Preparation method of baloxavir marboxil and its key intermediate

Abstract

The present invention discloses a preparation method of baloxavir marboxil and its key intermediate. First, the compound shown by formula (7) reacts with an ammoniating reagent under the action of a base to generate the compound shown by formula (6); then it reacts with the compound shown by formula (5) under the catalysis of catalyst A to generate the compound shown by formula (4); the compound shown by formula (4) reacts with 2-(2-aminoethoxy)-1,1-dimethoxyethane under the action of a base to generate the compound shown by formula (2); the compound shown by formula (2) undergoes ring closure under acidic conditions to obtain intermediate (1). The present invention first obtains the key chiral amino mother nucleus (7) through 4-step conventional reactions with lower-cost raw materials, and then when constructing baloxavir using the key chiral amino mother nucleus, resolution can be avoided, the yield can be significantly improved, and it is more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and relates to a preparation method of baloxavir marboxil and its key intermediate. Background Art

[0002] Baloxavir (Xofluza) / Baloxavir marboxil is a new anti-influenza virus drug developed by Shionogi & Co., Ltd. and was approved for marketing in Japan in 2018. Baloxavir is a polymerase acidic (PA) endonuclease inhibitor and is applicable to the treatment of acute uncomplicated influenza in patients 12 years of age and older with symptoms and within 48 hours. In addition to having the same efficacy as oseltamivir, this drug also has the characteristics of rapid onset and few side effects, and has a potentially huge market prospect.

[0003] Baloxavir marboxil, with the molecular formula C 27 H 23 F2N3O7S, molecular weight: 571.55, and the chemical structure is shown as follows:

[0004]

[0005] Currently, only a few reports on the synthesis method of baloxavir are available, as follows:

[0006] Patents WO2016175224 and WO 2017221869 first disclosed this synthesis route and its improved route. Specifically, using fragment 1 as the raw material (in this patent, R is benzyl or n-hexyl), baloxavir marboxil is obtained through more than 8 steps of reaction. When preparing the racemic compound 4 into the chiral compound 6, the yield is only 45%, and when condensing with the racemate 7, the yield is only 53%, and even after improvement, it is only 73%; the total molar yield of the process is only 9.5% - 13%, resulting in a high cost of baloxavir, and the market price of the active pharmaceutical ingredient reaches 180,000 yuan / kg.

[0007]

[0008] Patent CN113549088A provides the idea of the microwave method. Two intermediates react under the promotion of microwave in the presence of a sulfuric acid resin catalyst and a condensing agent to obtain the baloxavir precursor, but it still cannot avoid the use of expensive intermediates, and the microwave method limits the scale-up production of this process.

[0009] Summary of the Invention

[0010] In view of the deficiencies of the prior art, the object of the present invention is to provide a method for preparing baloxavir marboxil and its key intermediate. The present invention first obtains the key chiral amino mother nucleus (7) through 4 steps of conventional reactions with lower-cost raw materials, and then when constructing baloxavir with the key chiral amino mother nucleus (7), racemization can be avoided, the yield can be significantly improved, and it is more suitable for industrial production.

[0011] The technical solution of the present invention is: a method for synthesizing baloxavir marboxil. First, after removing R1 from intermediate (1), baloxavir is obtained, and then it is further reacted with methyl chloroformate to obtain baloxavir marboxil; the synthesis route of intermediate (1) is as follows:

[0012]

[0013] Among them, R1 is phenyl or n-hexyl, and n-hexyl is particularly preferred.

[0014] The synthesis method specifically includes the following steps:

[0015] S1: The compound shown in formula (7) reacts with an ammoniating reagent under the action of a base to form the compound shown in formula (6);

[0016] S2: The compound shown in formula (6) reacts with the compound shown in formula (5) under the catalysis of catalyst A to form the compound shown in formula (4);

[0017] S3: The compound shown in formula (4) reacts with 2-(2-aminoethoxy)-1,1-dimethoxyethane under the action of a base to form the compound shown in formula (2);

[0018] S4: The compound shown in formula (2) cyclizes under acidic conditions to obtain intermediate (1).

