Synthesis method of 3-O-propargyl nucleoside

Abstract

The invention provides a synthesis method of 3-O-propargyl nucleoside, and belongs to the field of chemical preparation, 1, 2: 5, 6-bis-O-isopropylidene-alpha-D-isofuranose is used as a raw material, firstly propargyl is introduced through SN2 reaction under the action of strong base, and ether bonds are generated; secondly, removing acetonylidene in sequence through multi-step reaction, and generating ester groups at the same time; and finally, carrying out nucleophilic reaction on the basic group subjected to BSA silanization and carbohydrate ring iso-carbon under the action of a catalyst TMSOTf to form the nucleoside derivative. The synthesis method is simple in step, isomers are prevented from being generated, and the purity and quality of the product are improved.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical preparation, specifically to a method for synthesizing 3-O-propynyl nucleoside. Background Technology

[0002] Nucleosides have important biological functions, such as anti-cancer, antiviral, and cholinesterase inhibition; in the past few decades, they have made great contributions to combating a variety of pathogens, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpesvirus, and influenza virus.

[0003] Structural modification of nucleosides can yield a variety of compounds. Taking furanose-ring nucleosides as an example, the anodic carbon effect caused by the epoxide atom of furanose strictly limits the spatial orientation of substituents on the natural nucleoside ring. The introduction of different types of substituents at different positions can significantly change the folding pattern of the five-membered sugar ring. This sensitivity to conformational changes makes the study of furanose ring substituent modification a key entry point for expanding the structure and function of nucleoside compounds. In the process of studying nucleoside compounds, it has been found that the sp hybridization of alkyne genes has unique electronic and structural characteristics, and is often introduced as an active group into the synthesis of nucleoside compounds. For example, the antiviral compound 2'-deoxy-4'-C-ethynylthymidine has been shown to have strong anti-HIV-1 and anti-HIV-2 activity.

[0004] Previous modifications to furanose rings have often focused on the 2' or 4' positions, such as 2'-F, 2'-O-methyl, 4'-cyano, and 4'-methyl. However, there is relatively little research on the structure of nucleoside compounds modified at the 3' position, especially those modified with an alkynyl group at the 3' position. Studying the structure and synthetic methods of nucleosides with modifications at novel sites is of great significance for discovering new nucleoside compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing 3-O-propynyl nucleoside to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for synthesizing 3-O-propynyl nucleoside includes the following steps:

[0008] S1. Compound 1 (1,2:5,6-bis-O-isopropylidene-α-D-isofuranose, commercially available reagent, CAS: 2595-05-3) was dissolved in a dry organic reagent. Under inert gas protection, sodium hydride was added in portions at 0°C. The mixture was stirred at room temperature for 0.5 h, then cooled to 0°C and 3-bromopropyne was slowly added dropwise. The reaction was allowed to proceed to completion at room temperature. The reaction system was then added to ice water, extracted with ethyl acetate, dried and evaporated to dryness, and purified by column chromatography to obtain compound 2. The structural formulas of compounds 1 and 2 are as follows:

[0009]

[0010] S2. Compound 2 was dissolved in formic acid solution and heated until the reaction was complete. The solvent was then evaporated to obtain crude compound 3. Crude compound 3 was dissolved in ethanol, cooled to 0°C, and an aqueous solution of sodium periodate was added. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with ethanol. The filtrate was collected as crude compound 4. The filtrate (crude compound 4) was cooled to 0°C, and sodium borohydride was slowly added in batches. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with ethanol. The filtrate was evaporated to dryness and then purified by column chromatography to obtain compound 5. The structural formulas of compounds 3, 4, and 5 are as follows:

[0011]

