A synthetic method of 2'-fluoro-2'-deoxyuridine and its intermediate

Abstract

The present invention relates to a method for synthesizing 2'-fluoro-2'-deoxyuridine and an intermediate thereof, which is implemented by the following method, wherein the synthetic route of the present invention is novel, easy to operate, high in yield, good in safety, does not require column chromatography, and is suitable for industrial production. Wherein R is a hydroxyl protecting group, and most preferably a tetrahydropyranyl group (THP group) is used as the hydroxyl protecting group; wherein R' is a conventional hydroxyl protecting group in the art, and preferably, R' is a tetrahydropyranyl (THP), methoxymethyl ether, a silyl group (for example, tert-butyldimethylsilyl) or an acyl group (for example, acetyl), preferably an acetyl group.

Description

Technical Field

[0001] The invention relates to a synthesis method of 2'-fluoro-2'-deoxyuridine and a novel intermediate thereof, belonging to the field of organic synthesis. Background Art

[0002] The 2'-fluoro-2'-deoxyuridine of the present invention is an important drug intermediate. 2'-fluoro-2'-deoxyuridine is water-soluble and has almost no crystalline compound. Most of the prior art purifies it by column chromatography to purify it into a high-purity, white crystalline powder with a high yield.

[0003] CN112500446A discloses a method for synthesizing 2'-fluoro-2'-deoxyuridine, comprising the following steps: step 1) adding uridine and diphenyl carbonate to dimethylformamide, heating and dissolving, after the solution is clarified, adding a catalyst sodium bicarbonate under the condition of maintaining the temperature, heating for the second time, and after the reaction is completed, naturally cooling to room temperature, stirring, filtering, and drying the filter cake to obtain compound 2; step 2) dissolving compound 2, anhydrous potassium fluoride, and catalyst boron trifluoride ether in a solvent, heating and reacting, filtering and concentrating after the reaction is completed to obtain compound 3, i.e. 2'-fluoro-2'-deoxyuridine. However, the hydroxyl conversion rate of this method is low, and 2'-fluoro-2'-deoxyuridine is a very sticky compound. It cannot be solidified and purified when the purity is not high, resulting in the need for column purification in the later stage of this method, and cannot be used for continuous amplification production in factories.

[0004] CN112409420A discloses a method for purifying 2'-fluoro-2'-deoxyuridine, comprising the following steps: 1) dissolving crude 2'-fluoro-2'-deoxyuridine in ethyl acetate, adding triethylamine, and dropping an acylating agent under temperature control to react; 2) adding methanol after the reaction is completed, stirring, cooling and crystallizing, filtering, washing the filter cake with ethyl acetate, and drying the filter cake to obtain compound 2; 3) dissolving compound 2 in methanol, adding sodium hydroxide, filtering after the reaction is complete, and drying the filter cake to obtain 2'-fluoro-2'-deoxyuridine. The acylation step uses 4-dimethylaminopyridine, and the yield is only 76.8%.

[0005] In a process for preparing 2'-fluoro-2'-deoxyuridine, the steps before and after the fluorination reaction are key processes. The prior art reports that a trifluoromethanesulfonylating agent is used to react with the 2'-hydroxyl group to obtain a trifluoromethanesulfonate, and then a fluorination agent is used to react to obtain a 2'-fluoro-2'-deoxyuridine intermediate compound. Trifluoromethanesulfonylating agents, such as trifluoromethanesulfonyl fluoride (CF3SO2F), trifluoromethanesulfonyl chloride (CF3SO2Cl) and trifluoromethanesulfonic anhydride ((CF3SO2)2O), wherein trifluoromethanesulfonyl fluoride (CF3SO2F) can generally be used in the trifluoromethanesulfonylation reaction of the 2'-hydroxyl group of 1-β-D-arabinofuranosyl uracil in the form of 3', 5'-hydroxyl protection, and the temperature condition is usually around -60°C, and the reaction temperature of trifluoromethanesulfonyl chloride also needs to be below -50°C. Under higher temperature conditions, trifluoromethanesulfonyl fluoride or trifluoromethanesulfonyl chloride needs to use a high-pressure reactor.

