example 22

Compound XXIII (5.7g,4.73mmol) is dissolved in a dichloromethane/methanol (v/v ═ 1:1,20mL) mixed solution, and pre-prepared 1M N is added dropwise₂H₄ ^.AcOH/MeOH (7mL,7mmol) in water was stirred at room temperature for 1 hour, TLC (PE: acetone ═ 3:2) was used to detect completion of the reaction, acetone (1 mL) was added, and after stirring for 5 minutes, the solvent was distilled off, the residue was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, concentrated and stirred, and subjected to column chromatography (PE: acetone ═ 5:2) to obtain a colorless syrup intermediate (5.1g, 97.5%),¹H NMR(400MHz,CDCl3)δ7.91 (s,1H),7.84(s,1H),7.42(dd,J＝11.9,6.6Hz,4H),5.78(t,J＝8.8Hz,1H), 5.74(t,J＝10.3Hz,1H),5.60(dd,J＝7.5,2.9Hz,2H),5.32(dd,J＝11.0,3.1 Hz,1H),5.26(dd,J＝10.9,3.0Hz,1H),5.22(d,J＝9.8Hz,1H),5.10(d,J＝ 9.8Hz,1H),4.28(t,J＝6.4Hz,1H),4.17(dd,J＝13.4,6.2Hz,3H),3.78(d,J ＝3.9Hz,2H),3.73-3.56(m,16H),2.07(s,3H),2.07(s,3H),2.05(s,3H),1.93 (s,3H),1.93(s,3H)；¹³C NMR(101MHz,CDCl3)δ170.5,169.8,169.7,169.2, 169.1,119.7,119.2,110.1,110.0,109.9,109.9,82.8,82.7,75.4,73.0,71.0, 70.6,70.6,70.5,70.3,70.0,69.7,69.6,69.0,66.7,66.6,63.3,63.2,61.7,61.4, 20.9,20.7,20.6,20.6；

the intermediate (5.1g,4.61mmol) obtained in the above step was dissolved in dichloromethane (40mL), triethylamine (1.92mL, 13.82mmol) was added, after stirring for 5 minutes, p-toluenesulfonyl chloride (1.76g,9.21mmol) was added, stirring at room temperature for 12 hours, detection by TLC (PE: acetone ═ 3:2) showed completion of the reaction, quenching the reaction by adding methanol, distilling off the solvent, dissolving the residue in dichloromethane, washing with brine, drying over anhydrous sodium sulfate, concentration and column chromatography (PE: acetone ═ 2:1) to give a pale yellow syrup (5.6g, 96.4%),¹H NMR(400M，CDCl₃) δ7.83(d,J＝8.1Hz,2H),7.83(s,2H),7.41(t,J＝6.9Hz,4H),7.36(d,J＝8.1 Hz,2H),5.80-5.73(m,2H),5.61(dd,J＝6.5,3.0Hz,2H),5.23(td,J＝10.6, 3.1Hz,2H),5.14(d,J＝9.8Hz,1H),5.09(d,J＝9.8Hz,1H),4.25-4.12(m, 6H),3.72(dd,J＝10.2,5.6Hz,3H),3.68-3.60(m,12H),3.57(dd,J＝9.3,4.2 Hz,2H),2.45(s,3H),2.07(s,6H),2.06(s,3H),1.91(s,6H).；¹³C NMR(100M， CDCl₃)δ170.5,169.7,169.7,169.1,145.3,136.7,132.8,130.1,128.2,119.4, 110.1,110.0,109.9,109.8,82.5,75.5,71.2,70.8,70.7,70.6,70.6,69.7,69.5, 69.4,68.9,68.7,66.7,66.6,63.4,63.2,61.5,21.8,20.9,20.7,20.7,20.6；