[0019] The ammoniating reagent in step S1 is selected from monochloroamine, hydroxylamine-O-sulfonic acid, O-p-nitrobenzoylhydroxylamine, diphenylphosphorylhydroxylamine, and monochloroamine is preferred; the base is selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine or N-methylmorpholine, etc., and sodium hydride is preferred; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, diethylene glycol dimethyl ether or 1,4-dioxane, etc., and N,N-dimethylformamide is preferred; the reaction temperature is -20 to 60 °C. The molar ratio of the compound shown in formula (7), the ammoniating reagent and the base is 1:1.0 - 1.2:1.0 - 1.2.

[0020] The catalyst A in step S2 is selected from pyridinium p-toluenesulfonate, pyridinium methanesulfonate, pyridinium trifluoromethanesulfonate, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, triethylamine p-toluenesulfonate, triethylamine methanesulfonate, and triethylamine trifluoroacetate, preferably pyridinium p-toluenesulfonate; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, or 1,4-dioxane, etc., preferably N,N-dimethylformamide; the reaction temperature is 0 to 100 °C. The molar ratio of the compound shown in formula (6), the compound shown in formula (5), and catalyst A is 1: 1.0 to 1.3: 1.2 to 1.8.

[0021] The base in step S3 is selected from triethylamine, pyridine, tri-n-butylamine, tri-n-propylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably DBU; the reaction solvent is selected from 2-methyltetrahydrofuran, dioxane, tetrahydrofuran, etc., preferably 2-methyltetrahydrofuran and dioxane, and the reaction temperature is 0 to 100 °C. The molar ratio of the compound shown in formula (6), 2-(2-aminoethoxy)-1,1-dimethoxyethane, and the base is 1: 1.0 to 1.5: 1.0 to 1.5.

[0022] The acid in step S4 is selected from methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, glacial acetic acid, phosphoric acid, etc., preferably methanesulfonic acid; the reaction solvent is selected from any one solvent or a mixed solvent of two or more solvents such as ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate, tert-butyl acetate, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, toluene, benzene, mesitylene, etc.; preferably a mixed solvent of ethyl acetate or isopropyl acetate and n-heptane.

[0023] The present invention also provides a method for synthesizing the key intermediate of baloxavir, formula (7), and its synthetic route is as follows:

[0024]

[0025] The specific synthesis method includes the following steps:

[0026] 1) 2-Mercaptobenzaldehyde reacts with S-tert-butylsulfinamide under the catalysis of a catalyst to form the compound shown in formula (10);

[0027] 2) The compound shown in formula (12) reacts with the compound shown in formula (10) after hydroxyl activation to form the compound shown in formula (9);

[0028] 3) The compound shown in formula (9) is cyclized after activation with a Grignard reagent to obtain the compound shown in formula (8);

[0029] 4) The compound shown in formula (8) is acid-hydrolyzed to obtain the compound shown in formula (7).

[0030] The reaction solvent for steps 1) and 2) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, and toluene, preferably dichloromethane and tetrahydrofuran.

[0031] The catalyst for step 1) is selected from one or more of copper sulfate, tetraethyl titanate, tetraisopropyl titanate, cesium carbonate, and diethyl tetrafluoroborate, preferably tetraethyl titanate; the reaction temperature is room temperature. The molar ratio of 2-mercaptobenzaldehyde, S-tert-butylsulfinamide, and the catalyst is 1:1.0 - 1.3:0.95 - 1.05.

[0032] The activator used for the activation of the hydroxyl group in step 2) is selected from methanesulfonyl chloride and p-toluenesulfonyl chloride, preferably methanesulfonyl chloride. The above activation is carried out under alkaline conditions (triethylamine) at a temperature of -20 to 0 °C; the molar ratio of the compound shown in formula (12), the activator, and the compound (10) is 1:1.1 - 1.3:0.9 - 1.1. The reaction temperature for the reaction with the compound shown in formula (10) is 5 to 30 °C.

