Process for the preparation of beta configuration deoxynucleosides

Abstract

The application provides a preparation method of beta configuration deoxynucleoside, and belongs to the technical field of nucleoside synthesis. The application regulates the stereoselectivity of the reaction by limiting the combination of the type of organic solvent and the base catalyst: in the organic solvent environment, compound A mainly exists in the thermodynamically stable alpha configuration, the low dielectric constant of the solvent effectively inhibits the formation of carbonium ion and the competition of the SN1 path; the solvent has specific strong coordination with the alkali metal cation, successfully strips the anion in compound B, forms a very high nucleophilic activity 'naked anion', and assists positioning through the ion pair effect of the metal cation in the base catalyst; under the kinetic control, the nucleophilic nucleophilic salt species specifically attacks the leaving group of compound A through SN2 back attack, causes the Walden inversion of the chiral center, is converted into the beta configuration, and finally high-yield and high-stereoselective beta configuration deoxynucleoside is obtained.

Description

Technical Field

[0001] This invention relates to the field of nucleoside synthesis technology, and in particular to a method for preparing β-configuration deoxynucleosides. Background Technology

[0002] β-deoxynucleotides are a class of nucleoside compounds with a specific stereoconfiguration. Their core structure consists of three parts: a base, a deoxyribose sugar, and a glycosidic bond. In this configuration, the base and the deoxyribose ring are arranged in a trans conformation. This specific spatial structure allows them to precisely fit the double helix backbone of nucleic acid molecules, making them the basic structural units of natural DNA (deoxyribonucleic acid) and a key structural basis for maintaining the storage and transmission of genetic information in DNA. Based on this characteristic, β-deoxynucleotides play an irreplaceable role in fields such as biomedicine and molecular biology.

[0003] The current method for preparing β-deoxynucleosides involves adding a trimethylsilyl protecting group to a nitrogenous base, then reacting it with a five- or six-membered cyclic sugar blocked by the protecting group, followed by deprotection to obtain the β-deoxynucleoside. This method is simple, energy-efficient, and environmentally friendly, but the yield of β-deoxynucleosides is low, with a maximum yield of only 43%. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing β-deoxynucleotides. The method provided by this invention yields β-deoxynucleotides in high quantities.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A method for preparing a β-configuration deoxynucleoside includes the following steps: Compound A, compound B, a base catalyst, and an organic solvent are mixed and subjected to a glycosylation reaction to obtain compound C; the organic solvent may be dichloroethane, 2-methyltetrahydrofuran, tetrahydrofuran, or acetonitrile; the base catalyst may include potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium hydride, or potassium hydroxide. Compound C was mixed with a basic reagent and methanol and then subjected to a deacylation protection reaction to obtain compound D; The compound D was mixed with trimethylchlorosilane, potassium iodide, a polar aprotic solvent and water and subjected to a nucleophilic substitution reaction to obtain a β-configuration deoxynucleoside. The compound A has the chemical structure shown in Formula I: Formula I, In Formula I, R1 and R2 are independently protecting groups for hydroxyl groups; The LG is a halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or acetoxy. The compound B has the chemical structure shown in Formula II: Formula II, In Formula II, R3, R4, and R5 are independently hydrogen, amino protecting groups substituted or unsubstituted amino, hydroxyl protecting groups substituted or unsubstituted hydroxyl, halogen, alkyl, or aryl groups. Compound C has the chemical structure shown in Formula III: Formula III, The compound D has the chemical structure shown in Formula IV: Formula IV.

[0006] Preferably, the protecting group of the hydroxyl group includes 4-methylbenzoyl, benzoyl, acetyl or fluorenylmethoxyyl, and R3, R4, R5 are independently hydrogen, halogen or isobutyryl-substituted amino groups.

[0007] Preferably, the molar ratio of compound A to compound B is (1~3):1.

[0008] Preferably, the molar ratio of the alkaline catalyst to compound B is (2.5~3.5):1.

[0009] Preferably, the molar ratio of compound C to the alkaline reagent is 1:(2.2~4).

[0010] Preferably, the alkaline reagent includes potassium carbonate, sodium methoxide, cesium carbonate, cesium fluoride, or lithium hydroxide.

[0011] Preferably, the molar ratio of compound D to trimethylchlorosilane is 1:(1.1~3).

[0012] Preferably, the molar ratio of compound D to potassium iodide is 1:(1.1~3).

