A method for the electrocatalytic synthesis of polysubstituted ribose derivatives and nucleoside analogs thereof

Abstract

This application provides a method for the electrocatalytic synthesis of multisubstituted ribose derivatives, comprising using an organotin compound as a catalyst to catalyze the reaction of the compound shown in formula (I) under electrochemical conditions to obtain the compound shown in formula (II); wherein, R 1 C is an optional replacement 1‑10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is the C that can be substituted. 1‑4 Alkyl; R 4 C is a hydrogen atom or an optional substituted C 1‑10 The method involves the use of a hydrocarbon group as the reaction solvent, a reaction temperature of 40-80℃, and a quaternary ammonium bromide as the electrolyte. This method enables the efficient and highly stereoselective synthesis of tetrasubstituted riboses modified with 2'- and 3'-ester groups, and is easily scaled up, showing promising prospects for industrial application. The products obtained by this method possess excellent potential for later derivatization and can be used to synthesize various novel nucleoside analogs, demonstrating significant application value in the development of antiviral and antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and specifically relates to a method for electrocatalytic synthesis of multisubstituted ribose derivatives and their nucleoside analogs. Background Technology

[0002] Carbohydrates, due to their unique and specific biological activities, continue to be important research subjects in many fields such as synthetic organic chemistry and biochemistry. Ribose, as a natural pentose, is the structural core of RNA (the genetic material) and many key coenzymes (such as ATP and NADH), and its applications extend far beyond the realm of basic biomolecules. However, limited by its inherent chemical structure, ribose still has significant limitations in terms of biological stability, pharmacokinetic properties, and functional diversity. By chemically modifying specific sites on ribose molecules, its physicochemical properties and biological activities can be significantly regulated.

[0003] Riboside derivatives containing tetrasubstituted chiral centers generally exhibit diverse biological activities and have significant applications in drug design. Specific examples include the anti-novel coronavirus drug Remdesivir, the anti-HIV drugs Azvudine and Sofosbuvir, and the anticancer agent 1-(3-C-ethynyl-β-d-ribose-furanosyl)cytosine (ECyd). However, due to the highly similar chemical environments of the four hydrogen atoms on the ribose backbone, the synthesis of ribose derivatives containing tetrasubstituted chiral centers typically requires cumbersome protection and deprotection steps and mainly relies on long, linear de novo synthetic routes, making modular construction difficult. Existing strategies still have room for improvement in terms of structural diversity, procedural simplicity, and stereoselectivity control of such ribose derivatives.

[0004] Therefore, there is a need to develop a new method for synthesizing ribose derivatives that is more efficient, stereoselective, and widely applicable. Summary of the Invention

[0005] This application provides the following technical solution:

[0006] A method for the electrocatalytic synthesis of multisubstituted ribose derivatives includes using an organotin compound as a catalyst to catalyze the reaction of the compound shown in formula (I) under electrochemical conditions to obtain the compound shown in formula (II): ; in, R 1 C is an optional replacement 1-10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is C, which can be substituted by any choice.1-4 alkyl; R 4 C is a hydrogen atom or an optional substituted C 1-10 hydrocarbon group; The electrochemical conditions include: using R-OH as the reaction solvent; a reaction temperature of 40-80℃; and using quaternary ammonium bromide as the electrolyte.

[0007] This application also provides a method for synthesizing nucleoside analogs based on the aforementioned multisubstituted ribose derivatives.

[0008] This application also provides the use of the aforementioned nucleoside analogue synthesis method in the preparation of pharmaceuticals.

[0009] The technical solution provided in this application has the following beneficial effects: (1) The electrocatalytic synthesis method for polysubstituted ribose derivatives provided in this application can use readily available unprotected pyranose as starting material to achieve efficient and highly stereoselective synthesis of tetrasubstituted ribose modified with 2'-ester and 3'-ester groups in a one-pot electrochemical process under organotin catalysis. The method is mild and environmentally friendly, exhibits excellent regioselectivity on pyranose units, and can achieve good stereocontrol while maintaining high yield, showing broad application potential in constructing structurally diverse ribose libraries.

[0010] (2) The method for electrocatalytic synthesis of multisubstituted ribose derivatives provided in this application can significantly improve the target reaction efficiency (including yield, selectivity, etc.) by optimizing electrochemical conditions, such as catalyst, electrolyte, solvent, current density, reaction temperature and reaction time, which facilitates the control of reaction performance in different application scenarios.

[0011] (3) The electrocatalytic synthesis method of multisubstituted ribose derivatives provided in this application can be scaled up to several grams to tens of grams and the target product can be obtained in a moderate yield, which proves the feasibility and process stability of the gram-scale preparation of electrooxidation products and has good prospects for industrial application.

[0012] (4) The multi-substituted ribose derivatives obtained by the aforementioned methods can also be conveniently used for subsequent derivatization, providing multiple feasible pathways for diversified modification of different sites on ribose. For example, the corresponding deoxyribose derivatives can be obtained in two steps through the Barton-McCombie deoxygenation reaction; olefin esters can be obtained through the Corey-Winter olefin synthesis reaction; and amide compounds with C3-position inversion and β-lactam compounds can be synthesized in two steps by utilizing the strong leaving property of sulfonates. The amine sources of the amide compounds are widely applicable, and both aromatic amines and aliphatic amines can participate in the reaction smoothly to obtain the target product. These efficient derivatization methods not only enrich the structural diversity of ribose compounds, but also lay a solid foundation for the construction of novel nucleoside analogs.

[0013] (5) The nucleoside analog synthesis method provided in this application, based on the aforementioned method, involves coupling the obtained multisubstituted ribose derivatives with nucleobases (glycosylation) and optionally introducing an amide unit to obtain a variety of nucleoside analogs. The glycosylation reaction can yield α-configuration nucleoside analogs with moderate yield and excellent diastereoselectivity. The introduction of the amide unit can further expand the structural diversity of nucleoside analogs. The nucleoside analog synthesis method has the advantages of simplicity and strong applicability, providing reliable synthetic support for drug discovery and structure-activity optimization based on glycosyl skeletons, and has significant application value in drug-directed synthesis. Attached Figure Description

[0014] Figure 1 Compound 2 synthesized in Example 1 1 H NMR spectrum.

[0015] Figure 2 Compound 2 synthesized in Example 1 13 C10 NMR spectrum.

[0016] Figure 3 Compound 5 synthesized in Example 2 1 H NMR spectrum.

[0017] Figure 4 Compound 5 synthesized in Example 2 13 C10 NMR spectrum.

[0018] Figure 5 Compound 6 synthesized in Example 2 1 H NMR spectrum.

[0019] Figure 6 Compound 6 synthesized in Example 2 13 C10 NMR spectrum.

[0020] Figure 7 Compound 8 synthesized in Example 2 1 H NMR spectrum.

[0021] Figure 8 Compound 8 synthesized in Example 2 13 C10 NMR spectrum.

[0022] Figure 9 Compound 9 synthesized in Example 2 1 H NMR spectrum.

[0023] Figure 10 Compound 9 synthesized in Example 2 13 C10 NMR spectrum.

[0024] Figure 11 Compound 11 synthesized in Example 2 1 H NMR spectrum.

[0025] Figure 12 Compound 11 synthesized in Example 2 13 C10 NMR spectrum.

[0026] Figure 13 Compound 13 synthesized in Example 2 1 H NMR spectrum.

[0027] Figure 14 Compound 13 synthesized in Example 2 13 C10 NMR spectrum.

[0028] Figure 15 Compound 14 synthesized in Example 2 1 H NMR spectrum.

[0029] Figure 16 Compound 14 synthesized in Example 2 13 C10 NMR spectrum.

[0030] Figure 17 Compound 16 synthesized in Example 2 1 H NMR spectrum.

[0031] Figure 18 Compound 16 synthesized in Example 2 13 C10 NMR spectrum.

[0032] Figure 19 Compound 18 synthesized in Example 2 1 H NMR spectrum.

[0033] Figure 20 Compound 18 synthesized in Example 2 13 C10 NMR spectrum.

[0034] Figure 21 Compound 20 synthesized in Example 2 1 H NMR spectrum.

[0035] Figure 22 Compound 20 synthesized in Example 2 13 C10 NMR spectrum.

[0036] Figure 23 Compound 22 synthesized in Example 2 1 H NMR spectrum.

[0037] Figure 24 Compound 22 synthesized in Example 2 13C10 NMR spectrum. Invention Details 1. Terminology Explanation All patents and other publications cited herein are incorporated herein in their entirety. In the event of any conflict between any description of terminology herein and any document incorporated herein by reference, this document shall prevail.

[0038] Numerical ranges can be represented by a hyphen "-" or a tilde "~". Unless otherwise stated, the range should be understood to encompass both the endpoint values ​​and any values ​​in between. There are no particular restrictions on the type of numeric values ​​within the range, including but not limited to integers, decimals, fractions, percentages, etc., unless explicitly excluded by the context or a particular numeric type is technically unavailable. The type of numeric values ​​within the range is not limited by the specific representation of the endpoints.

[0039] The terms “including,” “containing,” and similar expressions have a non-restrictive meaning.

[0040] A “combination” of the enumeration items refers to any two or more of the enumeration items that coexist or are used together, including but not limited to any two-item combination, any three-item combination, any more items, and any combination of all the enumeration items, unless the context explicitly excludes it or a particular combination is technically impossible.

[0041] The use of labels such as a), b), i), ii), 1), 2) to number the steps of a method is only for the convenience of description and reading, and does not mean that the corresponding steps must be performed in the order of the numbers, unless the text explicitly states or the information in the text can be clearly inferred that there is a logical or temporal relationship between the specific steps.

[0042] The term "optional" is used to indicate that the described situation may exist in some embodiments but not in others, thereby providing technical flexibility for different implementations without departing from the core concept of the invention. For example, "optionally substituted" is equivalent to "substituted or not substituted".

[0043] A "substituted" chemical structure (including molecules, groups, fragments, etc.) contains one or more substituents. A "substituent" can be a monatomic or polyatomic group and, unless otherwise specified, does not include hydrogen atoms. A "multi-substituted" chemical structure contains at least two substituents. For substituted chemical structures, the substituents can be selected from those commonly used in the art, such as hydrocarbon groups, heterohydrocarbon groups, hydroxyl groups (e.g., alkoxy groups), hydroxyl groups, mercapto groups, carboxyl groups, amino groups, amine groups, aldehyde groups, ester groups, carbonate groups, carbamate groups, alkenyl groups, acrylate groups, azide groups, alkynyl groups, etc. Substituents can be in unprotected or protected forms. A "substituted" structure is also called a "substituted form" relative to an "unsubstituted" structure.

