Preparation method of TNA monomer

Abstract

The invention discloses a preparation method of a TNA monomer, and belongs to the technical field of synthesis of medical intermediates. According to the method, the reaction sequence of DMT protecting groups is changed, the DMT protecting groups are directly introduced before docking, then a universal compound 4 is generated, a silicon protection step is omitted, docking reaction can also be carried out, the yield is not influenced, impurities removed from DMT and known products protected by DMT are not found by reasonably controlling a post-treatment mode, and the DMT protecting groups are easy to remove under an acidic condition, so that the method is suitable for industrial production. However, by controlling the reaction and post-treatment conditions, the DMT protection raw material stably exists in the reaction catalyzed by the lewis acid, the problem of acid stability of the DMTr-protection raw material is solved, and four TNA monomers are successfully prepared.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically, it relates to a method for preparing a TNA monomer. Background Technology

[0002] L-rhamnofuranoside monomers (TNA monomers) possess a unique four-carbon sugar backbone, significantly differentiating them chemically from RNA and DNA and exhibiting superior enzymatic stability. Sequence-specific TNA macromolecules demonstrate high affinity and specificity for complementary RNA targets, and possess high biocompatibility, non-cytotoxicity, and resistance to biodegradation. Importantly, the efficacy of TNA molecules targeting green fluorescent protein (GFP) suggests that sequence-controlled TNAs can serve as effective alternatives to functional biomaterials and traditional antisense oligonucleotide therapies.

[0003] Existing techniques (such as ACS Appl. Mater. Interfaces 2018, 10, 9736−9743, J. Org. Chem. 2016, 81, 2302−2307) for the preparation of TNA monomers involve first protecting the hydroxyl group at position 3 of the sugar ring with a silicon protecting group, then reducing the hydroxyl group at position 1 to form Ac, followed by docking with a base, then removing the silicon protecting group, and further adding DMTr and phosphine to generate the target compound 9. Literature indicates an overall yield of 16-23%. Based on current yield data, it is necessary to improve existing techniques and find a more efficient synthetic route. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing TNA monomers.

[0005] The objective of this invention can be achieved through the following technical solutions: A method for preparing a TNA monomer includes the following steps: Step 1: Dissolve compound 1 in the reaction solvent, then add 4,4'-dimethoxytriphenylchloromethane (DMT-Cl) and an alkaline catalyst, stir the reaction for 16-18 h, TLC shows that the starting material reacts completely, evaporate the reaction solution to dryness, dissolve the crude product in dichloromethane, and after post-processing, obtain compound 2; Step 2: Dissolve compound 2 in the reaction solvent, add a reducing agent dropwise under argon protection, and carry out the reaction. TLC shows that the starting material reacts completely. After post-processing, without purification, compound 3 is obtained. Step 3: Dissolve compound 3 in the reaction solvent, acetylation reagent and basic catalyst, and react at room temperature for 1-2 hours. TLC shows that the starting material has reacted completely. Dry the reaction solution by rotary evaporation, dissolve the crude product in dichloromethane, and perform post-treatment to obtain compound 4. Step 4: Add base 8 to the reaction solvent, stir well, add compound 4 and N,O-bis(trimethylsilyl)acetamide, and react for 40-60 min. Then add trimethylsilyl trifluoromethanesulfonate and continue the reaction for 1 h. TLC shows that the raw materials have basically reacted completely. Cool to room temperature and perform post-processing to obtain compound 5. Step 5: Dissolve compound 5 in the reaction solvent, add alkaline solution, react at -5℃ for 50 min, TLC shows that the starting material is basically completely reacted, post-processing to obtain compound 6; Step 6: Dissolve compound 6 in the reaction solvent, co-distill once at 45°C, then add another reaction solvent, and then add the catalyst and phosphine reagent in sequence. React at room temperature for 2 hours. The TLC raw material reacts basically completely. After post-processing, TNA monomer is obtained.

[0006] As a further technical solution, in step 1, compound 1 is (3R,4S)-benzoic acid (4-hydroxy-2-oxo-3-tetrahydrofuranyl) ester.

[0007] As a further technical solution, the reaction solvent in step 1 is one or more of pyridine, dichloromethane, acetonitrile, and ethyl acetate.

[0008] As a further technical solution, the alkaline catalyst in step 1 is selected from one or more of pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine, N,N-diisopropylethylamine, and triethylamine.

[0009] As a further technical solution, the temperature of the stirring reaction in step 1 is 20-40℃.

