Fluorination preparation process of sofosbuvir intermediate

Abstract

The invention provides a fluorination preparation process of a sofosbuvir intermediate, and relates to the technical field of pharmaceutical chemicals. The preparation process comprises the following steps: (1) dissolving a compound A in a first solvent, and then adding alkali and paratoluensulfonyl chloride to carry out affinity substitution reaction; after the reaction is finished, contacting the reaction liquid with water, and separating an organic phase; drying and concentrating to obtain a crude intermediate product; (2) carrying out fluorination reaction on the crude intermediate product and a fluorinating agent under the action of a Lewis acid catalyst; after the reaction is finished, contacting the reaction liquid with water, and separating an organic phase; then extracting and recrystallizing to obtain a target compound B; wherein the structural formula of the compound A is as shown in a formula I, and the structural formula of the compound B is as shown in a formula II. According to the fluorination preparation process of the sofosbuvir intermediate, the compound B can be efficiently obtained, the process is greatly simplified, the production cost is saved, and the fluorination preparation process has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, specifically to a fluorination preparation process for a sofosbuvir intermediate. Background Technology

[0002] Sofosbuvir is a direct-acting antiviral drug used to treat chronic hepatitis C. It works by inhibiting the RNA polymerase required for viral replication. Specifically, sofosbuvir is a nucleoside reverse transcriptase inhibitor that works by inhibiting the replication process of the hepatitis C virus; it binds to the viral RNA polymerase and prevents viral replication and transmission. Furthermore, sofosbuvir is unique in its broad applicability to different genotypes of hepatitis C virus infection. It needs to be used in combination with other drugs (such as ribavirin or daclatasvir) to target different genotypes of hepatitis C virus (HCV), achieving a cure rate of over 90%, and significantly reducing side effects compared to traditional interferon regimens. As a hepatitis C treatment, sofosbuvir has highly effective antiviral activity and a significant virological cure rate. In addition, sofosbuvir is well-tolerated with mild adverse reactions and is suitable for various patient populations, including patients with cirrhosis, impaired renal function, and liver transplant recipients. The synthesis of sofosbuvir has also been extensively studied by those skilled in the art.

[0003] Sofosbuvir has the following structure:

[0004]

[0005] Chemical name: (S)-isopropyl-2-((S)-((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphoamino)propionate.

[0006] Preparation of a Sofosbuvir Intermediate: Compound B is an intermediate in the synthesis of sofosbuvir, and its structure is as follows:

[0007]

[0008] Chemical name: (2R,3R,4R,5R)-5-(4-benzoamido-2-oxopyrimidin-1(2H)-yl)-2-((benzoyloxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-ylbenzoate.

[0009] Currently, there are few methods for synthesizing compound B, with DAST (diethylaminosulfur trifluoride) reagent being the primary reagent for synthesizing the fluorinated product compound B. For example, patent US20130273005A1 reports a method for preparing sofosbuvir, which involves a DAST reagent fluorination reaction at low temperature under toluene conditions to obtain the product. In this technical approach, DAST acts as a nucleophilic fluorinating reagent, attacking the C-2' hydroxyl group. Besides obtaining the target compound, hydrolysis and elimination products are inevitably generated, resulting in a low yield (16.3%) and significant difficulties for subsequent purification. Furthermore, from a process chemistry perspective, DAST is highly corrosive and easily decomposed, making it unsuitable for industrial production. This route also requires column chromatography purification of the compound, and the post-processing is cumbersome, further impacting the yield. Summary of the Invention

[0010] To address the shortcomings of existing technologies, this invention discloses a fluorination preparation process for sofosbuvir intermediates. This process combines nucleophilic substitution and fluorination reactions to obtain compound B in high yield. The overall preparation process has low raw material costs, high safety, and low by-product content.

[0011] To achieve the above technical objectives, this invention proposes a fluorination preparation process for a sofosbuvir intermediate, comprising: (1) dissolving compound A in a first solvent, then adding a base and p-toluenesulfonyl chloride for an affinity substitution reaction; after the reaction is completed, contacting the reaction solution with water and separating the organic phase; drying and concentrating to obtain a crude intermediate product; (2) subjecting the crude intermediate product and a fluorinating agent to a fluorination reaction under the action of a Lewis acid catalyst; after the reaction is completed, contacting the reaction solution with water and separating the organic phase; then extracting and recrystallizing to obtain the target compound B; wherein, the structural formula of compound A is shown in Formula I:

[0012]

[0013] The structural formula of compound B is shown in Formula II:

[0014]

[0015] Through exploratory experiments, the research team of this invention discovered that in the preparation of compound B using compound A as the starting material, if a fluorinating agent is added directly at the initial stage of the reaction, the reaction hardly occurs (reaction rate <5% after 4 hours of incubation at 60±5℃). In the above technical solution, starting with compound A, a nucleophilic substitution reaction is first performed to enhance the activity of the hydroxyl group using a sulfonate ester, followed by a fluorination reaction using a fluorinating agent to introduce fluorine, thus efficiently obtaining the sofosbuvir intermediate compound B. The entire process does not require the use of DAST reagent or hydrogen fluoride; a relatively inexpensive and safer fluorinating agent can be used.