[0044] The number of carbon atoms in a chemical structure can be represented by a numerical range marked at the C subscript position, and by default, it does not include the contribution of substituents.

[0045] Chemical bonds are based on " "When presented in formal form, it means that the stereochemical configuration of the chiral center to which the chemical bond is attached is unspecified or is a mixture of stereochemical configurations in any proportion, including racemic cases; that is, the bond can be in a solid wedge shape." (Towards the observer) or dashed wedge shape (A position away from the observer) or a combination of both. It is important to note that, "It can also be used to mark linking bonds (i.e., chemical bonds that connect a group to other chemical structures); for example, It represents -CH3.

[0046] Hydrocarbons refer to compounds containing only carbon and hydrogen elements. Hydrocarbons without benzene rings or other aromatic rings are collectively called "aliphatic hydrocarbons," while those containing benzene rings or other aromatic rings are collectively called "aromatic hydrocarbons." Aliphatic hydrocarbons can be further divided into alkanes, alkenes, and alkynes, where alkenes contain at least one carbon-carbon double bond and alkynes contain at least one carbon-carbon triple bond. Hydrocarbon compounds can be linear or branched, and may or may not contain cyclic structures.

[0047] "Hydrocarbon group" refers to a monovalent, divalent, or higher valence group formed by the loss of one or more hydrogen atoms from a hydrocarbon compound. Hydrocarbon groups without a specified valence are assumed to be monovalent. Exemplary hydrocarbon groups include, but are not limited to, alkyl, alkenyl, alkynyl, and phenyl groups.

[0048] "Organotin compounds" refer to organometallic compounds containing at least one tin-carbon covalent bond. Exemplary organotin compounds include, but are not limited to, those disclosed in documents CN1717431A, US20060052575A1, Journal of Organometallic Chemistry 2023, 1001, 122870, and their cited documents. Tetravalent organotin compounds and divalent organotin compounds refer to organotin compounds containing Sn(IV) and Sn(II), respectively.

[0049] "Electrochemical conditions" refer to the electrochemical parameters applied to achieve or promote a target chemical reaction. These electrochemical parameters include, but are not limited to: the type of electrochemical device (e.g., separated cell, non-separated cell, flow cell, microfluidic cell, batch reactor, etc.); the materials of the anode and cathode (e.g., graphite, electrochemical graphite, glassy carbon, platinum, gold, stainless steel, nickel, aluminum, boron-doped diamond) and their morphology (e.g., mesh, foam, thin film, electrocatalytic coating, etc.); the solvent system (e.g., aqueous solvent, organic solvent, ionic liquid, or mixtures thereof); the type of electrolyte (e.g., ammonium salt, alkali metal salt, etc.) and its concentration (e.g., trace to several moles per liter); the potential or current (e.g., constant potential, constant current, pulsed current, step potential, AC drive, etc.); the type and amount of reaction reagents (e.g., reactants, catalysts, etc.); the reaction temperature, pressure, time, atmosphere, stirring, flow rate, and other conditions; the reactor geometry, working electrode area / specific surface area, mass transfer / heat transfer characteristics, and scale-up process parameters, etc. To ensure the successful implementation of the target response, any of the aforementioned parameters can be optimized independently or in conjunction with one or more other parameters, or conventional values ​​can be used.

[0050] "Apparent current density" refers to the ratio of the applied current to the geometric projected area of ​​the electrode, and its calculation formula is as follows: j = I / A ,in I For the applied current, A The geometrical projected area of ​​the electrode (i.e., the geometrical area facing the counter electrode), usually expressed in mA / cm². 2 It should be noted that for porous electrodes (e.g., mesh glassy carbon electrodes), due to their three-dimensional porous structure and high specific surface area, the effective surface area actually participating in the electrochemical reaction is usually significantly larger than the geometrically projected area. Therefore, the current density calculated based on the geometrically projected area is an apparent value used to characterize electrochemical operating conditions, rather than reflecting the local current distribution at the actual microscopic interface of the electrode. Those skilled in the art will understand that although the actual surface areas of different electrodes vary, using the apparent current density as a uniform parameter is beneficial for comparing different experimental conditions and for repeating reaction conditions. In this application, unless otherwise stated, the current density refers to the apparent current density calculated based on the geometrically projected area of ​​the working electrode where the target electrochemical reaction occurs. For example, when the reaction is an oxidation reaction, the current density is calculated based on the geometrically projected area of ​​the anode; when the reaction is a reduction reaction, the current density is calculated based on the geometrically projected area of ​​the cathode.

[0051] "Derivative" refers to any compound obtained from a parent compound through one or more chemical reactions, enzymatic reactions, or biotransformations, whose structure can be considered directly or indirectly derived from the parent compound. The derivative includes, but is not limited to: salts, tautomers, stereoisomers, solvates, complexes, isotopically labeled forms, and protected forms of the parent compound; compounds obtained by substitution, substituent transformation, introduction or removal of functional groups, bond formation or breaking, heteroatom substitution, ring opening, closing, or rearrangement on the parent skeleton; and combinations of any two or more of the aforementioned derivative forms. When used for pharmaceutical purposes, derivatives may also exist as active compounds, prodrugs, or metabolic precursors.

[0052] "Reactive group" refers to a group capable of participating in a reaction, including but not limited to various common functional groups in organic chemistry. The reaction can be either the target reaction or a non-target reaction. When two or more reactive groups are present in the reactants, the reactive groups that may undergo non-target reactions are usually protected. "Protection" of a reactive group refers to the strategy of converting the reactive group into a "protected form" using specific reagents. The protected form is not reactive under the conditions of the target reaction and can be "deprotected" under specific conditions to obtain an unprotected / deprotected form. The portion of the protected form of a reactive group that differs from the unprotected form is called the "protecting group." For example, -OTBS is a protected form of the hydroxyl group (-OH), where TBS is the protecting group of the hydroxyl group. The protected form of a compound includes forms in which one, two, or more reactive groups are protected.

[0053] For reactions, an "unprotected" strategy refers to a situation where, in the presence of two or more reactive groups on the same reactant, only one or more reactive groups undergo the desired chemical transformation through reaction selectivity and / or control of reaction conditions, while the remaining reactive groups maintain their chemical integrity before and after the reaction, without undergoing unwanted side reactions. Unprotected reaction strategies can achieve single-step or one-pot transformations by omitting the protecting and deprotecting steps.

[0054] "Hydroxy protecting groups" include, but are not limited to, hydroxyl protecting groups commonly found in the art, such as alkyl acyl groups (e.g., acetyl, tert-butyryl), aralkyl acyl groups (e.g., benzyl acyl), benzyl (Bn), triphenylmethyl (Tr), allyl, silyl ether protecting groups (trimethylsilyl, tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), etc.) and acetal protecting groups (tetrahydropyranyl (THP), methoxymethyl (MOM), ethoxyethyl (EE), etc.). Protected forms of diols include, but are not limited to, dioxolane, dioxane, cyclic carbonates, and cyclic borates.

[0055] "Carboxyl protecting group" includes, but is not limited to, carboxyl protecting groups commonly found in the art, such as alkyl and aralkyl groups, specifically tert-butyl (tBu), methyl (Me), ethyl (Et), and benzyl (Bn).

[0056] "Residue" refers to the part formed after a compound loses some atoms or groups, which usually retains or largely retains the characteristic skeleton of the parent compound.

[0057] A "nucleobase," often simply called a "base" or "nitrogenous base," refers to a basic nitrogen-containing heterocyclic compound that can be linked to ribose, deoxyribose, or their derivatives via a glycosidic bond to form a nucleoside. Nucleobases include natural nucleobases, namely adenine, guanine, cytosine, thymine, and uracil, as well as non-natural nucleobases, such as derivatives of natural nucleobases and other artificially designed nitrogen-containing heterocyclic compounds used to construct nucleoside analogs.

[0058] "Nucleoside analogues" refer to nucleoside derivatives that are structurally similar to natural nucleosides, including compounds with one or more structural differences in the sugar moiety, nucleobase moiety, and / or the linkage between the two. Exemplary nucleoside analogues include, but are not limited to: compounds with substitution, deoxygenation, configurational changes, functional group modifications, or ring structure changes (e.g., ring opening, ring shrinking, or heteroatom substitution) on the sugar backbone; compounds with substitution, functionalization, or other chemical modifications on the nucleobase; and compounds obtained by modifying glycosidic bonds, such as nucleoside derivatives obtained by replacing N-glycosidic bonds with C-glycosidic bonds, or changing the stereoconfiguration of glycosidic bonds (e.g., from β-configuration to α-configuration). In the Haworth projection or equivalent three-dimensional conformation, when the substituent forming the glycosidic bond with the anomeric carbon is located below the reference ring plane, the glycosidic bond is α-configured; if it is located above the ring plane, the glycosidic bond is β-configured.

[0059] 2. Implementation Plan One embodiment of this application is as follows: A method for the electrocatalytic synthesis of multisubstituted ribose derivatives includes using an organotin compound as a catalyst to catalyze the reaction of the compound shown in formula (I) under electrochemical conditions to obtain the compound shown in formula (II): ; in, R 1 C is an optional replacement 1-10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is C, which can be substituted by any choice. 1-4alkyl; R 4 C is a hydrogen atom or an optional substituted C 1-10 hydrocarbon group; The electrochemical conditions include: using R-OH as the reaction solvent; a reaction temperature of 40-80℃; and using quaternary ammonium bromide as the electrolyte.

[0060] In some specific implementation plans, R 1 C is an optional replacement 1-10 Alkyl groups, preferably unsubstituted or phenyl-substituted methyl or ethyl groups, more preferably methyl or phenylethyl groups.

[0061] In some specific implementation plans, R 2 and R 3 Choose from any of the following: Case 1, R 2 -C(=O)OR; R 3 -H; Case 2, R 2 -H;R 3 =-C(=O)OR; In any of the foregoing cases, R is methyl, ethyl, isopropyl, n-butyl, or tert-butyl, preferably methyl.

[0062] In some specific implementation plans, R 4 It is -H, -CH3 or -CH2R'; wherein, R' is a hydroxyl group or its protected form, preferably -OH, -OTBS, -OTr or -OBn.