[0013] This invention provides a method for preparing a β-configuration deoxynucleoside, comprising the following steps: mixing compound A, compound B, a base catalyst, and an organic solvent, and then performing a glycosylation reaction to obtain compound C; mixing compound C, a base reagent, and methanol, and then performing a deprotection reaction to obtain compound D; mixing compound D, trimethylchlorosilane, potassium iodide, a polar aprotic solvent, and water, and then performing a nucleophilic substitution reaction to obtain a β-configuration deoxynucleoside; wherein compound A has the chemical structure shown in Formula I: Formula I, wherein R1 and R2 are independently hydroxyl protecting groups; LG is a halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or acetoxy; and compound B has a chemical structure as shown in Formula II. Formula II, wherein R3, R4, and R5 are independently hydrogen, amino-protecting groups substituted or unsubstituted amino groups, hydroxyl groups substituted or unsubstituted hydroxyl groups, halogens, alkyl groups, or aryl groups; and compound C has the chemical structure shown in Formula III. Formula III, compound D has the chemical structure shown in Formula IV: Formula IV.

[0014] This invention regulates the stereoselectivity of the reaction by limiting the type of organic solvent and the combination of base catalyst: In the organic solvent environment, compound A mainly exists in the thermodynamically stable α-configuration. The low dielectric constant of the organic solvent effectively suppresses the formation of carbocations and competition for the SN1 pathway. The solvent has specific and strong coordination with alkali metal cations, successfully stripping the anion from compound B to form a highly nucleophilic 'naked anion'. The ion-pairing effect of the metal cation in the base catalyst assists in localization. Under kinetic control, nucleophilic and nucleophilic salt species specifically target the leaving group of compound A. The SN2 back-side attack causes a Walden flip of the chiral center, converting it to the β configuration. This results in a high yield and high stereoselectivity of the β-configured deoxynucleoside, avoiding the problem of insufficient solvation of organic cations in organic base catalysts, which leads to the formation of large and tight ion pairs with the starting material anions, causing severe steric hindrance and reducing the conversion rate of the β configuration. It also avoids the problem of incomplete deprotonation and self-nucleophilic side reactions in non-aqueous systems using organic base catalysts, which cause significant degradation of compound A under prolonged heating, resulting in a low yield of the β-configured deoxynucleoside. The results of the examples show that the yield of the β-configured deoxynucleoside prepared by the method provided by this invention can reach 89%. Detailed Implementation

[0015] This invention provides a method for preparing β-configuration deoxynucleosides, comprising the following steps: Compound A, compound B, a base catalyst, and an organic solvent were mixed and subjected to a glycosylation reaction to obtain compound C; Compound C was mixed with an alkaline reagent and methanol and then subjected to a deprotection reaction to obtain compound D; The compound D was mixed with trimethylchlorosilane, potassium iodide, a polar aprotic solvent and water, and then subjected to a nucleophilic substitution reaction to obtain a β-configuration deoxynucleoside.

[0016] In this invention, compound A, compound B, an alkaline catalyst, and an organic solvent are mixed and subjected to a glycosylation reaction to obtain compound C.

[0017] In this invention, compound A has a chemical structure as shown in Formula I: Formula I, In this invention, in Formula I, R1 and R2 are independently protecting groups of hydroxyl groups, preferably 4-methylbenzoyl, benzoyl, acetyl, or fluorenylmethoxy; LG is a halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or acetyloxy. As one embodiment of this invention, in Formula I, R1 can be 4-methylbenzoyl, benzoyl, acetyl, or fluorenylmethoxy; R2 can be 4-methylbenzoyl, benzoyl, or fluorenylmethoxy.

[0018] In this invention, compound B has a chemical structure as shown in Formula II: Formula II, In this invention, in Formula II, R3, R4, and R5 are independently hydrogen, amino-protected or unsubstituted amino groups, hydroxyl-protected or unsubstituted hydroxyl groups, halogens, alkyl groups, or aryl groups, more preferably hydrogen, halogens, or isobutyryl-substituted amino groups. As one embodiment of this invention, in Formula II, R3 can be hydrogen; R4 can be a halogen; and R5 can be an isobutyryl-substituted amino group.

[0019] In one embodiment of the present invention, the molar ratio of compound A to compound B can be (1~3):1. In specific embodiments of the present invention, the molar ratio of compound A to compound B can be 1:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 2:1, 2.5:1, or 3:1. Limiting the molar ratio of compound A to compound B to the above range ensures that glycosylation occurs at the N9 position of compound A and compound B, while avoiding side reactions at the N7 position of compound B.