[0006] Trifluoromethanesulfonic anhydride ((CF3SO2)2O) can be used as a trifluoromethanesulfonylating agent for the 2'-hydroxyl group, but the use of trifluoromethanesulfonic anhydride ((CF3SO2)2O) is not efficient in terms of atom utilization.

[0007] In addition, the literature Chem. Pharm. Bull., 1981, Vol. 29, No. 11, pp. 3281-3285 reported the use of trifluoromethanesulfonyl chloride (CF3SO2Cl) reaction, but in the synthesis of 2'-deoxy-2'-fluoroguanosine, as the reaction proceeds, chloride anions (Cl - ) will then cause a substitution reaction with the 2'-trifluoromethanesulfonate ester as a product in the reaction system to obtain a by-product in which the chlorine atom is substituted at the 2' position. - ) is more nucleophilic than the fluoride anion (F - ) is much more nucleophilic, which becomes an important side reaction. Therefore, the use of trifluoromethanesulfonyl chloride (CF3SO2Cl) is also limited.

[0008] Therefore, the industry urgently needs a method for conveniently preparing 2'-deoxy-2'-fluorouridine. The present invention overcomes many defects of the prior art and provides a novel synthesis route. The synthesis route is simple to operate, mild in reaction, high in yield, good in safety, does not require column chromatography, and the obtained product is of good quality, which is very suitable for industrial production. Summary of the invention

[0009] The invention provides a method for synthesizing 2'-fluoro-2'-deoxyuridine, which is a completely new synthetic route and is suitable for industrial production.

[0010] The present invention also provides a new intermediate compound 4 as an important intermediate compound.

[0011] The present invention provides 2'-fluoro-2'-deoxyuridine, and the synthesis route is as follows:

[0012]

[0013] Wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;

[0014] Wherein R' is a conventional hydroxyl protecting group in the art, preferably, R' is tetrahydropyranyl (THP), methoxymethyl ether (MOM), silyl (eg, tert-butyldimethylsilyl) or acyl (eg, acetyl), preferably acetyl.

[0015] The present invention provides a technical solution 1: a method for preparing a 2'-fluoro-2'-deoxyuridine compound, which comprises reacting compound 3 with a hydroxyl activating reagent (most preferably a perfluorobutylsulfonyl fluoride reagent) in an organic solvent under the action of a base to obtain compound 4, and then obtaining compound 5 under the conditions including a second organic base and a fluorinating agent, and the reaction formula is as follows:

[0016]

[0017] Wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;

[0018] Compound 5 can be selectively deprotected to obtain compound 6.

[0019] The present invention provides a second technical solution: the preferred technical solution of the present invention provides a method for preparing a 2'-fluoro-2'-deoxyuridine compound, the method comprising reacting compound 3 in an organic solvent under a first organic base condition with a hydroxyl activating reagent (most preferably a perfluorobutylsulfonyl fluoride reagent) to obtain compound 4, and directly obtaining compound 5 under a second organic base and a fluorinating agent condition without further treatment in a "one-pot method";

[0020]

[0021] Wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;

[0022] Compound 5 can be selectively deprotected to obtain compound 6.

[0023] The present invention provides a technical solution 1 or a solution 2, wherein the molar feed ratio of the compound 3 to the hydroxyl activating agent is 1:(1-5), preferably 1:(1-3); the hydroxyl activating agent is selected from perfluorobutylsulfonyl fluoride; the base in the technical solution 1 provided by the present invention is selected from an inorganic base or an organic base, wherein the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.; the organic base or the second organic base in the solution 1 or the first organic base and the second organic base in the solution 2 can be respectively selected from diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, N,N-dimethyllaurylamine, diisopropylamine, N,N-dimethyl Aniline, dimethylbenzylamine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane, 4-dimethylaminopyridine (DMAP), pyridine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, imidazole, pyrimidine, pyridazine, N-methylmorpholine, tetramethylethylenediamine and tetramethylguanidine (TMG) or any combination thereof, preferably triethylamine, diisopropylethylamine and pyridine, particularly more preferably triethylamine;