the pale yellow syrup (5.6g,4.44mmol) obtained in the above step was dissolved in N, N-dimethylformamide (40mL), potassium thioacetate (1.0g,8.88mmol) was added, the mixture was stirred at room temperature for 3 hours, TLC (PE: acetone ═ 3:2) was used to check completion of the reaction, the reaction mixture was diluted with dichloromethane (400mL), washed with brine (3X 400mL), dried over anhydrous sodium sulfate, concentrated and dried to obtain compound XXIV (4.8g, 92.8%),¹H NMR(400MHz, CDCl₃)δ7.85(s,1H),7.83(s,1H),7.41(dd,J＝13.1,6.1Hz,4H),5.75(td,J＝ 10.3,6.1Hz,2H),5.61(d,J＝2.6Hz,2H),5.25(dd,J＝11.0,3.0Hz,1H),5.21 (dd,J＝11.0,3.0Hz,1H),5.15(d,J＝9.8Hz,1H),5.06(d,J＝9.8Hz,1H), 4.25-4.15(m,3H),4.10(t,J＝5.8Hz,1H),3.71-3.54(m,16H),3.08(t,J＝6.6 Hz,2H),2.33(s,3H),2.08(s,3H),2.06(s,6H),1.92(s,6H)；¹³C NMR(101 MHz,CDCl₃)δ195.8,170.5,169.7,169.7,169.0,119.3,119.2,110.1,110.0, 109.9,109.8,82.2,82.1,75.6,71.1,70.6,70.6,70.5,70.3,69.8,69.5,69.4, 68.9,66.7,66.6,63.5,63.2,61.5,30.7,28.8,20.9,20.7,20.7,20.6,20.6.

example 23

The product is ready to use. Compound XXIV1g,0.86mmol) was dissolved in methanol (10mL), MeONa was added, the pH of the reaction solution was adjusted to 8 to 10, stirred at room temperature for 2 hours, TLC (DCM: MeOH: 10:1) was detected to be complete, and type 732H was added⁺And neutralizing the reaction solution to be neutral by using cationic resin, filtering out the resin, and directly using the filtrate containing the compound XI for subsequent functional molecule construction.

Example 24

In the same manner as in example 6, a compound of formula XII-2 (96%), 1H NMR (400MHz, CDCl3) δ 8.20(s, 1H),6.05(d, J ═ 3.9Hz,1H),5.07(dd, J ═ 3.9,2.4Hz,1H),5.02(dd, J ═ 7.0, 2.4Hz,1H),4.41(dd, J ═ 7.0,3.9Hz,1H),4.28(td, J ═ 6.7,4.0Hz,1H),4.09 (dd, J ═ 8.5,6.9Hz,1H),4.03-3.98(m,1H),3.97(s,3H),1.66(s,3H),1.45(s, 3H),1.41(s,3H), 1.37.81 (s,3H), 3.65 (s,3H), 3665 (19.27.27, 3627.52, 3627, 3.52, 3627, 3.52H, 3627H, 3H, C160.9,140.4H, 3H, C.

Example 25

The compound of the formula XII-2 (1.0g, 2.71mmol) was dissolved in 10ml of methanol, and 10-fold equivalent of n-butylamine nBu-NH was added₂Placing the mixture in an oil bath at the temperature of 80 ℃, carrying out reflux stirring reaction overnight, detecting the completion of the reaction by TLC (PE: EA is 1:1), cooling the reaction liquid to room temperature, evaporating the solvent, dissolving the residue in 20ml of dichloromethane, and sequentially carrying out 1N HCl reaction_a.q.、 sat.NaHCO₃ _aq.Washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a compound of formula XII-3 (1.1g, 99%)¹H NMR(400MHz,CDCl₃)δ8.15(s,1H),7.12(s,1H),6.05(d,J ＝3.7Hz,1H),5.02(dd,J＝7.7,5.4Hz,2H),4.36(dd,J＝6.6,4.2Hz,1H), 4.28(dd,J＝10.8,6.6Hz,1H),4.07(t,J＝7.6Hz,1H),3.98-3.93(m,2H),3.46 (dd,J＝13.2,6.2Hz,2H),1.66(s,4H),1.63-1.56(m,2H),1.45(s,4H), 1.43-1.38(m,2H),1.41(s,4H),1.36(s,3H),0.96(t,J＝7.3Hz,3H).¹³C NMR (101MHz,CDCl₃)δ144.,125.8,115.4,110.3,105.1,86.1,82.0,73.7,65.7, 65.5,39.0,31.8,27.9,27.2,26.3,25.2,20.2,13.9.