[0033] The Grignard reagent for step 3) is selected from one or more of magnesium, isopropylmagnesium chloride, isopropyllithium chloride, tert-butylmagnesium chloride, and isopropylmagnesium bromide; preferably magnesium, and the reaction temperature is 20 - 35 °C.

[0034] The acid used for the acid hydrolysis in step 4) is selected from hydrochloric acid, sulfuric acid, and phosphoric acid; preferably hydrochloric acid.

[0035] The beneficial effects of the present invention are:

[0036] (1) The key chiral amino nucleus (7) is obtained through 4 conventional reactions using raw materials with lower prices;

[0037] (2) When constructing baloxavir with the key chiral amino nucleus (7), racemic resolution can be avoided, and the yield can be significantly improved;

[0038] (2) When the constructed key chiral amino compound (2) undergoes condensation, it has a high chiral selectivity, enabling the de value of the target product to reach 90% - 98.5%, and a chiral purity of 99.9% can be achieved through crystallization;

[0039] (3) Using the preparation method of the present invention, the yield of the key intermediate (7) can reach 73.4%; the total yield of preparing intermediate (1) through 8-step reactions can reach more than 48.7%.

[0040] Description of the drawings

[0041] Figure 1 For the chiral purity of intermediate (1) (R1 = n-hexyl) in Example 8;

[0042] Figure 2 For the chiral purity of the intermediate (1) (R1 = phenyl) in Example 12. Detailed implementation manners

[0043] The following examples are used to further prove but not limited to the present invention.

[0044] Example 1: Preparation of the compound shown in formula (10)

[0045]

[0046] 1500 g of 2-mercaptobenzaldehyde and 1450 g of S-tert-butylsulfinamide were added to 15 L of anhydrous dichloromethane. After purging with nitrogen, 2500 g of tetraethyl titanate was added dropwise, and the reaction was maintained at 20 - 25 °C for 5 hours. After the reaction was complete, it was poured into ice water for quenching, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 2520 g of a yellow oil, with a yield of 96%.

[0047] Example 2: Preparation of the compound shown in formula (9)

[0048]

[0049] 2240 g of 2,3-difluoro-6-iodobenzyl alcohol was dissolved in 20 L of dichloromethane, 1850 g of triethylamine was added, and then the temperature was lowered to -10 - -5 °C. Then, 1045 g of methanesulfonyl chloride was slowly added dropwise. After the addition was complete, the reaction was maintained at a constant temperature for 1 h until 2,3-difluoro-6-iodobenzyl alcohol was completely converted. Then, 2000 g of a dichloromethane solution of the compound shown in formula (10) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 10 - 15 °C until the reaction of the compound shown in formula (10) was complete. The reaction solution was quenched into ice water and washed successively with saturated brine, 5% aqueous citric acid solution, and 5% aqueous sodium bicarbonate solution. After drying over anhydrous sodium sulfate or concentrating to dryness under reduced pressure, 0.5 L of toluene and 4 L of ethanol were added for crystallization to obtain 3680 g of the compound shown in formula (9), with a yield of 90%.

[0050] Example 3: Preparation of the compound shown in formula (8)

[0051]

[0052] 2000 g of the compound shown in formula (9) was dissolved in 25 L of tetrahydrofuran. After purging with nitrogen, the temperature was lowered to 10 °C, 100 g of chopped magnesium strips was added, and 0.5 g of iodine grains was added. After initiation, the reaction was maintained at 10 °C until the magnesium strips disappeared, and then the temperature was raised to 20 - 35 °C to continue the reaction until complete. The reaction solution was added dropwise to 10% aqueous ammonium chloride solution for quenching, and washed once with saturated brine to obtain a tetrahydrofuran solution of the compound shown in formula (8), which was directly used for the next step of the reaction.