[0010] As a further technical solution, the post-processing method in step 1 is as follows: washing with citric acid solution, sodium bicarbonate solution and saline solution in sequence, concentrating the organic phase and separating by column chromatography.

[0011] As a further technical solution, the reaction solvent in step 2 is one or more of tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and dichloromethane.

[0012] As a further technical solution, the reducing agent in step 2 is one or more of diisobutylaluminum hydride, lithium aluminum hydride, and boranetetrahydrofuran.

[0013] As a further technical solution, the reaction temperature in step 2 is -78℃ to 20℃.

[0014] As a further technical solution, the post-treatment method in step 2 is as follows: water, sodium hydroxide aqueous solution, sulfate are added dropwise in sequence, the mixture is heated to room temperature and stirred, and then filtered through diatomaceous earth and evaporated.

[0015] As a further technical solution, the reaction solvent in step 3 is one or more of acetonitrile, dichloromethane, pyridine, and tetrahydrofuran.

[0016] As a further technical solution, the alkaline catalyst in step 3 is one or more of pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, imidazole, N,N-diisopropylethylamine, and N-methylmorpholine.

[0017] As a further technical solution, the acetylation reagent in step 3 is one of acetyl chloride and acetic anhydride.

[0018] As a further technical solution, the post-processing method in step 3 is as follows: washing with saturated sodium bicarbonate, citric acid, saturated sodium bicarbonate and saturated NaCl in sequence, followed by rotary evaporation and column chromatography separation.

[0019] As a further technical solution, the reaction solvent in step 4 is one or more of dichloroethane, acetonitrile, toluene, 2-methyltetrahydrofuran, and 1,4-dioxane.

[0020] As a further technical solution, in step 4, the molar ratio of compound 4, N,O-bis(trimethylsilyl)acetamide and base 8 is 1:2-5:1-5.

[0021] As a further technical solution, in step 4, base 8 is one of four types: a, b, c, and d, where a: N2-acetyl-O6-(diphenylcarbamoyloxy)guanine, b: N6-benzoyladenine, c: N4-benzoylcytosine, and d: thymine.

[0022] As a further technical solution, the reaction temperature in step 4 is 20-130℃.

[0023] As a further technical solution, the post-processing method in step 4 is as follows: add solvent to dilute the reaction solution, then add sodium bicarbonate solution, stir and separate the liquids, wash the organic phase with sodium bicarbonate and saturated saline, concentrate, adsorb onto silica gel, filter and collect the filtrate, and concentrate.

[0024] In one specific implementation, the reaction solvent in step 5 is a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane with methanol, ethanol, or isopropanol.

[0025] In one specific implementation, the alkaline solution in step 5 is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide solutions.

[0026] As a specific implementation method, the post-processing method in step 5 is as follows: adjust the pH of the system to ≈7, then add ethyl acetate and water, extract and wash, take the organic phase, wash with saturated brine, dry with sodium sulfate, filter and concentrate under reduced pressure, and then separate by column chromatography.

[0027] In one specific implementation, the reaction solvent in step 6 is one or more of dichloromethane, acetonitrile, tetrahydrofuran, and 2-methylfuran.

[0028] In one specific implementation, the catalyst in step 6 is one or more of the following: tetrazolium, diisopropylethylamine tetrazolium, ethylthiotetrazolium, 4,5-dicyanimidazolium, pyridine trifluoroacetate, N,N-diisopropylethylamine, and N-methylmorpholine.

[0029] In one specific implementation, the phosphine reagent in step 6 is one of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine or 2-cyanoethyl N,N-diisopropylchlorophosphine.

[0030] As a specific implementation method, the post-processing method in step 6 is as follows: quench the reaction by adding sodium bicarbonate solution, extract with dichloromethane, wash the organic phase three times with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and then evaporate to dryness and pass through a column.

[0031] The reaction equations for steps 1 to 6 are as follows: This invention uses compound 1 as the starting material, adds DMT to the 3-position of the sugar ring, then reduces the carbonyl group at the 1-position to a hydroxyl group, then acetylates it, and then docks it with different bases to generate key intermediate 5. Intermediate 5 is hydrolyzed and phosphine is added to obtain the final product 7, which is the TNA monomer.

