Synthetic method of morpholino nucleoside medical intermediate

Abstract

The invention is applicable to the technical field of nucleotide synthesis, and provides a synthesis method of a morpholino nucleoside medical intermediate, which has remarkable advantages and meets the industrial production requirements. A highly toxic reducing agent is abandoned, a low-toxicity efficient reagent is selected, the reaction is safe and environment-friendly, and the safety production requirement is met; the synthesis route is simple, conversion from raw materials to target intermediates can be completed only through two-step core reaction, and compared with a multi-step tedious route in the prior art, the steps are greatly simplified, the production period is greatly shortened, and the production efficiency is remarkably improved; a convenient crystallization mode is adopted for purification, complex column chromatography is not needed, the cost is low, and product loss is reduced; the yield and purity of the product are excellent, the yield of the intermediate and the yield of the target product exceed 60%, the HPLC purity is larger than or equal to 98.5%, and the product can be directly used for follow-up synthesis. The used raw materials are commercially available conventional reagents, are easy to obtain and controllable in cost, and the solvent can be recycled, so that the comprehensive production cost is remarkably reduced.

Description

Technical Field

[0001] This invention relates to the field of nucleotide synthesis technology, specifically a method for synthesizing a morpholinonucleotide pharmaceutical intermediate. Background Technology

[0002] Morpholino antisense oligonucleotides (MOs) are a special type of neutral DNA / RNA analogue. Their core structural feature is the replacement of the traditional 5-carbon sugar ring in nucleotides with a morpholine ring, and the phosphate groups are structurally modified to make the entire molecule uncharged. This unique structure endows morpholino antisense oligonucleotides with excellent stability and resistance to degradation, enabling them to maintain activity in vivo for extended periods. By blocking mRNA splicing, they inhibit the function of target genes, thereby achieving the biosynthesis of conditional proteins. They have significant application value in gene function research and gene therapy.

[0003] Morpholino antisense oligonucleotides are mainly synthesized from four morpholino nucleosides: morpholino adenosine (A), thymine (T), guanosine (G), and cytosine (C). Among them, morpholino nucleoside intermediates are the core raw materials for the synthesis of the above oligonucleotides. Their synthesis efficiency, purity, and safety directly determine the quality, production cost, and industrial feasibility of the final drug product.

[0004] Currently reported synthetic routes for morpholine nucleoside pharmaceutical intermediates have significant technical limitations and are difficult to meet the needs of industrial production:

[0005] 1. Synthetic route reported by Surajit Sinha's group: This route has lengthy synthetic steps, complex reaction process, and uses a reduction system that combines acid and sodium cyanoborohydride. The reaction process generates highly toxic byproducts, which poses extremely high operational risks and serious safety hazards. It does not meet the environmental protection and safety requirements of modern industrial production.

[0006] 2. Patent CN 120058705 A discloses a method for synthesizing the pharmaceutical intermediate PMO-G (N2-iBu). The synthetic route uses N2-iBu-G as raw material. Although the process is simplified, sodium cyanoborohydride is still used as a reducing agent, which poses a safety problem of generating highly toxic substances. In addition, the product yield is extremely low, and subsequent purification by column chromatography is required. The operation is cumbersome, the production cost is high, and large-scale production is difficult.

[0007] 3. Other existing routes: These routes generally suffer from problems such as complex selection of protecting groups, poor selectivity, numerous side reactions, and difficulties in product separation and purification, making it difficult to achieve both product purity and yield, which further limits the industrialization and promotion of morpholino antisense oligonucleotides.

[0008] Therefore, developing a method for synthesizing morpholine nucleoside pharmaceutical intermediates that uses readily available raw materials, has a simple synthetic route, is safe to operate, has excellent yield and purity, and is suitable for industrial production has become a technical bottleneck that urgently needs to be solved in this field. Summary of the Invention

[0009] This invention aims to overcome the aforementioned deficiencies of the prior art and provide a method for synthesizing morpholine nucleoside pharmaceutical intermediates. By optimizing the reaction system, screening low-toxicity and high-efficiency reagents, and designing a two-step core reaction process, the method avoids the use of highly toxic reagents, simplifies purification steps, improves product yield and purity, reduces production costs, and meets the needs of large-scale industrial production.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] A method for synthesizing morpholino nucleoside pharmaceutical intermediates includes two core reactions: the synthesis of the first intermediate A2 / B2 and the synthesis of the morpholino nucleoside pharmaceutical intermediate A3 / B3. The specific technical solution is as follows:

