Locked nucleic acid intermediate compound as well as preparation method and application thereof

Abstract

According to the present invention, the compound represented by the formula I is synthesized through the brand new nucleoside intermediate, the compound represented by the formula I is the important precursor nucleoside # imgabs0 #, and the definition of R1 is as defined in the specification. The preparation method provided by the invention overcomes the defects of more reaction byproducts and low yield in the prior art, and has a better application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a locked nucleic acid intermediate compound, a preparation method thereof, and an application thereof. Technical Background

[0002] As the third-generation therapeutic means following small molecule drugs and antibody drugs, nucleic acid drugs are leading a paradigm shift in the biomedical field with their unique advantage of precisely regulating gene expression. Since the approval of the first nucleic acid drug, fomivirsen sodium, in 1998, nucleic acid drugs have undergone three major technological revolutions: breakthroughs in delivery technology, optimization of chemical modifications, and improvement of target screening systems, gradually breaking through the limitations of traditional drug development and showing great potential for clinical applications. Currently, there are three major technical routes for nucleic acid drugs: ASO degrades target RNA through steric hindrance or RNase H-mediated degradation, mRNA guides protein expression by delivering genetic instructions, and siRNA silences pathogenic genes through RNA interference.

[0003] In recent years, with the rapid development of the nucleic acid drug field, the demand for nucleic acid molecules with high affinity, high specificity, and excellent biological stability has been increasing continuously. As a novel nucleic acid modification molecule, locked nucleic acid (LNA) has become a research and application hotspot due to its unique structural advantages and excellent biological properties. The core structure of LNA lies in the introduction of a methylene bridge between the 2'-oxygen and 4'-carbon on its ribose ring, which locks the ribose into the C3'-endo conformation, thereby significantly improving the binding affinity and thermal stability with complementary nucleic acid strands, and at the same time enhancing the anti-degradation ability of the molecule against nucleases. These characteristics make LNA have broad application prospects in multiple fields such as ASO, siRNA, miRNA, fluorescence in situ hybridization probes, and biosensors.

[0004] Currently, the synthesis of locked nucleic acid mainly relies on chemical synthesis. The traditional LNA synthesis process usually includes the synthesis of precursor nucleosides, the construction of the locked structure through ring closure, and the introduction of LNA monomers in solid-phase synthesis. Among them, the compound of formula I is an important precursor nucleoside, .

[0005] In the synthesis of the nucleoside of formula I, the method usually adopted is the one provided in (Modular Synthesis of Constrained Ethyl (cEt) Purine and Pyrimidine Nucleosides Helen Blade, Derek Bradley, Louis Diorazio, Timothy Evans, Barry R. Hayter, and Gareth P. Howell The Journal of Organic Chemistry 2015 80 (10), 5337-5343). As an intermediate, the preparation method of this intermediate compound requires eight-step synthesis, and its preparation route is specifically as follows:

[0006] .

[0007] In the key step of this route, due to the difficulty in selective reaction when the reaction is scaled up to gram and kilogram levels, there are many side reactions, and it is difficult to separate the by-products from the products, which brings a lot of trouble to the post-treatment and results in a high cost of producing the compound of formula I.

[0008] The paper Samudrala, R. P., Penjarla, S., Penta, S., Gundla, R., & Chandra Rao, B. P. (2023). p-Toluenesulfonic acid adorned on MCM-41: an efficient and mild catalyst for the regio / chemo-selective hydrolysis of terminal isopropylidene acetals. Nucleosides, Nucleotides & Nucleic Acids, 42(10), 797–806. It is reported in this literature that the key step in the above route was optimized by using MCM-41 molecular sieve loaded with p-toluenesulfonic acid as a catalyst, and the yield was further improved. However, MCM-41 is expensive, the loading operation is relatively cumbersome, and the reproducibility is poor; the overall process still has disadvantages such as complex steps, high operation difficulty, and high cost. Summary of the Invention

[0009] The object of the present invention is to overcome the deficiencies in the current technology and provide a new process synthesis route through a new intermediate. On the premise of ensuring high yield and high purity, the process flow is simplified, the reaction cost is reduced, and environmental protection and process stability are taken into account, so as to promote the application of the compound of formula I in LNA. Specifically, the present invention first provides a preparation method of the intermediate compound RD-109-5 of the compound of formula I, and its synthesis route is as follows:

[0010]

[0011] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0012] The above method for preparing RD-109-5 comprises the following steps:

[0013] RD-109-4 reacts in the presence of an acid to obtain RD-109-5.

[0014] The present invention further provides a preparation method of the compound of formula I, and its route is as follows:

[0015] ;

[0016] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0017] The above method for preparing the compound of formula I comprises the following steps:

[0018] S1: RD-109-5 reacts in the presence of a phase transfer catalyst, a base and a sulfonylation reagent to prepare RD-109-6;

[0019] S2: RD-109-6 is subjected to a reduction reaction to obtain RD-109-7;

[0020] S3: RD-109-7 reacts with methanesulfonyl chloride in the presence of a catalyst to obtain RD-109-0;

[0021] S4: RD-109-8 reacts with acetic anhydride to obtain the compound of formula I.

[0022] The present invention also provides a preparation method of RD-109-4, and its synthesis route is as follows:

[0023] ;

[0024] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0025] Specifically, it comprises the following steps:

[0026] 1. RD-109-SM undergoes an oxidation reaction to obtain RD-109-1;

[0027] 2. RD-109-1 reacts with formaldehyde under the action of a base to obtain RD-109-2;

[0028] 3. The reduction reaction of RD-109-2 is carried out to obtain RD-109-3;

[0029] 4. RD-109-3 reacts with R1X in the presence of a catalyst and a base to obtain RD-109-4; wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl.

[0030] The present invention also provides the following nucleotide intermediate compounds:

[0031] ;

[0032] wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl.