[0012] S3. Compound 5 was dissolved in dry pyridine. The system was cooled to 0°C, and benzoyl chloride (B2Cl) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. The reaction system was poured into ice water, and ethyl acetate was added for extraction. The organic phase was washed once with saturated sodium bicarbonate and once with saturated brine. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain crude compound 6. The crude compound 6 was placed in a round-bottom flask, dissolved in acetic acid, and then concentrated sulfuric acid was slowly added dropwise. After stirring at room temperature for 1 hour, acetic anhydride was added, and the reaction was continued until complete. The reaction system was poured into a saturated sodium chloride solution, and ethyl acetate was added for extraction. The organic phase was washed three times with saturated sodium chloride solution and then washed with saturated sodium bicarbonate solution until neutral. The organic phase was dried and evaporated to dryness. The mixture was purified by column chromatography to obtain compound 7. The structural formulas of compounds 6 and 7 are as follows:

[0013]

[0014] S4. Place the base in a round-bottom flask, add dry acetonitrile and N,O-bis(trimethylsilyl)acetamide (BSA) sequentially, react at room temperature for half an hour, then add compound 7, cool the reaction system to 0°C, slowly add trimethylsilyl trifluoromethanesulfonate (TMSOTf), heat until the reaction is complete, pour the reaction system into a saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness to obtain crude compound 8; dissolve crude compound 8 in methanol, slowly add sodium methoxide at room temperature, react completely at room temperature, adjust the system to neutral with dilute hydrochloric acid, mix the sample, and purify by column chromatography to obtain 3-O-propynyl nucleoside. The structural formulas of compound 8 and 3-O-propynyl nucleoside are:

[0015]

[0016] In the structural formulas of compound 8 and 3-O-propynyl nucleoside, Base represents a base.

[0017] Preferably, in step S1, the organic reagent is one of N,N-dimethylformamide or tetrahydrofuran, the mass fraction of sodium hydride is 60%, the molar ratio of compound 1 to sodium hydride is 1:1.2-1:2, the molar ratio of compound 1 to 3-bromopropyne is 1:1.2-1:3, and the eluent used for column chromatography purification is petroleum ether:ethyl acetate in a volume ratio of 3:1-2:1.

[0018] Preferably, in step S2, the molar ratio of compound 2 to sodium periodate is 1:1-1:1.5, the molar ratio of compound 2 to sodium borohydride is 1:2.5-1:4, and the eluent used for column chromatography purification is petroleum ether to ethyl acetate in a volume ratio of 1:1-1:2.

[0019] Preferably, in step S3, the molar ratio of compound 5 to benzoyl chloride is 1:1-1:2, and the eluent used for column chromatography purification is petroleum ether: ethyl acetate in a volume ratio of 6:1-5:1.

[0020] 8. Preferably, in step S4, the base is one of uracil, 5-methyluracil, cytosine, and guanine, and the compounds corresponding to the above bases are 8a, 8b, 8c, and 8d, respectively, and the 3-O-propynyl nucleosides are 3-O-propynyl nucleoside-a, 3-O-propynyl nucleoside-b, 3-O-propynyl nucleoside-c, and 3-O-propynyl nucleoside-d, respectively, with the following structural formulas:

[0021]

[0022] Preferably, in step S4, the molar ratio of base:BSA:compound 7:TMSOTf is (1.2-2):(2-4):1:(1.6-2), and the eluent used for column chromatography purification is dichloromethane:methanol volume ratio = 8:1-6:1.

[0023] In another aspect, this invention discloses the synthesis of 3-O-propynyl nucleoside by the method described in any of the above technical solutions.

[0024] The beneficial effects of the above-mentioned technical solution of the present invention are as follows:

[0025] 1. This invention uses commercially available reagent 1,2:5,6-bis-O-isopropylidene-α-D-isofuranose as a raw material, which simplifies the reaction steps and improves production efficiency; at the same time, it avoids the formation of isomers and improves the purity and quality of the product.