[0012] (a) Synthesis of the first intermediate A2 / B2

[0013] Step S1: Morpholinonucleotide precursor A1 or B1 is used as the starting material and dissolved in solvent I. Sodium periodate is added as an oxidant. The mixture is stirred at 20-30℃ for 4-5 hours. The reaction process is monitored by TLC (electrolyte: ethyl acetate / methanol = 8:2). After the starting material spots have completely disappeared, the mixture is filtered to remove insoluble impurities and obtain the first filtrate containing the oxidation product.

[0014] Step S2: Take solvent II (the same reagent as solvent I), add boric acid and ammonia water and stir to dissolve, forming a stable amination reaction system. Cool to -5~0℃ to control the reaction rate and avoid side reactions. Slowly add the first filtrate dropwise to the amination system and keep it at the temperature for 1 hour to allow the oxidation product to fully react with the amination reagent. Then add a reducing agent and continue the reaction at -5~0℃ for 3 hours to achieve reductive amination. Finally, add an acid to adjust the system and keep it at -5~0℃ overnight to crystallize. After filtration, dry under vacuum at 40℃ to obtain a white solid intermediate A2 or B2.

[0015] (II) Synthesis of Morpholinonucleotide Pharmaceutical Intermediate A3 / B3

[0016] Step S3: Dissolve intermediate A2 or B2 in solvent III, add alkali as an acid-binding agent, stir evenly, cool to 10~15℃, slowly add triphenylchloromethane as an amino protecting agent, keep the reaction at this temperature for 2h, monitor the reaction for completeness by TLC (developing solvent: dichloromethane / methanol = 10:1), and obtain a reaction solution containing the protected product.

[0017] Step S4: Add an equal volume of dichloromethane to the reaction solution for dilution, and wash once each with water, saturated sodium bicarbonate solution, and sodium chloride solution to remove water-soluble impurities and excess reagents; after standing and separating the layers, take the organic phase, concentrate it under reduced pressure to 0.5 times the original volume, add ethyl acetate as the crystallization solvent, stir at 25°C for 5 hours to crystallize, filter after the white solid is precipitated, and dry under vacuum at 40°C to obtain morpholine nucleoside pharmaceutical intermediate A3 or B3.

[0018] As a further aspect of the present invention: in step S1, the molar ratio of the morpholine nucleoside precursor to sodium periodate is 1:1.2; the solvent I is selected from one of methanol, tetrahydrofuran, 1,4-dioxane, isopropanol, and ethanol, and the amount of solvent I is 5 times (v / w) the mass of the morpholine nucleoside precursor.

[0019] As a further aspect of the present invention: in step S2, the molar ratio of the morpholine nucleoside precursor (A1 / B1) to boric acid, reducing agent, and acid is 1:1.5:1.0~1.5:1.2; the solvent II is the same reagent as solvent I, and the amount used is 5 times (v / w) the mass of the morpholine nucleoside precursor; the amount of ammonia water used is 0.9m / v.

[0020] As a further aspect of the present invention: in step S2, the reducing agent is selected from one of pyridine borane complex, borane tetrahydrofuran solution, dimethylamine borane complex, and borane dimethyl sulfide complex; the acid is selected from one of sulfuric acid, tartaric acid, hydrochloric acid, acetic acid, and oxalic acid.

[0021] As a further aspect of the present invention: in step S3, the molar ratio of the first intermediate to triphenylchloromethane and the base is 1:1.5:2.0; the solvent III is selected from one of tetrahydrofuran, dichloromethane, ethyl acetate, acetone, and N,N-dimethylformamide, and the amount used is 5 times the mass of the first intermediate (v / w).

[0022] As a further aspect of the present invention: in step S3, the alkali is selected from one of triethylamine, pyridine, 2,6-dimethylpyridine, N,N-diisopropylethylamine, and potassium carbonate.

[0023] As a further aspect of the present invention: in step S4, the amount of dichloromethane used is the same as the amount of solvent III used; the amounts of water, saturated sodium bicarbonate solution, and sodium chloride solution used are all the same as the amount of dichloromethane used; the amount of ethyl acetate used is 5 times (v / w) the mass of the first intermediate.