[0024] The present invention provides a technical solution 1, wherein the molar feed ratio of the compound 3 to the amount of the base is 1:(1-10), preferably 1:(1-6); the present invention provides a technical solution 2, wherein the molar feed ratio of the compound 3 to the amount of the first organic base is 1:(1-10), preferably 1:(1-6);

[0025] The present invention provides technical solution 1 or solution 2, wherein the molar feed ratio of the fluorinating agent to compound 4 is 1-10:1, preferably 2-4:1; the fluorinating agent can be selected from hydrofluoric acid or its salt, and the molar ratio of the second organic base to hydrofluoric acid is generally in the range of 60:1-1:60, preferably in the range of 25:1 to 1:25, and more preferably in the range of 15:1 to 1:15. The second organic base and the fluorinating agent can be a complex, preferably pyridine hydrofluoric acid, triethylamine hydrofluoric acid, and most preferably triethylamine hydrofluoric acid; "a complex containing 1 mol of triethylamine and 3 mol of hydrofluoric acid (triethylamine trihydrofluoride)" and "a complex containing about 30% (about 10 mol%) of pyridine and about 70% (about 90 mol%) of hydrofluoric acid can be used.

[0026] The present invention provides technical solution 1 or solution 2, wherein the organic solvent is selected from one or a combination of dimethyl sulfoxide, aliphatic alkanes, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, wherein aliphatic alkanes are such as n-hexane, cyclohexane or n-heptane; aromatic hydrocarbons are such as toluene; halogenated hydrocarbons are such as dichloromethane, chloroform or 1,2-dichloroethane; ethers are such as ether, tetrahydrofuran, methyl tert-butyl ether or dioxane; esters are such as ethyl acetate or n-butyl acetate; amides are such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; nitrile is such as acetonitrile, etc. Among these, tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ether, dimethyl sulfoxide or any mixture of the above solvents are preferred, preferably dichloromethane, N,N-dimethylformamide and acetonitrile, and most preferably acetonitrile.

[0027] The present invention provides technical solution 1 or solution 2, wherein the reaction time for preparing compound 5 from compound 3 is until the detection reaction is completed, and the reaction time is usually 1-24 hours, preferably 1-20 hours.

[0028] The present invention provides technical solution 1 or solution 2, wherein the temperature conditions for each step of the reaction time for preparing compound 5 from compound 3 are usually -100-100°C, preferably -80-80°C, further preferably -60-60°C, and most preferably 15-40°C.

[0029] The present invention provides a method for selectively removing the protecting group of compound 5 to obtain compound 6, comprising obtaining compound 6 by reacting compound 5 under acidic conditions, and the reaction formula is as follows:

[0030]

[0031] Wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as the hydroxyl protecting group;

[0032] The acidic reagent is selected from formic acid, glacial acetic acid, p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid;

[0033] The molar feed ratio of the compound 5 to the acidic reagent is 1:(0.1-5)

[0034] The solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide, methanol or any mixture of the above solvents, preferably methanol;

[0035] The reaction time is until the detection reaction is completed, usually 1-24 hours, preferably 2-10 hours.

[0036] The compound 3 of the present invention can be prepared by the following method. The present invention also provides a preferred technical solution, in which compound 2 is not treated and compound 3 is prepared by a "one-pot method".

[0037]

[0038] Alternatively, it can be obtained by reacting compound 2 under alkaline conditions, and the reaction formula is as follows:

[0039]

[0040] Wherein R is a hydroxyl protecting group, and a tetrahydropyranyl group (THP group) is most preferred as the hydroxyl protecting group.

[0041] The molar feed ratio of the compound 2 to the alkaline reagent is 1:(0.1-5);

[0042] The alkaline reagent is diisopropylethylamine, triethylamine, diisopropylamine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine (TMG), sodium hydroxide, preferably sodium hydroxide;

[0043] The solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide, methanol or any mixture of the above solvents, preferably N,N-dimethylformamide.