[0032] The beneficial effects of this invention are: This invention alters the reaction sequence of the DMT protecting group, introducing it directly before docking to generate a universal compound 4. The silicon protection step is omitted, yet the docking reaction can still proceed without affecting the yield. Through proper control of the post-treatment process, no impurities removed by DMT were found. It is known that DMT-protected products are easily removed under acidic conditions, but by controlling the reaction and post-treatment conditions, we ensured the stability of the DMT-protected raw material in a Lewis acid-catalyzed reaction. This invention overcomes the acid stability problem of the DMT-protected raw material and successfully prepared four TNA monomers. Attached Figure Description

[0033] The invention will now be further described with reference to the accompanying drawings.

[0034] Figure 1 The hydrogen spectrum of compound 4 obtained in Example 1 of this invention is shown.

[0035] Figure 2 The hydrogen spectrum of the TNA-a monomer prepared in Example 3 of this invention is shown.

[0036] Figure 3 The phosphorus spectrum of the TNA-a monomer prepared in Example 3 of this invention is shown.

[0037] Figure 4 The hydrogen spectrum of the TNA-b monomer prepared in Example 4 of this invention is shown.

[0038] Figure 5 The phosphorus spectrum of the TNA-b monomer prepared in Example 4 of this invention is shown.

[0039] Figure 6 The hydrogen spectrum of the TNA-c monomer prepared in Example 5 of this invention is shown.

[0040] Figure 7 The phosphorus spectrum of the TNA-c monomer obtained in Example 5 of this invention is shown.

[0041] Figure 8 The hydrogen spectrum of the TNA-d monomer prepared in Example 6 of this invention is shown.

[0042] Figure 9 The phosphorus spectrum of the TNA-d monomer obtained in Example 6 of this invention is shown. Detailed Implementation

[0043] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0044] Example 1 Preparation of compound 4: Step 1: Dissolve 117 g of (3R,4S)-benzoic acid (4-hydroxy-2-oxo-3-tetrahydrofuranyl) ester in 900 ml of pyridine, add 267.6 g of DMTCl, stir at room temperature for 16-18 hours, and TLC shows that the starting material has reacted completely. Dry the reaction mixture at 45°C. Dissolve the crude product in dichloromethane, wash twice with citric acid solution, separate the layers, wash the organic phase once with saturated sodium bicarbonate aqueous solution and once with saturated brine, dry the DCM phase with sodium sulfate, and evaporate to dryness at 50°C to obtain 363 g of crude product. Separate the crude product by column chromatography to obtain 248.5 g of oily substance 2 with a purity of 97% and a yield of 90%. Step 2: Dissolve 187 g of compound 2 in 1.8 L of THF. Under argon protection, lower the internal temperature to approximately -70 °C with dry ice / ethanol. Add 713 ml of DIBAL-H dropwise and maintain the internal temperature at approximately -70 °C for 2 hours. If there is residual starting material on TLC, add 0.5 eq of DIBAL-H and continue to maintain the internal temperature at approximately -70 °C for 1 hour. TLC shows that the starting material has reacted completely. Control the internal temperature below -60 °C and add 40 ml of water, 40 ml of 15% sodium hydroxide aqueous solution, and then add 160 g of anhydrous magnesium sulfate. Raise the temperature to room temperature and stir for 0.5 h. Filter through diatomaceous earth, wash the filter cake with DCM, and evaporate the filtrate at 45 °C to obtain 142 g of crude product 3. Add it directly to the next step without purification. Step 3: Dissolve 142 g of compound 3 in 710 ml of dichloromethane + 710 ml of pyridine, add 41.3 g of acetic anhydride and 16.4 g of DMAP, react at room temperature for 1 hour, add a 25°C water bath, and TLC shows that the starting material has reacted completely. Dry the reaction mixture at 45°C. Dissolve the crude product in 800 ml of dichloromethane, wash twice with citric acid solution, separate the layers, wash the DCM phase once with saturated sodium bicarbonate aqueous solution, separate the layers, wash the DCM phase once with saturated brine, and then dry with sodium sulfate. Dry at 45°C to obtain 180 g of crude product. Separate the crude product by column chromatography to obtain 124 g of compound 4 with a purity of 95%. Measure the proton NMR spectrum of compound 4 using nuclear magnetic resonance spectroscopy. Figure 1 The 1H NMR data are as follows: 1H NMR (400 MHz, DMSO) δ 8.04-7.96 (m, 1H), 7.92-7.86 (m, 1H), 7.78-7.41 (m, 5H), 7.35-7.16 (m, 7H), 6.88-6.76 (m, 4H), 6.32-5.92 (m, 1H), 5.54-4.83 (m, 1H), 4.56-4.35 (m, 1H), 3.83-3.71 (m, 1H), 3.65 (m, 6H), 3.06 (m, 1H), 2.00 (m, 3H).