[0024] As a further aspect of the present invention: the yield of intermediate A2 is ≥61%, the yield of intermediate B2 is ≥65%, the yield of morpholine nucleoside pharmaceutical intermediate A3 is ≥68%, the yield of B3 is ≥71%, and the HPLC purity of all products is ≥98.5%.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] 1. This invention completely eliminates highly toxic reducing agents such as sodium cyanoborohydride and selects low-toxicity and high-efficiency reducing reagents such as pyridine borane complexes. No highly toxic substances are generated during the reaction process, the operational risks are significantly reduced, and it meets the requirements of environmental protection and safe production, providing a safety guarantee for industrial production.

[0027] 2. The synthetic route of this invention is simple, and the conversion from raw materials to target intermediates can be completed through only two core reactions. Compared with the multiple and lengthy routes of the prior art, the steps are greatly simplified, the production cycle is greatly shortened, and the production efficiency is significantly improved.

[0028] 3. The purification process of this invention is convenient. It uses crystallization to purify the product without relying on complex column chromatography operations. It is simple to operate, low in cost, and suitable for large-scale industrial production. At the same time, it avoids product loss during column chromatography.

[0029] 4. This invention has excellent yield and purity. The yield of intermediate A2 is ≥61%, the yield of B2 is ≥65%, the yield of target product A3 is ≥68%, the yield of B3 is ≥71%, and the HPLC purity of all products is ≥98.5%. They can be directly used for the subsequent synthesis of morpholino antisense oligonucleotides without further purification, which effectively reduces the cost and difficulty of subsequent production.

[0030] 5. The raw materials used in this invention are readily available and the cost is controllable. The reagents used, such as sodium periodate, boric acid, triphenylchloromethane, and low-toxicity reducing agents, are all commercially available conventional chemical raw materials that are easy to obtain and inexpensive. The solvents can be recycled and reused, further reducing the overall cost of industrial production. Attached Figure Description

[0031] Figure 1 This is the overall synthetic route diagram for the morpholine nucleoside pharmaceutical intermediates of the present invention;

[0032] Figure 2 This is a route diagram for the synthesis of the morpholino nucleoside precursor into the first intermediate in this invention;

[0033] Figure 3 This is a route diagram for the synthesis of the first intermediate into a morpholinonucleotide pharmaceutical intermediate in this invention;

[0034] Figure 4 This is the HPLC spectrum of A3 in Example 1 of the present invention;

[0035] Figure 5 The nuclear magnetic resonance spectrum of A3 in Embodiment 1 of the present invention;

[0036] Figure 6 This is the HPLC spectrum of B3 in Example 1 of the present invention;

[0037] Figure 7 This is the nuclear magnetic resonance spectrum of B3 in Embodiment 1 of the present invention. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments and accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them, and are not intended to limit the scope of protection of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] Example 1: Synthesis of first intermediate A2 and morpholinonucleotide pharmaceutical intermediate A3

[0040] Please see Figure 1-5 A method for synthesizing a morpholine nucleoside pharmaceutical intermediate, comprising the following steps:

[0041] Step S1, Oxidation reaction: Morpholinonucleotide precursor A1 (50g, 1.0eq) was added to a 500ml three-necked flask (first reaction vessel), followed by ethanol (250ml, 5v / w, solvent I). The mixture was stirred until the starting material was fully dissolved. Then, sodium periodate (34.9g, 1.2eq) was added. The reaction temperature was controlled at 20~30℃, and the mixture was stirred for 4h. The reaction was monitored by TLC (electrolyte: ethyl acetate / methanol = 8:2). After the starting material spots completely disappeared, the mixture was filtered to remove insoluble impurities, yielding the first filtrate.

[0042] Step S2, amination, reduction and crystallization: In a 1L three-necked flask (second reaction vessel), add ethanol (250ml, 5v / w, solvent II), boric acid (12.5g, 1.5eq) and ammonia (45ml, 0.9m / v), stir until completely dissolved, and cool the reaction system to -5~0℃; slowly add the first filtrate obtained in step S1 to the flask, and keep the reaction at this temperature for 1h; then add the pyridineborane complex (10.5g, 1.0eq), and continue the reaction at -5~0℃ for 3h; after the reaction is complete, add oxalic acid (14.6g, 1.2eq) to the system, stir evenly, and keep the system at -5~0℃ overnight to crystallize; filter the next day, and dry the filter cake under vacuum at 40℃ to obtain 29.3g of white solid intermediate A2, with a yield of 61.2% and an HPLC purity of 98.5%.