[0020] In one embodiment of the present invention, the alkaline catalyst may be potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium hydride, or potassium hydroxide. In another embodiment, the molar ratio of the alkaline catalyst to compound B may be (2.5~3.5):1. In specific embodiments of the present invention, the molar ratio of the alkaline catalyst to compound B may be 2.5:1, 3:1, or 3.5:1. The present invention ensures that the alkaline catalyst can activate compound B and promote the desorption of the leaving group of compound A by limiting the molar ratio of the alkaline catalyst to compound B.

[0021] In this invention, the organic solvent can be dichloroethane, 2-methyltetrahydrofuran, tetrahydrofuran, or acetonitrile. As one embodiment of this invention, the mass ratio of compound A to the volume of the organic solvent can be 1 g: (1.5~10) mL. This invention ensures sufficient dissolution of the reactants for the glycosylation reaction by limiting the ratio of compound A to the organic solvent.

[0022] In one embodiment of the present invention, the mixing of compound A, compound B, alkaline catalyst and organic solvent can be carried out by first mixing compound A with the organic solvent, and then mixing it with compound B and alkaline catalyst.

[0023] In this invention, during the glycosylation reaction, the alkaline catalyst attacks the N atom of NH in compound B, converting it into an N-anion and enhancing its nucleophilicity. Then, the LG atom in compound A leaves under alkaline conditions, forming an oxocarbamonite ion intermediate, while simultaneously being nucleophilically attacked by the N-anion to form a β-glycosidic bond, yielding compound C. In one embodiment of this invention, the temperature of the glycosylation reaction is the reflux temperature of the organic solvent. In another embodiment of this invention, the glycosylation reaction is monitored by thin-layer chromatography (TLC). This invention does not impose any special limitations on the developing solvent for TLC, as long as it is capable of separating the starting material.

[0024] In one embodiment of the present invention, after the glycosylation reaction is completed, the product of the glycosylation reaction is sequentially cooled to room temperature, extracted, washed with organic phase, dried, filtered and concentrated under reduced pressure to obtain compound C.

[0025] In one embodiment of the present invention, the extractant can be water and dichloroethane. In one embodiment of the present invention, the washing solution for the organic phase can be a saturated sodium chloride solution. In one embodiment of the present invention, the drying can be performed using anhydrous magnesium sulfate. The present invention does not impose any particular limitation on the cooling, filtration, and vacuum concentration methods; any method well-known in the art can be used to cool the product to room temperature, to separate the solid and liquid phases using filtration, and to remove the organic solvent from the organic phase using vacuum concentration.

[0026] Compound C has the chemical structure shown in Formula III: Formula III.

[0027] After obtaining compound C, the present invention mixes compound C with an alkaline reagent and methanol and carries out a deprotection reaction to obtain compound D.

[0028] In one embodiment of the present invention, the alkaline reagent includes potassium carbonate, sodium methoxide, cesium carbonate, cesium fluoride, or lithium hydroxide. In another embodiment, the molar ratio of compound C to the alkaline reagent can be 1:(2.2~4). In embodiments of the present invention, the molar ratio of compound C to the alkaline reagent can specifically be 1:2.2, 1:3, or 1:4. The present invention ensures the removal of the protecting group of the hydroxyl group in compound C by limiting the molar ratio of compound C to the alkaline reagent.

[0029] In one embodiment of the present invention, the mass ratio of compound C to the volume of methanol can be 1 g : (1.5~10) mL. The present invention ensures complete deprotection by limiting the ratio of compound C to methanol to guarantee that compound C is fully dissolved in the alkaline reagent and that the formation of methoxy anions participates in the deprotection reaction.

[0030] The present invention does not have any particular limitation on the mixing of compound C with alkaline reagent and methanol. Compound C can be mixed with alkaline reagent and methanol using a mixing method well known in the art.

[0031] In this invention, during the deprotection reaction, the C group of the protecting group in compound C, which is attached to oxygen, is nucleophilically attacked by a basic reagent, forming an unstable intermediate. The protecting group is then removed to obtain compound D. In one embodiment of this invention, the deprotection reaction can be carried out at room temperature. In another embodiment, the deprotection reaction is monitored by an IPC (intra-isolated plasma concentration) using methanol, and the reaction is stopped when compound C has completely reacted.

