The invention relates to 2apos; -deoxy-2apos;-(2apos); synthetic method of-fluoro Arabinadenosine and intermediate thereof
By using the reaction method of alkali-activated compounds and perfluorobutylsulfonyl fluoride in the synthesis of 2'-deoxy-2'-fluoroarabine adenosine, the problems of cumbersome steps and strong toxicity of fluorinated reagents in the prior art are solved, and efficient, safe and environmentally friendly intermediate synthesis is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411525529.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-29
- Publication Date
- 2025-03-04
AI Technical Summary
In the prior art, the synthesis method of 2'-deoxy-2'-fluoroagranusine has problems such as complicated steps, strong toxicity of fluorinated reagents, requiring column chromatography purification and high equipment requirements, which leads to unsuitable for industrial production.
The hydroxyl group in compound 1 is used to react with perfluorobutylsulfonyl fluoride reagent, and the 2′-deoxy-2′-fluoroarabinophore intermediate is constructed in one step through the bimolecular nucleophilic substitution reaction path, avoiding column chromatography purification and the use of dangerous fluorinated reagents.
The efficient synthesis of 2′-deoxy-2′-fluoroagranusine intermediate is achieved, which simplifies the operation steps, improves production efficiency, is suitable for industrial production, and does not require column chromatography purification, which is safe and environmentally friendly.
Smart Images
Figure CN119552204A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing 2'-deoxy-2'-fluoroarabinoadenosine and an intermediate thereof. Background Art
[0002] The 2'-deoxy-2'-fluoroarabinoadenosine of the present invention is an important pharmaceutical intermediate. When 2'-deoxy-2'-fluoroarabinoadenosine is synthesized in most cases, multiple steps are required to construct the important compound 2'-deoxy-2'-fluoroarabinoadenosine intermediate, and column chromatography is often used for purification to purify it into a white powder.
[0003] CN101555267 discloses a method for synthesizing a nucleotide analog clorabine, wherein the important compound 2 is synthesized in one step, and the steps are as follows: 1) at room temperature, compound 1 is dissolved in dichloromethane, diethylamino sulfur trifluoride is added, and then the temperature is raised and stirred, and then the temperature is lowered to room temperature, sodium bicarbonate is added to the system to quench, and then the organic phase is separated and washed with water, and then the organic phase is dried, filtered, the solvent is drained under reduced pressure, and crystallized with ethanol. Although this method can achieve fluorine substitution in one step, the fluorine reagent is liquid, unstable, and easy to decompose, and sulfur dioxide and hydrofluoric acid gas will be released, which is harmful to the environment. In addition, the fluorine reagent has strong corrosiveness, has certain requirements on equipment, and is not conducive to industrial production.
[0004] CN102000103 discloses a method for synthesizing 2′-fluoro-4′-azido-nucleoside analogs, wherein the important compound 2 is synthesized in two steps, and the steps are as follows: 1) Compound 1 is dissolved in a mixed solution of dichloromethane and N, N-dimethylformamide at low temperature, sulfonyl chloride is added at low temperature, the temperature is kept stirring for a period of time, and then the temperature is raised to room temperature. After a period of reaction, the temperature is lowered to 0°C, imidazole is added, and then the temperature is raised to room temperature for reaction. After the end, the dichloromethane is diluted, washed with water, the organic layer is dried, and the solvent is drained under reduced pressure to obtain a light yellow syrup, which is purified by column chromatography to obtain a white solid. 2) The white solid obtained in the previous step is dissolved in ethyl acetate, triethylamine hydrofluoride is added, the temperature is raised and stirred, and the reaction is cooled to room temperature after the reaction is completed. Ice salt water is added to quench the reaction, and then the aqueous phase is extracted with dichloromethane, and then the organic layers are combined and washed with brine, water, and saturated sodium bicarbonate in turn, and the organic phase is dried, drained under reduced pressure, purified by silica gel column, and then recrystallized with ethanol to obtain compound 2. This method is not easy to operate and the steps are cumbersome. At the same time, the fluorinated reagent used contains triethylamine hydrofluoride, which is highly corrosive and has high requirements for equipment. In addition, the volatilized hydrofluoric acid gas is highly toxic and extremely harmful to the human body. Therefore, this method is not suitable for industrial production. Summary of the invention
[0005] In view of the defects and shortcomings of the prior art, the present invention proposes a method for synthesizing 2′-deoxy-2′-fluoroarabinoadenosine and its intermediates. The method is simple, efficient, green and environmentally friendly, has a high yield, is easy to purify, does not require column chromatography, is suitable for industrial production, and solves the technical problems of the prior art, such as complicated preparation steps, strong reagent toxicity, column chromatography purification, high equipment requirements, and difficulty in scale-up production.