[0063] In some specific implementations, the organotin compound is a tetravalent organotin compound or a divalent organotin compound.

[0064] In some specific embodiments, the organotin compound is (R 0 ) x (L 0 ) y Sn(A 0 ) z Where x is 1, 2, or 3; y is 0, 1, or 2; z is 1, 2, or 3; each R 0 Independently for C 1-12 Hydrocarbon group; each L 0 Independently, it can be a monodentate or bidentate neutral ligand; each A 0 It is an anion that is independently monovalent or divalent; the organotin compound is electrically neutral as a whole.

[0065] In some specific implementation schemes, each R 0Independently, it is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, n-octyl, isooctyl, 2-ethyl-1-hexyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, vinyl, 1-propenyl, 2-propenyl, naphthyl, anthracene, phenanthryl, o-tolyl, p-tolyl, m-tolyl, xylyl, ethylphenyl, 2,4,6-trimethylyl, phenyl, and benzyl.

[0066] In some specific implementation schemes, each R 0 It is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl or tert-butyl.

[0067] In some specific implementation plans, R 0 It is tert-butyl.

[0068] In some specific implementation plans, each A 0 Independently for O 2- OH - F - Cl - ,Br - I - ,ClO - ClO2 - ClO3 - ClO4 - CN - SCN - OCN -The alkoxide anion or carboxylate anion is optionally substituted, preferably any one of or a substituted form of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, neopentanol, tert-pentanol, 2-methyl-1-butanol, hexanol, heptanol, n-octanol, isooctanol, 2,2,4-trimethylpentanol, nonanol, decanol, dodecanool, n-dodecanool, cyclopentanol, cyclohexanol, cycloheptanol, methylcyclohexanol, pinacol, neopentyl glycol, ethylene alkoxide, propargyl alcohol, and 2-ethyl-1-hexanol; the carboxylate is optionally substituted, preferably glycolate, glycoside, or glycoside. Oleate, formate, acetate, propionate, butyrate, valerate, hexanoate, octanoate, decanoate, laurate, 2-ethylhexanoate, neodecanoate, palmitate, stearate, benzoate, terephthalate, phthalate, isophthalate, acrylate, methacrylate, crotonate, isoctotonate, vinyl acetate, oleate, sorbate, linoleate, linolenic acid, trifluoroacetate, p-toluenesulfonate, oxalate, malonate, succinate, glutarate, adipate, fumarate, maleate, citrate, lactate, tartrate, naphthenate, 2,6-naphthalenedicarboxylate, and 1,6-naphthalenedicarboxylate, or any of their substituted forms.

[0069] In some specific implementation plans, each A 0 Independently for O 2- OH - F - Cl - ,Br - I - Acetate anion, laurate anion, 2-((2-methoxyphenyl)carbamoyl)benzoate anion or 3-(4-fluorophenyl)-2-methylacrylate anion.

[0070] In some specific implementation plans, A 0 For Cl - .

[0071] In some specific embodiments, the neutral ligand is any one of 2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 3,8-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline.

[0072] In some specific embodiments, the organotin compound is (R 0 )2(L 0 ) ySn(A 0 )2; where each A 0 It is an independent monovalent anion.

[0073] In some specific embodiments, the organotin compound is (R 0 )2(L 0 ) y SnA 0 Among them, A 0 It is a divalent anion.

[0074] In some specific embodiments, the organotin compound is selected from any one of dibutyltin oxide, dimethyltin dichloride, di-tert-butyltin dichloride, dibutyltin diacetate, and dibutyltin dilaurate.

[0075] In some specific implementations, the organotin compound is di-tert-butyltin dichloride.

[0076] In some specific implementations, the electrochemical conditions include applying a constant current to the reaction system containing a compound of formula (I), a catalyst, an electrolyte, and a solvent.

[0077] In some specific implementations, the molar ratio of the compound of formula (I) to the catalyst is 1:(0.1-0.3), more preferably 1:0.2.

[0078] In some specific implementations, the brominated quaternary ammonium salt is tetraethylammonium bromide.

[0079] In some specific embodiments, the concentration of the electrolyte is 0.1-0.3 M, more preferably 0.2 M.

[0080] In some specific implementation schemes, the reaction temperature is 60°C.

[0081] In some specific implementation schemes, the reaction solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol.

[0082] In some specific implementations, the intensity of the constant current is 6-500 mA.

[0083] In some specific implementations, the apparent current density of the constant current is 4-20 mA / cm². 2 .

[0084] In some specific implementation plans, the reaction time is 6-60 hours.

[0085] In some specific implementations, the electrochemical conditions further include using a mesh glassy carbon or graphite plate as the anode material.

[0086] In some specific embodiments, the compound of formula (II) is a compound of formula (II-α) or a compound of formula (II-β): , ; Among them, R in the compound of formula (II-β) 4 Not -CH2OH.

[0087] In some specific embodiments, the compound of formula (II-α) is selected from any of the following structures: , , , , , , ; In some specific embodiments, the (II-β) compound is selected from any of the following structures: , .

[0088] In some specific implementations, the compound of formula (I) is selected from any of the following structures: , , , , , , , .

[0089] One embodiment of this application is as follows: A method for synthesizing a nucleoside analogue includes the following steps: a) Obtaining compound (II) by any of the aforementioned electrocatalytic synthesis methods for multisubstituted ribose derivatives; b) Modify the nucleobases of the compound of formula (II), optionally further performing amidation and / or protection and / or deprotection and / or changing the protecting group, to obtain the nucleoside analog shown in formula (III): ; in, R 1 C is an optional replacement 1-10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is C, which can be substituted by any choice. 1-4 alkyl; R 4C is a hydrogen atom or an optional substituted C 1-10 hydrocarbon group; Each R'' is independently a hydrogen atom or a hydroxyl protecting group; G 1 These are residues of nucleobases; G 2 and G 3 Choose from any of the following: Case 1, G 2 and G 3 One of them is -C(=O)OM, and the other is -H; where M is a carboxyl protecting group; Case 2, G 2 and G 3 Any one of them is -C(=O)NR a R b The other is -H; where R a and R b Each is independently a hydrogen atom or an optionally substituted C atom. 1-10 hydrocarbon group, or R a R b Together with N, they constitute C 4-7 Nitrogen heterocycles; G 4 For R 4 The protected or unprotected form.

[0090] In some specific implementations, the nucleobase is cytosine, thymine, uracil, or a derivative thereof.

[0091] In some specific implementation plans, G 1 The sugar unit is linked by an N-glycosidic bond; the N-glycosidic bond is α- or β-type, preferably α-type.

[0092] In some specific implementations, M is methyl or benzyl.

[0093] In some specific implementation plans, G 1 Choose from any of the following structures: , , , , , .

[0094] In some specific implementation schemes, -NR a R b Choose from any of the following structures: , , , , , , , , , , .

[0095] In some specific implementations, the nucleoside analogue represented by formula (III) is .

[0096] In some specific implementations, the nucleoside analogue represented by formula (III) is selected from any of the following structures: , , , , .

[0097] One embodiment of this application is as follows: The use of any of the aforementioned methods for synthesizing nucleoside analogs in the preparation of a medicament, wherein the medicament is used for the prevention and / or treatment of at least one disease selected from viral infections, neoplastic diseases, immune system diseases, and bacterial infections; and the nucleoside analog obtained by the synthetic method is used as an intermediate, active pharmaceutical ingredient, or prodrug in the preparation of the medicament. 3. Detailed Implementation The raw materials used in this application can be purchased or synthesized in-house. The following specific embodiments are used to further describe the implementation of the present invention and do not limit the scope of the invention.

[0099] In the following examples, all reactions were carried out under air-free conditions unless otherwise stated. Reagents used included: n-Bu2SnCl2 (>97%, Antech Chemicals), Et4NBr (99%, Antech Chemicals), and MeOH (Sinopharm Group). Other reagents were commercially available and used directly without further processing. Rapid column chromatography was performed using silica gel (300-400 mesh) purchased from Adamas.

[0100] Unless otherwise stated, all products involved in the following examples were characterized by nuclear magnetic resonance (NMR) spectra acquired at ambient temperature using a Bruker 400 MHz, 500 MHz, or 600 MHz spectrometer. 1¹H NMR chemical shifts were calibrated using CDCl₃ as solvent (δ = 0.00 ppm). Multiplet abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak. Fourier transform infrared (FT-IR) spectra were measured using a Nicolet AVATAR 330 spectrometer. High-resolution mass spectrometry (ESI) was obtained using a Micromass QTOF 2 quadrupole / time-of-flight tandem mass spectrometer. Optical rotation data were measured using an Anton Paar MCP 500 polarimeter at 589 nm and 25°C.

[0101] Example 1 This example examines the effect of electrochemical reaction conditions on reaction efficiency (Table 1).

[0102]

[0103] The reaction was carried out in a single-chamber electrolytic cell. Methyl-α-D-mannopyranoside (compound 1, 0.2 mmol, 1.0 eq), tetraethylammonium bromide (Et4NBr, 210.1 mg, 0.2 mol / L), dibutyltin dichloride (n-Bu2SnCl2, 12.1 mg, 0.2 eq), and methanol (MeOH, 5 mL) were added to a 10 mL Schlenk tube equipped with a magnetic stir bar. The tube was fitted with a mesh glassy carbon (RVC) anode (100 PPI, 1.0 cm × 1.0 cm × 1.2 cm) and a nickel cathode (1.0 cm × 1.0 cm × 0.1 cm), and a constant current of 6.0 mA (apparent current density 6 mA / cm²) was applied in air at 60°C. 2 The reaction mixture was electrolyzed for 8 h (calculated based on the geometric projected area of ​​the anode). After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid column chromatography to give a white solid (compound 2, entry 1.1, yield 65%). R f = 0.5 (silica, DCM / MeOH10:1); [α] 25 D = +73.1 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3456, 2951, 2852,1735, 1489, 1206, 1096, 1048, 1044, 837, 789 cm -1 ; 1 H NMR (400 MHz, D2O) δ 5.22(s, 1H), 4.27 (d, J= 8.5 Hz, 1H), 3.99 (ddd, J = 8.5, 4.8, 2.7 Hz, 1H), 3.83(dd, J = 12.7, 2.7 Hz, 1H), 3.78 (s, 3H), 3.66 (dd, J = 12.6, 4.9 Hz, 1H), 3.42(s, 3H) ppm; 13 C NMR (151 MHz, D2O) δ 173.25, 104.97, 81.46, 79.98, 73.17,60.14, 56.22, 53.34 ppm; HRMS ( m / z ): [M + Na] + calcd for C8H 14 O7Na: 245.0637, found: 245.0634. Compound 2. 1 H NMR and 13 The C NMR spectra are as follows: Figure 1 , 2 As shown.