[0016] Furthermore, extensive experimental data confirms that the introduction of Lewis acids into step (2) of the above technical solution to participate in the catalytic reaction, under the action of Lewis acid catalysts, activates the leaving group through the coordination of the Lewis acid with the oxygen atom of the sulfonate, effectively shortening the reaction time and improving the process yield. This will greatly reduce the process cost in large-scale industrial production.

[0017] Wherein, a common name for compound A is

[0018] BenzaMide,N-[1-(3,5-di-O-benzoyl-2-C-Methyl-β-D-arabinofuranosyl)-1,2-dihydro-2-oxo-4-pyriMidinyl]-, in actual processes, compound A can be obtained either in-house or by purchasing.

[0019] The structural formula of the crude intermediate product is shown in Formula III:

[0020]

[0021] Based on the above technical solution, the first solvent is dichloromethane; further, the mass ratio of dichloromethane to compound A is (3-10):1, preferably (5-10):1. The appropriate amount of the first solvent is beneficial to promote mass transfer and improve reaction efficiency.

[0022] Based on the above technical solution, the base includes one or two of pyridine and triethylamine; further, the molar ratio of the base to the compound A is (2-3):1.

[0023] Based on the above technical solution, the molar ratio of p-toluenesulfonyl chloride to compound A is (1.2~2.0):1. By optimizing the ratio of compound A to p-toluenesulfonyl chloride, it is beneficial to fully contact and react, thereby improving the conversion rate of reactants, converting more haloalkanes into the target product, and reducing the occurrence of side reactions.

[0024] Based on the above technical solution, the temperature of the affinity substitution reaction is 0-20℃ and the reaction time is 2-3h. The optimization of the reaction conditions is to improve the reaction efficiency and reduce the formation of by-products.

[0025] It should be noted that the specific operation of drying the organic phase in step (1) of this invention is not limited. The reaction solution quenches the reaction by contacting water, and the organic phase obtained after phase separation may contain a small amount of water. The specific operation of removing this part of water can meet the requirements of this invention for drying the organic phase. Those skilled in the art can choose according to their needs. Optionally, the drying operation includes adding magnesium sulfate to the organic phase and then filtering to remove the magnesium sulfate.

[0026] It should be noted that the specific operation of the concentration operation in step (1) is not limited in this invention. It can be any operation that separates the solvent from the dried organic phase and concentrates it to obtain the crude intermediate product. Optionally, the first solvent separated in the concentration operation can be recycled.

[0027] Based on the above technical solution, the fluorinating agent is at least one of potassium fluoride and sodium fluoride. Existing processes often use DAST or hydrogen fluoride as fluorinating agents to prepare sofosbuvir intermediate compound B. However, DAST is expensive, and hydrogen fluoride is highly corrosive, requiring sophisticated equipment. For large-scale industrial production, these processes suffer from drawbacks such as difficult purification, expensive reagents, toxicity, generation of sulfur-containing byproducts, and strong corrosiveness requiring strict protection. Therefore, these processes have relatively poor operability and high operating costs. Compared to DAST reagent or hydrogen fluoride, potassium fluoride and sodium fluoride are readily available and safe to use, reducing process costs and extending equipment lifespan. Furthermore, the molar ratio of the fluorinating agent to compound A is (2-5):1, preferably (3-4):1. Using an appropriate amount of fluorinating agent can improve the efficiency of the fluorination reaction.

[0028] Based on the above technical solution, the Lewis acid catalyst includes one or more of magnesium chloride, zinc chloride, and lithium chloride. Embodiments of the present invention illustrate the process for preparing compound B using different Lewis acid catalysts. Further, the amount of the Lewis acid catalyst used is 5% to 20% of the mass of compound A, preferably 10% to 20%. Appropriate amounts of catalyst can improve reaction efficiency and reduce the occurrence of side reactions.