[0043] Step S3, Protective Reaction: In a 500ml three-necked flask (third reaction vessel), add intermediate A2 (25g, 1.0eq) prepared in Example 1, add N,N-dimethylformamide (125ml, 5v / w, solvent III), and stir to fully dissolve the raw material; add triethylamine (14.3g, 2.0eq), stir evenly, and then cool the reaction system to 10~15℃; slowly add triphenylchloromethane (29.5g, 1.5eq), and maintain the temperature for 2h; monitor by TLC (developing solvent: dichloromethane / methanol = 10:1), and after the raw material spots completely disappear, the reaction solution is obtained;

[0044] Step S4, Post-treatment and Crystallization: Dichloromethane (125 ml, 5 v / w) was added to the above reaction solution for dilution. The solution was washed once each with water (125 ml), saturated sodium bicarbonate solution (125 ml), and sodium chloride solution (125 ml). After standing and separating the layers, the organic phase was collected. The organic phase was concentrated under reduced pressure to 25 ml (0.5 v / w), and ethyl acetate (125 ml, 5 v / w) was added. The solution was stirred at 25 °C for 5 h to crystallize. After the white solid was separated, it was filtered, and the filter cake was dried under vacuum at 40 °C to obtain 28.8 g of morpholine nucleoside pharmaceutical intermediate A3, with a yield of 68.5% and an HPLC purity of 99.0%.

[0045] Example 2: Synthesis of first intermediate B2 and morpholinonucleotide pharmaceutical intermediate B3

[0046] Step S1, Oxidation reaction: Morpholinonucleotide precursor B1 (50g, 1.0eq) was added to a 500ml three-necked flask (first reaction vessel), followed by ethanol (250ml, 5v / w, solvent I). The mixture was stirred until the starting material was fully dissolved. Then, sodium periodate (36.7g, 1.2eq) was added. The reaction temperature was controlled at 20~30℃, and the mixture was stirred for 5h. The reaction was monitored by TLC (electrolyte: ethyl acetate / methanol = 8:2). After the starting material spots completely disappeared, the mixture was filtered to remove insoluble impurities, yielding the first filtrate.

[0047] Step S2, amination, reduction and crystallization: In a 1L three-necked flask (second reaction vessel), add ethanol (250ml, 5v / w, solvent II), boric acid (12.5g, 1.5eq) and ammonia (45ml, 0.9m / v), stir until completely dissolved, and cool the reaction system to -5~0℃; slowly add the first filtrate obtained in step S1 to the flask, and keep the reaction at this temperature for 1h; then add the pyridineborane complex (12.1g, 1.2eq), and continue the reaction at -5~0℃ for 3h; after the reaction is complete, add oxalic acid (14.6g, 1.2eq) to the system, stir evenly, and keep the system at -5~0℃ overnight to crystallize; filter the next day, and dry the filter cake under vacuum at 40℃ to obtain 31.3g of white solid intermediate B2, with a yield of 65.5% and an HPLC purity of 98.8%.

[0048] Step S3, Protective Reaction: Add intermediate B2 (25 g, 1.0 eq) prepared in Example 2 to a 500 ml three-necked flask (third reaction vessel), add N,N-dimethylformamide (125 ml, 5 v / w, solvent III), and stir to fully dissolve the raw materials; add triethylamine (15.1 g, 2.0 eq), stir evenly, and then cool the reaction system to 10-15 °C; slowly add triphenylchloromethane (31.1 g, 1.5 eq), and maintain the temperature for 2 h; monitor by TLC (developing solvent: dichloromethane / methanol = 10:1), and obtain the reaction solution after the raw material spots have completely disappeared;

[0049] Step S4, Post-treatment and Crystallization: Dichloromethane (125 ml, 5 v / w) was added to the above reaction solution for dilution. The solution was washed once each with water (125 ml), saturated sodium bicarbonate solution (125 ml), and sodium chloride solution (125 ml). After standing and separating the layers, the organic phase was collected. The organic phase was concentrated under reduced pressure to 25 ml (0.5 v / w), and ethyl acetate (125 ml, 5 v / w) was added. The solution was stirred at 25 °C for 5 h to crystallize. After the white solid was separated, it was filtered, and the filter cake was dried under vacuum at 40 °C to obtain 30.6 g of morpholine nucleoside pharmaceutical intermediate B3, with a yield of 71.1% and an HPLC purity of 99.2%.