[0033] Advantages of the present invention:

[0034] 1. The preparation of the compound of formula I through the new intermediate compound improves the selectivity and the yield of the product, greatly reduces the synthesis cost of the compound of formula I, and has good promotion prospects. Specific embodiments

[0035] The following further describes in detail the specific embodiments of the present invention in conjunction with the examples. To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. Unless otherwise clearly stated, in the entire specification and claims, the term "comprising" or its variations such as "including" or "having" etc. will be understood to include the stated components or steps, without excluding other components or steps.

[0036] In addition, to better illustrate the present invention, numerous specific details are given in the following specific embodiments. Those skilled in the art should understand that the present invention can also be implemented without some specific details. In some embodiments, the raw materials, methods, means, etc. well-known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0037] In the present invention, the halogen refers to fluorine, chlorine, bromine or iodine.

[0038] In the present invention, TBS represents tert-butyldimethylsilyl, Bn represents benzyl, and TBDPS represents tert-butyldiphenylsilyl.

[0039] The present invention first provides a method for preparing an intermediate compound RD-109-5 of a compound of formula I, and its synthetic route is as follows:

[0040] 。

[0041] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0042] The above method for preparing RD-109-5 comprises the following steps: RD-109-4 reacts in the presence of an acid to obtain RD-109-5. The acid is preferably an organic acid, and the organic acid is preferably one or a mixture of formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid and oxalic acid. The solvent is one or a mixture of water (H2O), ethanol, methanol, toluene, isopropanol, trifluoroethanol, acetonitrile and tetrahydrofuran;

[0043] Preferably, in the above preparation method, the organic acid is selected from a mixture of formic acid and acetic acid, wherein the volume ratio of formic acid to acetic acid is (2-3):(5-6); the mass-volume ratio of RD-109-4 to the solvent is 1:(1.5-3).

[0044] The present invention further provides a method for preparing a compound of formula I, and its route is as follows:

[0045] ,

[0046] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0047] The above method for preparing a compound of formula I comprises the following steps:

[0048] S1: RD-109-6 is prepared by reacting RD-109-5 in the presence of a phase transfer catalyst, a base, and a sulfonylation reagent; in step S1, the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), tetrabutylammonium chloride (TBAC), tetrabutylammonium hydrogensulfate (TBAHS), trioctylmethylammonium chloride (TOMAC), tetrabutylphosphonium chloride (TBPC), triphenylmethylphosphonium chloride (TPMPCl), 18-crown-6 ether, polyethylene glycol, tetrabutylphosphonium bromide (TBPP), α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; the base is selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide, sodium tert-butoxide, piperidine, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium acetate, sodium acetate, potassium acetate, ammonium acetate, and lithium glycinate; the sulfonylation reagent is selected from one or more of methanesulfonyl chloride (MsCl), p-nitrobenzenesulfonyl chloride (NsCl), trifluoromethanesulfonyl chloride (TfCl), and p-toluenesulfonyl chloride (TsCl); preferably, the reaction is carried out in a solvent selected from one of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), dichloromethane (CH2Cl2), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), acetonitrile (MeCN), 1,2-dichloroethane (DCE), chloroform, methyl tert-butyl ether, and diethyl ether (Et2O).

[0049] Preferably, the base is selected from potassium hydroxide (KOH); the sulfonylation reagent is selected from TsCl; the molar ratio of RD-109-5 to the phase transfer catalyst is 1:0.1 - 0.3; the molar ratio of the sulfonylation reagent to RD-109-5 is 1:1.1 - 1.5.

[0050] S2: RD-109-7 is obtained by the reduction reaction of RD-109-6; in step S2, the reducing agent is selected from one or more of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, zinc borohydride, sodium triacetoxyborohydride, potassium borohydride, lithium tri-sec-butylborohydride, calcium borohydride, lithium cyanoborohydride, lithium tri-tert-butoxyaluminum hydride, and diisobutylaluminum hydride (DIBAL-H); preferably, the reduction reaction is carried out in a solvent, and the solvent is one or a mixture of methanol (MeOH), ethanol (EtOH), isopropanol, polyethylene glycol, N-methylpyrrolidone, acetonitrile, ethylene glycol dimethyl ether, 2-methoxyethanol, toluene, and tetrahydrofuran (THF); preferably, the reducing agent is selected from LiAlH4, the solvent is preferably THF, the molar ratio of RD-109-6 to the reducing agent is (0.7-1.0):1, and the mass-volume ratio of RD-109-6 to the solvent is 1:8-12.

[0051] S3: In the presence of a catalyst, methylsulfonyl chloride (MsCl) is added to RD-109-7 to react to obtain RD-109-0; the catalyst is selected from one of 4-dimethylaminopyridine (DMAP), imidazole, triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylimidazole, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferably, step S3 is carried out in a solvent reaction, and the solvent is selected from one or more of pyridine (Py), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), toluene (Ph), dichloromethane (DCM), chloroform (CHCl3), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me-THF), diethyl ether (Et2O), acetonitrile (MeCN), ethyl acetate (EtOAc), and dimethyl sulfoxide (DMSO); preferably, the catalyst is selected from DMAP; the solvent is selected from pyridine; the molar ratio of the compound RD-109-7 to the catalyst is 1:(0.1-0.3); the molar ratio of the compound RD-109-7 to methylsulfonyl chloride (MsCl) is 1:1.5-2.5; the mass-volume ratio of the compound RD-109-7 to the solvent is 1:3-6.

[0052] S4: RD-109-0 reacts with acetic anhydride to obtain the compound of formula I. Preferably, sulfuric acid is added as a catalyst in step S4, the molar ratio of the compound RD-109-0 to acetic anhydride is 1:2-5, preferably 1:3; the molar ratio of the compound RD-109-0 to sulfuric acid is 1:0.1-0.3, preferably 1:0.2. Preferably, step S4 is carried out in a solvent, and the solvent is preferably ethyl acetate.