Example 26

The compound of formula II (1.0g, 3.5mmol) was dissolved in 10ml of methanol, Pd/C (0.1g) was added, and the mixture was placed in H₂The reaction was stirred for 3 hours under ambient conditions (45Psi), TLC (PE: EA ═ 1:1) was used to detect completion of the reaction, Pd/C powder was filtered off, and the filtrate was dried by evaporation to give a compound of formula XII-4 (0.9g, 99%)¹H NMR(400MHz,CDCl₃)δ5.87 (d,J＝3.8Hz,1H),4.45–4.35(m,1H),4.07(dd,J＝8.3,6.7Hz,1H),3.83(dd, J＝8.3,6.9Hz,1H),3.74(dd,J＝7.0,4.5Hz,1H),3.35(d,J＝3.5Hz,1H), 1.56(s,2H),1.54(s,1H),1.45(s,2H),1.37(s,2H),1.34(s,1H).¹³C NMR (101MHz,CDCl₃)δ113.,5,109.9,105.4,89.0,87.7,75.9,66.0,58.1,27.5, 26.8,25.4.

Example 27

The compound of formula XII-4 (1.0g, 3.86mmol) was dissolved in pyridine 10ml, 2-naphthoyl chloride (1.47g, 7.71mmol) was added and stirred at room temperature for 6 hours, detection by TLC (DCM: MeOH10:1) indicated complete reaction, methanol 2ml was added dropwise, after stirring for 10 minutes, the solvent was evaporated to dryness, the residue was dissolved in dichloromethane 20ml, followed by 1N HCl_a.q.、sat.NaHCO_3aq.And saturated brine, dried over anhydrous sodium sulfate, concentrated, and then isolated and purified by column chromatography (PE: EA ═ 2:1) to give the compound of formula XII-5 (1.5g, 94%).¹H NMR (400MHz,CDCl₃)δ8.27(s,1H),7.87(t,J＝7.9Hz,3H),7.80(dd,J＝8.6,1.5 Hz,1H),7.55(tt,J＝13.7,6.7Hz,2H),6.75(d,J＝7.0Hz,1H),6.02(d,J＝3.7 Hz,1H),4.82(d,J＝3.0Hz,1H),4.50(q,J＝6.7Hz,1H),4.31(dd,J＝6.4,4.3 Hz,1H),4.19(dd,J＝7.3,4.1Hz,1H),4.13(dd,J＝8.4,6.7Hz,1H),3.91(dd, J＝8.4,6.7Hz,1H),1.61(s,3H),1.45(s,3H),1.37(s,3H),1.34(s,3H).¹³C NMR(101MHz,CDCl₃)δ167.6,135.0,132.6,130.7,129.1,128.8,128.1, 127.9,127.8,127.1,123.4,113.7,110.1,105.7,85.9,85.2,75.8,66.0,57.5, 27.3,26.8,26.5,25.4.

Example 28

The same procedure as in example 6 gave a compound of the formula XII-6 (95%),¹H NMR(400MHz,CDCl₃)δ6.86 (d,J＝2.2Hz,2H),6.59(t,J＝2.2Hz,1H),6.40(d,J＝7.0Hz,1H),5.99(d,J ＝3.7Hz,1H),4.77(dd,J＝3.6,0.8Hz,1H),4.46(q,J＝6.7Hz,1H),4.21(dd, J＝6.4,4.4Hz,1H),4.16-4.07(m,2H),3.89(dd,J＝8.5,6.6Hz,1H),3.82(s, 6H),1.61(s,3H),1.44(s,3H),1.38(s,3H),1.34(s,3H).¹³C NMR(101MHz, CDCl₃)δ167.3,161.1,135.7,113.7,110.1,105.7,105.0,104.2,85.8,84.9, 75.7,66.0,57.5,55.7,27.4,26.8,26.6,25.4.

example 29

In the same manner as in example 8, the crude product of formula XIII-5 was obtained as an anomer mixture and used directly in the next reaction.

Example 30

In the same manner as in example 8, the crude product of formula XIII-6 was obtained as a mixture of anomers and used directly in the next reaction.