[0104] Referring to the aforementioned synthesis method, the reaction conditions were optimized through controlled experiments. Without a catalyst (item 1.2) or without applied current (item 1.3), the target product could not be obtained, indicating that both the catalyst and current are crucial for the smooth progress of the reaction. Using other Lewis acids such as ZnBr2, MgCl2, SnCl2, or SnCl4 to replace the organotin catalyst (items 1.4-1.7), only MgCl2 yielded trace amounts of the product (yield <5%). Using DMF or acetonitrile as solvents (items 1.8-1.9), or conducting the reaction at room temperature (item 1.10), the target product also could not be obtained. Relatively high yields (49-52%) were still achieved by replacing the RVC anode with graphite (item 1.11) or the nickel cathode with platinum (item 1.12), indicating that the type of electrode material has no significant impact on the smooth progress of the reaction. When tetraethylammonium chloride (Et4NCl) or tetrabutylammonium iodide (n-Bu4NI) was used as the electrolyte (items 1.13-1.14), the reaction was completely inhibited. Reducing the current to 4 mA (entry 1.15) reduced the reaction efficiency but still yielded a considerable yield of the target compound (31%); increasing the current to 10 mA (entry 1.16) maintained a high yield (60%), indicating that the electrochemical process is tolerant of current density within a certain range.

[0105] Table 1. Results of reaction condition tests

[0106] Example 2 This embodiment refers to the synthesis method described in Example 1, but replaces compound 1 with compounds 3, 4, 7, 10, 12, 15, 17, 19 and 21 respectively, while keeping other conditions unchanged, and examines the substrate suitability of the reaction (Table 2).

[0107] Using methyl-α-D-glucopyranoside (compound 3) as a substrate, compound 2 was obtained in 30% yield (entry 2.1). The reaction proceeded smoothly with C6-modified substrates, including compounds 4 (entry 2.2) and 7 (entry 2.3), obtained by silylation and triphenylmethylation of the C6 hydroxyl group, respectively, with the major products being 3'-esterified products, namely compounds 5 (45%) and 8 (46%); accompanied by minor 2'-esterified products, namely compounds 6 (15%) and 9 (10%). Using methyl-β-D-galactopyranoside (compound 10, entry 2.4) and phenethyl-β-D-glucopyranoside (compound 12, entry 2.5) with β-glycosidic bonds as substrates, 2'- or 3'-esterification could be achieved, but their C5 hydroxymethyl group tended to undergo intramolecular condensation with the 3'-ester group to form lactone structures (compounds 11, 13, and 14). When the substrate does not contain a hydroxymethyl substituent at the C5 position, the formation of the aforementioned lactone product can be avoided regardless of whether the glycosidic bond is α- or β-configuration, and 2'- or 3'-ester modified products can be obtained with high selectivity. For example, using methyl-L-arabinopyranoside (compound 15, entry 2.6) without any substituent at the C5 position as a substrate, a 3'-ester modified product (compound 16) can be obtained in 40% yield. Compound 17 (entry 2.7), with a methyl substituent at the C5 position, can selectively convert to a 2'-ester modified product (compound 18) in 55% yield, while compounds 19 (entry 2.8) and 21 (entry 2.9) can selectively convert to 3'-ester modified products (compounds 20 and 22) in 46% and 43% yields, respectively.

[0108] The above results demonstrate that the synthetic method for multi-substituted ribose derivatives provided in this application can achieve highly selective production of 2'- or 3'-ester modified products by controlling the substituents and stereoconfiguration of the substrate. In particular, by omitting the simultaneous presence of a hydroxymethyl group and a β-glycosidic bond at the C5 position of the substrate, the formation of a lactone structure can be avoided.

[0109] Table 2. Results of Substrate Suitability Study

[0110] Example 3 Gram-scale synthesis of compound 2: Compound 1 (10.0 g, 51.5 mmol), tetraethylammonium bromide (5.0 g, 0.2 mol / L), dibutyltin dichloride (3.1 g, 10.3 mmol), and methanol (60 mL) were added to a 100 mL three-necked flask equipped with a magnetic stir bar and a rubber septum. The flask was fitted with an RVC anode (100 PPI, 1.0 cm × 5.0 cm × 1.0 cm) and a nickel cathode (1.0 cm × 5.0 cm × 0.1 cm). Synthesis was carried out in air at 60°C with a constant current of 50.0 mA (apparent current density 10 mA / cm²). 2 The reaction mixture was electrolyzed for 28 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a white solid (compound 2, 6.1 g, yield 53%).

[0111] Synthesis of Compound 2 on a 40-gram scale: The reaction was carried out in a 1000 mL beaker-type electrolytic cell equipped with an RVC anode (100 PPI, 5.0 cm × 5.0 cm × 1.0 cm) and a nickel cathode (5.0 cm × 5.0 cm × 0.1 cm), with the two electrodes placed in parallel. Compound 1 (100.0 g, 0.5 mol), tetraethylammonium bromide (50.0 g, 0.2 mol / L), dibutyltin dichloride (31.0 g, 0.1 mol), and methanol (600 mL) were added to the reaction cell, and the reaction was carried out in air at 60°C with a constant current of 500.0 mA (apparent current density 20 mA / cm²). 2 The reaction mixture was subjected to electrolysis for 60 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel rapid column chromatography to give a white solid (compound 2, 46.0 g, yield 40%).

[0112] The above results demonstrate that the method provided in this application has good scalability for preparing 2'- or 3'-ester-modified electro-oxidative rearrangement products.

[0113] Example 4 This embodiment examines the late-stage derivatization potential of the aforementioned multi-substituted ribose derivatives.

[0114] Example 4.1: Synthesis of deoxyribose derivatives The deoxyribose derivative 1b can be obtained in two steps by performing a Barton-McCombie deoxygenation reaction with compound 2. The synthetic method is as follows:

[0115] Preparation of compound 1a: Compound 2 (1 g, 4.5 mmol), triphenylchloromethane (2.5 g, 9 mmol), and pyridine (20 mL) were added to a 50 mL round-bottom flask and stirred at room temperature for 12 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting materials had reacted completely, the pyridine was removed by vacuum concentration. DCM (30 mL) was added to the reaction flask, followed by triethylamine (2.5 mL, 18 mmol) and N,N′-thiocarbonyldiimidazole (960 mg, 5.4 mmol). The mixture was stirred at room temperature for 0.5 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting materials had reacted completely, the reaction was quenched with saturated NaHCO3 aqueous solution (20 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with DCM (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. Purified by column chromatography, a yellow oily liquid (compound 1a, 934 mg, yield 41%) was obtained. R f = 0.5(silica, EtOAc / petroleum ether 10:1); [α] 25 D = +73.63 ( c = 0.5 in CH2Cl2); IR(film): ν max = 3413, 2917, 2849, 1754, 1490, 1248, 1300, 1184, 1011, 702 cm -1 ; 1 HNMR (500 MHz, CDCl3) δ 7.45 – 7.41 (m, 6H), 7.37 – 7.32 (m, 6H), 7.29 (t, J =1.6 Hz, 3H), 5.48 (s, 1H), 5.29 (d, J = 3.7 Hz, 1H), 4.43 (q, J = 4.0 Hz, 1H),3.84 (s, 3H), 3.53 (s, 3H), 3.52 – 3.47 (m, 1H), 3.34 (dd, J = 10.5, 3.8 Hz,1H) ppm; HRMS ( m / z ): [M + Na] + calcd for C 28 H 26 O7Na: 529.1297, found: 529.1295. Preparation of compound 1b: A 25 mL round-bottom flask was filled with compound 1a (200 mg, 0.40 mmol), tributyltin hydride (0.54 mL, 2 mmol), azobisisobutyronitrile (13 mg, 0.08 mmol), and a magnetic stir bar. After purging with argon, toluene (10 mL) was added, and the mixture was stirred at 80°C for 1 h. TLC monitoring (CAM colorimetric analysis) showed complete reaction of the starting materials. The mixture was then cooled to room temperature, and DBU (0.3 mL, 2 mmol) was added. The mixture was stirred at room temperature until complete. The reaction was quenched with saturated NaHCO3 aqueous solution (20 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with DCM (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. Purification by column chromatography yielded a colorless oily liquid (compound 1b, 101.1 mg, yield 63%). R f = 0.5(silica, EtOAc / petroleum ether 3:1); [α] 25 D = +48.2 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3395, 2920, 2849, 1748, 1490, 1282, 1221,1092, 1048, 1001, 702 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 7.47 – 7.42 (m, 6H), 7.31(t, J = 7.6 Hz, 6H), 7.24 (t, J = 7.4 Hz, 3H), 5.23 (d, J = 2.4 Hz, 1H), 4.38 (t, J =5.5 Hz, 1H), 4.13 (q, J = 5.7 Hz, 1H), 3.67 (s, 3H), 3.42 (s, 3H), 3.37 (dd, J =9.7, 5.3 Hz, 1H), 3.20 (dd, J = 9.7, 5.7 Hz, 1H), 3.06 (dd, J = 5.1, 2.4 Hz, 1H),2.51 (s, 1H) ppm; 13C NMR (151 MHz, CDCl3) δ 170.96, 143.82, 128.81, 128.03,127.25, 105.63, 87.06, 82.70, 75.91, 63.96, 59.21, 55.47, 52.53 ppm; HRMS ( m / z ): [M + Na] + calcd for C 27 H 28 O6Na: 471.1784, found: 471.1784. Example 4.2: Synthesis of ester derivatives The olefin 2b was obtained by the Corey-Winter olefin synthesis reaction. Its C3 olefin bond is located at a potentiophilic point, which provides a potential route for subsequent three-dimensional functionalization.