[0053] The present invention also provides a preparation method of RD-109-4, and its synthetic route is as follows:

[0054] ,

[0055] wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl;

[0056] The above preparation method of the RD-109-4 compound comprises the following steps:

[0057] 1), Dissolve RD-109-SM in a solvent, add an oxidant, and react to obtain RD-109-1; the oxidant is selected from 2-iodoxybenzoic acid, the combination of tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide, and Dess-Martin periodinane; the solvent is selected from acetonitrile, dimethyl sulfoxide, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and acetone;

[0058] 2), React RD-109-1 with formaldehyde in the presence of a base to obtain RD-109-2; preferably, the formaldehyde is a 37 wt% aqueous solution; the base is an inorganic base or an organic base; the inorganic base is sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and the organic base is triethylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium tert-butoxide, piperidine, sodium ethoxide, lithium acetate, sodium acetate, potassium acetate, ammonium acetate, and lithium glycinate; preferably, the reaction is carried out in a solvent, and the solvent is selected from 2-methyltetrahydrofuran, tetrahydrofuran, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, ethanol, methanol, and diethyl ether;

[0059] 3), Carry out a reduction reaction on RD-109-2 to obtain RD-109-3; the reduction reaction occurs in the presence of a reducing agent, and the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, zinc borohydride, sodium triacetoxyborohydride, cyclohexadiene, potassium borohydride, lithium tri-sec-butylborohydride, calcium borohydride, lithium cyanoborohydride, lithium tri-tert-butoxyaluminum hydride, and diisobutylaluminum hydride; preferably, the reaction is carried out in a solvent, and the solvent is selected from one or a mixture of methanol, ethanol, isopropanol, polyethylene glycol, N-methylpyrrolidone, acetonitrile, ethylene glycol dimethyl ether, 2-methoxyethanol, toluene, and tetrahydrofuran;

[0060] 4), React RD-109-3 with R1X in the presence of a catalyst and a base to obtain RD-109-4, where X is a halogen; the catalyst is selected from phase transfer catalysts, and the catalyst is preferably one of tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), tetrabutylammonium chloride (TBAC), tetrabutylammonium hydrogen sulfate (TBAHS), trioctylmethylammonium chloride (TOMAC), tetrabutylphosphonium chloride (TBPC), triphenylmethylphosphonium chloride (TPMPCl), 18-crown-6 ether, polyethylene glycol, tetrabutylphosphonium bromide (TBPP), α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; the base is selected from triethylamine (TEA), pyridine (Py), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), imidazole, tetrabutylammonium hydroxide (TBAOH), sodium methoxide (NaOMe), sodium ethoxide (NaOEt), cesium carbonate (Cs2CO3), and potassium phosphate (K3PO4);

[0061] Preferably, the reaction is carried out in a solvent selected from one of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and 1,4-dioxane (1,4-dioxane).

[0062] More specifically, in step 1), the solvent is selected from acetonitrile (MeCN), and the oxidant is selected from 2-iodoxybenzoic acid (IBX); the volume-mass ratio of the solvent to RD-109-SM is 4-6:1; the molar ratio of the oxidant to RD-109-SM is 1.2-1.5:1

[0063] More specifically, in step 2), the solvent is selected from 2-methyltetrahydrofuran (2-MeTHF), and the organic base is selected from triethylamine (TEA); the volume-mass ratio of formaldehyde to RD-109-1 is 4-6:1; the volume-mass ratio of the solvent to RD-109-1 is 5-10:1; the molar ratio of the organic base to RD-109-1 is 8-15:1

[0064] More specifically, in step 3), the solvent is selected from methanol (MeOH); the reducing agent is selected from sodium borohydride (NaBH4); the volume-mass ratio of the solvent to RD-109-2 is 3-:1; the molar ratio of RD-109-2 to the reducing agent is 1:1.1-1.3;

[0065] More specifically, in step 4), the solvent is selected from tetrahydrofuran (THF), the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB); the inorganic base is selected from sodium hydroxide (NaOH); R1X is selected from benzyl bromide (BnBr); the volume-mass ratio of the solvent to RD-109-3 is 3-5:1; the molar ratio of RD-109-3 to the phase transfer catalyst is 0.1-0.:1; the molar ratio of S RD-109-3 to benzyl bromide is 1:2-2.5; the molar ratio of RD-109-3 to the inorganic base is 1:8-12; the molar ratio of RD-109-3 to the inorganic base is 1:8-12.

[0066] The present invention also provides the following nucleotide intermediate compounds:

[0067] ,

[0068] Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl.

[0069] For the experimental methods without specific conditions in the following examples, the guidance given in the present invention is preferably referred to, and it can also be carried out according to the experimental manuals or conventional conditions in the art, and other experimental methods known in the art can also be referred to, or according to the conditions recommended by the manufacturer. In the following specific examples, for the measurement parameters of the raw material components, there may be slight deviations within the weighing accuracy range without special instructions. For the temperature and time parameters, acceptable deviations caused by the instrument test accuracy or operation accuracy are allowed. The experimental methods used in the following examples are all conventional methods unless otherwise specified. The reagents, materials, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0070] Example 1: Synthesis of compound int-1

[0071] .

[0072] S1: Dissolve 100 g of RD-109-SM in 500 ml of acetonitrile, add 140 g of IBX and 500 ml of acetonitrile, reflux at 85 °C until TLC shows that the reaction is complete, start the post-treatment, cool down and filter through diatomaceous earth, wash with acetonitrile, collect and rotary evaporate the organic phase to obtain 98.5 g of RD-109-1, with a yield of 99.1%;

[0073] S2: Dissolve 98.5 g of RD-109-1 in 980 ml of 2-MeTHF in a reaction flask; after adding 395 g of TEA, continue to add 500 ml of 37 wt.% aqueous formaldehyde solution, stir at room temperature until the reaction is complete, and then perform post-treatment; add saturated ammonium chloride solution at 0 °C to adjust the pH of the reaction solution to acidic, extract three times with ethyl acetate, then wash three times with saturated ammonium chloride solution, collect and rotary evaporate the organic phase to obtain 96 g of RD-109-2, with a yield of 82.9%;