Example 31

In the same manner as in example 15, the compound of formula XIX-2 (89%) was obtained,¹H NMR(400MHz,CDCl₃)δ8.20 (s,1H),6.11(d,J＝4.0Hz,1H),5.23(dd,J＝5.3,1.6Hz,1H),5.12-5.07(m, 1H),4.47(t,J＝5.1Hz,1H),3.96(s,3H),3.87-3.75(m,3H),2.79(s,1H),2.05 (s,1H),1.64(s,3H),1.39(s,3H).¹³C NMR(101MHz,CDCl₃)δ160.9,140.5, 128.0,114.9,105.7,85.8,85.3,69.3,66.1,63.9,52.5,27.6,26.9.

example 32

In the same manner as in example 15, the compound of formula XIX-6 (92%) is obtained,¹H NMR(400MHz,CDCl₃)δ6.87 (d,J＝2.3Hz,2H),6.60(t,J＝2.2Hz,1H),6.43(d,J＝6.7Hz,1H),6.01(d,J ＝4.0Hz,1H),4.80(dd,J＝4.0,1.0Hz,1H),4.40(dd,J＝6.0,4.3Hz,1H), 4.21(dd,J＝7.3,3.8Hz,1H),3.99-3.92(m,1H),3.82(s,6H),3.82-3.79(m, 2H),1.59(s,3H),1.35(s,3H).

example 33

The same reaction conditions as in example 16, except that the starting materials were replaced, gave a compound of the formula XVIII (96%),¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),6.11(d,J＝3.9Hz,1H),5.28(d,J＝ 3.9Hz,1H),5.11-5.04(m,1H),4.36(t,J＝5.2Hz,1H),3.97(s,3H),3.64(dd,J ＝9.6,6.0Hz,1H),3.46(dd,J＝12.8,6.3Hz,3H),3.27(t,J＝6.8Hz,2H),2.62 (d,J＝4.3Hz,1H),1.64(s,3H),1.58(dt,J＝14.2,7.0Hz,2H),1.47-1.34(m, 4H),1.38(s,3H).¹³C NMR(101MHz,CDCl₃)δ176.7,144.7,140.3,127.6, 105.5,85.7,85.2,71.8,71.5,68.5,66.0,65.4,53.3,52.4,51.3,29.1,28.6, 27.3,26.6,23.3.

example 34

In the same manner as in example 16, only the starting materials were replaced to obtain a compound of the formula XVIII-6 (94%),¹H NMR (400MHz,CDCl₃)δ8.02(s,1H),6.89(d,J＝2.2Hz,2H),6.60(t,J＝2.2Hz, 1H),6.54(d,J＝7.0Hz,1H),5.98(d,J＝4.0Hz,1H),4.81(dd,J＝3.9,1.2Hz, 1H),4.41(t,J＝5.2Hz,1H),4.14(dd,J＝6.5,4.7Hz,1H),4.01(p,J＝5.2Hz, 1H),3.82(s,6H),3.66(dd,J＝11.3,4.8Hz,1H),3.58(d,J＝5.1Hz,2H),3.51 –3.41(m,2H),3.29(t,J＝6.8Hz,1H),3.22(t,J＝6.9Hz,2H),2.96(s,3H), 2.88(s,3H),1.67-1.62(m,1H),1.60-1.55(m,4H),1.44-1.36(m,2H).¹³C NMR(101MHz,CDCl₃)δ161.1,113.6,105.5,105.1,104.0,86.3,84.9,71.8, 71.6,70.3,57.7,55.8,51.4,29.2,28.8,27.4,26.6,23.5.

example 35

As in example 16, only Ts-PEG4-ONap was replaced with Ts-PEG₃-ONAP gave a compound of formula XVIII-1 (94%).¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),7.84-7.74(m,3H), 7.71(s,1H),7.55-7.42(m,5H),6.13(d,J＝4.0Hz,1H),5.32(d,J＝3.3Hz, 1H),5.10-5.06(m,1H),4.67(s,2H),4.30(dd,J＝6.6,4.2Hz,1H),4.04(dd,J ＝12.0,6.6Hz,1H),3.74(dd,J＝9.6,5.6Hz,1H),3.73-3.56(m,12H),3.46(dd, J＝9.6,6.6Hz,1H),1.64(s,3H),1.34(s,3H).¹³C NMR(101MHz,CDCl₃)δ 135.5,133.1,133.0,128.2,127.8,127.6,126.5,126.0,125.7,125.6,121.4, 114.3,110.2,109.7,105.4,86.6,85.5,77.3,73.4,72.7,70.8,70.7,70.6,70.2, 70.1,69.8,68.9,65.7,31.1,27.5,26.4.