[0050] It is necessary to note that in Examples 1 and 2:

[0051] 1. During the oxidation reaction, sodium periodate needs to be added in batches to avoid excessively high local concentrations that could exacerbate side reactions and affect product yield;

[0052] 2. The temperature of the amination and reduction reactions must be strictly controlled between -5 and 0℃. Too high a temperature will cause the imine intermediate to degrade, while too low a temperature will reduce the reaction rate and prolong the reaction time.

[0053] 3. Triphenylchloromethane is hygroscopic and hydrolyzed, so it must be weighed and used in a dry environment, and the addition process must be slow to avoid a sudden rise in the temperature of the reaction system;

[0054] 4. All solvents must be dehydrated, with the water content controlled below 0.1% to ensure the stability of the reaction system and avoid side reactions caused by moisture;

[0055] 5. The reaction process must be strictly monitored by TLC. Subsequent operations should only be carried out after the raw materials have completely reacted to avoid the impact of raw material residue on product purity.

[0056] 6. During the crystallization process, the stirring rate must be controlled to avoid excessive stirring, which could cause crystal breakage and affect filtration efficiency and product purity.

[0057] Comparative Example 1: Synthesis of Morpholine Nucleoside Pharmaceutical Intermediates using Existing Technology (Refer to Patent CN 120058705 A)

[0058] Using N2-iBu-G as a raw material, a similar structural intermediate was synthesized according to the method disclosed in patent CN 120058705 A. The synthesis route is as follows:

[0059]

[0060] The specific steps are as follows:

[0061] S1. Add 50.3g N2-iBu-G to the reaction vessel, add 750ml methanol and 250ml pure water, stir to dissolve, then add 56g triphenylmethane, 5ml acetic acid and 45g sodium periodate, react at room temperature for 40min, and filter to obtain the first filtrate.

[0062] S2. Cool the first filtrate to 15°C, add 13g of sodium cyanoborohydride, keep the reaction at this temperature for 3 hours, and then continue the reaction at room temperature for 16 hours to obtain the reaction solution.

[0063] S3. Pour the reaction solution into water, filter after the solid precipitates, dissolve the filter cake in dichloromethane, dry the organic phase with sodium sulfate and concentrate to obtain the third white solid;

[0064] S4. The target intermediate was purified by column chromatography (eluting agent: methanol / dichloromethane gradient elution) to obtain 8.9 g, with a yield of 17.7% and an HPLC purity of 98.2%.

[0065] The synthetic route of Comparative Example 1 has the following drawbacks: 1. It uses sodium cyanoborohydride as a reducing agent, which generates highly toxic byproducts during the reaction, resulting in high operational risks; 2. The yield is only 17.7%, far lower than the 68% or more of the present invention; 3. It relies on column chromatography purification, which is complex, costly, and difficult to achieve large-scale industrial production.

[0066] Comparative Example 2: Existing multi-step synthetic route (refer to the report by Surajit Sinha's group)

[0067] The synthetic route for synthesizing the target intermediate using guanosine as the starting material, through five steps including protection, oxidation, amination, reduction, deprotection, and reprotection, is shown below:

[0068] The specific steps are as follows:

[0069] S1, guanosine, reacts with tert-butyldiphenylchlorosilane to achieve hydroxyl protection, yielding intermediate G1 in 75% yield;

[0070] S2 and intermediate G1 are oxidized with sodium periodate, ammonium borate is amination, and sodium cyanoborohydride is reduced to obtain intermediate G2, with a yield of 62%.

[0071] S3 and intermediate G2 react with triphenylchloromethane to achieve amino protection, yielding intermediate G3 in 68% yield;

[0072] S4 and intermediate G3 react with isobutyric anhydride to achieve acylation, yielding intermediate G4 in 70% yield;

[0073] S5 and intermediate G4 were deprotected by tetrabutylammonium fluoride to obtain the target intermediate with a yield of 65%.

[0074] The overall yield of this route is 75%×62%×68%×70%×65%≈13.8%, and it has the following problems: 1. The synthesis steps are lengthy (5 steps), resulting in a long production cycle; 2. Multiple column chromatography purification steps are required, making the operation cumbersome; 3. Sodium cyanoborohydride is used, which has poor safety; 4. The overall yield is only 13.8%, resulting in extremely high production costs.