[0074] S3: Dissolve 96 g of RD-109-2 in 300 ml of MeOH, cool the reaction system to 0 °C, and add 10.1 g of NaBH4; then place the reaction system at room temperature and stir until the reaction is complete, and perform post-treatment; cool the reaction system below 0 °C, quench with saturated ammonium chloride solution and extract three times with DCM, collect and rotary evaporate the organic phase to obtain 80.5 g of RD-109-3, with a yield of 90.3%;

[0075] S4: Dissolve 80.5 g of RD-109-3 in 410 ml of THF, add 14 g of TBAB, cool to -5 °C in a cold trap, and add 90 ml of 50 wt.% aqueous NaOH solution; after adding, ensure that the reaction system is within 5 °C, continue to add 75 g of BnBr, transfer to room temperature after adding and stir until the reaction is complete, and then perform post-treatment; add MTBE and water to the reaction system to extract three times and wash three times, collect the organic phase, rotary evaporate and then slurry with cyclohexane to obtain 110.2 g of RD-109-4, with a yield of 92.3%;

[0076] S5: In a reaction flask, mix 240 ml of formic acid, 580 ml of acetic acid and 180 ml of water evenly, and add 100 g of RD-109-4 to the reaction vessel; stir at room temperature until the reaction is complete as indicated by TLC, stop the reaction, quench the reaction with 50 wt.% NaOH solution and adjust the pH of the reaction system to 8 - 11; extract three times with DCM, wash the organic phase three times with saturated ammonium chloride, collect the organic phase and rotary evaporate to obtain 80 g of the target product RD-109-5, with a yield of 93.5%;

[0077] S6: Dissolve 80 g of RD-109-5 in 400 ml of THF. After adding 8.2 g of TBAB, place the reaction system in a cold trap and cool it to below 0 °C. Add 950 ml of 50 wt.% KOH aqueous solution to the reaction system. During the addition, maintain the reaction system below 5 °C. After the addition is complete, keep the system temperature below 0 °C. Then continue to add 39 g of TsCl to the reaction system. After the addition is complete, place the reaction at room temperature to start the reaction. After the reaction is indicated to be complete by TLC, extract with an EtOAc / water system three times, retain the organic phase, and wash it three times with saturated sodium chloride solution. Collect the organic phase and rotary evaporate it to obtain 68.3 g of RD-109-6, with a yield of 88.8%;

[0078] S7: Dissolve 65 g of RD-109-6 in 550 ml of THF. Under the protection of an inert gas, place the reaction system in a cold trap and cool it to below 0 °C. Slowly add 115 ml of a 1M LiAlH4 THF solution to the reaction system, maintaining the reaction system temperature below 0 °C during the addition. After the addition, place the reaction system at room temperature and stir to react. After the reaction is indicated to be complete by LCMS, add 100 ml of 10% NaOH aqueous solution to quench the reaction, then add EtOAc and water to extract the reaction system. After extracting three times, collect the organic phase and wash it three times with water. Retain the organic phase and rotary evaporate it to obtain 58.4 g of RD-109-7, with a yield of 89.4%;

[0079] S8: Dissolve 50 g of RD-109-7 in 250 ml of pyridine. Add 2.7 g of DMAP. Place the reaction system in a cold trap and cool it to below 0 °C. After adding 20 g of MsCl, transfer it to room temperature to start the reaction. After the reaction is indicated to be complete by LCMS, add 50 ml of saturated sodium bicarbonate solution to the reaction system to quench the reaction at below 0 °C. After quenching, extract with EtOAc three times. Collect the organic phase and wash it three times with saturated sodium carbonate solution. Retain the organic phase and rotary evaporate it to obtain 52.8 g of RD-109-0, with a yield of 89.9%;

[0080] S9: Dissolve 50 g of RD-109-0 in 250 ml of EtOAc. Add 28.7 g of Ac2O, and then dropwise add 1.8 g of concentrated sulfuric acid. React at room temperature until the reaction is complete. Add water and EtOAc to extract three times. Collect the organic phase and wash it three times with saturated sodium chloride aqueous solution. Retain the organic phase and rotary evaporate it to obtain 48.9 g of int-1, with a yield of 97.2 %.

[0081] Example 2: Synthesis of compound int-1

[0082] S1: Dissolve 300 g of RD-109-SM in 1800 ml of acetonitrile, add 370 g of IBX and 1800 ml of acetonitrile, reflux at 85 °C until TLC shows that the reaction is complete, start the work-up, cool down and filter through diatomaceous earth, wash with acetonitrile, collect and rotary evaporate the organic phase to obtain 286.3 g of RD-109-1, with a yield of 96.0%;

[0083] S2: Dissolve 286.3 g of RD-109-1 in 1700 ml of 2-MeTHF in a reaction flask; after adding 855.5 g of TEA, continue to add 1700 ml of 37 wt.% aqueous formaldehyde solution, stir at room temperature until the reaction is complete, and then perform the work-up; add saturated ammonium chloride solution at 0 °C to adjust the pH of the reaction solution to acidic, extract three times with ethyl acetate, and then wash three times with saturated ammonium chloride solution, collect and rotary evaporate the organic phase to obtain 284.5 g of RD-109-2, with a yield of 84.4%;

[0084] S3: Dissolve 284.5 g of RD-109-2 in 900 ml of MeOH, cool the reaction system to 0 °C, and add 35.3 g of NaBH4; then place the reaction system at room temperature and stir until the reaction is complete, and perform the work-up; cool the reaction system below 0 °C, quench with saturated ammonium chloride solution and extract three times with DCM, collect and rotary evaporate the organic phase to obtain 243.4 g of RD-109-3, with a yield of 92.0%;

[0085] S4: Dissolve 243.4 g of RD-109-3 in 1200 ml of THF, add 31.8 g of TBAB, cool to -5 °C in a cold trap, and add 240 ml of 50 wt.% aqueous NaOH solution; after adding, ensure that the reaction system is within 5 °C, continue to add 226 g of BnBr, transfer to room temperature after adding and stir until the reaction is complete, and then perform the work-up; add MTBE and water to the reaction system to extract three times and wash three times, collect the organic phase, rotary evaporate and then slurry with cyclohexane to obtain 337.2 g of RD-109-4, with a yield of 93.1%;