[0116]

[0117] Preparation of compound 2b: Compound 1a (400 mg, 0.79 mmol), 1,3-dimethyl-2-phenyl-2-phosphamidazolidine (0.58 mL, 3.16 mmol), and o-dichlorobenzene (20 mL) were added to a 25 mL round-bottom flask and stirred at 140°C for 6 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting material had reacted completely, 1 M HCl aqueous solution (10 mL) was added and the mixture was stirred at room temperature for 0.5 h. After TLC monitoring (CAM colorimetric analysis) showed that the reaction had been completed, the reaction was quenched with saturated NaHCO3 aqueous solution (20 mL), and the organic and aqueous phases were separated. The aqueous phase was extracted three times with DCM (10 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily liquid (compound 2b, 56.5 mg, yield 38%). R f = 0.5(silica, EtOAc / petroleum ether 15:1); [α] 25 D = -31.7( c = 0.5 in CH2Cl2); IR (film): ν max = 3396, 2919, 2849, 1724, 1439, 1384, 1269,1064, 1020, 964, 791 cm -1 ; 1H NMR (600 MHz, CDCl3) δ 7.03 (d, J = 1.1 Hz, 1H), 5.94 (dd, J = 3.9, 0.8 Hz, 1H), 5.13 (qd, J = 3.9, 1.4 Hz, 1H), 3.86 (dd, J = 11.8,3.7 Hz, 1H), 3.81 (s, 3H), 3.72 (dd, J = 11.8, 4.5 Hz, 1H), 3.50 (s, 3H) ppm; 13 CNMR (151 MHz, CDCl3) δ 162.28, 142.68, 134.00, 107.73, 85.60, 63.63, 55.29,51.95 ppm; HRMS ( m / z ): [M + Na] + calcd for C8H 12 O5Na: 211.0582, found: 211.0582. Example 4.3: Synthesis of amide derivatives By utilizing the strong leaving property of sulfonates, a series of amide compounds 3b with C3-position inversion can be synthesized in two steps.

[0118]

[0119] Synthesis of Compound 23: Compound 2 (6 g, 27.0 mmol), triphenylchloromethane (15 g, 54.0 mmol), and pyridine (60 mL) were added to a 250 mL round-bottom flask and stirred at room temperature for 12 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting material had reacted completely, the pyridine was removed by vacuum concentration. DCM (150 mL) was added to the reaction flask, and the mixture was cooled to -78°C. Triethylamine (18.8 mL, 135 mmol) and sulfonyl chloride (3.9 mL, 48.6 mmol) were added sequentially, and the mixture was stirred at -78°C for 0.5 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting material had reacted completely, the reaction was quenched with saturated NaHCO3 aqueous solution (50 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with DCM (80 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The compound was purified by silica gel column chromatography to give a yellow-green solid (compound 23, 6.4 g, yield 45%). R f= 0.5(silica, EtOAc / petroleum ether 5:1); [α] 25 D = +30.1 ( c = 0.5 inCH2Cl2); IR (film): ν max = 3395, 2920, 2849, 1748, 1490, 1282, 1221, 1092, 1048,1001, 702 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.45 (m, 6H), 7.37 (dd, J = 8.4,6.5 Hz, 6H), 7.34 – 7.29 (m, 3H), 5.38 (s, 1H), 5.28 (d, J = 4.5 Hz, 1H), 4.44(q, J = 4.5 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.54 – 3.50 (m, 1H), 3.44 (dd, J = 10.5, 4.1 Hz, 1H) ppm; 13 C NMR (126 MHz, CDCl3) δ 165.48, 143.27, 128.61,128.06, 127.39, 102.60, 88.35, 87.33, 83.54, 79.98, 61.68, 56.04, 54.18 ppm; HRMS ( m / z ): [M + Na] + calcd for C 27 H 26 O9Na: 549.1195, found: 549.1196. Synthesis of compound 3b: Take a 25 mL round-bottom flask, add compound 23 (105 mg, 0.2 mmol), amine (NHR) a R bThe reaction mixture was prepared with 0.6 mmol of DBU (0.1 mL, 0.33 mmol), 10 mL of THF, and a magnetic stirrer. The mixture was stirred at 60°C for 6 h. After the reactants had reacted completely, the mixture was cooled to room temperature, and 1 M HCl (10 mL) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with 20 mL of saturated NaHCO3 aqueous solution, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a series of amide compounds 3b (compounds 24-31).

[0120]

[0121] Colorless oily liquid; yield: 40%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +86.7 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3390, 2921, 2850, 1646, 1533, 1450, 1257,1105, 1045, 976, 699 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 7.38 (d, J = 7.3 Hz, 2H), 7.33 (dd, J = 8.5, 6.8 Hz, 2H), 7.27 – 7.23 (m, 1H), 5.30 (s, 1H), 5.08 (q, J =6.9 Hz, 1H), 4.35 (ddd, J = 6.2, 4.9, 3.7 Hz, 1H), 4.11 (d, J = 3.8 Hz, 1H), 3.77(qd, J = 11.7, 5.6 Hz, 2H), 3.51 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (151 MHz, MeOD) δ 171.12, 143.18, 128.15, 126.76, 125.78, 104.86, 82.35,81.56, 79.08, 60.16, 55.48, 48.60, 20.86 ppm; HRMS ( m / z ): [M + Na] + calcd forC 15 H 21 NO6Na: 334.1267, found: 334.1268.

[0122] Colorless oily liquid; yield: 41%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +20.8 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3395, 2928, 2852, 1645, 1537, 1451, 1260,1104, 1047, 977, 801 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.3 Hz, 1H), 5.25 (s, 1H), 5.00 (s, 1H), 4.32 (q, J = 3.9 Hz, 1H), 4.22 (d, J = 3.7 Hz, 1H), 4.07 (s, 1H), 3.98 (d, J = 4.0 Hz, 2H), 3.85 – 3.71 (m, 1H), 3.55 (s, 3H), 2.04 – 1.87 (m, 2H), 1.81 – 1.69 (m, 2H), 1.64 (dt, J = 12.8, 3.7 Hz, 1H), 1.50 –1.31 (m, 2H), 1.31 – 1.13 (m, 4H) ppm; 13C NMR (151 MHz, CDCl3) δ 170.67,104.32, 81.14, 80.95, 80.89, 61.43, 56.44, 48.41, 32.75, 25.36, 24.72 ppm; HRMS ( m / z ): [M + Na] + calcd for C 13 H 23 NO6Na: 312.1423, found: 312.1423.

[0123] Colorless oily liquid; yield: 46%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +7.2 ( c =0.5 in CH2Cl2); IR (film): ν max = 3363, 2921, 2849, 1644, 1540, 1469, 1260,1103, 1034, 749, cm -1 ; 1 H NMR (600 MHz, MeOD) δ 5.30 (s, 1H), 4.35 (ddd, J = 6.2,5.0, 3.6 Hz, 1H), 4.07 (d, J = 3.7 Hz, 1H), 3.78 (qd, J = 11.6, 5.6 Hz, 2H), 3.50(s, 3H), 3.26 (tq, J = 13.5, 7.2, 6.7 Hz, 2H), 1.58 – 1.50 (m, 2H), 1.44 – 1.34(m, 2H), 0.96 (t, J = 7.4 Hz, 3H) ppm; 13 C NMR (151 MHz, MeOD) δ 171.95, 105.36,82.24, 81.66, 79.18, 60.16, 55.48, 38.58, 31.18, 19.63, 12.69 ppm; HRMS ( m / z ): [M + Na] +calcd for C 11 H 21 NO6Na: 286.1267, found: 286.1268.

[0124] Colorless oily liquid; yield: 41%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3392, 2920, 2849, 1647, 1539, 1103, 1027,978, 845 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 5.28 (s, 1H), 4.34 (ddd, J = 6.2, 4.9,3.8 Hz, 1H), 4.14 (dtd, J = 12.1, 6.8, 5.3 Hz, 1H), 4.09 (d, J = 3.9 Hz, 1H), 3.79 (qd, J = 11.7, 5.6 Hz, 2H), 3.50 (s, 3H), 3.45 – 3.36 (m, 6H), 1.20 (d, J =6.8 Hz, 3H) ppm; 13 C NMR (151 MHz, MeOD) δ 171.43, 104.81, 82.42, 81.44, 79.23,74.90, 60.15, 57.80, 55.43, 44.68, 16.09 ppm; HRMS ( m / z ): [M + Na] + calcd forC 11 H 21 NO7Na: 302.1216, found: 302.1217.

[0125] Colorless oily liquid; yield: 43%. R f= 0.5(silica, EtOAc / petroleum ether 1:1); [α] 25 D = +7.4 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3390, 2919, 2849, 1667, 1537,1455, 1393, 1275, 1047, 806 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 5.23(s, 1H), 4.32(ddd, 10). J = 6.1, 4.9, 3.8 Hz, 1H), 4.07 (d, J = 3.8 Hz, 1H), 3.88 – 3.73(m,2H),3.50(s,3H), 1.39(s,9H) ppm; 13 C NMR (151 MHz, MeOD) δ 171.24, 104.86, 81.97, 81.55, 79.16, 60.15, 55.43, 50.82, 27.42 ppm; HRMS ( HRMS m / z ): [M + Na] + calcd for C 11 H 21 NO6Na: 286.1267, found:

[0126] Stock market share: 41%. R f = 0.5(silica, EtOAc / petroleum ether 1:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3372, 2919, 2849, 1673, 1537,1445, 1274, 1158, 1093, 1046, 845 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 7.69–7.61(m,2H), 7.34(dd,1). J= 8.5, 7.4 Hz, 2H), 7.21 – 7.09 (m, 1H), 5.46 (s, 1H), 4.42 (ddd, J = 6.2, 5.0, 3.7 Hz, 1H), 4.21 (d, J = 3.8 Hz, 1H), 3.82 (qd, J = 11.7,5.6 Hz, 2H), 3.54 (s, 3H) ppm; 13 C NMR (151 MHz, MeOD) δ 169.91, 137.61,128.39, 124.20, 120.22, 104.65, 83.44, 81.54, 79.26, 60.19, 55.53 ppm; HRMS( m / z ): [M + Na] + calcd for C 13 H 17 NO6Na: 306.0954, found: 306.0955.

[0127] Colorless oily liquid; yield: 42%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3395, 2920, 2849, 1679, 1536, 1462, 1273,1160, 1106, 1037, 808 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 5.34 (s, 1H), 4.36 (ddd, J =6.3, 5.0, 3.8 Hz, 1H), 4.12 (d, J = 3.8 Hz, 1H), 4.05 (dq, J = 14.9, 9.3 Hz, 1H), 3.86 (dq, J = 14.9, 9.3 Hz, 1H), 3.78 (qd, J= 11.7, 5.6 Hz, 2H), 3.50(s,3H)ppm; 13 C NMR (151 MHz, MeOD) δ 172.46; 39.63, 39.40 ppm; 19 F NMR (376MHz, MeOD) δ-73.62 ppm; HRMS ( HRMS m / z ): [M + Na] + calcd for C9H 14 F3NO6At: 312.0671,Found: 312.0670.