[0053] Example 4: Preparation of the compound shown in formula (7)

[0054]

[0055] Cool the tetrahydrofuran solution of the compound shown in formula (8) obtained in the previous step to 0 °C, add 450 g of concentrated hydrochloric acid and 5 L of water, and continue the reaction for 2 h until the raw materials are completely converted; slowly dropwise add an aqueous solution of NaOH to adjust the pH to 8 - 9, then separate the layers, wash with saturated brine, concentrate to dryness, add ethyl acetate and n-heptane for pulping, and evaporate to dryness to obtain 900 g of the compound shown in formula (7). The overall yield of the two steps is 85%, and the purity is 99.0%.

[0056] ESI-MS: m / z = 264.06 [M + H] + 。

[0057] Example 5: Preparation of the compound shown in formula (6)

[0058]

[0059] Add 1000 g (3.8 mol) of the compound shown in formula (7) to 5 L of N,N-dimethylformamide, cool to -5 - 0 °C, protect with nitrogen, and slowly add 167.2 g of NaH (content 60%, 4.18 mol) in batches; after stirring for 25 minutes, control the temperature at -5 - 0 °C and slowly dropwise add a 5% monochloroamine / methyl tert-butyl ether solution (containing about 4.18 mol of monochloroamine); after 10 minutes of dropping, stop the reaction when the residual raw materials detected by high performance liquid chromatography are less than 0.5%; pour the reaction solution into 20 L of ice water for quenching, extract with 10 L of ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, then pulp with 4 L of a mixed solvent of methyl tert-butyl ether / ethyl acetate = 10:1, and evaporate to dryness to obtain 972 g of the compound shown in formula (6). The molar yield is 92%, and the purity is 98.5%.

[0060] Example 6: Preparation of the compound shown in formula (4) (R1 = n-hexyl)

[0061]

[0062] 410 g (1.47 mol) of the compound shown in formula (6) and 550 g of pyridinium p-toluenesulfonate were added to 3 L of N,N-dimethylacetamide. The temperature was raised to 50 °C, and a 2 L N,N-dimethylacetamide solution of 400 g of methyl 3-(hexyloxy)-4-oxo-4H-pyran-2-carboxylate was slowly added dropwise while controlling the temperature of the feed liquid at 50 - 55 °C. Then, it was kept at 50 - 55 °C for about 5 hours until the reaction ended. After the reaction, the temperature of the feed liquid was lowered to 5 - 0 °C, poured into water for quenching, extracted with about 4 L of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum until the water content was less than 0.1% and then the concentration was stopped, obtaining 750 g of an oily substance of the compound shown in formula (4) (R1 = n-hexyl), which was directly used for the next step.

[0063] Example 7: Preparation of the compound shown in formula (2) (R1 = n-hexyl)

[0064]

[0065] 750 g of the oily substance obtained in Example 6 was dissolved in 5 L of 2-methyltetrahydrofuran. 263 g (1.76 mol) of 2-(2-aminoethoxy)-1,1-dimethoxyethane was added, and after cooling to 0 °C, 281 g (1.85 mol) of DBU was added dropwise. Then, the temperature was raised to 40 °C and the reaction was stirred at this temperature for 12 hours. After cooling the reaction solution to 10 °C, water was added for quenching, and the separated organic phase was washed successively with 5% citric acid water and 5% sodium bicarbonate water. After the organic phase was concentrated under reduced pressure to about 1.5 kg, 10 L of n-heptane was added for slurrying, and 770 g of a pale white compound shown in formula (2) (R1 = n-hexyl) was obtained by filtration, with a two-step molar yield of 83%.