[0032] In one embodiment of the present invention, after the deprotection reaction is completed, the product after the deprotection reaction is concentrated under reduced pressure to obtain compound D. In another embodiment of the present invention, the method of reduced pressure concentration is not particularly limited, and any method well known in the art can be used.

[0033] The compound D has the chemical structure shown in Formula IV: Formula IV.

[0034] After obtaining compound D, the present invention mixes compound D with trimethylchlorosilane, potassium iodide, a polar aprotic solvent and water and carries out a nucleophilic substitution reaction to obtain a β-configuration deoxynucleoside.

[0035] In one embodiment of the present invention, the molar ratio of compound D to potassium iodide can be 1:(1.1~3). The present invention ensures that trimethylchlorosilane reacts with potassium iodide to form trimethyliodosilane, thus fully activating the methoxy group in compound D. In another embodiment of the present invention, the molar ratio of compound D to trimethylchlorosilane can be 1:(1.1~3). The present invention, by limiting the molar ratio of compound D to trimethylchlorosilane, fully activates the methoxy group in compound D, leading to nucleophilic substitution and the formation of a β-configuration deoxynucleoside. In another embodiment of the present invention, the polar aprotic solvent can be acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, or N,N-dimethylformamide. In another embodiment of the present invention, the mass ratio of compound D to the volume ratio of the polar aprotic solvent can be 1 g:(1.5~10) mL. This invention ensures the complete dissolution of compound D, potassium iodide, and trimethylchlorosilane by limiting the ratio of compound D to a polar aprotic solvent, and enhances the nucleophilicity of iodide ions and stabilizes the positively charged carbomonium ion. In one embodiment, the volume ratio of the polar aprotic solvent to water can be (10~100):1. This invention also ensures that the methoxy group in compound D is converted to a carbonyl group after deoxygenation by limiting the volume ratio of the polar aprotic solvent to water.

[0036] In one embodiment of the present invention, the mixing of compound D with trimethylchlorosilane, potassium iodide, a polar aprotic solvent and water can be carried out by first mixing the polar aprotic solvent and water, and then mixing compound D with trimethylchlorosilane and potassium iodide.

[0037] In this invention, during the nucleophilic substitution, trimethylchlorosilane reacts with potassium iodide to generate trimethyliodosilane, which activates the methoxy group in compound D, converting it into a leaving siloxy group. Then, nucleophilic substitution occurs to form a carbonyl group, yielding a β-configuration deoxynucleoside. In one embodiment of this invention, the nucleophilic substitution temperature can be 60-80°C. In another embodiment of this invention, the nucleophilic substitution process is monitored by an IPC (intra-isolated plasma concentration) sample (diluent: methanol), and the reaction is stopped when compound D has completely reacted.

[0038] This invention regulates the stereoselectivity of the reaction by limiting the type of organic solvent and the combination of base catalyst: In the organic solvent environment, compound A mainly exists in the thermodynamically stable α-configuration, and the low dielectric constant of the solvent effectively suppresses the formation of carbocations and competition for the SN1 pathway; at the same time, the base catalyst converts compound B into a highly active nucleophilic salt species, and assists in localization through the ion-pair effect of the metal cation in the base catalyst; under kinetic control, the nucleophilic salt species launches a specific SN2 back-side attack on the leaving group of compound A, causing the Walden flip of the chiral center to convert to the β-configuration, ultimately yielding a high-yield, highly stereoselective β-configuration deoxynucleoside.

