A method for synthesizing 2'-fluoro-2'-deoxyuridine and its intermediates

Abstract

The present invention belongs to the field of organic synthesis and specifically relates to a method for synthesizing 2'-fluoro-2'-deoxyuridine and its intermediates. The method comprises the following steps: The method prepares 2'-fluoro-2'-deoxyuridine by constructing novel intermediates, namely, compounds of formula IV, III, and II. This method avoids the use of reagents such as dihydropyran, which are strong eye and skin irritants. The method results in milder reaction conditions, lower costs, simple operation, environmental friendliness, high yield, and suitability for industrial production.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing 2'-fluoro-2'-deoxyuridine and an intermediate thereof, and belongs to the field of organic synthesis. Background Art

[0002] 2'-Fluoro-2'-deoxyuridine is an important pharmaceutical intermediate. The existing methods for preparing this intermediate compound have problems such as environmental pollution, high cost, and harm to the health of operators.

[0003] CN113683648A discloses a method for synthesizing 2'-fluoro-2'-deoxyuridine, comprising the following steps:

[0004]

[0005] Wherein R is a hydroxyl protecting group, most preferably a tetrahydropyranyl group (THP group) as a hydroxyl protecting group; R' is a conventional hydroxyl protecting group in the art, preferably, R is a tetrahydropyranyl (THP), methoxymethyl ether (MOM), a silyl group (for example: tert-butyldimethylsilyl) or an acyl group (for example: acetyl), preferably an acetyl group.

[0006] This method uses a tetrahydropyran group as a hydroxyl protecting group. Dihydropyran is highly irritating, causing harm to human health and environmental pollution. The unit price of dihydropyran is 160-200 yuan / kg, and the process cost is relatively high.

[0007] Therefore, the industry urgently needs a low-cost and convenient method for preparing 2'-deoxy-2'-fluorouridine. Summary of the Invention

[0008] The present invention provides a method for synthesizing 2'-fluoro-2'-deoxyuridine. The method is a new synthetic route and has the advantages of simple operation, mild reaction, high yield, good safety, no need for column chromatography, good product quality, and is very suitable for industrial production.

[0009] The first aspect of the present invention provides a method for synthesizing 2'-fluoro-2'-deoxyuridine intermediate II, comprising the following steps:

[0010]

[0011] wherein R is selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

[0012] Compound III reacts with a hydroxyl activator and a fluorinating agent in the presence of an organic base to prepare compound II.

[0013] As a further improvement of the present invention, the organic base is selected from diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, N,N-dimethyllaurylamine, diisopropylamine, N,N-dimethylaniline, 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, and particularly more preferably triethylamine.

[0014] As a further improvement of the present invention, the molar feed ratio of the organic base to the compound III is (1-10):1, preferably (3-6):1, and more preferably (3-5.5):1.

[0015] As a further improvement of the present invention, the hydroxyl activator is selected from perfluoroalkanesulfonyl fluoride, preferably perfluorobutylsulfonyl fluoride.

[0016] As a further improvement of the present invention, the molar feed ratio of the hydroxyl activator to compound III is (1-5):1, preferably (1-3):1, and more preferably (1-1.3):1.

[0017] As a further improvement of the present invention, the fluorinating agent can be selected from hydrofluoric acid or its salts, and the 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.

[0018] As a further improvement of the present invention, the molar feed ratio of the fluorinating agent to compound III is (1-10):1, preferably (1-5):1.

[0019] As a further improvement of the present invention, the reaction is carried out in an organic solvent, and 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 diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 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; nitriles are such as acetonitrile, etc. Preferred are 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, N,N-dimethylformamide and acetonitrile, and most preferably N,N-dimethylformamide.

[0020] As a further improvement of the present invention, the volume (mL) of the organic solvent is 1 to 20 times, preferably 3 to 10 times, and more preferably 4 to 8 times the mass (g) of the compound III.

[0021] As a further improvement of the present invention, the reaction time is until the detection reaction is completed, usually the reaction time is 1 to 48 hours, preferably 8 to 20 hours.

