Synthesis method of 4 '-thiosugar

Abstract

The invention particularly relates to 4 '-thiosugar and a preparation method thereof. The preparation method comprises the following steps: taking D-ribose as a raw material, firstly carrying out methylation protection on C1-site hydroxyl, and then carrying out benzylation protection on other hydroxyl; the preparation method comprises the following steps: firstly, carrying out hydrolysis on a glucosidic bond at a C1 site, carrying out reduction through hydroboron to obtain open-loop ribitol (formula V), carrying out sulfonic acid esterification and bromination substitution on hydroxyl of the ribitol, forming a sulfur bridge bond by taking sodium sulfide as a nucleophilic reagent to obtain benzyl-protected thiosugar, oxidizing a thioether bond into sulfoxide, rearranging to obtain acetoxy thioether, and carrying out debenzylation reaction and hydroxybenzoylation reaction to obtain the high-purity acetoxy thioether. According to the present invention, the multi-step intermediate reaction only needs simple purification, the key intermediate can be obtained through recrystallization, the method is simple, the yield is high, the amplification production is convenient, and the obtained 4 '-thiosugar as the basic sugar can participate in the reaction with a variety of basic groups to form the sulfur-containing nucleoside so as to provide the good foundation for the subsequent drug development or activity screening.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing 4'-sugars. Background Technology

[0002] D-ribose is a core component of RNA in living organisms and a key precursor for nucleotide and ATP energy metabolism. It plays a crucial role in cardiac and skeletal muscle metabolism, promoting energy recovery in ischemic and hypoxic tissues. Furthermore, D-ribose is a key intermediate in nucleic acid drug development and is widely used in the synthesis of antiviral drugs (such as triazole nucleoside), antitumor drugs (such as fluoroadenosine nucleoside), and immunomodulatory drugs (such as adenosyldanine).

[0003] By modifying the structure of D-ribose and replacing the oxygen atom in the furanose ring with a sulfur atom (4'-thioribose), its drug-like properties can be significantly improved. Firstly, this manifests as enhanced metabolic stability, significantly increased resistance of the thioglycosidic bond to nucleases, and prolonged drug half-life. Secondly, bioactivity is optimized; the introduction of the sulfur atom enhances the drug's binding affinity to its target. For example, antiviral drugs such as emtricitabine and lamivudine, as 4'-thionucleoside analogs, are widely used in HIV treatment. In antitumor applications, thiobase analogs such as 6-thioguanine, by interfering with DNA synthesis, are used to treat leukemia and solid tumors.

[0004] Despite the excellent biological properties exhibited by 4'-thioribose, its industrial synthesis still faces the following challenges:

[0005] Stereoselectivity control: The sulfur atom is larger than the oxygen atom, leading to conformational changes in the sugar ring. Precise control of the α / β configuration of the thioglycoside bond is required to obtain the active product. The efficiency of sulfur source introduction is low, and traditional methods (such as Lawesson's reagent or P4S10) result in numerous side reactions, necessitating the development of highly selective thioreagents. Existing literature on the synthesis of sulphose generally presents long, complex, and low-yield routes. The synthesis of key intermediates in some routes is not yet mature, and these intermediates are prone to degradation during synthesis, exhibiting poor reproducibility and unsuitability for scale-up synthesis. Summary of the Invention

[0006] To address the difficulty in synthesizing 4'-thioribose, this invention proposes a method for synthesizing 4'-thioribose with high yield and high efficiency.

[0007] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0008] A method for synthesizing 4'-sulfurose includes the following steps:

[0009] S1: D-ribose is dissolved in methanol (solvent and reactant) in the presence of an acid catalyst and undergoes a glycosylation reaction with methanol to obtain compound I, methyl-D-riboside.

[0010] After preliminary purification through neutralization, filtration, and concentration, it is used in the next reaction step.

[0011] Specifically, NaHCO3 is added to neutralize the acid catalyst, and the pH is adjusted to approximately 7 to terminate the reaction and prevent product decomposition. The product is then filtered, concentrated under reduced pressure, and the crude product is used directly in the next reaction step.

[0012] The compound of formula I was dissolved in an aprotic polar organic solvent, and the hydroxyl groups of the compound of formula I were activated by adding a basic reagent. The compound of formula II was obtained by adding a benzylating reagent.

[0013] A basic reagent removes the proton from the hydroxyl group, generating a nucleophilic alkoxide anion (-O). - ), promotes benzylation.

[0014] After extraction, dilution, washing with water and salt, drying and concentration, the solution is used for the next reaction.

[0015] Specifically, the reaction is quenched with ice water to decompose the basic reagent; extraction and purification are performed, followed by dilution with ethyl acetate, washing with water and brine, drying of the organic layer (using MgSO4), and concentration to obtain the crude product. Compounds of Formula I and II are then used in the next reaction after simple purification.