[0086] S5: In a reaction flask, mix 820 ml of formic acid, 1950 ml of acetic acid and 1000 ml of water evenly, and add 337.2 g (0.613 mol) of RD-109-4 to the reaction vessel; stir at room temperature until TLC indicates that the reaction is complete, stop the reaction, quench the reaction with 50 wt.% NaOH solution, and adjust the pH value of the reaction system to 8 - 11; extract three times with DCM, wash the organic phase three times with saturated ammonium chloride, collect the organic phase and rotary evaporate to obtain the target product RD-109-5 262.7 g (0.559 mol), with a yield of 91.2%;

[0087] S6: Dissolve 260 g of RD-109-5 in 1300 ml of THF. After adding 53.4 g of TBAB, place the reaction system in a cold trap and cool it to below 0 °C. Add 3900 ml of 50 wt.% KOH aqueous solution to the reaction system. During the addition, maintain the reaction system below 5 °C. After the addition is complete, keep the system temperature below 0 °C. Then continue to add 158.4 g of TsCl to the reaction system. After the addition is complete, place the reaction at room temperature to start the reaction. After the reaction is indicated to be complete by TLC, extract with an EtOAc / water system three times, retain the organic phase, and wash it three times with saturated sodium chloride solution. Collect the organic phase and rotary evaporate it to obtain 228.2 g of RD-109-6, with a yield of 91.3%;

[0088] S7: Dissolve 225 g of RD-109-6 in 2300 ml of THF. Under the protection of an inert gas, place the reaction system in a cold trap and cool it to below 0 °C. Slowly add 448 ml of a THF solution of 1M LiAlH4 to the reaction system, maintaining the reaction system temperature below 0 °C during the addition. After the addition, place the reaction system at room temperature and stir to react. After the reaction is indicated to be over by LCMS, add 460 ml of 10% NaOH aqueous solution to quench the reaction, then add EtOAc and water to extract the reaction system. After extracting three times, collect the organic phase and wash it three times with water. Retain the organic phase and rotary evaporate it to obtain 204.1 g of RD-109-7, with a yield of 90.3%;

[0089] S8: Dissolve 200 g of RD-109-7 in 1000 ml of pyridine. Add 12.5 g of DMAP. Place the reaction system in a cold trap and cool it to below 0 °C. After adding 100 g of MsCl, transfer it to room temperature to start the reaction. After the reaction is indicated to be complete by LCMS, add 200 ml of saturated sodium bicarbonate solution to the reaction system below 0 °C to quench the reaction. After quenching, extract with EtOAc three times. Collect the organic phase and wash it three times with saturated sodium carbonate solution. Retain the organic phase and rotary evaporate it to obtain 221.4 g of RD-109-0, with a yield of 94.3%;

[0090] S9: Dissolve 220 g of RD-109-0 in 1100 ml of EtOAc. Add 126.3 g of Ac2O, and then dropwise add 8.1 g of concentrated sulfuric acid. React at room temperature until the reaction is complete. Add water and EtOAc to extract three times. Collect the organic phase and wash it three times with saturated sodium chloride aqueous solution. Retain the organic phase and rotary evaporate it to obtain 213.1 g of int-1, with a yield of 96.3%.

[0091] Example 3: Synthesis of compound int-1

[0092] S1: Dissolve 1 kg of RD-109-SM in 6 L of acetonitrile, add 1.07 kg of IBX and 1800 ml of acetonitrile, reflux at 85 °C until TLC shows that the reaction is complete, start the post-treatment, cool down, filter through diatomaceous earth, wash with acetonitrile, collect and rotary evaporate the organic phase to obtain 945.2 g of RD-109-1, with a yield of 95.1%;

[0093] S2: Dissolve 945.2 g of RD-109-1 in 7.5 L of 2-MeTHF in a reaction kettle; after adding 2824.0 g of TEA, continue to add 4726 ml of 37 wt.% aqueous formaldehyde solution, stir at room temperature until the reaction is complete, and then carry out the post-treatment; add saturated ammonium chloride solution at 0 °C to adjust the pH of the reaction solution to acidic, extract three times with ethyl acetate, and then wash three times with saturated ammonium chloride solution, collect and rotary evaporate the organic phase to obtain 955.6 g of RD-109-2, with a yield of 85.9%;

[0094] S3: Dissolve 955.6 g of RD-109-2 in 3 L of MeOH, cool the reaction system to 0 °C, and add 35.3 g of NaBH4 (0.930 mol); then place the reaction system at room temperature and stir until the reaction is complete, and carry out the post-treatment; cool the reaction system below 0 °C, quench with saturated ammonium chloride solution and extract three times with DCM, collect and rotary evaporate the organic phase to obtain 828.1 g (2.238 mol) of RD-109-3, with a yield of 95.1%;

[0095] S4: Dissolve 828.1 g of RD-109-3 in 4 L of THF, add 144.1 g of TBAB, cool to -5 °C in a cold trap, and add 900 ml of 50 wt.% aqueous NaOH solution; after adding, ensure that the reaction system is within 5 °C, continue to add 811.3 g of BnBr, transfer to room temperature and stir until the reaction is complete, and then carry out the post-treatment; add MTBE and water to the reaction system to extract three times and wash three times, collect the organic phase, rotary evaporate and then slurry with cyclohexane to obtain 1131.6 g of RD-109-4, with a yield of 91.9%;

[0096] S5: In a reaction flask, 2.5 L of formic acid, 6.0 L of acetic acid and 3 L of water were mixed evenly, and then 1131.6 g (2.057 mol) of RD-109-4 was added to the reaction vessel; the reaction was stirred at room temperature until the TLC indicated that the reaction was complete, then the reaction was stopped, quenched with 50 wt.% NaOH solution, and the pH value of the reaction system was adjusted to 8 - 11; after extraction with DCM three times and washing the organic phase with saturated ammonium chloride three times, the organic phase was collected and rotary evaporated to obtain 890.4 g of the target product RD-109-5, with a yield of 92.1%;