[0066] Example 8: Preparation of the compound shown in formula (1) (R1 = n-hexyl)

[0067]

[0068] 500 g (0.79 mol) of the compound shown in formula (2) (R1 = n-hexyl) was added to a mixed solvent of 5 L of isopropyl acetate and 5 L of n-heptane, and then 230 g of methanesulfonic acid was added. The mixed turbid solution was heated to 60 °C and kept at this temperature for 10 hours. The reaction was stopped when the de value of the intermediate (1) reached more than 95%. After cooling to 0 - 10 °C, an aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 8, and then tetrahydrofuran was added for extraction. After the separated organic phase was washed with water and dried over anhydrous sodium sulfate, it was evaporated under reduced pressure, and 1.5 L of ethyl acetate and 0.5 L of n-heptane were added for crystallization to obtain a white solid. After drying, 390 g of intermediate (1) (R1 = n-hexyl) was obtained, with ee = 99.91% (as Figure 1 shown), and the molar yield was 87%.

[0069] ESI-MS: m / z = 568.20 [M + H]+ 。

[0070] Example 9: Preparation of Baloxavir Marboxil

[0071]

[0072] Add 300 g of the intermediate (1) (R1 = n-hexyl) prepared in Example 8 to 3 L of N-methylpyrrolidone, add 112 g of anhydrous lithium chloride, heat up to 80 - 85 °C and react for 35 hours. Stop heating after monitoring by high-performance liquid chromatography that the residue of the intermediate (1) (R1 = n-hexyl) is less than 0.5%. After cooling to 20 °C, add 165 g of potassium carbonate, control the temperature at 20 - 25 °C and slowly dropwise add 131 g of methyl chloroformate carbonate. After dropping, heat up to 40 - 45 °C and react for 17 - 20 hours. After monitoring by high-performance liquid chromatography that the intermediate residue is less than 0.5%, cool to 10 °C. Slowly dropwise add 1.5 L of water and stir until a large amount of solid precipitates. Filter, wash with water, and dry to obtain 256 g of baloxavir marboxil, with a molar yield of 85% and a purity of 99.3%.

[0073] ESI-MS: m / z = 572.13 [M+H] + 。

[0074] Example 10: Preparation of the compound shown in formula (4) (R1 = phenyl)

[0075]

[0076] Add 500 g of the compound shown in formula (6) and 670 g of pyridinium p-toluenesulfonate to 3 L of N,N-dimethylformamide, heat up to 62 °C, slowly dropwise add a 2 L N,N-dimethylformamide solution of 490 g of methyl 3-(phenoxy)-4-oxo-4H-pyran-2-carboxylate, and then heat up to 65 - 70 °C and keep warm for about 7 - 8 hours until the reaction ends. After quenching with water, extract with 4 L of dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain 900 g of the crude product of the compound shown in formula (4) (R1 = phenyl), which is directly used in the next step.

[0077] Example 11: Preparation of the compound shown in formula (2) (R1 = phenyl)

[0078]

[0079] Under argon protection, add the compound shown in formula (4) (R1 = phenyl) obtained in Example 9 and 220 g of 2-(2-aminoethoxy)-1,1-dimethoxyethane to 7.5 L of dioxane. Cool the temperature to -5 to 0 °C, dropwise add 350 g of DBU, then slowly warm up to 60 to 65 °C, and stir and react at this temperature for 15 to 18 hours until the reaction ends; cool the reaction solution to 10 °C and then add water to quench it. Wash the separated organic phase successively with 5% citric acid water and 5% sodium bicarbonate water; after concentrating the organic phase under reduced pressure to near dryness, add 5 L of ethyl acetate / methyl tert-butyl ether (1:1) to grind and filter, and evaporate to dryness to obtain 885 g of the compound shown in formula (2) (R1 = phenyl), with a two-step yield of 79%.