[0016] S2: The resulting compound of formula II is hydrolyzed in a mixed solution of acid and water (acid hydrolysis / deprotection reaction) to remove the protection of the C1 hydroxyl group in the compound; preliminary purification is performed, followed by concentration under reduced pressure and column chromatography (petroleum ether: ethyl acetate, ...

[0017] The compound of target formula III was obtained from 10 / 1 to 5 / 1, with an overall yield of 78-90% in the three-step reaction.

[0018] The compound of formula III was dissolved in methanol (the solvent also serves as a hydrogen source, providing protons to promote the reduction of NaBH4), and a borohydride reducing agent (a mild reducing agent) was added to reduce the glycosidic anomeric carbon of the compound of formula III, resulting in a ring-opening reaction to give the sugar alcohol derivative, namely the compound of formula IV. After purification by removing the solvent, dissolving, washing, drying, and concentrating, the compound was used for the next reaction.

[0019] Specifically, methanol is removed by vacuum distillation, the residue is dissolved in ethyl acetate, washed with water and brine, dried with MgSO4, and concentrated to obtain the crude product, which can usually be used directly in the next reaction.

[0020] S3: Dissolve the compound of formula IV in an organic solvent, add an alkalizing agent, and then add a hydroxyl activator to activate the hydroxyl group in formula IV to obtain a compound of formula V. The alkalizing agent is used to capture the acid generated in the hydroxyl activation reaction and promote the activation of the hydroxyl group to the right. After washing, drying and concentrating, it is used for the next step of the reaction.

[0021] Specifically, the reaction was terminated with ice water, and the post-treatment included washing the organic layer sequentially with water, saturated NaHCO3, and brine, drying with anhydrous MgSO4, concentrating under reduced pressure, and using the crude product of formula V for the next step of the reaction.

[0022] The compound of formula V was dehydrated to prevent LiBr from hydrolyzing and becoming ineffective, and then dissolved in aprotic polar organic solvent I. Lithium bromide was added and refluxed to undergo a substitution reaction to give 1,3,4-oxo-benzyl-2,5-dibromopentane, with the chemical structure shown in formula VI. After neutralization, drying and concentration, it was used for the next reaction.

[0023] Specifically, the post-treatment involves neutralizing potential acidic byproducts (such as HBr) with NaHCO3; drying and low-temperature concentration to avoid benzyl deprotection; the crude product of formula VI can be directly used for the next cyclization reaction.

[0024] S4: The compound of formula VI is dissolved in an organic solvent with sodium sulfide or its hydrate, and heated to undergo a bimolecular nucleophilic substitution reaction, in which two bromine atoms (-Br) are replaced with sulfur atoms (-S-) to form a sulfur bridge bond, yielding a cyclic thioether compound with the structure shown in formula VII; after preliminary purification after the reaction, the compound of formula VII is obtained by column chromatography and used in the next step of the reaction.

[0025] The reaction residue was dissolved in ethyl acetate, the organic phase was washed with water and brine, dried with magnesium sulfate, concentrated under vacuum, and column chromatography (petroleum ether: ethyl acetate, 100 / 1-30 / 1) was used to obtain the compound with the structure of formula VII, which was used in the next step of the reaction. The overall yield of the four-step reaction was 70-76%.

[0026] The compound of formula VII was dissolved in an organic solvent, and an oxidant was added under low temperature conditions to react with the mixture, oxidizing the thioether bond in formula VII to sulfoxide. The structure of the resulting compound is shown in formula VIII. Low temperature conditions are conducive to the formation of sulfoxide and avoid excessive oxidation to sulfone. The organic layer of the product was washed with saturated NaHCO3 solution, dried with anhydrous MgSO4, concentrated under reduced pressure, and the structure is shown in formula VIII. The crude product was directly used in the next step of the reaction.

[0027] S5: Dissolve the compound of formula VIII in acetic anhydride, stir the reaction, activate the sulfoxide molecules and rearrange to generate acetoxy sulfide compounds. After preliminary purification of the product, the compound with the structure of formula IX is obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1).

[0028] Specifically, after the reaction, the product was purified: the product was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and then washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, concentrated, and obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1) with an overall yield of 70%-75%.

[0029] S6: After purifying the compound of formula IX, dissolve it in an organic solvent, cool it, add a debenzylidene reagent to react, and after preliminary purification, use it for the next reaction.

[0030] The preliminary purification process is as follows: after the reaction is complete, the reaction system is quenched in crushed ice, extracted with dichloromethane, dried with anhydrous magnesium sulfate, evaporated to dryness, and passed through a column to obtain a white solid. The yield of the two steps is about 80-85%.