[0006] According to the first aspect of the present invention, a method for preparing a 2'-deoxy-2'-fluoroarabinoadenosine intermediate is provided. The synthesis method comprises the following steps: in an organic solvent, activating the hydroxyl group in compound 1 by alkali, reacting the hydroxyl group with a perfluorobutylsulfonyl fluoride reagent to obtain a 2'-deoxy-2'-fluoroarabinoadenosine intermediate. The preparation method is as follows:
[0007]
[0008] The 2'-deoxy-2'-fluoroarabinoadenosine intermediate has a structure shown in Compound 2, wherein R is a hydroxyl protecting group.
[0009] Preferably, the hydroxyl protecting group is selected from benzoyl, acetyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, preferably benzoyl.
[0010] Preferably, the molar ratio of the compound 1 to perfluorobutylsulfonyl fluoride is 1:1.1-3, preferably 1:1.1-1.5; the molar ratio of the compound 1 to the base is 2-5:1, preferably 2-3:1.
[0011] Preferably, the reaction temperature for preparing compound 2 from compound 1 is -78 to 100°C, preferably -20 to 80°C, more preferably 0 to 40°C; the reaction time is 0.5 to 24h, preferably 0.5 to 20h.
[0012] Preferably, the organic solvent is selected from one or a combination of aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, the aromatic hydrocarbons are selected from toluene; the halogenated hydrocarbons are selected from one or more of dichloromethane, chloroform or 1,2-dichloroethane; the ethers are selected from one or more of ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or dioxane; the esters are selected from ethyl acetate; the amides are selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; the nitrile solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, N,N-dimethylformamide, methyl tert-butyl ether, preferably tetrahydrofuran.
[0013] According to another aspect of the present invention, a method for preparing a 2′-deoxy-2′-fluoroarabinoadenosine compound is provided, wherein the 2′-deoxy-2′-fluoroarabinoadenosine intermediate is subjected to a nucleophilic substitution reaction with an acetic acid solution of hydrobromic acid to obtain compound 3, compound 3 is subjected to a nucleophilic substitution reaction with compound 6 to obtain compound 4, and compound 4 is deprotected in an alkaline solution to obtain a 2′-deoxy-2′-fluoroarabinoadenosine compound, wherein the 2′-deoxy-2′-fluoroarabinoadenosine compound has a structure shown in compound 5.
[0014]
[0015] Wherein R' in compound 4 is an amino protecting group,
[0016] Preferably, the amino protecting group is selected from a benzoyl group, an acetyl group, a pivaloyl group, a trityl group, a benzyl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group.
[0017] Preferably, the reaction of compound 2 to obtain compound 3 is carried out in a solvent, the solvent is selected from one or more of tetrahydrofuran, dichloromethane, toluene, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, methanol, preferably methanol, the molar ratio of compound 2 to hydrobromic acid is 1:2-8, the reaction time is 4-24h, preferably 8-12h; the temperature is 0-45°C, preferably 0-25°C.
[0018] Preferably, the reaction of compound 3 and compound 6 is carried out in a solvent, the solvent is selected from one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-methylpyrrolidone, N,N-dimethylformamide, preferably tetrahydrofuran, the molar ratio of compound 3 to compound 6 is 1:1.5-3, the reaction time is 12-84h, preferably 48-72h; the reaction temperature is 0-85°C, preferably 65-80°C.
[0019] Preferably, the reaction of compound 4 with a base to obtain compound 5 is carried out in a solvent, the solvent is one or more of acetonitrile, tetrahydrofuran, methanol, and dichloromethane, the molar ratio of compound 4 to the base is 1:5-40, and the reaction temperature is 0-100°C.