[0097] S6: 890 g of RD-109-5 was dissolved in 5.3 L of THF, 152 g of TBAB was added, and the reaction system was placed in a cold trap and cooled to below 0 °C. Then 13.3 L of 50 wt.% KOH aqueous solution was added to the reaction system, and the reaction system was maintained below 5 °C during the addition. After the addition was completed, the system temperature was maintained below 0 °C, and 506 g of TsCl was continuously added to the reaction system. After the addition was completed, the reaction was placed at room temperature to start the reaction. After the TLC indicated that the reaction was complete, it was extracted three times with an EtOAc / water system, the organic phase was retained, and washed three times with saturated sodium chloride solution. The organic phase was collected and rotary evaporated to obtain 802.4 g of RD-109-6, with a yield of 93.7%;

[0098] S7: 800 g of RD-109-6 was dissolved in 9.5 L of THF. Under the protection of an inert gas, the reaction system was placed in a cold trap and cooled to below 0 °C. 1.4 L of a 1M LiAlH4 THF solution was slowly added to the reaction system, and the reaction system temperature was maintained below 0 °C during this period; after the addition, the reaction system was placed at room temperature and stirred for reaction; after the LCMS indicated that the reaction was over, 100 ml of 10% NaOH aqueous solution was added to quench the reaction, and then EtOAc and water were used to extract the reaction system. After extraction three times, the organic phase was collected and washed with water three times. The organic phase was retained and rotary evaporated to obtain 721.3 g of RD-109-7, with a yield of 89.7%;

[0099] S8: 720 g of RD-109-7 was dissolved in 4 L of pyridine, 38 g of DMAP was added, the reaction system was placed in a cold trap and cooled to below 0 °C, and then 451 g of MsCl was added. After transfer to room temperature, the reaction started. After the LCMS indicated that the reaction was complete, 800 ml of saturated sodium bicarbonate solution was added to the reaction system to quench the reaction at below 0 °C. After quenching, it was extracted three times with EtOAc. The organic phase was collected and washed three times with saturated sodium carbonate solution. The organic phase was retained and rotary evaporated to obtain 747.1 g of RD-109-0, with a yield of 88.4%;

[0100] S9: Dissolve 745 g of RD-109-0 in 3 L of EtOAc, add 427 g of Ac2O, then dropwise add 27.3 g of concentrated sulfuric acid, react at room temperature until the reaction is complete, extract with water and EtOAc three times, collect the organic phase and wash it three times with saturated sodium chloride aqueous solution, retain the organic phase and rotary evaporate to dryness to obtain 710.9 g of int-1, with a yield of 98.1%.

[0101] Example 4: Synthesis of compound int-2

[0102] 。

[0103] S1: Dissolve 100 g of RD-109-SM in 500 ml of acetonitrile, add 140 g of IBX and 500 ml of acetonitrile, reflux at 85 °C until TLC shows that the reaction is complete, start the post-treatment, cool down and filter through diatomaceous earth, wash with acetonitrile, collect and rotary evaporate the organic phase to dryness to obtain 96.8 g of RD-109-1, with a yield of 97.4%;

[0104] S2: Dissolve 96.8 g of RD-109-1 in 900 ml of 2-MeTHF in a reaction flask; after adding 400 g of TEA, continue to add 500 ml of 37 wt.% formaldehyde aqueous solution, stir at room temperature until the reaction is complete, and then carry out the post-treatment; add saturated ammonium chloride solution at 0 °C to adjust the pH value of the reaction solution to acidic, then extract three times with ethyl acetate, and then wash three times with saturated ammonium chloride solution, collect and rotary evaporate the organic phase to dryness to obtain 95.0 g of RD-109-2, with a yield of 83.3%;

[0105] S3: Dissolve 95 g of TD-109-2 in 300 ml of MeOH, cool the reaction system to 0 °C, and then add 9.5 g of NaBH4; then place the reaction system at room temperature and stir until the reaction is complete, and carry out the post-treatment; cool the reaction system below 0 °C, quench with saturated ammonium chloride solution and then extract three times with DCM, collect and rotary evaporate the organic phase to dryness to obtain 85.5 g of RD-109-3, with a yield of 92.4%;

[0106] S4: Dissolve 85 g of RD-109-3 in 450 ml of THF, add 14 g of TBAB, cool to -5 °C in a cold trap, and add 92 ml of 50 wt.% NaOH aqueous solution; after adding, ensure that the reaction system is within 5 °C, continue to add 86 g of TBSCl, transfer to room temperature after adding and stir until the reaction is complete, and then carry out the post-treatment; add MTBE and water to the reaction system to extract three times and wash three times, collect the organic phase, rotary evaporate to dryness and then slurry with cyclohexane to obtain 107.9 g of RD-109-4-1, with a yield of 83.5%;

[0107] S5: In a reaction flask, after mixing 240 ml of formic acid, 580 ml of acetic acid and 180 ml of water uniformly, 1100 g of RD-109-4-1 was added to the reaction vessel; the reaction was stirred at room temperature until TLC indicated that the reaction was complete, then the reaction was stopped, quenched with 50 wt.% NaOH solution, and the pH value of the reaction system was adjusted to 8 - 11; after extracting three times with DCM and washing the organic phase three times with saturated ammonium chloride, the organic phase was collected and rotary evaporated to obtain 81.2 g of the target product RD-109-5-1, with a yield of 94.0%;

[0108] S6: 80 g of RD-109-5-1 was dissolved in 400 ml of THF, after adding 9.9 g of TBAB, the reaction system was placed in a cold trap and cooled to below 0 °C, 950 ml of 50 wt.% KOH aqueous solution was added to the reaction system, during the addition, 44 g of TsCl was added, after the addition was completed, the reaction was placed at room temperature to start the reaction, after TLC indicated that the reaction was complete, it was extracted three times with an EtOAc / water system, the organic phase was retained, washed three times with saturated sodium chloride solution, the organic phase was collected and rotary evaporated to obtain 164.0 g of RD-109-6-1, with a yield of 82.7%;