[0031] Add hydroxybenzoylation reagent and react at room temperature; after the reaction is complete, purify (pour into water, extract with dichloromethane, dry the organic phase with anhydrous magnesium sulfate, and evaporate to dryness), and perform column chromatography (petroleum ether / ethyl acetate = 10:1-5:1) to obtain the target compound with the structure shown in Formula X. The two-step yield is about 80%-86%.

[0032] The reaction process is as follows:

[0033]

[0034] Further, in step S1, the acid catalyst is sulfuric acid or hydrochloric acid; the concentration of D-ribose in methanol is 0.3-0.5 mmol / mL; the molar ratio of D-ribose to acid is 10-25:1; and the glycosylation reaction conditions are 0-5℃ and 9-15 h.

[0035] The alkaline reagent is sodium hydride or potassium tert-butoxide; the reaction temperature after adding the alkaline reagent is 0-5℃ until hydrogen production stops; the benzylating reagent is benzyl bromide, benzyl chloride, or benzyl trichloroacetylimine ester; the reaction temperature after adding the benzylating reagent is room temperature (20-40℃) and the reaction time is 3-7h.

[0036] Further, in step S1, the organic solvent used to dissolve the compound of formula I is DMF, acetonitrile, or tetrahydrofuran, the concentration of the compound of formula I in the organic solvent is 0.20-0.3 mmol / mL, the molar ratio of the compound of formula I to the basic reagent and the benzylating reagent is 1:2-4:3-4, the reaction temperature is room temperature, and the reaction time is 3-6 h.

[0037] Further, the acid in step S2 is formic acid, acetic acid, hydrochloric acid, or trifluoroacetic acid; the concentration of formic acid, acetic acid, or trifluoroacetic acid in the mixed solution is 60-80 wt%, and the concentration of hydrochloric acid in the mixed solution is 0.1-0.2 wt%; the concentration of the compound of formula II in the mixed solution of water and acid is 0.4-0.6 mmol / mL, and the reaction conditions after adding acid are 50-70℃ for 16-20 h; after preliminary purification after the reaction, the compound of formula II is obtained by column chromatography for the next reaction; the borohydride reducing agent is one or more combinations of sodium borohydride, potassium borohydride, and lithium borohydride; the molar ratio of the compound of formula III to the borohydride reducing agent is (0.3-0.7):1, and the reaction conditions after adding borohydride are 0.8-1.5 h at room temperature.

[0038] Further, in step S3, the organic solvent is any one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, and dioxane; the alkalizing agent is triethylamine or N,N-diisopropylethylamine; the hydroxyl activator is methanesulfonyl chloride or p-toluenesulfonyl chloride; the concentration of the compound of formula IV in the organic solvent is 0.15-0.25 mmol / mL, the molar ratio of the compound of formula IV to the alkalizing agent and the hydroxyl activator is 1:3.5-4.5:2.5-3.5, the reaction temperature is 0-5℃, and the time is 20-40 min; the aprotic polar organic solvent I is 2-butanone, tetrahydrofuran, acetonitrile, or acetone; the molar ratio of the compound of formula V to lithium bromide is 1:8-12; the concentration of the compound of formula V in organic solvent I is 0.25-0.4 mmol / mL, and the reaction is carried out under reflux for 14-18 h.

[0039] Further, in step S4, the organic solvent is one or more of DMF, dioxane, acetonitrile, and tetrahydrofuran, the molar ratio of the compound of formula VI to sodium sulfide or its hydrate is 0.6-1:1, the concentration of the compound of formula VI in the organic solvent is 0.25-0.35 mmol / L, the reaction conditions are 80-120℃, and the time is 20-40 min.

[0040] Further, in step S4, the organic solvent is any one of dichloromethane, tetrahydrofuran, acetonitrile, and dioxane; the oxidant is m-CPBA; the molar ratio of the compound of formula VII to the oxidant is 0.8-1.0:1; the reaction conditions are 0℃-5℃ and the time is 40-80 min.

[0041] Furthermore, in step S5, the concentration of compound VIII in acetic anhydride is 0.12-0.2 mmol / mL, the reaction temperature is 90-110℃, and the reaction time is 2-4 h.

[0042] Further, in step S6, the organic solvent is dichloromethane, the debenzylidene reagent is BBr3, BCl3, or TMSI (trimethyliodosilane); the hydroxybenzoylating reagent is benzoyl chloride or benzoic anhydride; the molar ratio of the debenzylidene reagent, the hydroxybenzoylating reagent, and the compound of formula X is 6-7:2-2.5:1; the reaction temperature after adding the debenzylidene reagent is 0℃-5℃, and the reaction time is 50-70 min; the reaction conditions after adding the benzoylating reagent are 8-14 h at room temperature.

[0043] Further, the 4'-sulfurose synthesized by any of the methods described herein.