[0075] This invention achieves the synthesis of morpholine nucleoside pharmaceutical intermediates through a two-step efficient reaction. The process route is simple, safe to operate, and has excellent yield and purity. It does not require complex purification equipment and effectively solves the problems of poor safety, lengthy steps, low yield, and high cost of existing technologies. It is suitable for large-scale industrial production and provides a high-quality raw material guarantee for the industrialization and promotion of morpholine antisense oligonucleotides, which has significant economic value and social significance.

[0076] It should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This way of describing the specification is only for clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a morpholino nucleoside pharmaceutical intermediate, characterized in that, Includes the following steps: S1. Place the morpholinonucleotide precursor in the first reaction vessel, add solvent I, stir thoroughly, then add sodium periodate to the first reaction vessel, stir thoroughly to mix evenly, stir and react at 20~30℃ for 4~5h, filter after the reaction is complete under TLC control, and obtain the first filtrate. S2. Add solvent II, boric acid and ammonia water to the second reaction vessel, stir and dissolve thoroughly, cool to -5~0℃, slowly add the first filtrate, keep the reaction at the temperature for 1 hour, add the reducing agent, keep the reaction at -5~0℃ for 3 hours, add acid, keep the reaction at -5~0℃ overnight to crystallize, filter and dry at 40℃ to obtain the first intermediate. S3. Place the first intermediate in the third reaction vessel, add solvent III and alkali, stir thoroughly, cool to 10~15℃, slowly add triphenylchloromethane, keep the reaction at the temperature for 2 hours, and obtain the reaction solution. S4. Dilute the reaction solution with dichloromethane, wash with water, saturated sodium bicarbonate solution and sodium chloride solution in sequence, separate the organic phase and concentrate it to 0.5 times the original volume, add ethyl acetate, stir at 25°C for 5 hours to crystallize, filter and dry at 40°C to obtain morpholine nucleoside pharmaceutical intermediate.

2. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 1, characterized in that, In step S1, the molar ratio of the morpholinonucleotide precursor to sodium periodate is 1:1.2; the solvent I is selected from one of methanol, tetrahydrofuran, 1,4-dioxane, isopropanol, and ethanol, and the amount of solvent I is 5 times (v / w) the mass of the morpholinonucleotide precursor.

3. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 1, characterized in that, In step S2, the molar ratio of the morpholine nucleoside precursor to boric acid, reducing agent, and acid is 1:1.5:1.0 to 1:1.5:1.2; solvent II is the same reagent as solvent I, and its amount is 5 times (v / w) of the mass of the morpholine nucleoside precursor; the amount of ammonia water is 0.9m / v.

4. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 1, characterized in that, In step S2, the reducing agent is selected from one of pyridine borane complex, borane tetrahydrofuran solution, dimethylamine borane complex, and borane dimethyl sulfide complex; the acid is selected from one of sulfuric acid, tartaric acid, hydrochloric acid, acetic acid, and oxalic acid.

5. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 4, characterized in that, In step S3, the molar ratio of the first intermediate to triphenylchloromethane and the base is 1:1.5:2.0; the solvent III is selected from one of tetrahydrofuran, dichloromethane, ethyl acetate, acetone, and N,N-dimethylformamide, and the amount used is 5 times the mass of the first intermediate (v / w).

6. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 1, characterized in that, In step S3, the base is selected from one of triethylamine, pyridine, 2,6-dimethylpyridine, N,N-diisopropylethylamine, and potassium carbonate.

7. The method for synthesizing the morpholine nucleoside pharmaceutical intermediate according to claim 1, characterized in that, In step S4, the amount of dichloromethane used is the same as the amount of solvent III used; the amounts of water, saturated sodium bicarbonate solution, and sodium chloride solution used are all the same as the amount of dichloromethane used; the amount of ethyl acetate used is 5 times the mass of the first intermediate (v / w).

8. The method for synthesizing morpholine nucleoside pharmaceutical intermediates according to claims 1-7, characterized in that, The yield of the first intermediate was ≥61%, the yield of the morpholine nucleoside pharmaceutical intermediate was ≥68%, and the HPLC purity of all products was ≥98.5%.

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