[0022] As a further improvement of the present invention, the reaction temperature is usually -100 to 100°C, preferably -80 to 80°C, more preferably -60 to 60°C, and most preferably 15 to 40°C.

[0023] As a further improvement of the present invention, the reaction further comprises a separation step, for example, comprising liquid separation, extraction and concentration; preferably, the liquid separation step comprises adding the reaction solution to a carbonate aqueous solution, adding a halogenated hydrocarbon, and separating the system; preferably, the extraction comprises collecting the halogenated hydrocarbon phase, extracting the aqueous phase again with the halogenated hydrocarbon, and combining the organic phases.

[0024] As a further improvement of the present invention, the carbonate aqueous solution is preferably a potassium carbonate aqueous solution, and the halogenated hydrocarbon is preferably dichloromethane.

[0025] As a further improvement of the present invention, the preparation of compound III comprises the following steps:

[0026]

[0027] wherein R is selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

[0028] 1) Adding a vinyl ether reagent to compound V in the presence of an acidic reagent to react to obtain compound IV;

[0029] 2) Under alkaline conditions, compound IV undergoes a ring-opening reaction to prepare compound III.

[0030] As a further improvement of the present invention, the molar feed ratio of compound V to vinyl ether reagent in step 1) is 1:(1-10), preferably 1:(1-5), and more preferably 1:(1-2.5).

[0031] As a further improvement of the present invention, the acidic reagent in step 1) can be selected from formic acid, glacial acetic acid, p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.

[0032] As a further improvement of the present invention, the molar feed ratio of the acidic reagent to compound V in step 1) is (0.1-1):1, preferably (0.1-0.5):1.

[0033] As a further improvement of the present invention, step 1) is carried out in an organic solvent, and the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the above solvents, preferably N,N-dimethylformamide.

[0034] As a further improvement of the present invention, the volume amount (mL) of the organic solvent is 1 to 20 times, preferably 5 to 10 times, the mass amount (g) of compound V.

[0035] As a further improvement of the present invention, the reaction time of step 1) is until the detection reaction is completed, and the reaction time is usually 1 to 24 hours, preferably 3 to 7 hours, and more preferably 3 to 5 hours.

[0036] As a further improvement of the present invention, the reaction temperature of step 1) is 0-100°C, preferably 20-40°C, and more preferably 30-35°C.

[0037] As a further improvement of the present invention, the alkaline reagent in step 2) is selected from 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.

[0038] As a further improvement of the present invention, the molar feed ratio of the alkaline reagent in step 2) to the compound V in step 1) is (0.1-5):1, preferably (0.1-3):1.

[0039] As a further improvement of the present invention, the step 2) is carried out in an organic solvent, and the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or methanol or any mixture of the above solvents, preferably N,N-dimethylformamide.

[0040] As a further improvement of the present invention, the reaction temperature in step 2) is 0-100°C, preferably 20-40°C.

[0041] As a further improvement of the present invention, the ring-opening reaction in step 2) to prepare compound III further includes a separation step, such as acid adjustment, liquid separation, extraction, water washing, drying, spin drying, pulping, etc.

[0042] As a further improvement of the present invention, in the step 2) separation step, the pH is adjusted with acid, preferably to a pH of 1 to 6.5, more preferably to a pH of 2 to 3, and the acid is selected from an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid or malonic acid; and dichloromethane is used for separation and re-extraction.

[0043] The second aspect of the present invention provides a method for synthesizing 2'-fluoro-2'-deoxyuridine I, comprising the following steps:

[0044]

[0045] wherein R is selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

[0046] Compound II prepared in the first aspect is reacted in an organic solvent under acidic conditions to prepare compound I.

[0047] As a further improvement of the present invention, the acidic reagent is selected from formic acid, glacial acetic acid, p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.

[0048] As a further improvement of the present invention, the molar feed ratio of the acidic reagent to compound II is (0.01-1):1, preferably (0.05-1):1.

[0049] As a further improvement of the present invention, the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide, methanol or any mixture of the above solvents, preferably methanol.

[0050] As a further improvement of the present invention, the reaction time is until the detection reaction is completed, and the reaction time is usually 1 to 24 hours, preferably 2 to 10 hours, and more preferably 2 to 7 hours.