[0044] This invention first protects the C1-position hydroxyl group by methylation, then protects the remaining hydroxyl groups by benzylation; next, the glycosidic bond at the C1 position is hydrolyzed and reduced by borohydride to obtain an open-ring ribitol (formula V), then its hydroxyl group is sulfonated and brominated, using sodium sulfide as a nucleophile to form a sulfide bridge, to obtain a benzyl-protected sulphose, then the thioether bond is oxidized to sulfoxide, rearranged to obtain acetoxythioether, and then subjected to debenzylation and hydroxybenzoylation to obtain the 4'-sulphose product as shown in formula X.

[0045] The beneficial effects of this invention are:

[0046] 1. This invention provides a method for synthesizing 4'-sulfurose, using D-ribose as a raw material, optimizing the synthetic route, reducing the complexity of the reaction, and improving the yield of the target 4'-sulfurose product (structure as shown in Formula VII). The new route is easy to operate, the reaction conditions are mild, and the multi-step intermediate reactions only require simple purification. The key intermediates can be obtained by recrystallization. The operation is convenient, easier to scale up, and improves the yield.

[0047] 2. The 4'-sulfosugar synthesized in this invention can be used as a basic sugar to react with various bases to form sulfur-containing nucleosides. Subsequent modification of the nucleosides can form a wide variety of nucleoside compounds, greatly enriching the nucleoside compound class and providing a good foundation for subsequent drug development or activity screening. Attached Figure Description

[0048] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0049] Figure 1 This is a schematic diagram of the synthesis route of the present invention. Detailed Implementation

[0050] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. 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.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing 4'-sugar, and the preparation steps are as follows:

[0053] Experimental route

[0054]

[0055] Experimental process

[0056] 1) Synthetic method of compound I

[0057] D-ribose (15.0 g, 100 mmol) was dissolved in methanol (250 ml). The solution was cooled to 0 °C, and sulfuric acid (0.27 ml, 5 mmol) was slowly added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, sodium bicarbonate was added to terminate the reaction, and the pH of the reaction system was adjusted to approximately 7. The reaction mixture was filtered, concentrated under reduced pressure, and used directly in the next reaction without further purification.

[0058] 2) Synthetic method of compounds of formula II

[0059] The crude product of formula I (100 mmol) was dissolved in DMF (400 mL), cooled to 0 °C, and then sodium hydride (350 mmol, 8.40 g, 60% purity) was slowly added. After hydrogen production ceased, benzyl bromide (350 mmol, 41.6 mL) was slowly added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, ice was added to terminate the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (magnesium sulfate), concentrated under vacuum, and used directly without further purification.

[0060] 3) Synthetic methods of compounds of formula III

[0061] The crude product of Formula II (100 mmol) was dissolved in formic acid (200 mL) and water (50 mL) and stirred at 60 °C for 18 hours. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated NaHCO3 solution, dried over magnesium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1) to give the target compound (36.2 g, 86.2 mL, overall yield of 86%).

[0062] 4) Synthetic methods for compounds of formula IV

[0063] Compound III (21.5 mmol) was dissolved in methanol (110 mL), and sodium borohydride (43 mmol, 1.63 g) was added in portions at 0 °C over 30 minutes. After stirring at room temperature for 1 hour, the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated under vacuum. It was used directly in the next step without further purification.

[0064] 5) Synthetic methods of compounds of formula V

[0065] The crude compound of formula IV (21.5 mmol) was dissolved in dichloromethane (110 mL), and then triethylamine (86 mmol, 12.0 mL) was added. Methanesulfonyl chloride (64.5 mmol, 5.0 mL) was slowly added at 0 °C, and the reaction was stirred for 30 minutes. The reaction was then terminated by adding ice. The organic layer was washed with water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, concentrated under reduced pressure, and used directly in the next step without further purification.

[0066] 6) Synthetic methods of compounds of formula VI

[0067] The crude compound of formula V (38.4 mmol) was co-evaporated with toluene to remove trace amounts of water and dissolved in dried 2-butanone (130 ml). Lithium bromide (384 mmol, 33.4 g) was added, and the reaction was carried out under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under vacuum, and used directly in the next step of the reaction without further purification.

[0068] 7) Synthetic methods of compounds of formula VII

[0069] The crude compound of formula VII (38.4 mmol, 21 g) and sodium sulfide nonahydrate (46.1 mmol, 11.1 g) were dissolved in DMF (130 ml). The reaction mixture was stirred at 100 °C for 30 min. The residue was dissolved in ethyl acetate, the organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum. Column chromatography (petroleum ether: ethyl acetate, 100 / 1-30 / 1) gave the target compound of formula VII (28.03 mmol, 12.2 g, 73% overall yield over four steps). The HNMR (400MHz, CDCl3) values ​​of the target compound in Formula VII are as follows: δ: 7.59–7.13 (m, 15H), 4.64–4.38 (m, 6H), 3.99 (ddd, J = 6.9, 5.4, 3.4Hz, 1H), 3.93 (dd, J = 4.8, 3.5Hz, 1H), 3.67 (td, J = 6.6, 4.6Hz, 1H), 3.45 (AB, J = 10.0, 6.5Hz, 2H), 3.00 (AB, J = 10.7, 6.8Hz, 1H), 2.84 (AB, J = 10.7, 5.4Hz, 1H).