[0045] Example 2 Preparation of compound 4: Step 1: Dissolve 90g of (3R,4S)-benzoic acid (4-hydroxy-2-oxo-3-tetrahydrofuranyl) ester in a mixed solution of 900ml dichloromethane and 100mL pyridine, add 206g of DMTCl, stir at room temperature for 16-18 hours, and TLC shows that the starting material reacts completely. Wash the reaction solution twice with citric acid solution, separate the liquid and liquid phases, wash the organic phase once with saturated sodium bicarbonate aqueous solution and once with saturated brine, dry the DCM phase with sodium sulfate, and evaporate to dryness at 50℃ to obtain 363g of crude product. Separate the crude product by column chromatography to obtain 189g of oily substance 2 with a purity of 98% and a yield of 89%. Step 2: Dissolve 20g of compound 2 in 200mL of THF under nitrogen protection and temperature control at -20℃. Add lithium aluminum hydride (2 equivalents) dropwise. After the addition is complete, keep the temperature at -20℃ for 1 hour. After the reaction is complete, add water, 15% sodium hydroxide aqueous solution, and then add anhydrous sodium sulfate. Raise the temperature to room temperature and stir for 0.5h. Filter with diatomaceous earth, wash the filter cake with DCM, and evaporate the filtrate at 45℃ to obtain 15.9g of crude product 3. Add it directly to the next step without purification. Step 3: Dissolve 15.9 g of compound 3 in 100 mL of dichloromethane and 100 mL of pyridine, add 4.62 g of acetyl chloride and 1.8 g of DMAP, react at room temperature for 1 hour, and TLC shows that the starting material has reacted completely. Rotate the reaction solution to dryness at 45 °C. Dissolve the crude product in dichloromethane, wash twice with citric acid solution, separate the phases, wash the DCM phase once with saturated sodium bicarbonate aqueous solution, separate the phases, wash the DCM phase once with saturated brine, and dry with sodium sulfate. Rotate the solution to dryness at 45 °C to obtain 180 g of crude product. Separate the crude product by column chromatography to obtain 416.2 g of compound with a purity of 96%.

[0046] Example 3 Preparation of TNA-a: Step 4: Add 36g of N2-acetyl-O6-(diphenylcarbamoyloxy)guanine to 150ml of dichloroethane and stir until homogeneous. Add 45g of compound 4 and 39g of BSA. Increase the external temperature to 60℃ and react for 40-60 minutes. Then add 10.3g of TMSOTf and react at 60℃ for 1 hour. TLC shows that the starting material has basically reacted completely. Cool to room temperature and process directly. Add 150ml of dichloromethane to dilute the reaction solution and pour it into 450ml of saturated sodium bicarbonate aqueous solution. Stir for 10 minutes. Filter the emulsion and insoluble solids through diatomaceous earth. Separate the layers. Wash the DCM phase once again with 450ml of saturated sodium bicarbonate aqueous solution. At this time, the pH of the aqueous phase is 7. Separate the layers. Wash the DCM phase once with 200ml of saturated saline solution. Separate the layers. Dry the DCM phase with sodium sulfate. Add 120g of silica gel to the filtrate and stir at room temperature (20℃) for 2 hours. Filter, wash the product in the silica gel and adsorb some impurities. Concentrate the filtrate to dryness to obtain the roughly purified product 5a. 70.7g, purity 85%, yield 85%, directly added to the next reaction step; Step 5: Dissolve 20g of compound 4 in 200ml of tetrahydrofuran and 200ml of methanol, add 22.9ml of 1N sodium hydroxide solution, react at -5℃ for 50 minutes. The reaction proceeds were basically complete by TLC. Add 400ml of saturated ammonium chloride aqueous solution and stir for 5-10 minutes until the mixture becomes turbid. At this point, the pH is 7-8. At 45℃, remove most of the tetrahydrofuran and methanol (some solids appear). Add 100ml of water to the aqueous phase and extract once with 500ml of ethyl acetate. Separate the liquid and wash the organic phase once with 300ml of saturated brine. Separate the liquid and dry the organic phase with sodium sulfate. Rotate the filtrate to dryness and perform column chromatography to obtain 14.26g of compound 6a, with a yield of 81% and a purity of 97%.