[0044] The reaction time is until the detection reaction is completed, usually 1-24 hours, preferably 2-5 hours.

[0045] The reaction temperature is 0-100°C, preferably 20-35°C.

[0046] The compound 2 of the present invention can be prepared by the following method, comprising reacting the compound 1 with a hydroxyl activating agent under acidic conditions, and the reaction formula is as follows:

[0047]

[0048] The hydroxyl activating agent may be selected from 3,4-dihydro-2H-pyran (DHP), acetic anhydride, benzyl chloroformate, preferably 3,4-dihydro-2H-pyran DHP;

[0049] The molar feed ratio of the compound 1 to the hydroxyl protecting group reagent is 1:(1-5);

[0050] The acidic reagent can be selected from formic acid, glacial acetic acid, p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid;

[0051] The solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide or any mixture of the above solvents, preferably N,N-dimethylformamide;

[0052] The reaction time is until the detection reaction is completed, usually the reaction time is 1-24 hours;

[0053] The reaction temperature is 0-100°C, preferably 20-30°C.

[0054] The present invention also provides a method for selectively purifying compound 6, comprising reacting compound 7 with a hydroxyl protecting group reagent under alkaline conditions, and then removing the hydroxyl protecting group to obtain compound 6, the chemical formula of which is as follows:

[0055]

[0056] Wherein R' is a conventional hydroxyl protecting group in the art, preferably, R' is tetrahydropyranyl (THP), methoxymethyl ether, silyl (e.g., tert-butyldimethylsilyl) or acyl (e.g., acetyl), preferably acetyl;

[0057] The hydroxyl protecting group reagent is selected from 3,4-dihydro-2H-pyran (DHP), tert-butyldimethylsilyl chloride, chloromethyl methyl ether, acetic anhydride, etc.;

[0058] The base can be sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc., or diisopropylethylamine, triethylamine, diisopropylamine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine (TMG), preferably triethylamine;

[0059] The molar feed ratio of the compound 6 to the hydroxyl protecting group reagent is 1:(1-5);

[0060] The molar feed ratio of the base to the compound 6 is (1-10):1, preferably (2-4):1;

[0061] The solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide, or any mixture of the above solvents, preferably dichloromethane;

[0062] The reaction time is until the detection reaction is completed, usually 1-24 hours, preferably 2-5 hours.

[0063] The method and conditions for removing the hydroxyl protecting group may be conventional methods and conditions for such reactions in the art, and the reaction formula is as follows:

[0064]

[0065] Wherein R' is a conventional hydroxyl protecting group in the art, preferably, R' is tetrahydropyranyl (THP), silyl, acyl, acyl alkyl ether, preferably acetyl.

[0066] The base is an inorganic base or an organic base, the inorganic base is selected from sodium hydroxide, sodium bicarbonate, sodium phosphate, and the organic base is selected from ammonia gas / ammonia water, methylamine solution, ethylenediamine or triethylamine; the molar ratio of the base to compound 7 is 5 to 40:1; the reaction solvent is acetonitrile, tetrahydrofuran, methanol, dichloromethane, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide or any mixture of the above solvents; the reaction temperature is 0-100°C.

[0067] The present invention also provides a new 2'-fluoro-2'-deoxyuridine intermediate compound 4, whose structural formula is as follows:

[0068]

[0069] Wherein R is a hydroxyl protecting group, and a tetrahydropyranyl group (THP group) is most preferably used as the hydroxyl protecting group, and the structural formula is as follows:

[0070]

[0071] The advantages of the method of the present invention mainly lie in:

[0072] 1. The present invention provides a new industrially feasible route for synthesizing 2'-fluoro-2'-deoxyuridine;

[0073] 2. This synthetic route: short route, good conversion rate, high yield, total yield of 65%, avoids trifluoromethanesulfonyl chloride, does not need column treatment, the product derivative has high purity and is easy to crystallize;

[0074] 3. This synthetic route: simple operation, environmentally friendly, and suitable for industrial production;

[0075] 4. A novel intermediate 4 for synthesizing 2'-fluoro-2'-deoxyuridine is disclosed;

[0076] 5. Provide methodological reference for the synthesis of similar compounds;

[0077] 6. The present invention does not require low-temperature reaction or reaction in a high-pressure reactor, has a moderate production cost, and is suitable for industrial production. Specific embodiments

[0078] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under normal conditions.