[0070] 8) Synthesis method of compounds of formula IX

[0071] The compound of formula VIII (15.7 mmol, 6.61 g) was dissolved in dichloromethane (100 mL), and m-CPBA (17.3 mmol, 3.00 g) of m-chloroperoxybenzoic acid was added at 0 °C. The reaction mixture was stirred for 1 hour. The reaction was quenched by adding saturated Na₂S₂O₃ solution, and the organic layer was washed with saturated NaHCO₃ solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and used directly in the next step without further purification.

[0072] 9) Synthetic method of compound X

[0073] The crude product of compound IX (15.7 mmol) was dissolved in acetic anhydride (100 mL) and stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, the organic phase was dried over anhydrous magnesium sulfate, concentrated, and the target compound (11.3 mmol, 5.4 g, overall yield of 72%) was obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1). NMR(400MHz, CDCl3)δ:7.44–7.14(m,15H),6.21(d,J=4.7Hz,1H),5.97(d,J=2.0Hz),4.78–4 .39(m,6H,CH2Bn),4.11(dd,J=4.1,2.2Hz,1H),4.07(dd,J=3.5,2.0Hz,1H),4.05–4.00(m,1 H),3.98(dd,J=8.4,3.5Hz,1H),3.88–3.82(m,1H),3.81–3.72(m,2H),3.59(AB,J=9.8,6.9H z, 1H), 3.39 (AB, J = 10.0, 5.4Hz, 1H), 3.31 (AB, J = 10.0, 7.7Hz, 1H), 2.12 (s, 3H), 2.02 (s, 3H).

[0074] 10) Synthetic method of compounds of formula XI

[0075] Compound X (10.8 g, 22.6 mmol) was dissolved in dry dichloromethane, cooled to 0 °C, and 150 mL of 1 mol / L BBr3-CH2Cl2 solution was slowly added dropwise. The reaction was carried out at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was quenched in crushed ice, extracted with dichloromethane, and dried to dryness. The residue was dissolved in dry pyridine, and 39.6 mL of benzoyl chloride (50.85 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, evaporated to dryness, and column chromatography was performed to give a white solid. The two-step yield was approximately 83%.

[0076] Example 2

[0077] This embodiment provides a method for synthesizing 4'-sugar, and the preparation steps are as follows:

[0078] Experimental route

[0079]

[0080] Experimental process

[0081] 1) Synthetic method of compound I

[0082] D-ribose (15.0 g, 100 mmol) was dissolved in methanol (350 ml). The solution was cooled to 5°C, and hydrochloric acid (1.06 ml, 30 wt%, 10 mmol) was slowly added. The reaction mixture was stirred at 5°C for 9 hours. After the reaction was complete, sodium bicarbonate was added to terminate the reaction, and the pH of the reaction system was adjusted to approximately 7. The reaction mixture was filtered, concentrated under reduced pressure, and used directly in the next reaction without further purification.

[0083] 2) Synthetic method of compounds of formula II

[0084] The crude product of Formula I (100 mmol) was dissolved in acetonitrile (350 mL), cooled to 0 °C, and then sodium hydride (350 mmol, 8.40 g, 60% purity) was slowly added. Once hydrogen production ceased, benzyl chloride (400 mmol, 46.0 mL) was slowly added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, ice was added to terminate the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (magnesium sulfate), concentrated under vacuum, and used directly without further purification.

[0085] 3) Synthetic methods of compounds of formula III

[0086] The crude product of Formula II (100 mmol) was dissolved in trifluoroacetic acid (150 mL) and water (100 mL) and stirred at 70 °C for 16 hours. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated NaHCO3 solution, dried over magnesium sulfate, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1) to give the target Formula III compound (37.75 g, 89.9 mL, 90% overall yield in three steps).

[0087] 4) Synthetic methods for compounds of formula IV

[0088] Compound III (21.5 mmol) was dissolved in methanol (100 mL), and then lithium borohydride (30.7 mmol, 0.67 g) was added in portions at 0 °C over 30 minutes. The reaction was stirred at room temperature for 50 min, and then the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated under vacuum. It was used directly in the next step without further purification.