[0026] 2. The synthetic route provided by this invention allows for the replacement of base types to prepare different types of nucleosides. Attached Figure Description

[0027] The above and other objects, features, and advantages of exemplary embodiments of the present invention will become readily apparent upon reading the following detailed description with reference to the accompanying drawings. In the drawings, several embodiments of the invention are illustrated by way of example and not limitation, and like or corresponding reference numerals denote like or corresponding parts, wherein:

[0028] Figure 1 The flowchart of this invention Detailed Implementation

[0029] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0030] Example

[0031] A method for synthesizing 3-O-propynyl nucleoside includes the following steps:

[0032] S1. Dissolve 50 g (192 mmol) of compound 1 in 500 mL of dry organic reagent. Under inert gas protection, cool to 0 °C and add 9.23-15.37 g (230-384 mmol) of 60% sodium hydride in portions. Stir the reaction at room temperature for 0.5 h. Cool to 0 °C and slowly add 27.42-68.56 g (230-576 mmol) of 3-bromopropyne. React at room temperature until complete. Then, add the reaction system to ice water, extract with ethyl acetate, dry the organic phase and evaporate to dryness, and purify by column chromatography with petroleum ether:ethyl acetate volume ratio of 3:1-2:1 to obtain compound 2. The structural formulas of compounds 1 and 2 are as follows:

[0033]

[0034] S2. Dissolve 23g (77mmol) of compound 2 in 75% formic acid solution, react at 55℃ until complete, then evaporate the solvent to obtain crude compound 3; dissolve crude compound 3 in ethanol, cool to 0℃, add 16.47-24.7g (77-115.5mmol) of sodium periodate aqueous solution, after the reaction is complete, filter, wash the filter cake twice with ethanol, collect the filtrate, which is crude compound 4; cool the filtrate (crude compound 4) to 0℃, slowly add 7.28-11.65g (192-308mmol) of sodium borohydride in batches, after the reaction is complete, filter, wash the filter cake twice with ethanol, evaporate the filtrate to dryness, and then purify by column chromatography with petroleum ether:ethyl acetate volume ratio of 1:1-1:2 to obtain compound 5. The structural formulas of compounds 3, 4, and 5 are:

[0035]

[0036] S3. Dissolve 11.4 g (50 mmol) of compound 5 in dry pyridine, cool the system to 0 °C, and slowly add 7.02-14.05 g (50-100 mmol) of benzoyl chloride. After the addition is complete, stir at room temperature until the reaction is complete. Pour the reaction system into ice water, add ethyl acetate for extraction, wash the organic phase once with saturated sodium bicarbonate and once with saturated brine, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness to obtain crude compound 6; take crude compound 6 in a round-bottom flask, add 100 mL of ethyl acetate... The solution was dissolved in acid, and then 0.64 mL of concentrated sulfuric acid was slowly added dropwise. After stirring at room temperature for 1 hour, 11.3 mL of acetic anhydride was added, and the reaction continued until complete. The reaction system was then poured into a saturated sodium chloride solution, and ethyl acetate was added for extraction. The organic phase was washed three times with saturated sodium chloride solution, and then washed with saturated sodium bicarbonate solution until neutral. The organic phase was dried and evaporated to dryness. The solution was purified by column chromatography with petroleum ether:ethyl acetate in a volume ratio of 6:1-5:1 to obtain compound 7. The structural formulas of compounds 6 and 7 are as follows:

[0037]

[0038] S4. Place the base (19-32 mmol) in a round-bottom flask, add dry acetonitrile and 7.8-15.6 mL (32-64 mmol) BSA sequentially, react at room temperature for half an hour, then add 6.2 g (16 mmol) of compound 7, cool the reaction system to 0℃, slowly add 4.7-5.8 mL (26-32 mmol) TMSOTf, heat to 80℃ until the reaction is complete, pour the reaction system into a saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness to obtain crude compound 8; dissolve crude compound 8 in methanol, slowly add 3.1 g (57 mmol) sodium methoxide at room temperature, react completely at room temperature, adjust the system to neutral with dilute hydrochloric acid, mix the sample, purify by column chromatography with dichloromethane:methanol volume ratio of 8:1-6:1, to obtain 3-O-propynyl nucleoside. The structural formulas of compound 8 and 3-O-propynyl nucleoside are:

[0039]