[0079] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0080] The room temperature in the examples refers to 20-35° C. Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used without treatment.

[0081] Example 1

[0082]

[0083] Compound 1 (50.00 g) and DMF (500 mL), 3,4-dihydro-2H-pyran (55.80 g, 663.3 mmol) were added to a 1L three-necked flask, and p-toluenesulfonic acid (1.90 g, 11.0 mmol) was added under stirring at room temperature. The reaction solution was stirred at room temperature for 18 hours, and the conversion was complete. The temperature was lowered to 5-10 degrees, and sodium hydroxide solution (2N, 115 mL) was added dropwise, and the system temperature rose to 27 degrees. Stirred for two hours at room temperature, glacial acetic acid (39.84 g, 663.4 mmol) was added, and stirred evenly, pH = 7, extracted with EA phase (200 mL * 3), the organic phases were combined, and concentrated under reduced pressure to obtain solid compound 3-1 (82.00 g, yield: 89.9%, HPLC purity: 90%), which was directly used in the next step.

[0084] Example 2

[0085]

[0086] Compound 3-1 (50 g), acetonitrile (500 mL), triethylamine (73.59 g, 727.2 mmol) and perfluorobutylsulfonyl fluoride (54.92 g, 181.8 mmol) obtained in Example 1 were added to a 1L three-necked flask, and the system was stirred at room temperature for 2 hours. The TLC spot plate showed that the raw material was completely converted. Triethylamine trihydrofluoride (58.62 g, 363.6 mmol) was added to the system, and the reaction system was reacted at room temperature for 18 hours. Saturated sodium bicarbonate solution (500.0 mL) was added, stirred for half an hour, extracted with ethyl acetate (300.0 mL*3), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-1, to obtain an oil (45.23 g, yield: 90.1%, HPLC purity: 90%), which was directly used in the next step.

[0087] Example 3

[0088]

[0089] Compound 5-1 (40 g), methanol (200 mL), p-toluenesulfonic acid (1.66 g, 9.64 mmol) obtained in Example 2 were added to a 500 mL three-necked flask, and the system was stirred at room temperature for 10 hours. The TLC spot showed that the raw material was completely converted. The system was concentrated under reduced pressure to obtain an oily product 6 (26 g) with HPLC purity of 91.20%. The recovery amount of the crude product exceeded the theoretical yield and was directly used in the next step.

[0090] Example 4

[0091]

[0092] Into a 500mL three-necked flask were added compound 6 (26 g) obtained in Example 3, dichloromethane (300 mL), acetic anhydride (26.95 g, 264.0 mmol) and triethylamine (26.71 g, 264.0 mmol). The system was stirred at room temperature for 10 hours. The TLC spot showed that the raw material was completely converted. The system was concentrated under reduced pressure, and ethanol (400 mL) was added to the system. The mixture was stirred for 3 hours to precipitate a large amount of solid. The solid was collected by filtration and recrystallized with glacial acetic acid and ethanol to obtain a white solid (19.50 g, two-step yield: about 61.2%, purity: 99.92%).

[0093] Example 5

[0094]

[0095] Compound 7-1 (19.5 g) obtained in Example 4 and ammonia methanol (7M / L, 140 mL) were added to a 500 mL three-necked flask, and the system was stirred at room temperature for 10 hours. The TLC spot showed that the raw material was completely converted. The system was concentrated under reduced pressure, and methanol / n-heptane (40 mL / 150 mL) was added to the system. The mixture was stirred at 70°C for 3 hours. A large amount of solid was precipitated. The solid was filtered and collected to obtain a white solid 6 (13.65 g, yield: 93.9%, purity: 99.95%).