[0089] 5) Synthetic methods of compounds of formula V

[0090] The crude compound of formula IV (21.5 mmol) was dissolved in dioxane (100 mL), followed by the addition of N,N-diisopropylethylamine (96.8 mmol, 16.8 mL). p-Toluenesulfonyl chloride (53.8 mmol, 10.26 g dissolved in 20 mL of dioxane) was slowly added at 5 °C. After stirring for 20 minutes, the reaction was terminated by adding ice. The organic layer was washed with water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, concentrated under reduced pressure, and used directly in the next step without further purification.

[0091] 6) Synthetic methods of compounds of formula VI

[0092] The crude compound of formula V (38.4 mmol) was co-evaporated with toluene to remove trace amounts of water and dissolved in dry tetrahydrofuran (150 mL). Lithium bromide (460 mmol, 40.0 g) was added, and the reaction was carried out under reflux for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under vacuum, and used directly in the next reaction without further purification.

[0093] 7) Synthetic methods of compounds of formula VII

[0094] The crude compound of formula VII (38.4 mmol) and sodium sulfide nonahydrate (38.4 mmol, 9.22 g) were dissolved in acetonitrile (150 mL). The reaction mixture was stirred at 120 °C for 20 min. The residue was dissolved in ethyl acetate, the organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum. Column chromatography (petroleum ether: ethyl acetate, 100 / 1-30 / 1) gave the target compound (29.14 mmol, 12.6 g, 76% overall yield across four steps).

[0095] 8) Synthesis method of compounds of formula IX

[0096] The compound of formula VIII (15.7 mmol, 6.61 g) was dissolved in acetonitrile (100 mL), and m-CPBA (15.7 mmol, 2.71 g) of m-chloroperoxybenzoic acid was added at 0 °C. The reaction mixture was stirred for 50 min. The reaction was quenched by adding saturated Na₂S₂O₃ solution, and the organic layer was washed with saturated NaHCO₃ solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and used directly in the next step without further purification.

[0097] 9) Synthetic method of compound X

[0098] The crude product of compound IX (15.7 mmol) was dissolved in acetic anhydride (130 mL) and stirred at 110 °C for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, the organic phase was dried over anhydrous magnesium sulfate, concentrated, and the target compound (11.78 mmol, 5.6 g, overall yield of 75%) was obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1).

[0099] 10) Synthetic method of compounds of formula XI

[0100] Compound X (10.8 g, 22.6 mmol) was dissolved in dry acetonitrile, cooled to 0 °C, and 158 mL of 1 mol / L TMSI acetonitrile solution was slowly added dropwise. The reaction was carried out at 3 °C for 70 min. After the reaction was complete, the reaction mixture was quenched in crushed ice, extracted with dichloromethane, and dried to dryness. The residue was dissolved in dry pyridine, and 39.6 mL of benzoyl chloride (56.5 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, evaporated to dryness, and column chromatography was performed to give a white solid. The two-step yield was approximately 85%.

[0101] Example 3

[0102] This embodiment provides a method for synthesizing 4'-sugar, and the preparation steps are as follows:

[0103] 1) Synthetic method of compound I

[0104] D-ribose (15.0 g, 100 mmol) was dissolved in methanol (200 ml). The solution was cooled to 3°C, and sulfuric acid (0.22 ml, 98 wt%, 4 mmol) was slowly added. The reaction mixture was stirred at 0°C for 15 hours. After the reaction was complete, sodium bicarbonate was added to terminate the reaction, and the pH of the reaction system was adjusted to approximately 7. The reaction mixture was filtered, concentrated under reduced pressure, and used directly in the next reaction without further purification.

[0105] 2) Synthetic method of compounds of formula II

[0106] The crude product of Formula I (100 mmol) was dissolved in tetrahydrofuran (500 mL), cooled to 5 °C, and then potassium tert-butoxide (400 mmol, 44.88 g) was slowly added. After hydrogen production ceased, benzyltrichloroacetylimine ester (300 mmol, 75.75 g) was slowly added, and the mixture was stirred at room temperature for 7 hours. After the reaction was complete, ice was added to terminate the reaction. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (magnesium sulfate), concentrated under vacuum, and used directly without further purification.

[0107] 3) Synthetic methods of compounds of formula III

[0108] The crude product of Formula II (100 mmol) was dissolved in acetic acid (120 ml) and water (50 ml), trifluoroacetic acid (Example 4), and stirred at 50 °C for 20 hours. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated NaHCO3 solution, dried over magnesium sulfate, concentrated under reduced pressure, and obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1) to give the target compound (32.7 g, 77.9 ml, 78% overall yield over three steps).

[0109] 4) Synthetic methods for compounds of formula IV

[0110] Compound III (21.5 mmol) was dissolved in methanol (130 mL), and then potassium borohydride (71.6 mmol, 3.87 g) was added in portions at 0 °C over 30 minutes. The reaction was stirred at room temperature for 1.5 hours, after which the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated under vacuum, and used directly in the next step without further purification.