[0039] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0040] Example 1 A method for preparing a β-configuration deoxynucleoside is as follows: 500 g of compound 1 was mixed with 750 mL of dichloroethane, then compound 2 and potassium tert-butoxide were added, and the mixture was refluxed at 85 °C. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then extracted with water and dichloroethane to obtain the organic phase. The organic phase was washed, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 3, 587.08 g (0.99 mol), with a yield of 92.5%. The molar ratio of compound 1 to compound 2 was 1.2:1; the molar ratio of potassium tert-butoxide to compound 2 was 2.5:1; and the mass ratio of compound 1 to the volume ratio of dichloroethane was 1 g: 1.5 mL. Compound 3, 2.5 L of methanol, and potassium carbonate were mixed and reacted at room temperature. The reaction progress was monitored by an IPC (diluent: methanol). The reaction was stopped when compound 3 was completely reacted. The resulting liquid was then concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was retained. After further concentration under reduced pressure, compound 4 was obtained, 260.08 g (0.92 mol), with a yield of 93.25%. The molar ratio of compound 3 to potassium carbonate was 1:3, and the mass ratio of compound 3 to methanol was 1 g: 4.25 mL. A mixture of acetonitrile and water (volume ratio 100:1) was mixed with compound 4, potassium iodide, and trimethylchlorosilane and reacted at 65°C. The reaction progress was monitored by IPC (diluent: methanol). The reaction was stopped when compound 4 reacted completely. The proportion of α configuration in the reaction system was 1.5%. The reaction system was directly concentrated under reduced pressure and then added to a mixture of ethanol and water (volume ratio 10:1) for slurrying. The mixture was then filtered to obtain 237.59 g of compound 5, with a yield of 96.14% and a purity of 98.58%. The molar ratio of compound 4 to potassium iodide was 1:1.1, the molar ratio of compound 4 to trimethylchlorosilane was 1:1.1, and the mass-to-volume ratio of compound 4 to acetonitrile was 1 g:10 mL. 1 H NMR (400 MHz,Chloroform-d) δ9.72 (s, 1H), 7.78 (s, 1H), 7.11 (s, 2H), 6.35 (t, J = 7.0 Hz,1H), 4.11 (q, J = 7.0 Hz, 1H), 3.97 (qd, J = 7.0, 5.0 Hz, 1H), 3.84 (ddd, J =12.4, 7.0, 5.6 Hz, 1H), 3.51 (ddd, J = 12.5, 6.9, 5.5 Hz, 1H), 2.62 (dt, J =13.6, 7.0 Hz, 1H), 2.36 (dt, J = 13.5, 7.0 Hz, 1H), 1.59 (d, J = 5.0 Hz, 1H), 1.42 (t, J = 5.5 Hz, 1H). Example 2 A method for preparing a β-configuration deoxynucleoside is as follows: 500 g of compound 6 was mixed with 1 L of 2-methyltetrahydrofuran, then compound 7 and sodium tert-butoxide were added, and the mixture was refluxed at 90 °C. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then extracted with water and dichloroethane to obtain the organic phase. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 8, 636.26 g (1.14 mol), with a yield of 93.26%. The molar ratio of compound 6 to compound 7 was 1.15:1; the molar ratio of sodium tert-butoxide to compound 7 was 2.5:1; and the mass ratio of compound 6 to the volume ratio of 2-methyltetrahydrofuran was 1 g: 2 mL. Compound 8, 3.5 L of methanol, and sodium methoxide were mixed and reacted at room temperature. The reaction progress was monitored by an IPC (diluent: methanol). The reaction was stopped when compound 8 was completely reacted. The resulting liquid was then concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was retained. After concentration under reduced pressure, compound 9 was obtained, 295.97 g (1.05 mol), with a yield of 92.71%. The molar ratio of compound 8 to sodium methoxide was 1:3, and the mass ratio of compound 8 to methanol was 1 g: 5.5 mL. A mixture of acetonitrile and water (volume ratio 100:1) was mixed with compound 9, potassium iodide, and trimethylchlorosilane and reacted at 65°C. The reaction progress was monitored by IPC (diluent: methanol). The reaction was stopped when compound 4 reacted completely. The proportion of α configuration in the reaction system was 2.3%. The reaction system was directly concentrated under reduced pressure and then added to a mixture of ethanol and water (volume ratio 10:1) for slurrying. The mixture was then filtered to obtain 267.47 g (1.00 mol) of compound 10, with a yield of 95.32% and a purity of 97.10%. The ratio of compound 9 to potassium iodide was 1:1.5, the ratio of compound 9 to trimethylchlorosilane was 1:1.5, and the mass ratio of compound 9 to acetonitrile was 1 g:8 mL.