[0040] In the structural formulas of compounds 8 and 3-O-propynyl nucleosides, Base represents a base; in step S4, the base is one of uracil, 5-methyluracil, cytosine, and guanine, and the compounds 8 corresponding to the above bases are 8a, 8b, 8c, and 8d, respectively, and the 3-O-propynyl nucleosides are 3-O-propynyl nucleoside-a, 3-O-propynyl nucleoside-b, 3-O-propynyl nucleoside-c, and 3-O-propynyl nucleoside-d, respectively, with the following structural formulas:

[0041]

[0042] The chemical reaction routes for steps S1 to S4 in this application are shown in equation (1):

[0043]

[0044] In step S1, the hydroxyl group on the 3' carbon of compound 1 is deprotonated under alkaline conditions (NaH) to generate an alkoxy anion. This alkoxy anion acts as a nucleophile, attacking the partially positively charged carbon atom in 3-bromopropyne, resulting in S... NIn reaction 2, Br departs to form an ether bond. This step produces no isomers and has a high yield. In step S2, acetone isomers are removed by mild, weak acid-mediated hydrolysis to obtain 5,6-diol. The 1,2-O-isopropylidene group is relatively stable and does not hydrolyze under weak acid conditions. Compound 3 is then oxidatively cleaved with sodium periodate to obtain compound 4, and compound 4 is reduced with sodium borohydride to form compound 5. In step S3, the hydroxyl group in compound 5 is first protected with benzoyl chloride, followed by hydrolysis under strong acid conditions to remove the remaining acetone isomers, and then esterification with acetic anhydride occurs. In step S4, the base after BSA silanization undergoes a nucleophilic reaction with the anomeric carbon of the sugar ring under the action of the catalyst TMSOTf to form a nucleoside derivative. Subsequently, a weak base salt is used to promote the hydrolysis of the ester group to obtain the target product.

[0045] Example 1

[0046] The synthesis method of 3-O-propynyl nucleoside in the above embodiments is adopted, wherein the base is uracil.

[0047] S1. Dissolve 50 g (192 mmol) of compound 1 in 500 mL of dry N,N-dimethylformamide. Under nitrogen protection, cool to 0 °C and add 9.23 g (230 mmol) of sodium hydride (60% purity) in portions. Stir the reaction at room temperature for 0.5 h. Cool to 0 °C and slowly add 27.42 g (230 mmol) of 3-bromopropyne. React at room temperature until complete (about 4 h). Then add the reaction system to ice water, extract with ethyl acetate, dry the organic phase with sodium sulfate and evaporate to dryness, and purify by column chromatography with petroleum ether:ethyl acetate volume ratio of 3:1 to obtain about 46.4 g of compound 2, yield 81%.

[0048] S2. Dissolve 23g (77mmol) of compound 2 in 75% formic acid solution and react at 55℃ for 1h. After the reaction of the starting material is complete, the solvent is evaporated to obtain crude compound 3. Dissolve crude compound 3 in ethanol, cool to 0℃, and add 20.72g (96.9mmol) of sodium periodate aqueous solution. After the reaction is complete, filter, wash the filter cake twice with ethanol, and collect the filtrate, which is crude compound 4. Cool the filtrate (crude compound 4) to 0℃ and slowly add 9.2g (243mmol) of sodium borohydride in portions. After the reaction is complete, filter, wash the filter cake twice with ethanol, evaporate the filtrate to dryness, and then purify by column chromatography with petroleum ether:ethyl acetate volume ratio of 1:1 to obtain approximately 12.31g of compound 5. The three-step yield is 70%.