[0029] Based on the above technical solution, the temperature of the fluorination reaction is 50-80℃ and the reaction time is 3-8h. Appropriate reaction temperature and reaction time can improve reaction efficiency and reduce the generation of by-products.

[0030] Based on the above technical solution, the fluorination reaction is carried out in a second solvent, which includes one or more of DMSO, toluene, and xylene. Further, the mass ratio of the second solvent to compound A is (2-8):1, preferably (5-8):1.

[0031] Based on the above technical solution, the fluorination reaction is carried out under an inert atmosphere. In this invention, the inert atmosphere refers to a gaseous environment composed of gases that do not chemically interact with the reactants, such as a nitrogen atmosphere, or an atmosphere formed by gases of Group 0 elements in the periodic table (such as argon).

[0032] Based on the above technical solution, the extractant used in the extraction operation includes one or more of toluene, dichloromethane, and ethyl acetate. The embodiments of this invention illustrate the preparation process of compound B using different extractants. It should be noted that this invention does not limit the specific extraction process; those skilled in the art can choose to add the extractant in stages and perform multiple extractions to extract the target product from the organic phase obtained in step (2).

[0033] Based on the above technical solution, the solvent used in the recrystallization operation includes one or more of methanol, ethanol, and n-hexane. Embodiments of this invention illustrate the process of preparing compound B using different recrystallization solvents. It should be noted that this invention is not limited to the specific recrystallization operation. For example, methanol can be added to the extracted material to entrain the solvent, followed by the addition of fresh methanol, low-temperature slurrying to precipitate the solid, and filtration to obtain the target product. In optional examples of this invention, the separation of the solid target product is further included; in further optional examples, the separated solid target product is further washed; separation can be achieved by methods such as pressure filtration, filtration, or centrifugation.

[0034] Compared with existing technologies, the beneficial effects of this invention are as follows: The fluorination preparation process of the sofosbuvir intermediate of this invention uses compound A as the starting material. First, through a nucleophilic substitution reaction and by utilizing sulfonate esters to enhance the activity of the hydroxyl position, fluorination is introduced via a fluorination reaction using a fluorinating agent. This process can efficiently (yield above 50.6%) obtain high-quality (purity above 98.6%) sofosbuvir intermediate compound B. In this invention, the fluorination reaction is carried out under Lewis acid catalysis, thereby significantly improving reaction efficiency and reducing side reactions. The entire process of this invention does not require the use of DAST reagent or hydrogen fluoride, greatly simplifying the process, saving production costs, and extending equipment lifespan, thus possessing significant industrial application value. Detailed Implementation

[0035] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0036] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0037] The present invention will be further described below with reference to exploratory examples and embodiments.

[0038] Example 1

[0039] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0040] (1) Compound A (100g, 0.176mol, 1eq) and solvent dichloromethane (800g) were added to a reaction vessel and dissolved. Triethylamine (3eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (1.5eq) was added and the reaction was carried out at room temperature for 2-3 hours. After the reaction was completed, the reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered to separate the magnesium sulfate. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0041] (2) Under nitrogen protection, 800g of toluene was added to the crude intermediate and the temperature was raised to 50-80℃ to dissolve it. Then, 20g of magnesium chloride (20%) and 40.8g of potassium fluoride (4eq) were added, and the reaction was maintained at 60±5℃ for 4h. After the reaction was complete, 500g of water was added, and 3*1L of toluene was added for extraction. The mixture was concentrated, and then 2kg of methanol was added to continue concentrating until a solid precipitate was formed. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 54.6g of white solid compound B with a purity of 98.6% and a yield of 54.3%.

[0042] Comparative Example 1

[0043] A fluorination preparation process for a sofosbuvir intermediate, specifically: Compound A (100g, 0.176mol, 1eq) and 800g of dichloromethane solvent are added to a reaction vessel and dissolved. After dissolution, triethylamine (3eq) is added, and the temperature is lowered to 0–20°C. p-Toluenesulfonyl chloride (1.5eq) is added, and the reaction is carried out at room temperature for 2–3 hours. The reaction solution is then added to water, the organic phase is separated, magnesium sulfate is added as a drying agent, the mixture is filtered, and concentrated to dryness to obtain a crude intermediate product. Under nitrogen protection, 800g of toluene is added to the crude intermediate product, and the temperature is raised to 50–80°C to dissolve it. 40.8g of potassium fluoride (4eq) is added, and the reaction is maintained at 60±5°C for 8 hours. After the reaction was complete, 500g of water was added, and 3*1L of toluene was added for extraction. The mixture was concentrated, and then 2kg of methanol was added to continue concentrating until a solid precipitated. The mixture was cooled to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 36.7g of white solid compound B with a purity of 98.1% and a yield of 36.5%.