Example 36

In the same manner as in example 16, only the starting materials were replaced to obtain a compound of the formula XVIII-1 (96%)¹H NMR (400MHz,CDCl₃)δ8.19(s,1H),7.80-7.72(m,3H),7.68(s,1H),7.53-7.41(m, 5H),6.12(d,J＝4.0Hz,1H),5.35(d,J＝3.3Hz,1H),5.05-4.95(m,1H),4.72(t, J＝6.9Hz,2H),4.62(s,2H),4.26(dd,J＝6.6,4.2Hz,1H),4.01(dd,J＝12.0, 6.6Hz,1H),3.60(dd,J＝9.6,5.6Hz,1H),3.51(t,J＝6.9Hz,2H),3.31(dd,J ＝9.6,6.6Hz,1H),1.67-1.58(m,4H),1.64(s,3H),1.40-1.31(m,2H),1.34(s, 3H).¹³C NMR(101MHz,CDCl₃)δ134.9,132.6,132.2,126.4,125.1,124.8, 123.8,123.3,122.9,122.6,121.6,114.7,110.4,108.6,104.9,87.5,77.1,72.5, 75.4,70.3,70.1,69.6,61.8,29.0,28.4,27.8,26.6,23.4.

Example 36

In the same manner as in example 8, the crude product of formula XIII-7 was obtained as a mixture of anomers and used directly in the next reaction.

Example 37

In the same manner as in example 8, crude product of formula XIII-8 was obtained as anomer mixture and used directly in the next reaction.

Example 38 comparison of synthetic strategies

The conventional method or the existing method is adopted to perform glycosylation coupling to obtain XXVI, and then perform side chain derivatization, so that the side chain derivatization reaction cannot be performed.

Glycosylation coupling:

and (3) deacetylation reaction:

the compound shown in the formula XXVI is used as a raw material to carry out side chain derivatization reaction,

wherein, the side chain derivatization reagent LG- (CH)₂CH₂-X)_n-CH₂CH₂-R₃"' Synthesis experiments have been conducted, experiments have been conducted with the side chain derivatizing agents of the following Table, operating either under the following conditions A or B, allThe product was not obtained

The condition A is NaH (1.1-3.0 eq.), LG- (CH)₂CH₂-X)n-CH₂CH₂-R₃"(1.1-2.0 eq), the reaction solvent is selected from DMF and THF, and the target product cannot be obtained by separation and purification.

Condition B is Bu₂The SnO/CsF reagent combination was operated in the same manner as in example 16, and no reaction occurred.

Example 39 test experiment

Mixing a compound in a formula XI with Gold Nanorods (GNR) with stable Cetyl Trimethyl Ammonium Bromide (CTAB) surfaces, standing for 24 hours for reaction, and performing centrifugal purification to construct a sugar-gold nanorod probe compound, wherein the probe compound can be used for detecting a tumor biomarker Galectin 1(Galectin-1) protein in serum, so as to realize tumor diagnosis: uniformly dispersing the sugar-gold nanorod probes in an aqueous solution, adding Galectin-1, wherein the sugar group part of a probe compound is a ligand of the Galectin-1, and can be combined with the Galectin-1 to cause the uniformly dispersed gold nanorod probes to agglomerate, and the LSPR effect of the gold nanorods can show obvious optical absorption signal change before and after agglomeration, so that the detection of the Galectin-1 is realized, and the tumor diagnosis is further realized.