[0128] Cash flow ratio: 40%. R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3369, 2919, 2849, 1673, 1538, 1494, 1275,1260, 1089, 1038, 750 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 7.68–7.61(m,1H), 7.42–7.29(m,2H), 6.86(tdd,1). J = 8.4, 2.6, 1.1 Hz, 1H, 5.47(s, 1H), 4.41(ddd, J = 6.3, 5.0, 3.7 Hz, 1H), 4.21 (d, J = 3.8 Hz, 1H), 3.81 (qd, J = 11.6, 5.7 Hz,2H), 3.54(s,3H) ppm; 13 C NMR (151 MHz, MeOD) δ 169.99, 162.84 (d, 169.84). J= 242.7Hz), 139.54 (d, J = 11.0 Hz), 129.71 (d, J = 9.4 Hz), 115.51 (d, J = 2.9 Hz), 110.36 (d, J = 21.5 Hz), 107.05 (d, J = 26.5 Hz), 104.52, 83.73, 81.47, 79.20,60.16, 55.52 ppm; 19 F NMR (376 MHz, MeOD) δ -114.28 ppm; HRMS ( m / z ): [M + Na] + calcd for C 13 H 16 FNO6Na: 324.0859, found: 324.0859. Example 4.4: Synthesis of β-lactam derivatives

[0129] Compound 4b-1 (R 5 Preparation of compound 23 (105 mg, 0.2 mmol), benzylamine (0.22 mL, 2 mmol), acetonitrile (0.5 mL), and a magnetic stir bar were added to a 5 mL round-bottom flask. DBU (0.2 mL, 0.66 mmol) was added dropwise at 80°C, and the mixture was stirred for 1 h. After the starting materials had reacted completely, the mixture was cooled to room temperature, and 1 M HCl (10 mL) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated NaHCO3 aqueous solution (20 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain a white solid (compound 4b-1, 24 mg, yield 43%). R f = 0.5(silica, DCM / MeOH 10:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max= 3396, 2918, 2849, 1745,1537, 1445, 1273, 1107, 1025, 749, 700 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 7.40 –7.30 (m, 5H), 4.91 (s, 1H), 4.83 (d, J = 15.3 Hz, 1H), 4.18 (d, J = 15.2 Hz, 1H), 4.13 (td, J = 6.7, 2.8 Hz, 1H), 3.83 (d, J = 2.8 Hz, 1H), 3.77 (dd, J = 11.1, 6.5Hz, 1H), 3.61 (dd, J = 11.1, 6.9 Hz, 1H), 3.47 (s, 3H) ppm; 13 C NMR (151 MHz, MeOD) δ 168.42, 135.67, 128.44, 127.98, 127.47, 99.44, 92.65, 75.98, 63.58,59.48, 54.28, 45.77 ppm; HRMS ( m / z ): [M + Na] + calcd for C 14 H 17 NO5Na: 279.1107, found: 279.1108. Compound 4b-2 (R 5 Preparation of (n-Bu): In a 5 mL round-bottom flask, compound 23 (105 mg, 0.2 mmol), n-butylamine (0.2 mL, 2 mmol), acetonitrile (0.5 mL), and a magnetic stir bar were added. DBU (0.2 mL, 0.66 mmol) was added dropwise at 80°C, and the mixture was stirred for 1 h. After the starting material had reacted completely, the mixture was cooled to room temperature, and 1 M HCl (10 mL) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with a saturated NaHCO3 aqueous solution (20 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. Purification by column chromatography yielded a colorless oily liquid (compound 4b-2, 24.5 mg, yield 50%). R f= 0.5(silica,EtOAc / petroleum ether 2:1); [α] 25 D = +10.1 ( c = 0.5 in CH2Cl2); IR (film): ν max =3398, 2919, 2848, 1738, 1552, 1414, 1261, 1030, 840, 788, 620 cm -1 ; 1 H NMR (600MHz, MeOD) δ 4.85 (s, 1H), 4.16 (td, J = 6.9, 2.8 Hz, 1H), 3.96 (d, J = 2.8 Hz, 1H), 3.78 (dd, J = 10.9, 6.6 Hz, 1H), 3.67 – 3.57 (m, 2H), 3.47 (s, 3H), 3.02(ddd, J = 13.6, 7.6, 5.6 Hz, 1H), 1.74 – 1.58 (m, 2H), 1.47 – 1.36 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm; 13 C NMR (151 MHz, MeOD) δ 168.51, 99.40, 92.15,76.06, 63.54, 59.51, 54.26, 41.84, 29.39, 19.58, 12.50 ppm; HRMS ( m / z ): [M +Na] + calcd for C 11 H 19 NO5Na: 268.1161, found: 268.1160. Example 5 This embodiment prepares a series of nucleoside analogs.

[0130] Example 5.1: Synthesis of C2-carboxylic acid ester modified nucleoside analogs

[0131] Preparation of compound 32: Compound 2 (5 g, 22.5 mmol), DMF (100 mL), and NaOH (9 g, 25 mmol) were added to a 250 mL round-bottom flask. After dissolution, benzyl bromide (16 mL, 135 mmol) was added, and the mixture was stirred at room temperature for 12 h. After TLC monitoring (CAM colorimetric analysis) showed that the starting material had reacted completely, the reaction was quenched with saturated NaHCO3 aqueous solution (50 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with ethyl acetate (80 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain a colorless oily liquid (compound 32, 10.6 g, yield 83%). R f = 0.5(silica, EtOAc / petroleum ether 1:10); [α] 25 D = +89.0 ( c =0.5 in CH2Cl2); IR (film): ν max = 3400, 2919, 2849, 1732, 1538, 1454, 1264,1109, 1039, 736, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 12H), 7.28– 7.17 (m, 8H), 5.46 (s, 1H), 5.05 (s, 2H), 4.84 (d, J = 12.3 Hz, 1H), 4.67 (d, J = 10.9 Hz, 1H), 4.55 (dd, J = 17.7, 11.6 Hz, 2H), 4.49 – 4.37 (m, 2H), 4.26(td, J = 4.9, 3.3 Hz, 1H), 4.17 (d, J = 5.2 Hz, 1H), 3.60 – 3.50 (m, 4H), 3.41(dd, J = 10.7, 4.7 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 170.91, 138.10,137.96, 137.93, 135.20, 128.62, 128.53, 128.31, 128.21, 128.15, 127.74,127.70, 127.69, 127.59, 127.54, 103.54, 86.38, 81.43, 78.68, 73.45, 72.79,69.37, 69.17, 67.32, 55.37 ppm; HRMS ( m / z ): [M + Na] + calcd for C 35 H 38 O7Na:591.2359, found: 591.2358. Preparation of C2-carboxylic acid ester modified nucleoside analogs (compounds 33-38): A 25 mL round-bottom flask was filled with a base (2 mmol), hexamethyldisilazane (10 mL), and ammonium bisulfate (1.1 mg, 0.01 mmol). The mixture was heated to reflux at 140°C until the reaction system became clear and transparent. Excess hexamethyldisilazane was removed by vacuum concentration to obtain a crude product with a silicon-protected base. p-xylene (3 mL), compound 32 (113.7 mg, 0.2 mmol), and TMSOTf (0.22 mL, 1.2 mmol) were added, and the mixture was stirred at 65°C for 24 h. After the reactants had reacted completely, the mixture was cooled to room temperature and the reaction was quenched with a saturated NaHCO3 aqueous solution (5 mL). The organic and aqueous phases were separated. The aqueous phase was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to obtain the crude product. A series of C2-carboxylic acid ester modified nucleoside analogs 33-38 were obtained by rapid silica gel column chromatography purification.

[0132]

[0133] Colorless oily liquid; yield: 61%; α:β = 34:1. R f =0.5(silica, EtOAc / petroleum ether1:3); [α] 25 D = -32.5 ( c = 0.5 in CH2Cl2); IR (film): ν max= 3191, 3031, 2920, 1742,1689, 1454, 1382, 1275, 1104, 749, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 9.13 (s,1H), 7.49 (d, J = 8.2 Hz, 1H), 7.42 – 7.25 (m, 16H), 7.19 (ddd, J = 9.5, 7.4, 3.7Hz, 4H), 6.43 (s, 1H), 5.56 (d, J = 8.2 Hz, 1H), 5.29 (s, 2H), 5.12 (d, J = 11.0Hz, 1H), 5.01 (d, J = 9.0 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.64 (d, J = 11.5 Hz,1H), 4.58 – 4.45 (m, 3H), 4.40 (ddd, J = 9.0, 4.2, 2.4 Hz, 1H), 3.69 (dd, J =11.1, 2.4 Hz, 1H), 3.52 (dd, J = 11.1, 4.2 Hz, 1H) ppm; 13 C NMR (101 MHz, CDCl3)δ 168.40, 163.64, 150.70, 142.23, 138.07, 137.78, 136.88, 134.87, 129.01,128.74, 128.71, 128.54, 128.49, 128.26, 128.15, 127.82, 127.79, 127.74,127.56, 100.71, 87.36, 83.50, 81.92, 80.71, 73.69, 73.56, 70.37, 68.56, 68.49ppm; HRMS ( m / z ): [M + Na] + calcd for C 38 H 36 N2O8Na: 671.2369, found: 671.2368.

[0134] Colorless oily liquid; yield: 53%; α:β = 20:1. R f = 0.5(silica, EtOAc / petroleum ether2:1); [α] 25 D = -7.2 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3372, 3031, 2920, 1742,1689, 1454, 1276, 1218, 1086, 736, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 8.19 (s,1H), 7.42 – 7.29 (m, 13H), 7.28 – 7.24 (m, 3H), 7.21 – 7.14 (m, 4H), 6.43 (s,1H), 5.26 (d, J = 2.3 Hz, 2H), 5.12 (d, J = 10.8 Hz, 1H), 4.98 (d, J = 8.8 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.58 – 4.45 (m, 3H), 4.41(ddd, J = 8.9, 4.3, 2.4 Hz, 1H), 3.67 (dd, J = 11.0, 2.4 Hz, 1H), 3.51 (dd, J =11.0, 4.4 Hz, 1H), 1.73 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ168.41, 163.46, 150.23, 138.35, 137.97, 137.66, 136.84, 134.70, 128.97,128.80, 128.69, 128.51, 128.47, 128.24, 128.18, 128.10, 127.83, 127.80,127.68, 127.43, 108.57, 86.96, 83.53, 81.75, 80.65, 73.61, 73.56, 70.10,68.59, 68.46, 12.08 ppm; HRMS ( m / z ): [M + Na] + calcd for C 39 H 38 N2O8Na: 685.2526, found: 685.2527.