[0051] The third aspect of the present invention provides an intermediate compound represented by formula (IV), formula (III) or formula (II), whose structure is as follows:

[0052]

[0053] Wherein R is selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

[0054] As a further improvement of the present invention, the intermediate compound is preferably:

[0055]

[0056] As a further improvement of the present invention, the intermediate compound represented by formula (IV), formula (III) or formula (II) is used in the preparation of 2'-fluoro-2'-deoxyuridine I.

[0057] The advantages of the method of the present invention are mainly:

[0058] 1. Through this series of new compounds IV, III, and II, on the one hand, the use of dihydropyran, a strong eye and skin irritant, in the preparation of the key 2'-fluoro-2'-deoxyuridine compound can be avoided. On the other hand, the newly selected vinyl ether reagents are much cheaper than dihydropyran, and the reaction and deprotection conditions are milder than those using tetrahydropyran as a protecting group. After deprotection of the intermediate, 2'-fluoro-2'-deoxyuridine of higher purity is obtained.

[0059] 2. The present invention uses vinyl ether reagents. Since dihydropyran has a large steric position, the present invention uses vinyl ether reagents to react to obtain compound IV with small steric hindrance. The key intermediate compound IV is used to greatly improve the reaction environment of the ring-opening reaction and the fluorination reaction, thereby obtaining a high-purity compound II. After deprotection, the pure compound 2'-fluoro-2'-deoxyuridine is obtained. There is no need to add an acetyl protecting group. Deprotection eliminates two steps, saving production costs.

[0060] 3. The present invention provides a new industrially feasible route for the synthesis of 2'-fluoro-2'-deoxyuridine;

[0061] 4. The synthetic route is short and has a high yield, with an overall yield of up to 80%. No column treatment is required, and the product purity is high. Furthermore, the synthetic route is simple to operate, has a short reaction time, is environmentally friendly, and is suitable for industrial production.

[0062] 5. The present invention does not require low-temperature reaction or reaction in a high-pressure reactor, and the post-processing is simple, making it suitable for industrial production;

[0063] 6. The present applicant has ingeniously discovered that vinyl ether reagents, when used in the present invention, have good selectivity and are easy to remove. Furthermore, vinyl butyl ether is non-irritating, has a wider operating margin, and is more suitable for scale-up production than dihydropyran. Dihydropyran is a stronger irritant. The unit price of dihydropyran is 160 to 200 yuan / kg, while the unit price of vinyl butyl ether is 30 to 35 yuan / kg. Using vinyl butyl ether reagent significantly reduces overall costs, saves costs, and is more suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 is the compound III-1 of Example 1 1 H NMR spectrum.

[0065] Figure 2 This is the HPLC spectrum of Compound Ⅰ in Example 5. Specific embodiments

[0066] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions.

[0067] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0068] 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 further treatment.

[0069] Example 1

[0070]

[0071] 20 g of compound V and 100 mL of DMF were added to a 1L three-necked flask, stirred at room temperature, 3.36 g of p-toluenesulfonic acid monohydrate was added, 18.60 g of vinyl n-butyl ether was slowly added, and the temperature was subsequently controlled at 30-35 ° C. The reaction was 3-5 h. TLC detection showed that the reaction was basically complete. 92 mL of 2 mol / L NaOH aqueous solution was slowly added to the reaction solution, the temperature was controlled at 20-30 ° C, 100 mL of dichloromethane was directly added, and the pH was adjusted to 2-3 with hydrochloric acid. The dichloromethane phase was separated and collected, and the aqueous phase was extracted again with 60 mL of dichloromethane. The dichloromethane phases were combined, washed with 80 mL of saturated brine, dried over 20 g of anhydrous sodium sulfate, spin-dried, and slurried with n-heptane (200 mL) to obtain 37.3 g of compound III-1 as a white solid. The yield was 95%. Compound III-1 1 H NMR spectrum is shown in Figure 1 shown.