Claims

1. A method for preparing a 2'-fluoro-2'-deoxyuridine compound 6, the structural formula of which is as follows: The method includes: (a) Compound 3 reacts with a perfluorobutylsulfonyl fluoride reagent in an organic solvent under a first organic base condition to obtain compound 4; (b) adding a second organic base and a fluorinating agent without treatment and in a "one-pot process", so that compound 4 reacts with the fluorinating agent under the conditions of the second organic base and the fluorinating agent to directly obtain compound 5; Wherein R is a tetrahydropyran THP group; The first organic base is selected from triethylamine; the molar feed ratio of the compound 3 to the perfluorobutylsulfonyl fluoride reagent is 1:(1-3); the molar feed ratio of the fluorinating agent to the compound 4 is 2-4:1, the fluorinating agent is selected from hydrofluoric acid or its salt, and the molar ratio of the second organic base to the hydrofluoric acid is in the range of 15:1 to 1:15; the reaction temperature is 15-40°C; the reaction time is 1-20 hours; the organic solvent is selected from acetonitrile; the second organic base and the hydrofluoric acid are selected from hydrogen fluoride pyridine or hydrogen fluoride triethylamine; (c) Compound 5 is deprotected to obtain Compound 6, which comprises: Compound 5 is reacted under acidic conditions to obtain Compound 6, and the reaction formula is as follows: The acidic reagent is selected from p-toluenesulfonic acid; the molar feed ratio of the compound 5 to the acidic reagent is 1:(0.1-5); the reaction is carried out in the following solvent, the solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ether, dimethyl sulfoxide, methanol or any mixture thereof; the reaction time is 2-10 hours; in, The compound 3 is prepared by the following method, comprising: preparing compound 3 by a "one-pot method" without treating compound 2, and the reaction formulas of step 1 and step 2 are as follows: The molar feed ratio of compound 2 in step 2 to the alkaline reagent is 1:(0.1-5); the alkaline reagent in step 2 is sodium hydroxide, the solvent in step 2 is N,N-dimethylformamide, the reaction time in step 2 is 2-5 hours; the reaction temperature in step 2 is 20-35°C; The compound 2 is prepared by the following method, comprising: obtaining the compound 1 by reacting with a hydroxyl activating reagent under acidic conditions, wherein the hydroxyl activating reagent is selected from 3,4-dihydro-2H-pyran; the molar feed ratio of the compound 1 to the hydroxyl protecting group reagent is 1:(1-5); the acidic reagent is selected from p-toluenesulfonic acid; the solvent is N,N-dimethylformamide; the reaction time is 1-24 hours; and the reaction temperature is 20-30°C.

2. The preparation method according to claim 1, characterized in that: The compound 6 is purified by the following method, comprising reacting the compound 6 with a hydroxyl protecting group reagent under alkaline conditions to obtain a compound 7, the reaction time is 1-24 hours, and the molar feed ratio of the base to the compound 6 is 1-10:1; and then removing the hydroxyl protecting group to obtain a compound 6, the chemical formula of which is as follows: Wherein R' is acetyl; The hydroxyl protecting group reagent is selected from acetic anhydride; The base is selected from diisopropylethylamine, triethylamine and diisopropylamine.

3. The preparation method according to claim 2, characterized in that: The molar feed ratio of the compound 6 to the hydroxyl protecting group reagent is 1:(1-5); the molar feed ratio of the base to the compound 6 is 2-4:1; the solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide, or any mixture of the above solvents; the reaction time is 2-5 hours; The method for removing the hydroxyl protecting group, the reaction formula is as follows: Wherein R' is acetyl; The dehydroxylation is carried out in an organic base, and the organic base is selected from ammonia gas or ammonia water; the molar ratio of the base to compound 7 is 5-40:1; the reaction solvent is methanol; and the reaction temperature is 0-100°C.

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