[0135] Colorless oily liquid; yield: 41%; α:β = 18:1. R f = 0.5(silica, EtOAc / petroleum ether1:2); [α] 25 D = -21.6 ( c = 1.0 in CH2Cl2); IR (film): ν max = 3401, 2919, 1674, 1621,1484, 1392, 1272, 1104, 749, 698 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 8.07 – 7.80(m, 3H), 7.64 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.44 (d, J = 6.9 Hz, 3H), 7.34 (ddd, J = 29.0, 11.2, 5.2 Hz, 11H), 7.26 – 7.13 (m, 8H), 6.58 (s,1H), 5.41 (d, J = 11.9 Hz, 1H), 5.28 (d, J= 11.9 Hz, 1H), 5.12 (d, J = 11.2 Hz, 1H), 5.05 (d, J = 9.1 Hz, 1H), 4.91 (d, J = 11.2 Hz, 1H), 4.58 (dd, J = 24.3, 11.8Hz, 2H), 4.53 – 4.40 (m, 3H), 3.72 (d, J = 11.2 Hz, 1H), 3.55 (dd, J = 11.1, 4.3Hz, 1H) ppm; 13 C NMR (151 MHz, CDCl3) δ 168.48, 166.30, 162.23, 154.75, 147.04,138.29, 137.71, 136.79, 135.07, 133.21, 129.19, 129.05, 128.61, 128.58,128.50, 128.47, 128.23, 128.15, 128.10, 127.81, 127.77, 127.55, 127.35,88.85, 82.67, 82.47, 80.73, 73.63, 73.54, 70.11, 68.56, 68.45 ppm; HRMS ( m / z ): [M + Na] + calcd for C 45 H 41 N3O8Na: 774.2791, found: 774.2790.

[0136] Colorless oily liquid; yield: 51%; α:β = 30:1. R f = 0.5(silica, EtOAc / petroleum ether1:1); [α] 25 D = +53.3 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3356, 3031, 1693, 1610,1496, 1383, 1274, 1087, 735, 697 cm -1 ;1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.90 (s, 1H), 7.40 – 7.27 (m, 16H), 7.22 – 7.15 (m, 4H), 6.40 (s, 1H), 5.26 (s, 2H), 5.13 (d, J = 10.8 Hz, 1H), 5.00 (d, J = 8.7 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.57 – 4.45 (m, 3H), 4.41 (ddd, J = 8.7, 4.0, 2.4Hz, 1H), 3.67 (dd, J = 11.1, 2.4 Hz, 1H), 3.50 (dd, J = 11.1, 4.0 Hz, 1H) ppm; 13 CNMR (151 MHz, CDCl3) δ 168.13, 159.64, 149.84, 146.97, 137.59, 136.75,134.61, 128.95, 128.85, 128.73, 128.54, 128.52, 128.50, 128.29, 128.14,127.87, 127.80, 127.79, 127.45, 87.22, 83.28, 81.56, 80.85, 73.70, 73.56,70.27, 68.51, 68.30, 66.30 ppm; HRMS ( m / z ): [M + Na] + calcd for C 38 H 35 IN2O8Na:797.1336, found: 797.1337.

[0137] Colorless oily liquid; yield: 58%; α:β = 34:1. R f = 0.5(silica, EtOAc / petroleum ether1:3); [α] 25 D = -73.8 (c = 1.0 in CH2Cl2); IR (film): ν max = 3187, 3032, 2920, 1721,1704, 1660, 1454, 1358, 1271, 1086, 736, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ9.38 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 6.5 Hz, 1H), 7.43 – 7.28 (m, 16H), 7.24 –7.15 (m, 4H), 6.42 (d, J = 1.6 Hz, 1H), 5.39 – 5.25 (m, 2H), 5.12 (d, J = 10.8Hz, 1H), 4.99 (d, J = 8.7 Hz, 1H), 4.88 (d, J = 10.9 Hz, 1H), 4.64 (d, J = 11.5 Hz,1H), 4.59 – 4.43 (m, 3H), 4.41 (ddd, J = 8.8, 4.1, 2.4 Hz, 1H), 3.68 (dd, J =11.1, 2.5 Hz, 1H), 3.51 (dd, J = 11.1, 4.1 Hz, 1H) ppm; 13 C NMR (101 MHz, CDCl3)δ 168.18, 156.74 (d, J = 26.7 Hz), 149.13, 139.37 (d, J = 235.4 Hz), 137.78,137.65, 136.75, 134.75, 128.96, 128.80, 128.71, 128.53, 128.48, 128.34,128.28, 128.11, 127.88, 127.85, 127.77, 127.49, 126.72 (d, J = 35.3 Hz), 87.42,83.57, 81.65, 80.90, 73.70, 73.55, 70.42, 68.54, 68.33 ppm;19 F NMR (376 MHz, CDCl3) δ -174.05 ppm; HRMS ( m / z ): [M + Na] + calcd for C 38 H 35 FN2O8Na: 689.2275, found: 689.2274.

[0138] Colorless oily liquid; yield: 58%; α:β = 34:1. R f =0.5(silica, EtOAc / petroleum ether1:3); [α] 25 D = -33.1 ( c = 1.0 in CH2Cl2); IR (film): ν max = 3065, 3033, 2923, 1727,1701, 1654, 1463, 1278, 1138, 1086, 737, 697 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ8.51 (s, 1H), 7.94 (s, 1H), 7.41 – 7.29 (m, 13H), 7.29 – 7.24 (m, 3H), 7.22 –7.11 (m, 4H), 6.42 (s, 1H), 5.27 (s, 2H), 5.13 (d, J = 10.6 Hz, 1H), 5.04 (d, J =8.7 Hz, 1H), 4.80 (d, J = 10.6 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.56 – 4.44(m, 3H), 4.42 (ddd, J = 8.7, 3.8, 2.5 Hz, 1H), 3.68 (dd, J = 11.1, 2.5 Hz, 1H), 3.50 (dd, J = 11.1, 3.8 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl3) δ 167.97, 157.97,149.14, 143.29 (d, J = 5.8 Hz), 137.54, 137.35, 136.64, 134.51, 128.96, 128.93,128.76, 128.55, 128.50, 128.40, 128.34, 128.16, 127.99, 127.90, 127.79,127.53, 121.70 (q, J = 270.4 Hz), 103.88 (q, J = 33.5 Hz), 87.25, 83.17, 81.45,81.04, 73.75, 73.56, 70.53, 68.56, 68.08ppm; 19 F NMR (376 MHz, CDCl3) δ -63.58ppm; HRMS ( m / z ): [M + Na] + calcd for C 39 H 35 F3N2O8Na: 739.2243, found: 739.2243. Example 5.2: Synthesis of C2-amide-modified nucleoside analogs

[0139] Preparation of compound 39: Compound 33 (7 g, 10.8 mmol), 1 M K₂CO₃ aqueous solution (50 mL), and MeOH (50 mL) were added to a 250 mL round-bottom flask and stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC (CAM colorimetric analysis), methanol was removed by vacuum concentration. The reaction was quenched with saturated NH₄Cl aqueous solution (50 mL), and the organic and aqueous phases were separated. The aqueous phase was extracted three times with ethyl acetate (80 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous MgSO₄, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain a colorless oily liquid (compound 39, 5.5 g, yield 91%). R f = 0.5(silica, DCM / MeOH 2:1); [α] 25 D = -27.0 ( c = 1.0 in CH2Cl2); IR (film): ν max= 3031, 2923, 1697, 1704, 1616, 1394, 1276, 1105, 1027, 737, 697 cm -1 ; 1 H NMR (600 MHz, MeOD) δ 7.79 (d, J = 8.1 Hz, 1H), 7.38 – 7.14 (m, 15H), 6.62 (s, 1H), 5.50 (d, J = 8.1 Hz, 1H), 5.02 – 4.96 (m, 2H), 4.82 (d, J = 11.5 Hz, 1H), 4.66(d, J = 11.5 Hz, 1H), 4.54 – 4.46 (m, 2H), 4.43 (ddd, J = 7.1, 5.1, 3.5 Hz, 1H),3.68 (dd, J = 10.8, 3.6 Hz, 1H), 3.57 (dd, J = 10.8, 5.3 Hz, 1H) ppm; 13 C NMR (151MHz, MeOD) δ 173.25, 164.90, 151.30, 144.11, 139.23, 138.05, 137.86, 128.07,128.01, 127.97, 127.67, 127.63, 127.53, 127.39, 127.26, 126.87, 99.64, 88.07,85.06, 82.30, 81.97, 73.02, 72.83, 69.41, 69.10 ppm; HRMS ( m / z ): [M + Na] + calcd for C 31 H 30 N2O8Na: 581.1900, found: 581.1903. Preparation of compound 40a: In a 50 mL round-bottom flask, compound 39 (279.3 mg, 0.5 mmol), DCM (15 mL), and COMU (321.2 mg, 0.75 mmol) were added. The mixture was stirred at room temperature for 30 min, and then aniline (NHR) was added. a R b R a =H,R b=C6H5; 0.09 mL, 1 mmol), and continued the reaction at room temperature for 6 h. After the reaction of the starting material was complete as monitored by TLC (CAM colorimetric analysis), the reaction was quenched with saturated NaHCO3 aqueous solution (10 mL), the organic phase and aqueous phase were separated, the aqueous phase was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated under vacuum to obtain the crude product. Purified by column chromatography, a colorless oily liquid (compound 40a, 256.6 mg, yield 81%) was obtained. R f =0.5(silica,EtOAc / petroleum ether 1:3); [α] 25 D = -169.8 ( c = 0.5 in CH2Cl2); IR (film): ν max =3395, 2919, 1682, 1530, 1455, 1273, 1105, 808, 753, 698, cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 8.98 (s, 1H), 8.87 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.52 – 7.45 (m,2H), 7.42 – 7.29 (m, 11H), 7.28 – 7.23 (m, 4H), 7.17 – 7.11 (m, 3H), 6.45 (s,1H), 5.74 (dd, J = 8.2, 2.0 Hz, 1H), 5.05 (d, J = 4.3 Hz, 1H), 4.86 (d, J = 11.5Hz, 1H), 4.76 – 4.63 (m, 3H), 4.63 – 4.52 (m, 3H), 3.70 (dd, J = 10.4, 4.8 Hz, 1H), 3.57 (dd, J = 10.4, 5.9 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl3) δ 167.06,163.15, 151.18, 141.12, 137.68, 137.12, 137.04, 136.65, 129.09, 128.63,128.55, 128.49, HRMS ( m / z ): [M + Na] + calcd forC 37 H 35 N3O7Na: 656.2373, found: 656.2375. Preparation of compound 40b: Compound 40a (126.7 mg, 0.2 mmol), Pd(OH)₂ (10 mg), acetic acid (1.1 μL, 0.02 mmol), and MeOH (15 mL) were added to a 50 mL round-bottom flask. After purging with hydrogen, the mixture was reacted at 60°C for 5 h under a hydrogen atmosphere. TLC monitoring (CAM colorimetric analysis) showed complete reaction of the starting material. The palladium catalyst was removed by filtration, and the mixture was concentrated under vacuum to obtain the crude product. Purification by column chromatography yielded a colorless oily liquid (compound 40b, 53 mg, yield 73%). R f =0.5(silica,DCM / MeOH 4:1); [α] 25 D = -54.9 ( c = 0.5 in CH2Cl2); IR (film): ν max = 3031, 2923,1697, 1704, 1616, 1394, 1276, 1105, 1027, 737, 697 cm -1 ; 1 H NMR (600 MHz, MeOD)δ 7.71 (d, J = 8.1 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.37 – 7.30 (m, 2H), 7.18 –7.10 (m, 1H), 6.39 (s, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.76 (d, J= 9.1 Hz, 1H), 4.19 (ddd, J = 9.1, 4.7, 2.3 Hz, 1H), 3.95 (dd, J = 12.4, 2.3 Hz, 1H), 3.74 (dd, J = 12.4, 4.7 Hz, 1H) ppm; 13 C NMR (151 MHz, MeOD) δ 170.22, 165.13, 150.56,142.09, 137.50, 128.30, 124.41, 120.75, 99.69, 89.53, 83.97, 81.33, 73.44,60.65 ppm; HRMS ( m / z ): [M + Na] + calcd for C 16 H 17 N3O7Na: 386.0964, found: 386.0965. Referring to the aforementioned synthesis method, the NHR was modified. a R b The types of C2-amide modified nucleoside analogs 40~44a / b were obtained (Table 3).