[0020] In general, the above technical solution conceived by the present invention has the following technical advantages compared with the prior art:
[0021] 1. The present invention uses alkali to activate the hydroxyl group in compound 1, and uses perfluorobutylsulfonyl fluoride to convert the hydroxyl group into an easy leaving group in situ in the system without separation, so that the fluorine atoms in the system can pass through the bimolecular nucleophilic substitution reaction path to construct the important compound 2'-deoxy-2'-fluoroarabinoadenosine intermediate in one step. This method has a higher reaction conversion rate and a better yield, and does not require column purification. At the same time, it avoids dangerous fluorination reagents such as diethylaminosulfur trifluoride and hydrofluoric acid, so that the compound 2'-deoxy-2'-fluoroarabinoadenosine intermediate can be synthesized more efficiently, quickly and safely.
[0022] 2. The realization of the novel method for preparing 2'-deoxy-2'-fluoroarabinoadenosine intermediates of the present invention simplifies the operation steps for preparing 2'-deoxy-2'-fluoroarabinoadenosine, improves production efficiency, and makes the method more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 Synthesis route for 2′-deoxy-2'-fluoroarabinoadenosine
[0024] Figure 2 The H NMR spectrum of the 2′-deoxy-2′-fluoroarabinoadenosine intermediate (Compound 2) synthesized in Example 1
[0025] Figure 3 The NMR fluorine spectrum of the 2′-deoxy-2′-fluoroarabinoadenosine intermediate (Compound 2) synthesized in Example 1
[0026] Figure 4 Example 3: 2′-deoxy-2′-fluoroarabinoadenosine synthesized in H NMR spectrum
[0027] Figure 5 NMR fluorine spectrum of 2′-deoxy-2′-fluoroarabinoadenosine synthesized in Example 3 DETAILED DESCRIPTION
[0028] In order to make the purpose, technical scheme and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.
[0029] According to the first aspect of the present invention, a method for preparing a 2'-deoxy-2'-fluoroarabinoadenosine intermediate is provided. The synthesis method comprises the following steps: in an organic solvent, activating the hydroxyl group in compound 1 by alkali, reacting the hydroxyl group with a perfluorobutylsulfonyl fluoride reagent to obtain a 2'-deoxy-2'-fluoroarabinoadenosine intermediate. The 2'-deoxy-2'-fluoroarabinoadenosine intermediate has the structure shown in compound 2, wherein R is a hydroxyl protecting group.
[0030] In some embodiments, the hydroxyl protecting group is selected from benzoyl, acetyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, preferably benzoyl.
[0031] In some embodiments, the base used in the reaction of compound 1 and compound 2 is an inorganic base or an organic base, wherein the inorganic base is selected from one or more of sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide; the organic base is selected from triethylamine, diisopropylethylamine, diisopropylamine, pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, (tert-butylimino)tri(pyrrolidine)phosphine, potassium tert-butoxide, and sodium acetate. Preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, and 2-tert-butyl-1,1,3,3-tetramethylguanidine, and particularly more preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.
[0032] In some embodiments, the molar ratio of the compound 1 to perfluorobutylsulfonyl fluoride is 1:1.1-3, preferably 1:1.1-1.5; the molar ratio of the compound 1 to the base is 2-5:1, preferably 2-3:1.
[0033] In some embodiments, the reaction temperature for preparing compound 2 from compound 1 is -78 to 100°C, preferably -20 to 80°C, more preferably 0 to 40°C; the reaction time is 0.5 to 24h, preferably 0.5 to 20h.
[0034] Preferably, the organic solvent is selected from one or a combination of aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, the aromatic hydrocarbons are selected from toluene; the halogenated hydrocarbons are selected from one or more of dichloromethane, chloroform or 1,2-dichloroethane; the ethers are selected from one or more of ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or dioxane; the esters are selected from ethyl acetate; the amides are selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; the nitrile solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, N,N-dimethylformamide, methyl tert-butyl ether, preferably tetrahydrofuran.
[0035] According to another aspect of the present invention, a method for preparing a 2′-deoxy-2′-fluoroarabinoadenosine compound is provided, wherein the compound 2 is subjected to a nucleophilic substitution reaction with an acetic acid solution of hydrobromic acid to obtain a compound 3, and the compound 3 is subjected to a nucleophilic substitution reaction with a compound 6 to obtain a compound 4, and the compound 4 is deprotected in an alkaline solution to obtain a 2′-deoxy-2′-fluoroarabinoadenosine compound, wherein the 2′-deoxy-2′-fluoroarabinoadenosine compound has the structure shown in compound 5, wherein R′ in compound 4 is an amino protecting group.