[0044] Based on the verification in Example 1 and Comparative Example 1, the addition of a Lewis acid catalyst in step (2) of the fluorination preparation process of the sofosbuvir intermediate of this invention significantly shortens the reaction time, and effectively improves the yield and purity of the obtained compound B. The research team speculates that the Lewis acid plays a certain role in activating the leaving group during the fluorination reaction of the intermediate product of this invention, thereby facilitating the introduction of fluorine and thus increasing the reaction rate, product purity, and quality. This invention is low-cost and efficient, and is beneficial for industrial production applications.

[0045] Example 2

[0046] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0047] (1) Compound A (100g, 0.176mol, 1eq) and dichloromethane (1000g) were added to a reaction vessel and dissolved. Triethylamine (3eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (2eq) was added and the reaction was carried out at room temperature for 2-3 hours. After the reaction was completed, the reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered. The product was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0048] (2) Under an inert atmosphere, 800g of DMSO was added to the crude intermediate product and the temperature was raised to 50-80℃ to dissolve it. Then, 20g of zinc chloride (20%) and 30.6g of potassium fluoride (3eq) were added, and the reaction was maintained at 60±5℃ for 3h. After the reaction was complete, 1600g of water was added, and 3*2L of ethyl acetate was added for extraction. The mixture was concentrated, and then 2kg of methanol was added to continue concentrating until a solid precipitate was formed. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 60.65g of white solid compound B with a purity of 99.1% and a yield of 60.3%.

[0049] Example 3

[0050] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0051] (1) Compound A (100g, 0.176mol, 1eq) and solvent dichloromethane (800g) were added to a reaction vessel and dissolved. Triethylamine (2eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (1.2eq) was added and the reaction was carried out at room temperature for 2-3 hours. After the reaction was completed, the reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered to separate the magnesium sulfate. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0052] (2) Under an inert atmosphere, 600g of DMSO was added to the crude intermediate product and the temperature was raised to 50-80℃ to dissolve it. 20g of zinc chloride (20%) and 30.6g of potassium fluoride (3eq) were added, and the mixture was kept at 80±5℃ for 3h. After the reaction was complete, 1600g of water was added, and 3*2L of ethyl acetate was added for extraction. The mixture was concentrated, and then 2kg of ethanol was added to continue concentrating until a solid precipitate was formed. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 60.06g of white solid compound B with a purity of 99.2% and a yield of 59.7%.

[0053] Example 4

[0054] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0055] (1) Compound A (100g, 0.176mol, 1eq) and dichloromethane (1000g) were added to a reaction vessel and dissolved. Pyridine (2eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (1.5eq) was added and the reaction was carried out at room temperature for 2-3 hours. The reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added as a drying agent and dried. Then, magnesium sulfate was separated by filtration. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0056] (2) Under an inert atmosphere, 800 g of xylene was added to the crude intermediate product and the temperature was raised to 70–80 °C to dissolve it. 10 g of lithium chloride (10%) and 40.8 g of potassium fluoride (4 eq) were added, and the mixture was kept at 80 ± 5 °C for 3 h. After the reaction was complete, 1600 g of water was added, and 3*2 L of toluene was added for extraction. The mixture was concentrated, and then 2 kg of methanol was added to continue concentrating until a solid precipitate was formed. The temperature was lowered to 0–5 °C and stirred for 1 h to precipitate the solid. The solid was filtered and washed to obtain 50.90 g of white solid compound B with a purity of 98.6% and a yield of 50.6%.

[0057] Example 5

[0058] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0059] (1) Compound A (100g, 0.176mol, 1eq) and solvent dichloromethane (500g) were added to a reaction vessel and dissolved. Triethylamine (3eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (1.8eq) was added and the reaction was carried out at room temperature for 3h. The reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered to separate the magnesium sulfate. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0060] (2) Under an inert atmosphere, 500g of DMSO was added to the crude intermediate product and the temperature was raised to 60-70℃ to dissolve it. 10g of zinc chloride (10%) and 22.12g of sodium fluoride (3eq) were added, and the reaction was maintained at 70±5℃ for 4h. After the reaction was complete, 1000g of water was added, and 3*1.5L of ethyl acetate was added for extraction. The mixture was concentrated, and then 2kg of n-hexane was added to continue concentrating until a solid precipitated. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 57.14g of white solid compound B with a purity of 99.2% and a yield of 56.8%.