[0047] Step 6: Dissolve 14 g of compound 6a in 28 ml of acetonitrile, distill once at 45°C, add 140 ml of dichloromethane and stir to dissolve. Then add tetrazolium (0.8 equivalents) and 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine (1.2 equivalents) sequentially. React at room temperature for 2 hours. The reaction proceeds to near completion by TLC. Wash twice with saturated sodium bicarbonate solution, separate the layers, wash once with saturated brine, separate the layers, dry the organic phase with sodium sulfate, and evaporate to dryness at 45°C to obtain the crude product. Separate by column chromatography to obtain 14.02 g of TNA-a, with a yield of 80% and a purity of 97.5%. Measure the proton and phosphorus spectra of TNA-a using nuclear magnetic resonance spectroscopy, as shown below. Figure 2 and Figure 3 The phosphorus / hydrogen NMR data are as follows: 31P NMR (162 MHz, CDCl3) δ 151.32, 150.88; 98.85%; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 6.4 Hz, 1H), 8.24 (s, 1H), 7.47 (s, 4H), 7.39 (t, J = 7.6 Hz, 4H), 7.32–7.15 (m, 11H), 6.81 (dt, J = 7.0, 3.5 Hz, 4H), 6.06 (d, J = 28.9 Hz, 1H), 4.79 (dd, J = 33.7, 8.2 Hz, 1H), 4.50–4.33 (m, 1H). 3.79-3.73 (m, 6H), 3.73-3.55 (m, 6H), 2.59 (d, J =38.8 Hz, 3H), 2.48 (dd, J = 11.1, 5.6 Hz, 2H), 1.21-1.09 (m, 12H).

[0048] Example 4 Preparation of TNA-b: The only difference was that the guanine derivative 8 in step 4 was replaced with an equal mass of N6-benzoyladenine; the remaining steps were the same as in Example 3, yielding TNA-b with a yield of 58% and a purity of 98.2%. The proton and phosphorus spectra of TNA-b were measured using nuclear magnetic resonance spectroscopy, as shown below. Figure 4 and Figure 5 The phosphorus / hydrogen NMR data are as follows: 31P NMR (162 MHz, CDCl3) δ 152.12, 151.03; 98.62%; 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 18.5 Hz, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.51 (m, 3H), 7.25–7.06 (m, 9H), 6.77 (dd, J = 7.6, 6.2 Hz, 4H), 6.18 (d, J = 30.4 Hz, 1H), 4.71 (m, 1H), 4.30 (m, 1H). 3.92-3.76 (m, 2H), 3.73 (d, J = 2.4 Hz, 6H), 3.71-3.51 (m,4H), 2.63-2.28 (m, 2H), 1.20-1.07 (m, 12H).

[0049] Example 5 Preparation of TNA-c: The only difference was that the guanine derivative 8 in step 4 was replaced with an equal mass of N4-benzoylcytosine; the remaining steps were the same as in Example 3, yielding TNA-c with a yield of 55% and a purity of 98.0%. The proton and phosphorus spectra of TNA-b were measured using nuclear magnetic resonance spectroscopy, as shown below. Figure 6 and Figure 7The phosphorus / hydrogen NMR data are as follows: 31P NMR (162 MHz, CDCl3) δ 152.60, 150.61; 99.59%; 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.09–7.91 (m, 3H), 7.59 (dt, J = 36.8, 7.5 Hz, 4H), 7.32–7.16 (m, 9H), 6.86–6.79 (m, 4H), 5.89 (d, J = 5.5 Hz, 1H), 4.65 (dd, J = 65.3, 8.8 Hz, 1H), 4.20 (dd, J = 53.2, 3.2 Hz, 1H), 4.05 (d, J = 53.2, 3.2 Hz, 1H), 99.59 (dt, J = 5.5 Hz, 4 ... 8.2 Hz, 1H), 3.96-3.83 (m, 2H), 3.76 (d, J =3.9 Hz, 6H), 3.59 (ddd, J = 25.4, 21.8, 13.6 Hz, 3H), 3.24 (dd, J = 42.9,10.0 Hz, 1H), 2.89-2.64 (m, 2H), 2.34 (d, J = 52.9 Hz, 1H), 1.27-1.11 (m,8H), 1.01 (d, J = 6.8 Hz, 4H).