[0041] Example 3 A method for preparing a β-configuration deoxynucleoside is as follows: 500 g of compound 11 was mixed with 2.5 L of tetrahydrofuran, then compound 12 and sodium tert-butoxide were added, and the mixture was refluxed at 70 °C. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then extracted with water and dichloroethane to obtain the organic phase. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 13, 597.67 g (0.82 mol), with a yield of 94.53%. The molar ratio of compound 11 to compound 12 was 1.1:1; the molar ratio of sodium tert-butoxide to compound 12 was 2.5:1; and the mass ratio of compound 1 to the volume ratio of tetrahydrofuran was 1 g: 5 mL. Compound 13, 3 L of methanol, and cesium carbonate were mixed and reacted at room temperature. The reaction progress was monitored by an IPC (diluent: methanol). The reaction was stopped when compound 13 was completely reacted. The resulting liquid was then concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was retained. After concentration under reduced pressure, compound 14 was obtained, 223.90 g (0.80 mol), with a yield of 96.48%. The molar ratio of compound 13 to cesium carbonate was 1:3, and the mass ratio of compound 13 to methanol was 1 g: 5 mL. A mixture of acetonitrile and water (volume ratio 100:1) was mixed with compound 14, potassium iodide, and trimethylchlorosilane and reacted at 65°C. The reaction progress was monitored by IPC (diluent: methanol). The reaction was stopped when compound 4 reacted completely. The proportion of α configuration in the reaction system was 1.9%. The reaction system was directly concentrated under reduced pressure and then added to a mixture of ethanol and water (volume ratio 10:1) for slurrying. The mixture was then filtered to obtain 208.18 g (0.78 mol) of compound 15, with a yield of 97.85% and a purity of 96.23%. The molar ratio of compound 14 to potassium iodide was 1:1.5, the molar ratio of compound 14 to trimethylchlorosilane was 1:1.5, and the mass ratio of compound 14 to acetonitrile was 1:10.

[0042] Example 4 A method for preparing a β-configuration deoxynucleoside is as follows: 500 g (0.84 mol) of compound 16 was mixed with 1 L of acetonitrile, then compound 17 and potassium carbonate were added, and the mixture was refluxed at 85 °C. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then extracted with water and dichloroethane to obtain the organic phase. The organic phase was washed, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 18, 502.90 g (0.63 mol), with a yield of 93.84%. The molar ratio of compound 16 to compound 17 was 1.25:1; the molar ratio of potassium carbonate to compound 17 was 3:1; and the mass ratio of compound 16 to acetonitrile was 1 g: 2 mL. Compound 18, 5 L of methanol, and cesium carbonate were mixed and reacted at room temperature. The reaction progress was monitored by an IPC (diluent: methanol). The reaction was stopped when compound 18 was completely reacted. The resulting liquid was then concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was retained. After further concentration under reduced pressure, compound 19 was obtained, 168.60 g (0.60 mol), with a yield of 95.23%. The molar ratio of compound 18 to cesium carbonate was 1:2.2, and the mass ratio of compound 18 to methanol was 1 g:9.94 mL. A mixture of acetonitrile and water (volume ratio 100:1) was mixed with compound 19, potassium iodide, and trimethylchlorosilane and reacted at 65°C. The reaction progress was monitored by IPC (diluent: methanol). The reaction was stopped when compound 4 reacted completely. The proportion of α configuration in the reaction system was 3.9%. The reaction system was directly concentrated and then added to a mixture of ethanol and water (volume ratio 10:1) for slurrying. The mixture was then filtered to obtain 146.98 g (0.55 mol) of compound 20, with a yield of 91.67% and a purity of 97.56%. The molar ratio of compound 19 to potassium iodide was 1:2, the molar ratio of compound 19 to trimethylchlorosilane was 1:2, and the mass ratio of compound 19 to acetonitrile was 1:7.5.

[0043] Example 5 A method for preparing a β-configuration deoxynucleoside is as follows: 500 g of compound 21 was mixed with 1.5 L of dichloroethane, then compound 22 and cesium carbonate were added, and the mixture was refluxed at 85 °C. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then extracted with water and dichloroethane to obtain the organic phase. The organic phase was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 23, 562.00 g (1.00 mol), with a yield of 97.09%. The molar ratio of compound 21 to compound 22 was 1.2:1; the molar ratio of cesium carbonate to compound 22 was 2.5:1; and the mass ratio of compound 21 to dichloroethane was 1 g: 3 mL. Compound 23, 1 L of methanol, and lithium hydroxide were mixed and reacted at room temperature. The reaction progress was monitored by an IPC (diluent: methanol). The reaction was stopped when compound 23 was completely reacted. The resulting liquid was then concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was retained. After concentration under reduced pressure, compound 24 was obtained, 260.08 g (0.92 mol), with a yield of 93.25%. The molar ratio of compound 23 to lithium hydroxide was 1:3, and the mass ratio of compound 23 to methanol volume was 1:1.77. A mixture of acetonitrile and water (volume ratio 100:1) was mixed with compound 24, potassium iodide, and trimethylchlorosilane and reacted at 65°C. The reaction progress was monitored by IPC (diluent: methanol). The reaction was stopped when compound 4 reacted completely. The proportion of α configuration in the reaction system was 3.3%. The reaction system was directly concentrated and then added to a mixture of ethanol and water (volume ratio 10:1) for slurrying. The mixture was then filtered to obtain 237.59 g of compound 25, with a yield of 96.14% and a purity of 98.58%. The molar ratio of compound 24 to potassium iodide was 1:1.2, the molar ratio of compound 24 to trimethylchlorosilane was 1:1.2, and the mass-to-volume ratio of compound 24 to acetonitrile was 1:10.