[0049] S3. Dissolve 11.4 g (50 mmol) of compound 5 in dry pyridine, cool the system to 0 °C, and slowly add 8.43 g (60 mmol) of benzoyl chloride. After the addition is complete, stir at room temperature for 3 h. After confirming the reaction is complete by TLC, pour the reaction system into ice water, add ethyl acetate for extraction, wash the organic phase once with saturated sodium bicarbonate and once with saturated brine, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness to obtain crude compound 6; take crude compound 6 in a round-bottom flask and add 100 mL Acetic acid was dissolved, and then 0.64 mL of concentrated sulfuric acid was slowly added dropwise. After stirring at room temperature for 1 hour, 11.3 mL of acetic anhydride was added, and the reaction was continued for 3 hours until complete. The reaction system was then poured into a saturated sodium chloride solution, and ethyl acetate was added for extraction. The organic phase was washed three times with saturated sodium chloride solution, and then washed with saturated sodium bicarbonate solution until neutral. The organic phase was dried over sodium sulfate and evaporated to dryness. The solution was purified by column chromatography with petroleum ether:ethyl acetate in a volume ratio of 6:1 to give approximately 14.7 g of compound 7, with a yield of 78%.

[0050] S4. 2.1 g (19 mmol) of uracil was placed in a round-bottom flask, and dry acetonitrile and 9.8 mL (40 mmol) of BSA were added sequentially. The mixture was reacted at room temperature for half an hour, and then 6.2 g (16 mmol) of compound 7 was added. The reaction system was cooled to 0 °C, and 4.9 mL (27 mmol) of TMSOTf was slowly added dropwise. The mixture was heated at 80 °C for 3 h until the reaction was complete. The reaction system was poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude compound 8. The crude compound 8 was dissolved in methanol, and 3.1 g (57 mmol) of sodium methoxide was slowly added at room temperature. The mixture was reacted at room temperature for 0.5 h, and then the system was adjusted to neutral with dilute hydrochloric acid. The mixture was stirred and purified by column chromatography with dichloromethane:methanol in a volume ratio of 7:1 to obtain 3-O-propynyl nucleoside, i.e., 3-O-propynyl nucleoside. The mass of 3-O-propynyl nucleoside was approximately 3.35 g, and the two-step yield was 72%.

[0051] In this embodiment, the 1H NMR analysis data of the prepared 3-O-propynyl nucleoside are as follows:

[0052] δ11.30(brs,1H),7.89(s,1H),5.64(s,1H),5.53(d,1H),5.37(m,2H),4.4 8(m, 1H), 4.17(m, 1H), 4.00(s, 1H), 3.96(m, 2H), 3.78(m, 2H), 2.40(m, 1H).

[0053] Example 2

[0054] The method for synthesizing 3-O-propynyl nucleoside in the above embodiments is adopted, wherein the base is guanine.

[0055] S1. Dissolve 50 g (192 mmol) of compound 1 in 500 mL of dry organic reagent. Under nitrogen protection, cool to 0 °C and add 15.37 g (384 mmol) of sodium hydride (60% purity) in portions. Stir the reaction at room temperature for 0.5 h. Cool to 0 °C and slowly add 68.56 g (576 mmol) of 3-bromopropyne. React at room temperature until complete. Then add the reaction system to ice water, extract with ethyl acetate, dry the organic phase and evaporate to dryness, and purify by column chromatography with petroleum ether:ethyl acetate volume ratio of 2:1 to obtain approximately 50.98 g of compound 2, yield 89%.

[0056] S2. Dissolve 23g (77mmol) of compound 2 in 75% formic acid solution, react at 55℃ until complete, then evaporate the solvent to obtain crude compound 3; dissolve crude compound 3 in ethanol, cool to 0℃, add 24.7g (115.5mmol) of sodium periodate aqueous solution, after the reaction is complete, filter, wash the filter cake twice with ethanol, collect the filtrate, which is crude compound 4; cool the filtrate (crude compound 4) to 0℃, slowly add 11.65g (308mmol) of sodium borohydride in portions, after the reaction is complete, filter, wash the filter cake twice with ethanol, evaporate the filtrate to dryness, and then purify by column chromatography with petroleum ether:ethyl acetate volume ratio = 1:2, to obtain approximately 12.63g of compound 5, with a three-step yield of 72%;