[0109] S7: 64 g of RD-109-6-1 was dissolved in 550 ml of THF, under the protection of an inert gas, the reaction system was placed in a cold trap and cooled to below 0 °C, 102 ml of a 1M LiAlH4 THF solution was slowly added to the reaction system, during which the temperature of the reaction system was maintained below 0 °C; after the addition, the reaction system was placed at room temperature and stirred for reaction; after LCMS indicated that the reaction was over, 100 ml of 10% NaOH aqueous solution was added to quench the reaction, then EtOAc and water were added to extract the reaction system, after extracting three times, the organic phase was collected and washed three times with water, the organic phase was retained and rotary evaporated to obtain 58.9 g of RD-109-7-1, with a yield of 91.7%;

[0110] S8: 50 g of RD-109-7-1 was dissolved in 250 ml of pyridine, 2.7 g of DMAP was added, the reaction system was placed in a cold trap and cooled to below 0 °C, after adding 20 g of MsCl, it was transferred to room temperature to start the reaction, after LCMS indicated that the reaction was complete, 50 ml of saturated sodium bicarbonate solution was added to the reaction system to quench the reaction at below 0 °C, after quenching, it was extracted three times with EtOAc, the organic phase was collected and washed three times with saturated sodium carbonate solution, the organic phase was retained and rotary evaporated to obtain 52.8 g of RD-109-0-1, with a yield of 89.9%;

[0111] S9: Dissolve 50 g of RD-109-0-1 in 250 ml of EtOAc, add 26.3 g of Ac2O, and then dropwise add 1.7 g of concentrated sulfuric acid. React at room temperature until the reaction is complete. Extract with water and EtOAc three times. Collect the organic phase and wash it three times with saturated sodium chloride aqueous solution. Retain the organic phase and rotary evaporate to obtain 43.4 g of int-2, with a yield of 86.4%.

[0112] Example 5 Synthesis of Compound int-3

[0113] 。

[0114] Add 100 g of SM1 to a mixed solution of 580 ml of acetic acid, 240 ml of formic acid and 180 ml of water, start stirring. After 30 minutes, pour the reaction into 1350 ml of 50 wt% sodium hydroxide solution under an ice bath, continue stirring for 10 minutes, stop the reaction, extract with DCM, retain the organic phase. TLC shows that there is remaining raw material and multiple products are formed. LCMS shows that a by-product with M+H = 391 is formed. Concentrate and column separate the organic phase to obtain 16 g of raw material SM1, 27.2 g of by-product BP-1, and 26 g of compound int-3.

[0115] Example 6 Synthesis of Compound int-4

[0116] 。

[0117] Add 100 g of SM2 to a mixed solution of 218 ml of acetic acid, 528 ml of formic acid and 164 ml of water, start stirring. After 30 minutes, pour the reaction into 1270 ml of 50 wt% sodium hydroxide solution under an ice bath, continue stirring for 10 minutes, stop the reaction, extract with DCM, retain the organic phase. TLC shows that there is remaining raw material and multiple products are formed. LCMS shows that the reaction is rather messy and a by-product with M+H = 439 is formed. Concentrate the organic phase, and after column separation, obtain 18 g of raw material SM2, 12 g of compound int-4, and 14 g of by-product BP-2.

[0118] Although the exemplary embodiments have been shown and described above, it will be apparent to those skilled in the art that modifications and variations can be made without departing from the scope defined by the appended claims of the present invention. Therefore, without departing from the spirit and scope defined by the claims of the present disclosure, those skilled in the art can make various types of substitutions, modifications and changes, and these substitutions, modifications and changes will be considered to fall within the scope of the present disclosure.

Claims

1. A method for preparing a compound of formula RD-109-5, characterized in that: The method comprises the following steps: RD-109-4 is reacted in the presence of an acid to obtain RD-109-5; the synthesis route is as follows: ， Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl; The acid is an organic acid, preferably one or a mixture of formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid and oxalic acid.

2. The preparation method according to claim 1, characterized in that: RD-109-4 is reacted in a solvent in the presence of an acid, wherein the solvent is one or a mixture of water, ethanol, methanol, toluene, isopropanol, trifluoroethanol, acetonitrile and tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that: The organic acid is selected from a mixture of formic acid and acetic acid, and the volume ratio of the formic acid to the acetic acid is 2-3:5-6.

4. A method for preparing a compound of formula I, characterized in that: The steps include: S1: RD-109-5 is reacted in the presence of a phase transfer catalyst, a base and a sulfonylating agent to prepare RD-109-6. The phase transfer catalyst is selected from tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, tetrabutylphosphonium chloride, triphenylmethylphosphonium chloride, 18-crown-6 ether, polyethylene glycol, tetrabutylphosphonium bromide, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Cyclodextrin; the base is selected from triethylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium tert-butoxide, piperidine, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium acetate, sodium acetate, potassium acetate, ammonium acetate and lithium aminoacetate; the sulfonylating agent is selected from one of methylsulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethanesulfonyl chloride and p-toluenesulfonyl chloride; S2: RD-109-6 is reduced to obtain RD-109-7; the reducing agent is selected from one or more of sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, zinc borohydride, sodium triacetoxyborohydride, potassium borohydride, lithium tri-sec-butylborohydride, calcium borohydride, lithium cyanoborohydride, lithium tri-tert-butoxyaluminum hydride and diisobutylaluminum hydride; preferably, the reduction reaction is carried out in a solvent, and the solvent is one or more of methanol, ethanol, isopropanol, polyethylene glycol, N-methylpyrrolidone, acetonitrile, ethylene glycol dimethyl ether, 2-methoxyethanol, toluene and tetrahydrofuran; S3: RD-109-7 is added with methanesulfonyl chloride in the presence of a catalyst to react and obtain RD-109-0; the catalyst is selected from one of 4-dimethylaminopyridine, imidazole, triethylamine, N,N-diisopropylethylamine, N-methylimidazole and 1,8-diazabicycloundec-7-ene; S4: RD-109-0 reacts with acetic anhydride to obtain a compound of formula I; preferably, sulfuric acid is added as a catalyst in step S4; Its synthetic route is as follows: ， Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl; Wherein, the RD-109-5 compound is prepared according to the preparation method according to any one of claims 1 to 3.