[0072] Example 2

[0073] Weigh 20g of compound V, add 150mL of DMF, stir at room temperature, add 3.36g of p-toluenesulfonic acid monohydrate, slowly add 18.60g of vinyl n-butyl ether, and then control the temperature at 30-35°C for 3-5h. The reaction is basically complete by TLC detection. Slowly add 120mL of 2mol / L NaOH aqueous solution to the reaction solution, control the temperature at 20-30°C, directly add 100mL of dichloromethane, adjust the pH to 2-3 with hydrochloric acid, separate the liquids and collect the dichloromethane phase, extract the aqueous phase again with 60mL of dichloromethane, combine the dichloromethane phases, wash with 160mL of saturated brine, dry over 20g of anhydrous sodium sulfate, spin-dry, and slurry with n-heptane (200mL) to obtain 36g of compound III-1 as a white solid with a yield of 91%.

[0074] Example 3

[0075] Weigh 20g of compound V, 200mL of DMF, stir at room temperature, add 6.72g of p-toluenesulfonic acid monohydrate, slowly add 26.56g of vinyl n-butyl ether, and then control the temperature at 30-35°C for 3-5h. The reaction is basically complete by TLC detection. Slowly add 92mL of 2mol / L NaOH aqueous solution to the reaction solution, control the temperature at 20-30°C, directly add 100mL of dichloromethane, adjust the pH to 2-3 with hydrochloric acid, separate the liquids and collect the dichloromethane phase, extract the aqueous phase again with 60mL of dichloromethane, combine the dichloromethane phases, wash with saturated brine, dry over anhydrous sodium sulfate, spin dry, and slurry with n-heptane (200mL) to obtain 36.2g of compound III-1 as a white solid with a yield of 92%.

[0076] Example 4

[0077] Weigh 100g of compound V, 1000mL of DMF, stir at room temperature, add 33.6g of p-toluenesulfonic acid monohydrate, slowly add 93g of vinyl n-butyl ether, and then control the temperature at 30-35°C for 3-5h. The reaction is basically complete by TLC detection. Slowly add 460mL of 2mol / L NaOH aqueous solution to the reaction solution, control the temperature at 20-30°C, directly add 500mL of dichloromethane, adjust the pH to 2-3 with hydrochloric acid, collect the dichloromethane phase, and extract the aqueous phase again with 300mL of dichloromethane. Combine the dichloromethane phases, wash with saturated brine, dry over anhydrous sodium sulfate, spin dry, and slurry with n-heptane (1000mL) to obtain 178g of compound III-1 as a white solid with a yield of 90%.

[0078] Example 5

[0079]

[0080] To 226.7 g of compound III-1, 1000 mL of DMF and 268.4 g of triethylamine were added dropwise, and 173.6 g of perfluorobutylsulfonyl fluoride was added dropwise. 1 h after the addition, 260 g of triethylamine trihydrofluoride was added dropwise, and the mixture was stirred overnight at 20 ° C. TLC detection showed that the reaction was basically complete. The reaction solution was slowly added to an aqueous sodium bicarbonate solution (60 g of sodium bicarbonate + 1180 mL of water) and 400 mL of dichloromethane was added. The system was separated, the dichloromethane phase was collected, and the aqueous phase was extracted again with 200 mL of dichloromethane. The organic phases were combined and concentrated to obtain 402.6 g of a dark brown liquid. 402.6 g of crude Compound II was added to 1000 mL of methanol, followed by 16.8 g of p-toluenesulfonic acid monohydrate. The mixture was stirred for 5 h. The reaction was complete after HPLC analysis. 2000 mL of n-heptane was added to the mixture, stirred for 30 minutes, and the solid was filtered to obtain 113 g of white solid Compound I. The yield was 90% (two steps) and the purity was 98.9%. See [see for details] Figure 2 As shown, the peak with an elution time of 7.351 min is the peak of the target product.