[0140] Table 3. C2-amide modified nucleoside analogs

Claims

1. A method for electrocatalytic synthesis of multi-substituted ribose derivatives, characterized in that, Using an organotin compound as a catalyst, the compound shown in formula (I) was reacted under electrochemical conditions to obtain the compound shown in formula (II): ； in, R 1 C is an optional replacement 1-10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is C, which can be substituted by any choice. 1-4 alkyl; R 4 C is a hydrogen atom or an optional substituted C 1-10 hydrocarbon group; The electrochemical conditions include: using R-OH as the reaction solvent; a reaction temperature of 40-80℃; and using quaternary ammonium bromide as the electrolyte.

2. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, R 1 C is an optional replacement 1-10 Alkyl groups, preferably unsubstituted or phenyl-substituted methyl or ethyl groups, more preferably methyl or phenylethyl groups.

3. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, R 2 and R 3 Choose from any of the following: Case 1, R 2 -C(=O)OR; R 3 -H; Case 2, R 2 -H;R 3 =-C(=O)OR; In any of the foregoing cases, R is methyl, ethyl, isopropyl, n-butyl, or tert-butyl, preferably methyl.

4. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, R 4 It is -H, -CH3 or -CH2R'; wherein, R' is a hydroxyl group or its protected form, preferably -OH, -OTBS, -OTr or -OBn.

5. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, The organotin compound is a tetravalent organotin compound or a divalent organotin compound; preferably, the organotin compound is (R 0 ) x (L 0 ) y Sn(A 0 ) z Where x is 1, 2, or 3; y is 0, 1, or 2; z is 1, 2, or 3; each R 0 Independently for C 1-12 Hydrocarbon group; each L 0 Independently, it can be a monodentate or bidentate neutral ligand; each A 0 It is an anion that is independently monovalent or divalent; the organotin compound is electrically neutral as a whole; Preferably, each R 0 Independently, it is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, n-octyl, isooctyl, 2-ethyl-1-hexyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, vinyl, 1-propenyl, 2-propenyl, naphthyl, anthracene, phenanthryl, o-tolyl, p-tolyl, m-tolyl, xylyl, ethylphenyl, 2,4,6-trimethylyl, phenyl, and benzyl; more preferably, each R 0 Independently, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, or tert-butyl; more preferably, R 0 For tert-butyl; Preferably, each A 0 Independently for O 2- OH - F - Cl - ,Br - I - ,ClO - ClO2 - ClO3 - ClO4 - CN - SCN - OCN - The alkoxide anion or carboxylate anion is optionally substituted, preferably any one of or a substituted form of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, neopentanol, tert-pentanol, 2-methyl-1-butanol, hexanol, heptanol, n-octanol, isooctanol, 2,2,4-trimethylpentanol, nonanol, decanool, dodecanool, n-dodecanool, cyclopentanol, cyclohexanol, cycloheptanol, methylcyclohexanol, pinacol, neopentyl glycol, ethylene alkoxide, propargyl alcohol, and 2-ethyl-1-hexanol; the carboxylate is optionally substituted, preferably glycolate, glycerolate, etc. Formate, acetate, propionate, butyrate, valerate, hexanoate, caprylate, octanoate, decanoate, laurate, 2-ethylhexanoate, neodecanoate, palmitate, stearate, benzoate, terephthalate, phthalate, isophthalate, acrylate, methacrylate, crotonate, isoctoate, vinyl acetate, oleate, sorbate, linoleate, linolenic acid salt, trifluoroacetate, p-toluenesulfonate, oxalate, malonate, succinate, glutarate, adipate, fumarate, maleate, citrate, lactate, tartrate, naphthenate, 2,6-naphthalenedicarboxate and 1,6-naphthalenedicarboxate, or any of their substituted forms; more preferably, each A 0 Independently for O 2- OH - F - Cl - ,Br - I - Acetate anion, laurate anion, 2-((2-methoxyphenyl)carbamoyl)benzoate anion or 3-(4-fluorophenyl)-2-methylacrylate anion; more preferably, A 0 For Cl - ; Preferably, the neutral ligand is any one of 2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 3,8-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline. Preferably, the organotin compound is selected from any of the following: Case 1, (R) 0 )2(L 0 ) y Sn(A 0 )2; where each A 0 It is an independent monovalent anion; Case 2, (R) 0 )2(L 0 ) y SnA 0 Among them, A 0 It is a divalent anion; More preferably, the organotin compound is selected from any one of dibutyltin oxide, dimethyltin dichloride, di-tert-butyltin dichloride, dibutyltin diacetate, and dibutyltin dilaurate; More preferably, the organotin compound is di-tert-butyltin dichloride.

6. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, The electrochemical conditions include: applying a constant current to a reaction system containing a compound of formula (I), a catalyst, an electrolyte, and a solvent; wherein, Preferably, the molar ratio of the compound of formula (I) to the catalyst is 1:(0.1-0.3), more preferably 1:0.2; Preferably, the quaternary ammonium bromide is tetraethylammonium bromide; Preferably, the concentration of the electrolyte is 0.1-0.3 M, more preferably 0.2 M; Preferably, the reaction temperature is 60°C; Preferably, the reaction solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; Preferably, the apparent current density of the constant current is 4-20 mA / cm². 2 ; Preferably, the reaction time is 6-60 h.

7. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, The compound of formula (II) is either a compound of formula (II-α) or a compound of formula (II-β): 、 ； Among them, R in the compound of formula (II-β) 4 Not -CH2OH; Preferably, the compound of formula (II-α) is selected from any of the following structures: 、 、 、 、 、 、 ； Preferably, the compound of formula (II-β) is selected from any of the following structures: 、 。 8. The method for electrocatalytic synthesis of polysubstituted ribose derivatives according to claim 1, characterized in that, The compound of formula (I) is selected from any of the following structures: 、 、 、 、 、 、 、 。 9. A method for synthesizing a nucleoside analog, characterized in that, Includes the following steps: a) Obtaining compound (II) by the method of claim 1; b) Modify the nucleobases of the compound of formula (II), optionally further performing amidation and / or protection and / or deprotection and / or changing the protecting group, to obtain the nucleoside analog shown in formula (III): ； in, R 1 C is an optional replacement 1-10 hydrocarbon group; R 2 and R 3 One of them is -C(=O)OR, and the other is -H; R is C, which can be substituted by any choice. 1-4 alkyl; R 4 C is a hydrogen atom or an optional substituted C 1-10 hydrocarbon group; Each R'' is independently a hydrogen atom or a hydroxyl protecting group; The nucleobase is preferably cytosine, thymine, uracil, or a derivative thereof; G 1 The residue is a nucleobase, preferably any of the following structures: 、 、 、 、 、 ； Preferably, G 1 The sugar unit is linked by an N-glycosidic bond; the N-glycosidic bond is α- or β-type, preferably α-type; G 2 and G 3 Choose from any of the following: Case 1, G 2 and G 3 One of them is -C(=O)OM, and the other is -H; wherein M is a carboxyl protecting group, preferably methyl or benzyl; Case 2, G 2 and G 3 Any one of them is -C(=O)NR a R b The other is -H; where R a and R b Each is independently a hydrogen atom or an optionally substituted C atom. 1-10 hydrocarbon group, or R a R b Together with N, they constitute C 4-7 Nitrogen heterocycle; wherein, -NR a R b Preferably, any of the following structures are used: 、 、 、 、 、 、 、 、 、 、 ； G 4 For R 4 The protected form or the unprotected form; Preferably, the nucleoside analogue represented by formula (III) is More preferably, it is any of the following structures: 、 、 、 、 。 10. The use of the method for synthesizing the nucleoside analogue according to claim 9 in the preparation of a drug, characterized in that, The drug is used to prevent and / or treat at least one disease selected from viral infections, neoplastic diseases, immune system diseases, and bacterial infections; the nucleoside analog obtained by the synthetic method serves as an intermediate, active pharmaceutical ingredient, or prodrug in the preparation of the drug.

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