[0036] In some embodiments, the amino protecting group is selected from a benzoyl group, an acetyl group, a pivaloyl group, a trityl group, a benzyl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group.
[0037] In some embodiments, the reaction of compound 2 to obtain compound 3 is carried out in a solvent, wherein the solvent is selected from one or more of tetrahydrofuran, dichloromethane, toluene, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, and methanol, preferably methanol, the molar ratio of compound 2 to hydrobromic acid is 1:2-8, the reaction time is 4-24 hours, preferably 8-12 hours; the temperature is 0-45°C, preferably 0-25°C.
[0038] In some embodiments, the mass concentration of the hydrobromic acid in acetic acid solution is 20-40%.
[0039] In some embodiments, the reaction of compound 3 and compound 6 is carried out in a solvent, and the solvent is selected from one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-methylpyrrolidone, N,N-dimethylformamide, preferably tetrahydrofuran, the molar ratio of compound 3 to compound 6 is 1:1.5-3, the reaction time is 12-84 hours, preferably 48-72 hours; the reaction temperature is 0-85°C, preferably 65-80°C.
[0040] In some embodiments, the reaction of compound 4 with a base to obtain compound 5 is carried out in a solvent, wherein the solvent is one or more of acetonitrile, tetrahydrofuran, methanol, and dichloromethane, the molar ratio of compound 4 to the base is 1:5-40, and the reaction temperature is 0-100°C.
[0041] In some embodiments, the base used to react compound 4 to obtain compound 5 is an organic base or an inorganic base, wherein the organic base is selected from one or more of ammonia gas or ammonia water, triethylamine, and sodium methoxide; the inorganic base is selected from one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide.
[0042] Embodiment 1:
[0043] Synthesis of compound 2: Add 46g of compound 1 to a 500ml reaction bottle, R is benzoyl, add 125ml of tetrahydrofuran, cool to 0°C, add 125ml of tetrahydrofuran to a 250ml reaction bottle, and add 27ml of perfluorobutylsulfonyl fluoride. Then add the solvent in reaction bottle 2 to a 500ml reaction bottle, and then add 22ml of 1,8-diazobispiro[5.4.0]undec-7-ene base solution dropwise. After the addition is complete, the reaction system is warmed to room temperature and stirred for 12 hours. After the reaction is completed, the vacuum is drained, and the obtained solid is recrystallized with methanol to finally obtain a total of 40g of white powder solid compound 2 with a yield of 87%. Figure 2 and Figure 3 The NMR hydrogen spectrum and the NMR fluorine spectrum of the 2′-deoxy-2′-fluoroarabinoadenosine intermediate (Compound 2) synthesized in Example 1 are shown in the figure. 1 H NMR (CDCl3) δppm: 8.16-7.35 (m, 15H), 6.76 (d, J=9.1Hz, 1H), 5.63 (dd, J=19.5, 3.3Hz, 1H), 5.39 ( d, J=48.3Hz, 1H), 4.79 (q, 1H, J=3.9), 4.75 (dd, J=12.0, 3.7Hz, 1H), 4.70 (dd, J=12.0, 4.8Hz, 1H), 19 F NMR (CDCl3) δppm: -190.86 (ddd, J=48.4, 19.5, 9.2 Hz), indicating that the product compound 2 was prepared.
[0044] Embodiment 2:
[0045] Synthesis of compound 2: Add 3.2 kg of compound 1, R is benzoyl, to reactor 1, add 8.0 L of tetrahydrofuran, and cool to 0 ° C. At the same time, prepare perfluorobutylsulfonyl fluoride solvent in reactor 2, add 8.0 L of tetrahydrofuran to reactor 2, and add 2.1 L of perfluorobutylsulfonyl fluoride. Then the solvent in reactor 2 is transported to reactor 1 through a pipeline, and then 1.7 L of DBU is added to reactor 1. After the addition is completed, warm to room temperature and stir. After the reaction is completed, distill under reduced pressure, then add methanol, stir for 1 hour, filter, rinse with methanol, and dry the filter cake to obtain 2.6 kg of white powdery solid with a yield of 80%.