[0081] Example 6

[0082] To 226.7 g of compound III-1, 1200 mL of DMF and 268.4 g of triethylamine were added dropwise, and 200 g of perfluorobutylsulfonyl fluoride was added dropwise. 1 h after the addition, 300 g of triethylamine trihydrofluoride was added dropwise, and the mixture was stirred at 30 ° C overnight. TLC detection showed that the reaction was basically complete. The reaction solution was slowly added to an aqueous sodium bicarbonate solution (60 g of sodium bicarbonate + 1180 mL of water) and 400 ml of dichloromethane was added. The system was separated, the dichloromethane phase was collected, and the aqueous phase was extracted again with 200 mL of dichloromethane. The organic phases were combined and concentrated to obtain 420 g of a dark brown liquid. 201.3 g of crude compound II was added to 500 ml of methanol, and 8.4 g of p-toluenesulfonic acid monohydrate was added. The mixture was stirred for 5 h. The reaction was confirmed to be complete by HPLC. 1000 mL of n-heptane was added to the system, and the mixture was stirred for 30 minutes. The solid was filtered to obtain 54.5 g of white solid compound I with a yield of 90.4% (two steps) and a purity of 98.8%.

[0083] Example 7

[0084] To 226.7g of compound III-1, 1700mL of DMF and 268.4g of triethylamine were added dropwise, followed by the dropwise addition of 173.6g of perfluorobutylsulfonyl fluoride. 1h after the addition, 213.8g of triethylamine trihydrofluoride was added dropwise, and the mixture was stirred overnight at 20°C. TLC indicated that the reaction was essentially complete. The reaction solution was slowly added to a sodium bicarbonate aqueous solution (60g of sodium bicarbonate + 1180mL of water) and 400mL of dichloromethane was added. The system was separated, and the aqueous phase was extracted again with 200mL of dichloromethane. The organic phases were combined and concentrated to give 450g of a dark brown liquid (directly used in the next step). 201.3g of crude compound II was added to 400mL of methanol, followed by the addition of 8.4g of p-toluenesulfonic acid monohydrate, and stirred for 5h. The reaction was complete by HPLC. 1000mL of n-heptane was added to the system, stirred for 30 minutes, and the solid was filtered to give 53.5g of compound I as a white solid, with a yield of 95% (two steps) and a purity of 98%.

Claims

1. A method for synthesizing a 2'-fluoro-2'-deoxyuridine intermediate I, characterized in that: The steps include: wherein R is selected from a C1-C6 alkyl group; Step 3): Compound III reacts with a hydroxyl activator and a fluorinating agent in the presence of an organic base to prepare compound II; Step 4): Intermediate II is reacted in an organic solvent under acidic conditions to prepare compound I.

2. The preparation method according to claim 1, wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

3. The preparation method according to claim 1 or 2, characterized in that The reaction conditions of step 3) meet at least one of the following conditions: The organic base is selected from at least one of diisopropylethylamine, trimethylamine, triethylamine, tri-n-butylamine, N,N-dimethyllaurylamine, diisopropylamine, N,N-dimethylaniline, 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; The molar feed ratio of the organic base to the compound III is (1-10):1; The hydroxyl activator is perfluoroalkanesulfonyl fluoride; The molar feed ratio of the hydroxyl activator to compound III is (1-5):1; The fluorinating agent is hydrofluoric acid or its salt; The molar feed ratio of the fluorinating agent to compound III is (1-10):1; The reaction is carried out in an organic solvent, which is selected from one or a combination of dimethyl sulfoxide, aliphatic alkanes, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides or nitrile solvents, wherein the aliphatic alkanes are selected from n-hexane, cyclohexane or n-heptane; the aromatic hydrocarbons are toluene; the halogenated hydrocarbons are selected from dichloromethane, chloroform or 1,2-dichloroethane; the ethers are selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or dioxane; the esters are selected from ethyl acetate or n-butyl acetate; the amides are selected from N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; and the nitrile is acetonitrile.

4. The preparation method according to claim 3, characterized in that Step 3) the organic base is selected from at least one of triethylamine, diisopropylethylamine and pyridine; The molar feed ratio of the organic base to the compound III is (3-6):1; The hydroxyl activator is perfluorobutylsulfonyl fluoride; The molar feed ratio of the hydroxyl activator to compound III is (1-3):1; The molar feed ratio of the fluorinating agent to compound III is (1-5):1; The fluorinating agent and the organic base are a complex selected from pyridine hydrofluoric acid and triethylamine hydrofluoric acid; The organic solvent is tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N- At least one of dimethylformamide, methyl tert-butyl ether, diethyl ether or dimethyl sulfoxide.