[0057] S3. Dissolve 11.4 g (50 mmol) of compound 5 in dry pyridine, cool the system to 0 °C, and slowly add 14.05 g (100 mmol) of benzoyl chloride. After the addition is complete, stir at room temperature for 3 h. After confirming the reaction is complete by TLC, pour the reaction system into ice water, add ethyl acetate for extraction, wash the organic phase once with saturated sodium bicarbonate and once with saturated brine, dry the organic phase with anhydrous sodium sulfate and evaporate to dryness to obtain crude compound 6; take crude compound 6 in a round-bottom flask and add 100 mL Acetic acid was dissolved, and then 0.64 mL of concentrated sulfuric acid was slowly added dropwise. After stirring at room temperature for 1 hour, 11.3 mL of acetic anhydride was added, and the reaction was continued for 3 hours until complete. The reaction system was then poured into a saturated sodium chloride solution, and ethyl acetate was added for extraction. The organic phase was washed three times with saturated sodium chloride solution, and then washed with saturated sodium bicarbonate solution until neutral. The organic phase was dried over sodium sulfate and evaporated to dryness. The solution was purified by column chromatography with petroleum ether:ethyl acetate in a volume ratio of 5:1 to give approximately 14.95 g of compound 7, with a yield of 79%.

[0058] S4. 4.83 g (32 mmol) of guanine was placed in a round-bottom flask, and dry acetonitrile and 15.7 mL (64 mmol) of BSA were added sequentially. The reaction was carried out at room temperature for half an hour, and then 6.2 g (16 mmol) of compound 7 was added. The reaction system was cooled to 0 °C, and 5.8 mL (32 mmol) of TMSOTf was slowly added dropwise. The reaction was carried out at 80 °C for 3 h until completion. The reaction system was poured into a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude compound 8. The crude compound 8 was dissolved in methanol, and 3.1 g (57 mmol) of sodium methoxide was slowly added at room temperature. The reaction was carried out at room temperature for 0.5 h, and then the system was adjusted to neutral with dilute hydrochloric acid. The sample was stirred and purified by column chromatography with dichloromethane:methanol volume ratio of 6:1 as the eluent to obtain 3-O-propynyl nucleoside, i.e., 3-O-propynyl nucleoside. The mass of 3-O-propynyl nucleoside was about 3.85 g, and the two-step yield was 73%.

[0059] Comparative Example 1

[0060] 39 g (160 mmol) of uridine (compound 1) was dissolved in 500 mL of N,N-dimethylformamide. Under nitrogen protection, the mixture was cooled to 0 °C and then successively added 7.7 g (192 mmol) of sodium hydride (60% purity), 31.6 g (85.5 mmol) of tetrabutylammonium iodide (TBAI), and 22.8 g (192 mmol) of 3-bromopropyne. The reaction was allowed to proceed to completion at room temperature. After the reaction was complete, the reaction system was added to ice water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The mixture was purified by column chromatography with dichloromethane:methanol (v / v) at a ratio of 6:1 to obtain 28.5 g of a white solid mixture of 2-O-propyneuridine (compound 2) and 3-O-propyneuridine (compound 3), with an overall yield of 63%.

[0061] The chemical reaction technical route is shown in equation (2):

[0062]

[0063] The comparative example has a simple synthesis procedure, but the synthesized nucleoside compound is a mixture of two isomers, which makes the subsequent separation steps complicated; moreover, the starting materials limit the type of base, and other types of nucleoside compounds cannot be synthesized.