[0046] Example 3
[0047] Synthesis of compound 3: Add 23g of compound 2, R is benzoyl, to a 500ml reaction bottle, add 250ml of dichloromethane, cool to 0°C, add 37ml of hydrobromic acid acetic acid solution to the system, warm to room temperature, and stir overnight. After the reaction is completed, dichloromethane is added to dilute, water is added, and after stirring for a period of time, the aqueous phase is removed, and the organic phase is washed with sodium bicarbonate and sodium chloride, and the organic phase is dried and drained under reduced pressure to obtain a crude product of compound 3, a slightly yellow slurry. The crude product is not further separated and purified, and is directly fed to the next step.
[0048] Synthesis of compound 4: The crude product was transferred to a 1000 ml reaction bottle, and 370 ml of tetrahydrofuran and 12 ml of N-methylpyrrolidone were added, as well as 26 g of compound 6, where R′ and benzoyl were selected. The temperature was then raised to 70°C and stirred for 54 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed with 1 M hydrochloric acid and saturated sodium chloride, and the organic phase was dried and filtered. The solid compound 4 obtained by vacuum extraction was directly subjected to the next step of reaction.
[0049] Synthesis of compound 5: The obtained solid compound 4 was transferred to a 500 mL reaction bottle, and then 250 ml of 7 M ammonia methanol solution was added and stirred at room temperature for 24 h. After the reaction was completed, the mixture was dried under reduced pressure, and the crude product was recrystallized from ethanol to obtain a white powder solid 5, 8.4 g, with a total yield of 62%. Figure 4 and Figure 5 The NMR hydrogen spectrum and the NMR fluorine spectrum of 2′-deoxy-2′-fluoroarabinoadenosine synthesized in Example 3 are shown in the figure. 1 H NMR (DMSO-d 6)δppm: 8.25-8.22 (m, 1H), 8.16 (s, 1H), 7.34 (s, 2H), 6.41 (dd, J=14.1, 4.6Hz 1H), 5.95 (d, J=4.7Hz, 1H), 5.20 (dd, J=52.7, 4.7Hz, 1H), 5.11 (t, J=5.8Hz 1H), 4.45 (dd, J=18.7, 5.0Hz, 1H), 3.85 (q, J=5.2, 4.8Hz, 1H), 3.75-3.60 (m, 2H), indicating that the synthetic product 2′-deoxy-2′-fluoroarabinoadenosine.
[0050] Example 4
[0051] Synthesis of compound 3: Add 2.4 kg of compound 2, R is benzoyl, to the reactor, add 9.0 L of dichloromethane, cool to 0 ° C, add 3.5 L of hydrobromic acid acetic acid solution to the system, warm to room temperature, and stir overnight. After the reaction is completed, dichloromethane is added to dilute, water is added, and then the organic phase is separated, and the organic phase is washed again with water and saturated sodium bicarbonate, and then the organic phase is diluted with tetrahydrofuran, and distilled under reduced pressure until 4.8 L of tetrahydrofuran remains, and then the tetrahydrofuran solution containing compound 3 is transferred to the next reactor.
[0052] Synthesis of compound 4: 2.7 kg of compound 6, R′ and benzoyl were added to the reaction kettle, and 38.0 L of tetrahydrofuran and 1.2 L of N-methylpyrrolidone were added, and then the temperature was raised to 70°C and stirred for 54 hours. After the reaction was completed, it was cooled to room temperature, filtered, and washed three times with 1M hydrochloric acid to obtain a slurry containing compound 4.
[0053] Synthesis of compound 5: 25.0 L of 7M ammonia methanol solution was added to the reactor, stirred at room temperature for 24 h, and after the reaction was completed, the mixture was distilled under reduced pressure to a small amount of methanol, ethanol was added to the system, and the mixture was distilled under reduced pressure to a small amount of solvent again, and repeated twice. Then ethanol was added, the temperature was lowered to 20°C, stirred overnight, filtered, the filter cake was rinsed with ethanol, and dried to obtain a white powder solid compound 5, 0.8 kg, with a total yield of 60%.