5. The preparation method according to claim 4, characterized in that Step 3) The organic solvent is N,N-dimethylformamide.

6. The preparation method according to claim 1 or 2, characterized in that The reaction conditions of step 4) meet at least one of the following conditions: The acidic reagent is selected from formic acid, glacial acetic acid or p-toluenesulfonic acid; The molar feed ratio of the acidic reagent to compound II is (0.01-1):1; The organic solvent is selected from at least one of tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or methanol; The reaction time is from 1 to 24 hours until the detection reaction is completed.

7. The preparation method according to claim 6, characterized in that Step 4) the acidic reagent is p-toluenesulfonic acid; The molar feed ratio of the acidic reagent to compound II is (0.05-1):1; The organic solvent is methanol; The reaction time is from 2 to 10 hours until the detection reaction is completed.

8. The preparation method according to any one of claims 1 to 7, characterized in that The preparation of compound III comprises the following steps: wherein R is selected from a C1-C6 alkyl group; 1) Adding a vinyl ether reagent to compound V in the presence of an acidic reagent to react to obtain compound IV; 2) Under alkaline conditions, compound IV undergoes a ring-opening reaction to prepare compound III.

9. The preparation method according to claim 8, characterized in that The preparation of compound III comprises the following steps: Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

10. The preparation method according to claim 8 or 9, characterized in that: The reaction conditions of the step meet at least one of the following conditions: In the step 1), the molar ratio of compound V to the vinyl ether reagent is 1:(1-10); In step 1), the acidic reagent is selected from formic acid, glacial acetic acid or p-toluenesulfonic acid; In the step 1), the molar feed ratio of the acidic reagent to the compound V is (0.1-1):1; The step 1) is carried out in an organic solvent, wherein the organic solvent is selected from at least one of tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether or dimethyl sulfoxide; The volume of the organic solvent in step 1) is 1 to 20 times the mass of compound V in g. The reaction time of step 1) is until the detection reaction is completed; The reaction temperature of step 1) is 0-100°C; In the step 2), the alkaline reagent is selected from 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, and sodium hydroxide; The molar feed ratio of the alkaline reagent in step 2) to the compound V in step 1) is (0.1-5):1; The step 2) is to carry out the reaction in an organic solvent, wherein the organic solvent is selected from at least one of tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or methanol; The reaction temperature of step 2) is 0-100°C.

11. The preparation method according to claim 8 or 9, characterized in that: In the step 1), the molar ratio of compound V to the vinyl ether reagent is 1:(1-5); In the step 1), the acidic reagent is p-toluenesulfonic acid; In the step 1), the molar feed ratio of the acidic reagent to the compound V is (0.1-0.5):1; The organic solvent in step 1) is N,N-dimethylformamide; The volume of the organic solvent in step 1) is 5 to 10 times the mass of compound V in mL. The reaction time of step 1) is 1 to 24 hours; The reaction temperature of step 1) is 20-40°C; In the step 2), the alkaline reagent is sodium hydroxide; The molar feed ratio of the alkaline reagent in step 2) to the compound V in step 1) is (0.1-3):1; The organic solvent in step 2) is N,N-dimethylformamide; The reaction temperature of step 2) is 20-40°C.

12. The preparation method according to claim 11, characterized in that In the step 1), the molar feed ratio of compound V to the vinyl ether reagent is 1:(1-2.5); and the reaction time of the step 1) is 3-7 hours.

13. The preparation method according to claim 12, characterized in that The reaction time of step 1) is 3 to 5 hours.

14. An intermediate compound represented by formula (IV), formula (III) or formula (II), having the following structure: in, R is selected from C1-C6 alkyl.

15. The intermediate compound according to claim 14, characterized in that R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

16. The intermediate compound according to claim 14 or 15, characterized in that The structure of the intermediate compound is shown below:

17. A method for preparing 2'-fluoro-2'-deoxyuridine I, comprising preparing it from the intermediate compound of formula (III) or (II) according to any one of claims 14 to 16.

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