[0111] 5) Synthetic methods of compounds of formula V

[0112] The crude compound of formula IV (21.5 mmol) was dissolved in tetrahydrofuran (110 mL), and then triethylamine (75.3 mmol, 10.5 mL) was added. Methylsulfonyl chloride (75.2 mmol, 5.8 mL) was slowly added at 0 °C, and the reaction was stirred for 40 minutes. The reaction was then terminated by adding ice. The organic layer was washed with water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, concentrated under reduced pressure, and used directly in the next step without further purification.

[0113] 6) Synthetic methods of compounds of formula VI

[0114] The crude compound of formula V (38.4 mmol) was co-evaporated with toluene to remove trace amounts of water and dissolved in dry acetonitrile (100 mL). Lithium bromide (307 mmol, 26.7 g) was added, and the reaction was carried out under reflux for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under vacuum, and used directly in the next reaction without further purification.

[0115] 7) Synthetic methods of compounds of formula VII

[0116] The crude compound of formula VII (38.4 mmol) and sodium sulfide nonahydrate (30.72 mmol, 7.38 g) were dissolved in dioxane (130 mL). The reaction mixture was stirred at 80 °C for 40 min. The residue was dissolved in ethyl acetate, the organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum. Column chromatography (petroleum ether: ethyl acetate, 100 / 1-30 / 1) gave the target compound in 70% yield.

[0117] 8) Synthesis method of compounds of formula IX

[0118] The compound of formula VIII (15.7 mmol, 6.61 g) was dissolved in tetrahydrofuran (110 mL), and m-CPBA (m-chloroperoxybenzoic acid, 19.6 mmol, 3.38 g) was added at 0 °C. The reaction mixture was stirred for 70 min. The reaction was quenched by adding saturated Na₂S₂O₃ solution, and the organic layer was washed with saturated NaHCO₃ solution. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and used directly for the next step without further purification.

[0119] 9) Synthetic method of compound X

[0120] The crude product of formula IX (15.7 mmol) was dissolved in acetic anhydride (78.50 mL) and stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, the organic phase was dried over anhydrous magnesium sulfate, concentrated, and the target compound (11.0 mmol, 70% overall yield in both steps) was obtained by column chromatography (petroleum ether: ethyl acetate, 10 / 1-5 / 1).

[0121] 10) Synthetic method of compounds of formula XI

[0122] Compound X (10.8 g, 22.6 mmol) was dissolved in dry tetrahydrofuran, cooled to 0 °C, and 135 mL of 1 mol / L BCl3 tetrahydrofuran solution was slowly added dropwise. The reaction was carried out at 5 °C for 50 min. After the reaction was complete, the reaction mixture was quenched in crushed ice, extracted with dichloromethane, and dried to dryness. The residue was dissolved in dry pyridine, and 39.6 mL of benzoic anhydride (45.2 mmol) was added. The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, evaporated to dryness, and column chromatography was performed to give a white solid. The two-step yield was approximately 80%.

[0123] Example 4

[0124] This embodiment provides a method for synthesizing 4'-sugar. The difference between the synthesis steps and those in Example 1 is that, in the synthesis of the compound of Formula III, the crude product of the compound of Formula II is dissolved in hydrochloric acid with a concentration of 0.1 wt%, while the rest is the same as in Example 1.

[0125] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 4'-sugar, characterized in that, Includes the following steps: S1: Dissolve D-ribose in a mixed solution of methanol and an acid catalyst, and then react it with methanol to undergo a glycosylation reaction to obtain the compound of formula I, methyl-D-riboside; The compound of formula I was dissolved in an aprotic polar organic solvent, activated by the addition of a basic reagent, and then reacted with a benzylating agent to obtain a compound with the structure of formula II. S2: Hydrolyze the obtained compound of formula II in a mixed solution of acid and water to obtain the compound of formula III; The compound of formula III was dissolved in methanol, and a borohydride reducing agent was added to open the ring to obtain a sugar alcohol derivative, namely the compound of formula IV. S3: Dissolve the compound of formula IV in an organic solvent, add an alkalizing agent, and then add a hydroxyl activator to carry out an activation reaction to obtain a compound with the structure of formula V; The compound of formula V was dehydrated and dissolved in aprotic polar organic solvent I. Lithium bromide was added and refluxed to undergo a substitution reaction to give 1,3,4-oxo-benzyl-2,5-dibromopentane, with the chemical structure shown in formula VI. S4: Dissolve the compound of formula VI with sodium sulfide or its hydrate in an organic solvent and heat to undergo a bimolecular nucleophilic substitution reaction to obtain a cyclic sulfide compound with the structure shown in formula VII. The compound of formula VII is dissolved in an organic solvent, and an oxidant is added in an ice bath to react and oxidize the thioether bond in formula VII to sulfoxide, to obtain a compound with the structure of formula VIII. S5: Dissolve the compound of formula VIII in acetic anhydride, stir the reaction, and rearrange to generate an acetoxythioether compound with the structure shown in formula IX; S6: After purifying the compound of Formula IX, dissolve it in an organic solvent, cool it down and add a debenzylidene reagent to react. After preliminary purification, add a hydroxybenzoylation reagent and react at room temperature to obtain a 4'-sulphose compound with the structure shown in Formula X. The reaction process is as follows:

2. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S1, the acid catalyst is sulfuric acid or hydrochloric acid; the molar ratio of D-ribose to acid is 10-25:1; the concentration of D-ribose in methanol is 0.3-0.5 mmol / mL; the glycosylation reaction conditions are 0-5℃ for 9-15 h; the basic reagent is sodium hydride or potassium tert-butoxide; the benzylating reagent is benzyl bromide, benzyl chloride, or benzyl trichloroacetylimine ester; the reaction temperature after adding the basic reagent is 0-5℃ until hydrogen production stops; the reaction at room temperature after adding the benzylating reagent is 3-7 h.

3. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S1, the aprotic polar organic solvent used to dissolve the compound of formula I is DMF, acetonitrile, or tetrahydrofuran. The concentration of the compound of formula I in the organic solvent is 0.20-0.3 mmol / mL. The molar ratio of the compound of formula I to the basic reagent and the benzylating reagent is 1:2-4:3-4. The reaction temperature is room temperature, and the reaction time is 3-6 h.

4. The method for synthesizing 4'-sugar according to claim 1, characterized in that: The acid in step S2 is formic acid, acetic acid, hydrochloric acid, or trifluoroacetic acid; the concentration of formic acid, acetic acid, or trifluoroacetic acid in the mixed solution is 60-80 wt%, and the concentration of hydrochloric acid in the mixed solution is 0.1-0.2 wt%; the concentration of the compound of formula II in the mixed solution of water and acid is 0.4-0.6 mmol / mL, and the reaction conditions after adding acid are 50-70℃ for 16-20 h; after preliminary purification after the reaction, the compound of formula III is obtained by column chromatography for the next reaction; the borohydride reducing agent is one or more combinations of sodium borohydride, potassium borohydride, and lithium borohydride; the molar ratio of the compound of formula III to the borohydride reducing agent is (0.3-0.7):1, and the reaction conditions after adding borohydride are 0.8-1.5 h at room temperature.

5. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S3, the organic solvent is any one of dichloromethane, acetonitrile, tetrahydrofuran, ethyl acetate, and dioxane; the alkalizing agent is triethylamine or N,N-diisopropylethylamine; and the hydroxyl activator is methanesulfonyl chloride or p-toluenesulfonyl chloride.

6. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S3, the molar ratio of compound IV to alkalizing agent and hydroxyl activator is 1:3.5-4.5:2.5-3.5, the reaction temperature is 0-5℃, and the reaction time is 20-40 min. The organic solvent I is 2-butanone, tetrahydrofuran, acetonitrile, or acetone; the molar ratio of the compound of formula V to lithium bromide is 1:8-12; the concentration of the compound of formula V in organic solvent I is 0.25-0.4 mmol / mL, and the reaction is carried out under reflux for 14-18 h.

7. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S4, the organic solvent is one or more of DMF, dioxane, acetonitrile, and tetrahydrofuran. The molar ratio of the compound of formula VI to sodium sulfide or its hydrate is 0.6-1:

1. The concentration of the compound of formula VI in the organic solvent is 0.25-0.35 mmol / L. The reaction conditions are 80-120℃ and the reaction time is 20-40 min.

8. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S4, the organic solvent is any one of dichloromethane, tetrahydrofuran, acetonitrile, and dioxane; the oxidant is m-CPBA; the molar ratio of the compound of formula VII to the oxidant is 0.8-1.0:1; the reaction conditions are 0℃-5℃ and the time is 40-80 min. In step S5, the concentration of the compound of formula VIII in acetic anhydride is 0.12-0.2 mmol / mL, the reaction temperature is 90-110℃, and the time is 2-4 h.

9. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S6, the organic solvent is one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, and dioxane, and the debenzylidene reagent is BBr3, BCl3, or TMSI. The molar ratio of the debenzylidene reagent, the hydroxybenzoylating reagent, and the compound of formula X is 6-7:2-2.5:1; the reaction temperature after adding the debenzylidene reagent is 0℃-5℃, and the reaction time is 50-70 min.

10. The method for synthesizing 4'-sugar according to claim 1, characterized in that: In step S6, the hydroxybenzoylating agent is benzoyl chloride or benzoic anhydride; after adding the benzoylating agent, the reaction is carried out at room temperature for 8-14 hours.

Images