[0054] It will be easily understood by those skilled in the art that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for synthesizing a 2'-deoxy-2'-fluoroarabinoadenosine intermediate, characterized in that: The synthesis method is to activate the hydroxyl group in compound 1 by alkali in an organic solvent, and react with a perfluorobutylsulfonyl fluoride reagent to obtain a 2'-deoxy-2'-fluoroarabinoadenosine intermediate. The preparation method and synthesis route are as follows: The 2'-deoxy-2'-fluoroarabinoadenosine intermediate has the structure shown in compound 2, wherein R is a hydroxyl protecting group; the hydroxyl protecting group is selected from benzoyl, acetyl, benzyl, trimethylsilyl, and tert-butyldimethylsilyl.
2. A method for synthesizing the 2'-deoxy-2'-fluoroarabinoadenosine intermediate according to claim 1, characterized in that: The molar ratio of the compound 1 to perfluorobutylsulfonyl fluoride is 1:1.1-3, preferably 1:1.1-1.5; the molar ratio of the compound 1 to the base is 2-5:1, preferably 2-3:
1.
3. A method for synthesizing the 2'-deoxy-2'-fluoroarabinoadenosine intermediate as claimed in claim 2, characterized in that: The reaction temperature is -78 to 100°C, preferably -20 to 80°C, more preferably 0 to 40°C; the reaction time is 0.5 to 24h, preferably 0.5 to 20h.
4. A method for synthesizing the 2'-deoxy-2'-fluoroarabinoadenosine intermediate as claimed in claim 3, characterized in that: The organic solvent is selected from one or more of aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents; the aromatic hydrocarbons are selected from toluene; the halogenated hydrocarbons are selected from one or more of dichloromethane, chloroform or 1,2-dichloroethane; the ethers are selected from one or more of ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or dioxane; the esters are selected from ethyl acetate; the amides are selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; the nitrile solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, 2-methyltetrahydrofuran, N,N-dimethylformamide, methyl tert-butyl ether, preferably tetrahydrofuran.
5. A method for synthesizing a 2'-deoxy-2'-fluoroarabinoadenosine compound, characterized in that: The 2'-deoxy-2'-fluoroarabinoadenosine intermediate prepared by the preparation method according to any one of claims 1 to 4 undergoes a nucleophilic substitution reaction with a hydrobromic acid acetic acid solution to obtain compound 3, compound 3 undergoes a nucleophilic substitution reaction with compound 6 to obtain compound 4, and compound 4 is deprotected in an alkaline solution to obtain a 2'-deoxy-2'-fluoroarabinoadenosine compound, the 2'-deoxy-2'-fluoroarabinoadenosine compound having the structure shown in compound 5, and the reaction formula is as follows: R' in compound 4 is an amino protecting group; the amino protecting group is selected from a benzoyl group, an acetyl group, a pivaloyl group, a trityl group, a benzyl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group.
6. The method for synthesizing a 2'-deoxy-2'-fluoroarabinoadenosine compound according to claim 5, characterized in that: The reaction of compound 2 to obtain compound 3 is carried out in a solvent, wherein the solvent is selected from one or more of tetrahydrofuran, dichloromethane, toluene, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, and methanol, preferably methanol, the molar ratio of compound 2 to hydrobromic acid is 1:2 to 8, the reaction time is 4 to 24 hours, preferably 8 to 12 hours; the temperature is 0 to 45°C, preferably 0 to 25°C.
7. The method for synthesizing a 2'-deoxy-2'-fluoroarabinoadenosine compound according to claim 6, characterized in that: The reaction of compound 3 and compound 6 is carried out in a solvent, the solvent is selected from one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N-methylpyrrolidone, N,N-dimethylformamide, preferably tetrahydrofuran, the molar ratio of compound 3 to compound 6 is 1:1.5-3, the reaction time is 12-84h, preferably 48-72h; the reaction temperature is 0-85°C, preferably 65-80°C.
8. The method for synthesizing a 2'-deoxy-2'-fluoroarabinoadenosine compound according to claim 7, characterized in that: The reaction of compound 4 with a base to obtain compound 5 is carried out in a solvent, wherein the solvent is one or more of acetonitrile, tetrahydrofuran, methanol, and dichloromethane, the molar ratio of compound 4 to the base is 1:5-40, and the reaction temperature is 0-100°C.