Claims

1. A saccharide compound has a structure shown in formula X,

wherein R is₁、R₂Independently selected from substituted triazolyl; the substituted triazolyl is

Wherein R is₅Selected from aryl, substituted aryl, arylamidesA substituted arylamido group;

a is

R₃Is selected from mercapto;

x is selected from oxygen atom;

n is selected from 3,4,5, 6 and 7;

the aryl in the aryl or the substituted aryl is selected from phenyl, naphthyl, pyrenyl, anthryl, phenanthryl, furan and thiophene;

the substituent on the substituted aryl is hydrogen, halogen, alkyl of C1-C6, alkoxy of C1-C6, halogenated alkyl of C1-C6, nitro or hydroxyl, and the halogen is selected from Cl, Br, I and F;

the substituents on the substituted aryl are optionally independently substituted with 1 to 3 substituents.

2. The saccharide compound according to claim 1, wherein,

R₅is selected from

Wherein R is₇-R₁₁As set forth in the following table, Z is independently selected from F, Cl, Br, I:

3. a process for the preparation of a saccharide compound according to any one of claims 1-2 comprising the steps of:

2) converting the side chain group of the compound shown in the formula VIII to obtain a compound shown in the formula IX;

the structure of the compound is shown as follows

Wherein R is₃"is selected from the group consisting of acetylpropionyloxy, 4-methoxyphenoxy, A, R₁、R₂、R₃As defined in any one of claims 1-2.

4. The production method according to claim 3, wherein the side chain group conversion in step 2) comprises the steps of:

step 2-1) Selective deprotection group R₃Obtaining a key intermediate;

wherein the reagent for removing the protective group in the step 2-1) is hydrazine acetate N₂H₄AcOH, cerium ammonium nitrate CAN; the protecting group removing agent is the same as R₃"corresponds to the radical R₃When the reagent is acetyl propionyloxy, the reagent for removing protective group is hydrazine acetate N₂H₄AcOH when R₃When the value is 4-methoxyphenoxy, a protecting group removing reagent selects ceric ammonium nitrate CAN;

wherein, in the acylation reaction condition in the step 2-2), the acylation reagent is selected from trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride, the acylation reaction is carried out under alkaline condition, and the base is selected from triethylamine, pyridine, diisopropylethylamine and triisopropylamine;

wherein, in the step 2-2), the substituting reagent in the substituting reaction is selected from potassium thioacetate, sodium thioacetate, thioacetic acid, sodium hydrosulfide, lithium azide, sodium azide, tetrabutylammonium azide, trimethylsilyl azide and a fluoride combined reagent, and the fluoride is selected from lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, sodium hydrogen fluoride, potassium hydrogen fluoride, ammonium hydrogen fluoride, tetrabutylammonium fluoride and tetramethylammonium fluoride.

5. The process according to claim 3, wherein the compound of formula IV is obtained by,

1-11) preparing a crude bromo-sugar product from the compound shown in the formula III under the action of a bromination reagent, wherein the bromination reagent is selected from 33% hydrobromic acid acetic acid solution HBr/AcOH, a methanol/acetyl bromide combined reagent, titanium tetrabromide and phosphorus tribromide;

6. the process according to claim 3, wherein the compound of formula VII is obtained by,

wherein R is₃' is selected from 2-naphthylmethyl, benzyl, allyl.

7. The preparation method according to claim 6, wherein in the step 1-21), the reaction reagent for the acid ring-opening of the 1, 2-propylidene is selected from toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and trifluoroacetic acid, and the ring-opening reaction is carried out by refluxing; the acetylation reaction conditions are selected from the group consisting of a mixture of sodium acetate and acetic anhydride, a mixture of acetic anhydride and pyridine, a mixture of acetyl bromide and pyridine, a mixture of acetyl chloride and pyridine, and a mixture of perchloric acid and acetic anhydride.

8. The method according to claim 6, wherein in the step 1-22), R is removed by deprotecting 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone or ceric ammonium nitrate₃' 2-naphthylmethyl protection, or by deprotecting agents palladium on carbon Pd/C, palladium hydroxide Pd (OH)₂Removal of R₃' benzyl protecting group, or by deprotecting agent PdCl₂Removal of R₃' allyl-protection.

9. The method according to claim 6, wherein in steps 1-22) deprotection is followed by reaction with levulinic acid or levulinic anhydride to give R3 "as levulinyl, or reaction with 4-methoxyphenol to give R3" as 4-methoxyphenoxy.