[0064] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Any other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention, as long as they do not depart from the spirit and scope of the technical solutions of the present invention, should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing 3-O-propynyl nucleoside, characterized in that, The synthesis method includes the following steps: S1. Compound 1 (1,2:5,6-bis-O-isopropylidene-α-D-isofuranose) was dissolved in a dry organic reagent. Under inert gas protection, sodium hydride was added in portions at 0°C. The mixture was stirred at room temperature for 0.5 h, then cooled to 0°C and 3-bromopropyne was slowly added dropwise. The reaction was allowed to proceed to completion at room temperature. The reaction system was then added to ice water, extracted with ethyl acetate, dried and evaporated to dryness, and purified by column chromatography to obtain compound 2. The structural formulas of compounds 1 and 2 are as follows: S2. Compound 2 was dissolved in formic acid solution and heated until the reaction was complete. The solvent was then evaporated to obtain crude compound 3. Crude compound 3 was dissolved in ethanol, cooled to 0°C, and an aqueous solution of sodium periodate was added. After the reaction was complete, the mixture was filtered, the filter cake was washed, and the filtrate was collected, which was crude compound 4. The filtrate (crude compound 4) was cooled to 0°C, and sodium borohydride was slowly added in portions. After the reaction was complete, the mixture was filtered, the filter cake was washed, and the filtrate was evaporated to dryness. The filtrate was then purified by column chromatography to obtain compound 5. The structural formulas of compounds 3, 4, and 5 are as follows: S3. Compound 5 was dissolved in dry pyridine. The system was cooled to 0°C, and benzoyl chloride was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. The reaction system was poured into ice water, extracted with ethyl acetate, washed, dried, and the organic phase was evaporated to dryness to obtain crude compound 6. The crude compound 6 was placed in a round-bottom flask, dissolved in acetic acid, and then concentrated sulfuric acid was slowly added dropwise. After stirring at room temperature for 1 hour, acetic anhydride was added, and the reaction was continued until complete. The reaction system was poured into a saturated sodium chloride solution, extracted with ethyl acetate, washed with the organic phase until neutral, dried, and purified by column chromatography to obtain compound 7. The structural formulas of compounds 6 and 7 are as follows: S4. Place the base in a round-bottom flask, add dry acetonitrile and N,O-bis(trimethylsilyl)acetamide (BSA) sequentially, react at room temperature, then add compound 7, cool the reaction system to 0°C, slowly add trimethylsilyl trifluoromethanesulfonate (TMSOTf), heat until the reaction is complete, pour the reaction system into a saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase and evaporate to dryness to obtain crude compound 8; dissolve crude compound 8 in methanol, slowly add sodium methoxide at room temperature, react completely at room temperature, adjust the system to neutral with dilute hydrochloric acid, mix the sample, and purify by column chromatography to obtain 3-O-propynyl nucleoside. The structural formulas of compound 8 and 3-O-propynyl nucleoside are: In the structural formulas of compound 8 and 3-O-propynyl nucleoside, Base represents a base.

2. The method for synthesizing a 3-O-propynyl nucleoside according to claim 1, characterized in that, In step S1, the organic reagent is one of N,N-dimethylformamide or tetrahydrofuran, the mass fraction of sodium hydride is 60%, the molar ratio of compound 1 to sodium hydride is 1:1.2-1:2, and the molar ratio of compound 1 to 3-bromopropyne is 1:1.2-1:

3.

3. The method for synthesizing 3-O-propynyl nucleoside according to claim 1, characterized in that, In step S2, the molar ratio of compound 2 to sodium periodate is 1:1 to 1:1.5, and the molar ratio of compound 2 to sodium borohydride is 1:2.5 to 1:

4.

4. The method for synthesizing a 3-O-propynyl nucleoside according to claim 1, characterized in that, In step S3, the molar ratio of compound 5 to benzoyl chloride is 1:1 to 1:

2.

5. The method for synthesizing a 3-O-propynyl nucleoside according to claim 1, characterized in that, In step S4, the base is one of uracil, 5-methyluracil, cytosine, and guanine, and the compounds corresponding to the above bases are 8a, 8b, 8c, and 8d, respectively. The 3-O-propynyl nucleosides are 3-O-propynyl nucleoside-a, 3-O-propynyl nucleoside-b, 3-O-propynyl nucleoside-c, and 3-O-propynyl nucleoside-d, with the following structural formulas:

6. The method for synthesizing a 3-O-propynyl nucleoside according to claim 1, characterized in that, In step S4, the molar ratio of base:BSA:compound 7:TMSOTf is (1.2-2):(2-4):1:(1.6-2).

7. The 3-O-propynyl nucleoside synthesized by the method for synthesizing a 3-O-propynyl nucleoside according to any one of claims 1-6.

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