[0044] Example 6 The difference between this embodiment and Example 1 is as follows: the molar ratio of compound 1 to compound 2 is 3:1; the molar ratio of potassium tert-butoxide to compound 2 is 3.5:1; 242.74 g (0.41 mol) of compound 3 was obtained, with a yield of 92.5%; potassium carbonate was replaced with cesium fluoride, yielding compound 4, 109.70 g (0.39 mol), with a yield of 95.12%; acetonitrile was replaced with dimethyl sulfoxide, yielding compound 593.90 g, with a yield of 90.10%; the HPLC purity was 97.60%. Example 7 The difference between this embodiment and Example 1 is as follows: the molar ratio of compound 1 to compound 2 is 2.5:1; the molar ratio of potassium tert-butoxide to compound 2 is 3.5:1; 284.16 g (0.48 mol) of compound 3 is obtained, with a yield of 94.12%; potassium carbonate is replaced with sodium methoxide; the molar ratio of compound 3 to sodium methoxide is 1:4, yielding compound 4, 129.38 g (0.46 mol), with a yield of 95.83%; acetonitrile is replaced with N,N-dimethylformamide, yielding 109.57 g of β-deoxynucleoside, with a yield of 89.13%; the HPLC purity is 96.37%.

[0045] The β-configuration deoxyribonucleosides prepared by the method provided by this invention have a high yield.

[0046] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a β-configuration deoxynucleoside, comprising the following steps: Compound A, compound B, a base catalyst, and an organic solvent are mixed and subjected to a glycosylation reaction to obtain compound C; the organic solvent may be dichloroethane, 2-methyltetrahydrofuran, tetrahydrofuran, or acetonitrile; the base catalyst may include potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium hydride, or potassium hydroxide. Compound C was mixed with an alkaline reagent and methanol and then subjected to a deprotection reaction to obtain compound D; The compound D was mixed with trimethylchlorosilane, potassium iodide, a polar aprotic solvent and water and subjected to a nucleophilic substitution reaction to obtain a β-configuration deoxynucleoside. The compound A has the chemical structure shown in Formula I: Equation I, In Formula I, R1 and R2 are independently protecting groups for hydroxyl groups; LG is a halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or acetoxy. The compound B has the chemical structure shown in Formula II: Formula II, In Formula II, R3, R4, and R5 are independently hydrogen, amino protecting groups substituted or unsubstituted amino, hydroxyl protecting groups substituted or unsubstituted hydroxyl, halogen, alkyl, or aryl groups. Compound C has the chemical structure shown in Formula III: Formula III, The compound D has the chemical structure shown in Formula IV: Formula IV.

2. The preparation method according to claim 1, characterized in that, The protecting group of the hydroxyl group includes 4-methylbenzoyl, benzoyl, acetyl, p-chlorobenzoyl, p-nitrobenzoyl, or fluorenylmethoxyyl; R3, R4, and R5 are independently hydrogen-, halogen-, or isobutyryl-substituted amino groups.

3. The preparation method according to claim 1, characterized in that, The molar ratio of compound A to compound B is (1~3):

1.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the alkaline catalyst to compound B is (2.5~3.5):

1.

5. The preparation method according to claim 1, characterized in that, The molar ratio of compound C to the basic reagent is 1:(2.2~4).

6. The preparation method according to claim 1 or 6, characterized in that, The alkaline reagent includes potassium carbonate, sodium methoxide, cesium carbonate, cesium fluoride, or lithium hydroxide.

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound D to trimethylchlorosilane is 1:(1.1~3).

8. The preparation method according to claim 1, characterized in that, The molar ratio of compound D to potassium iodide is 1:(1.1~3).

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