10. The method of claim 6, wherein the brominating reagent in steps 1-23) is selected from HBr/AcOH in 33% hydrobromic acid acetic acid solution, methanol/acetyl bromide combination reagent, titanium tetrabromide, and phosphorus tribromide.

11. The process according to claim 6, wherein the compound of formula V is obtained by,

1-21-1) selective ring opening of propylidene at the 5,6 position of the compound of formula II;

1-21-2) performing side chain derivatization;

wherein

12. The process according to claim 11, wherein the conditions for the selective ring-opening reaction of propylidene at 5, 6-positions in the step 1-21-1) are acidic conditions obtained by adding p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid or trifluoroacetic acid and reacting in the presence of water at ordinary temperature.

13. The method according to claim 12, wherein the reaction in step 1-21-2) is carried out in the presence of a catalyst selected from the group consisting of dibutyltin oxide and cesium fluoride, and LG is selected from the group consisting of a chlorine atom, a bromine atom and p-toluenesulfonyloxy group.

14. The method of claim 11, wherein the group converting reaction in step 1-21-3) is carried out under the condition of a catalyst selected from the group consisting of CuI, a combination of N, N-diisopropylethylamine DIPEA, CuSO, and R1-C ≡ C₄And Vc-Na; or first of all the hydrogenation of the-N on the compound of the formula II₃is-NH₂Then with R₆-Cl.

15. The process according to claim 5, wherein the compound of formula III is obtained by,

1-11-1) opening the propylidene ring of the compound of formula II;

1-11-2) carrying out acetylation on sugar ring hydroxyl;

wherein

16. The process according to claim 15, wherein the conditions for the ring-opening reaction in step 1-11-1) are conducted under reflux under acidic conditions obtained by adding p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, or trifluoroacetic acid, and the reaction is conducted in the presence of water.

17. The process according to claim 15, wherein the acetylation reaction conditions in the step 1-11-2) are selected from the group consisting of a mixture of sodium acetate and acetic anhydride, a mixture of acetic anhydride and pyridine, a mixture of acetyl bromide and pyridine, a mixture of acetyl chloride and pyridine, and a mixture of perchloric acid and acetic anhydride.

18. The method according to claim 15, wherein the conditions for the group conversion reaction in the step 1-11-3) are the reaction with R under the presence of a catalyst₂-C ≡ C reaction, said catalyst selected from the group consisting of CuI and N, N-diisopropylethylamine DIPEA in combination, CuSO₄And Vc-Na; or first of all the hydrogenation of the-N on the compound of the formula II₃is-NH₂In the presence of R₆-Cl.

19. The process according to any one of claims 11 to 18, wherein the compound of formula II is obtained by,

II) preparing the compound of the formula II by acylation and azide substitution reaction of the compound of the formula I.

20. The method of claim 19, wherein step i) comprises the following two steps:

i-1) oxidation to give the compound of formula I-1

Adding an oxidant to carry out an oxidation reaction,

21. The method of claim 19, wherein step ii) comprises the following two steps:

ii-1) adding an acylation reagent to perform reaction, wherein the acylation reagent is selected from trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride, the acylation reagent is performed under basic conditions, and the base is selected from triethylamine, pyridine, diisopropylethylamine and triisopropylamine;

ii-2) adding an azide reagent selected from trimethylsilyl azide, lithium azide, sodium azide, tetrabutylammonium azide or a combination of trimethylsilyl azide and a fluoride selected from lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, sodium hydrogen fluoride, potassium hydrogen fluoride, ammonium bifluoride, tetrabutylammonium fluoride and tetramethylammonium fluoride to carry out the reaction.

22. Use of a carbohydrate compound according to any of claims 1-2 in the manufacture of a medicament or detection reagent for targeting, identifying or detecting galectin protein 1.

23. Use of a carbohydrate compound according to any of claims 1-2 for the preparation of an active targeting ligand which specifically recognizes galectin 1 and which is capable of being linked to an active ingredient or a detection reagent.

24. The use according to claim 23, wherein the active ingredient is selected from the group consisting of anti-tumor drugs and anti-inflammatory drugs, and the detection agent comprises a fluorescent label or a probe.