[0050] Example 6 Preparation of TNA-d: The only difference was that the guanine derivative 8 in step 4 was replaced with an equal mass of thymine; the remaining steps were the same as in Example 3, yielding TNA-d with a yield of 60% and a purity of 97.6%. The proton and phosphorus spectra of TNA-d were measured using nuclear magnetic resonance spectroscopy, as shown below. Figure 8 and Figure 9The phosphorus / hydrogen NMR data are as follows: 31P NMR (162 MHz, CDCl3) δ 152.32, 151.17; 100%; 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.44 (d, J = 14.0 Hz, 1H), 7.37 (d, J = 7.4 Hz, 2H), 7.33–7.20 (m, 7H), 6.86 (t, J = 8.8 Hz, 4H), 5.84 (d, J = 15.9 Hz, 1H), 4.57–4.13 (m, 2H), 3.93 (dd, J = 10.2, 7.6 Hz, 1H), 3.85–3.70 (m, 8H). 3.66-3.49 (m, 3H), 3.23 (dd, J = 85.2, 10.0 Hz, 1H), 2.61 (ddd, J = 151.7, 78.2, 9.9 Hz, 2H), 1.83 (d, J = 11.3 Hz, 3H), 1.25-1.12 (m, 8H), 1.02 (d, J = 6.8 Hz, 4H).

[0051] In the description of this specification, the references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0052] The above description is merely an example and illustration of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described, or use similar methods to replace them, as long as they do not deviate from the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.

Claims

1. A method for preparing a TNA monomer, characterized in that, Includes the following steps: Step 1: Dissolve compound 1 in the reaction solvent, then add 4,4'-dimethoxytriphenylchloromethane and a basic catalyst, stir the reaction for 16-18 hours until the reaction is complete, and obtain compound 2; Step 2: Dissolve compound 2 in the reaction solvent, add a reducing agent dropwise under argon protection, and carry out the reaction. Once the reaction is complete, compound 3 is obtained. Step 3: Dissolve compound 3 in the reaction solvent, acetylation reagent and basic catalyst, and react at room temperature for 1-2 hours until the reaction is complete, to obtain compound 4; Step 4: Add base 8 to the reaction solvent, stir well, then add compound 4 and N,O-bis(trimethylsilyl)acetamide to react. After the reaction is complete, compound 5 is obtained. Step 5: Dissolve compound 5 in the reaction solvent, add alkaline solution, and react at -5℃ for 50 min. The reaction is complete, and compound 6 is obtained. Step 6: Dissolve compound 6 in the reaction solvent, co-distill once at 45°C, then add another reaction solvent, and then add the catalyst and phosphine reagent in sequence. React at room temperature for 2 hours until the reaction is complete, and obtain the TNA monomer.

2. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 1, compound 1 is (3R,4S)-benzoic acid (4-hydroxy-2-oxo-3-tetrahydrofuranyl) ester.

3. The method for preparing a TNA monomer according to claim 1, characterized in that, The temperature of the stirring reaction in step 1 is 20-40℃; the alkaline catalyst is selected from one or more of pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine, N,N-diisopropylethylamine, and triethylamine.

4. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 2, the reducing agent is one or more of diisobutylaluminum hydride, lithium aluminum hydride, and boranetetrahydrofuran; the reaction temperature is -78℃ to 20℃.

5. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 3, the alkaline catalyst is one or more of pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, imidazole, N,N-diisopropylethylamine, and N-methylmorpholine; the acetylation agent is one of acetyl chloride and acetic anhydride.

6. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 4, the molar ratio of compound 4, N,O-bis(trimethylsilyl)acetamide and base 8 is 1:2-5:1-5; the reaction temperature is 20-130℃.

7. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 4, base 8 is one of four types: a, b, c, and d, where a: N2-acetyl-O6-(diphenylcarbamoyloxy)guanine, b: N6-benzoyladenine, c: N4-benzoylcytosine, and d: thymine.

8. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 5, the alkaline solution is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide solutions.

9. The method for preparing a TNA monomer according to claim 1, characterized in that, The catalyst in step 6 is one or more of the following: tetrazolium, diisopropylethylamine tetrazolium, ethylthiotetrazolium, 4,5-dicyanimidazolium, pyridine trifluoroacetate, N,N-diisopropylethylamine, and N-methylmorpholine.

10. The method for preparing a TNA monomer according to claim 1, characterized in that, In step 6, the phosphine reagent is one of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine or 2-cyanoethyl N,N-diisopropylchlorophosphine.

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