[0061] Example 6

[0062] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0063] (1) Compound A (100g, 0.176mol, 1eq) and dichloromethane (600g) were added to a reaction vessel and dissolved. Triethylamine (2eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (1.5eq) was added and the reaction was carried out at room temperature for 2-3 hours. The reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered to separate the magnesium sulfate. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0064] (2) Under an inert atmosphere, 800g of DMSO was added to the crude intermediate product and the temperature was raised to 70-80℃ to dissolve it. 15g of zinc chloride (15%) and 35.7g of potassium fluoride (3.5eq) were added, and the mixture was kept at 70±5℃ for 4h. After the reaction was complete, 1600g of water was added, and 3*2L of ethyl acetate was added for extraction. The mixture was concentrated, and then 2kg of n-hexane was added to continue concentrating until a small amount of solid precipitated. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 64.42g of white solid compound B with a purity of 99.3% and a yield of 64.1%.

[0065] Example 7

[0066] A fluorination preparation process for a sofosbuvir intermediate, specifically:

[0067] (1) Compound A (100g, 0.176mol, 1eq) and solvent dichloromethane (800g) were added to a reaction vessel and dissolved. Triethylamine (2.5eq) was added and the temperature was lowered to 0-20℃. p-Toluenesulfonyl chloride (2eq) was added and the reaction was carried out at room temperature for 2-3 hours. The reaction solution was added to water and the organic phase was separated. Magnesium sulfate was added to the organic phase for drying and then filtered to separate the magnesium sulfate. The organic phase was concentrated to dryness to obtain crude intermediate product. Dichloromethane was collected and separated during the concentration operation. This part of dichloromethane can be recycled.

[0068] (2) Under an inert atmosphere, 700g of DMSO was added to the crude intermediate product and the temperature was raised to 60-70℃ to dissolve it. 10g of zinc chloride (10%) and 35.7g of potassium fluoride (3.5eq) were added, and the mixture was kept at 60±5℃ for 5h. After the reaction was complete, 1400g of water was added, and 3*2L of ethyl acetate was added for extraction. The mixture was concentrated, and then 2kg of n-hexane was added to continue concentrating until a solid precipitated. The temperature was lowered to 0-5℃ and stirred for 1h to precipitate the solid. The solid was filtered and washed to obtain 63.89g of white solid compound B with a purity of 99.2% and a yield of 63.5%.

[0069] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, several simple improvements can be made without departing from the concept of the present invention, and all such improvements should be considered to fall within the scope of protection of the present invention.

Claims

1. A fluorination preparation process for a sofosbuvir intermediate, characterized in that, Includes the following steps: (1) Compound A was dissolved in the first solvent, and then an alkali and p-toluenesulfonyl chloride were added to carry out an affinity substitution reaction. After the reaction was completed, the reaction solution was contacted with water and the organic phase was separated. After drying, the solution was concentrated to obtain the crude intermediate product. (2) The crude intermediate product and the fluorinating agent undergo a fluorination reaction under the action of a Lewis acid catalyst; after the reaction is completed, the reaction solution is contacted with water and the organic phase is separated; then the target compound B is obtained by extraction and recrystallization. The structural formula of compound A is shown in Formula I: The structural formula of compound B is shown in Formula II:

2. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The first solvent is dichloromethane; Preferably, the mass ratio of dichloromethane to compound A is (3-10):

1.

3. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The base includes one or both of pyridine and triethylamine; Preferably, the molar ratio of the base to the compound A is (2-3):

1.

4. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The molar ratio of p-toluenesulfonyl chloride to compound A is (1.2–2.0):

1.

5. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The affinity substitution reaction is carried out at a temperature of 0–20 °C for 2–3 h.

6. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The fluorinating agent is at least one of potassium fluoride and sodium fluoride; Preferably, the molar ratio of the fluorinating agent to compound A is (2-5):

1.

7. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The Lewis acid catalyst includes one or more of magnesium chloride, zinc chloride, and lithium chloride; Preferably, the amount of the Lewis acid catalyst is 5% to 20% of the mass of compound A.

8. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The fluorination reaction is carried out at a temperature of 50–80°C for 3–8 hours.

9. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The fluorination reaction is carried out in a second solvent, which includes one or more of DMSO, toluene, and xylene. Preferably, the mass ratio of the second solvent to compound A is (2-8):

1.

10. The fluorination preparation process of the sofosbuvir intermediate according to claim 1, characterized in that, The extractant used in the extraction operation includes one or more of toluene, dichloromethane, and ethyl acetate; And / or, the solvent used in the recrystallization operation includes one or more of methanol, ethanol, and n-hexane.

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