5. The preparation method according to claim 4, characterized in that: Step S1: The reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, 1,2-dichloroethane, chloroform, methyl tert-butyl ether and diethyl ether; Preferably, the base is selected from potassium hydroxide; Preferably, the molar ratio of RD-109-5 to the phase transfer catalyst is 1:0.1-0.3; the molar ratio of the sulfonylating agent to RD-109-5 is 1:1.1-1.

5.

6. The preparation method according to claim 4, characterized in that: The reduction reaction in step S2 is carried out in a solvent, wherein the solvent is one or a mixture of methanol, ethanol, isopropanol, polyethylene glycol, N-methylpyrrolidone, acetonitrile, ethylene glycol dimethyl ether, 2-methoxyethanol, toluene and tetrahydrofuran; Preferably, the original agent is selected from lithium aluminum tetrahydride; Preferably, the solvent is selected from tetrahydrofuran; Preferably, the molar ratio of RD-109-6 to the reducing agent is 0.7-1.0:1, and the mass volume ratio of RD-109-6 to the solvent 7 is 1:8-12.

7. The preparation method according to claim 4, characterized in that: Step S3: reacting in a solvent, wherein the solvent is selected from one or more of pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethyl acetate and dimethyl sulfoxide; Preferably, the catalyst is selected from 4-dimethylaminopyridine; Preferably, the solvent is selected from pyridine; Preferably, the molar ratio of the compound RD-109-7 to the catalyst is 1:0.1-0.3; the molar ratio of the compound RD-109-7 to methanesulfonyl chloride is 1:1.5-2.5; the mass volume ratio of the compound RD-109-7 to the solvent is 1:3-6.

8. The preparation method according to claim 4, characterized in that: In step S4, sulfuric acid is added as a catalyst, and the molar ratio of the compound RD-109-0 to acetic anhydride is 1:2-5, preferably 1:3; the molar ratio of the compound RD-109-0 to sulfuric acid is 1:0.1-0.3, preferably 1:0.

2.

9. A method for preparing RD-109-4, characterized in that: The steps include: 1) RD-109-SM is dissolved in a solvent, an oxidant is added, and the reaction is performed to obtain RD-109-1; the oxidant is selected from 2-iodoxybenzoic acid, a combination of tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide, and a Dess-Martin oxidant; the solvent is selected from acetonitrile, dimethyl sulfoxide, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and acetone; 2) RD-109-1 reacts with formaldehyde in the presence of a base to obtain RD-109-2; the formaldehyde is a 37 wt% aqueous solution; the base is an inorganic base or an organic base; the inorganic base is sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and the organic base is triethylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide, sodium tert-butoxide, piperidine, sodium ethoxide, lithium acetate, sodium acetate, potassium acetate, ammonium acetate and lithium aminoacetate; preferably, the reaction is carried out in solvent B, and the solvent B is selected from 2-methyltetrahydrofuran, tetrahydrofuran, dimethyl sulfoxide, dichloromethane, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, ethanol, methanol and diethyl ether; 3) Reducing RD-109-2 to obtain RD-109-3; the reduction reaction is carried out in the presence of a reducing agent, and the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, lithium triethylborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, zinc borohydride, sodium triacetoxyborohydride, potassium borohydride, lithium tri-sec-butylborohydride, calcium borohydride, lithium cyanoborohydride, lithium tri-tert-butoxyaluminum hydride and diisobutylaluminum hydride; 4) RD-109-3 is reacted with R1X in the presence of a catalyst and a base to obtain RD-109-4, wherein X is a halogen; the catalyst is tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, tetrabutylphosphonium chloride, triphenylmethylphosphonium chloride, 18-crown-6 ether, polyethylene glycol, tetrabutylphosphonium bromide, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin; the base is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, imidazole, tetrabutylammonium hydroxide, sodium methoxide, sodium ethoxide, cesium carbonate and potassium phosphate; Its synthetic route is as follows: ， Wherein, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl.

10. The preparation method according to claim 9, characterized in that: In step 1), the solvent is selected from acetonitrile, and the oxidant is selected from 2-iodoacylbenzoic acid; the volume mass ratio of the solvent to RD-109-SM is 4-6:1; and the molar ratio of the oxidant to RD-109-SM is 1.2-1.5:

1.

11. The preparation method according to claim 9, characterized in that: In step 2), the solvent is selected from 2-methyltetrahydrofuran, the organic base is selected from triethylamine; the volume mass ratio of the formaldehyde aqueous solution to RD-109-1 is 4-6:1; the volume mass ratio of the solvent to RD-109-1 is 5-10:1; and the molar ratio of the organic base to RD-109-1 is 8-15:

1.

12. The preparation method according to claim 9, characterized in that: In step 3), the solvent is selected from methanol; the reducing agent is selected from sodium borohydride; and the molar ratio of RD-109-2 to the reducing agent is 1:(1.1-1.3).

13. The preparation method according to claim 9, characterized in that: In step 4), the solvent is selected from tetrahydrofuran, the phase transfer catalyst is selected from tetrabutylammonium bromide; the inorganic base is selected from sodium hydroxide; R1X is benzyl bromide; the volume mass ratio of the solvent to RD-109-3 is 3-5:1; the molar ratio of RD-109-3 to the phase transfer catalyst is 0.1-0.3:1; the molar ratio of SRD-109-3 to benzyl bromide is 1:2-2.5; the molar ratio of RD-109-3 to the inorganic base is 1:8-12; the molar ratio of RD-109-3 to the inorganic base is 1:8-12.

14. Nucleotide intermediate compounds: ,in, R1 is selected from TBS, Bn, TBDPS or naphthylmethyl.

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