[0080] Example 12: Preparation of the compound shown in formula (1) (R1 = phenyl)

[0081]

[0082] Add 800 g of the compound shown in formula (2) (R1 = phenyl) to a mixed solvent of 7.5 L of isopropyl acetate and 2.5 L of methyl tert-butyl ether, and add 300 g of methanesulfonic acid; heat the mixed turbid solution to about 50 °C and reflux for 24 hours. Stop the reaction when the de value of intermediate (1) reaches more than 90%; cool to 0 to 10 °C, dropwise add an aqueous sodium bicarbonate solution to adjust the pH to 8, and then add tetrahydrofuran for extraction; after washing the separated organic phase with water and drying it over anhydrous sodium sulfate, remove the solvent under reduced pressure in vacuo, and add 25 g of ethyl acetate and 25 g of methyl tert-butyl ether for crystallization to obtain 610 g of intermediate (1) (R1 = phenyl), with a molar yield of 85% and ee = 99.73%.

[0083] ESI-MS: m / z = 560.14 [M+H] + 。

[0084] Example 13: Preparation of baloxavir marboxil

[0085]

[0086] Add 500 g of intermediate (1) (R1 = phenyl) prepared in Example 12 to 5 L of N-methylpyrrolidone, add 189 g of anhydrous lithium chloride, heat to 70 to 75 °C and react for 20 to 25 hours. Stop heating after monitoring by high-performance liquid chromatography that the residue of intermediate (1) is less than 0.5%; cool to 20 °C and then add 247 g of potassium carbonate. Control the temperature at 20 to 25 °C and slowly dropwise add 167 g of methyl chloroformate; after dropping, heat to 40 to 45 °C and react for 17 to 20 hours. After monitoring by high-performance liquid chromatography that the intermediate residue is less than 0.5%, cool to 10 °C; slowly dropwise add 2.5 L of water and stir until a large amount of solid precipitates; filter, wash with water, and dry to obtain 450 g of baloxavir marboxil, with a molar yield of 88.2% and a purity of 99.2%.

Claims

1. A method for synthesizing baloxavir marboxil. First, after removing R1 from intermediate (1), baloxavir is obtained, and then it is further reacted with methyl chloroformate to obtain baloxavir marboxil; the synthetic route of intermediate (1) is as follows: Among them, R1 is phenyl or n-hexyl; The specific synthetic method includes the following steps: S1: The compound shown in formula (7) reacts with an ammoniating reagent under the action of a base to form the compound shown in formula (6); S2: The compound shown in formula (6) reacts with the compound shown in formula (5) under the catalysis of catalyst A to form the compound shown in formula (4); S3: The compound shown in formula (4) reacts with 2-(2-aminoethoxy)-1,1-dimethoxyethane under the action of a base to form the compound shown in formula (2); S4: The compound shown in formula (2) undergoes ring closure under acidic conditions to obtain intermediate (1).

2. The method for synthesizing baloxavir marboxil according to claim 1, characterized in that The ammoniating reagent in step S1 is selected from any one of chloramine, hydroxylamine-O-sulfonic acid, O-p-nitrobenzoylhydroxylamine, and diphenylphosphorylhydroxylamine; The base in step S1 is selected from any one of sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine, or N-methylmorpholine; The reaction solvent used in step S1 is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, diethylene glycol dimethyl ether, or 1,4-dioxane; The reaction temperature of step S1 is -20 to 60 °C.

3. The method for synthesizing baloxavir marboxil according to claim 1, characterized in that The catalyst A in step S2 is selected from any one of pyridinium p-toluenesulfonate, pyridinium methanesulfonate, pyridinium trifluoromethanesulfonate, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, triethylamine p-toluenesulfonate, triethylamine methanesulfonate, or triethylamine trifluoroacetate; The reaction solvent used in step S2 is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, or 1,4-dioxane; The reaction temperature of step S2 is 0 to 100 °C.

4. The method for synthesizing baloxavir marboxil according to claim 1, characterized in that The base in step S3 is selected from any one of triethylamine, pyridine, tri-n-butylamine, tri-n-propylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; The solvent used in step S3 is any one of 2-methyltetrahydrofuran, dioxane, or tetrahydrofuran; The reaction temperature of step S3 is 0 to 100 °C.

5. The method for synthesizing baloxavir marboxil according to any one of claims 1-4, characterized in that The acid in step S4 is selected from any one of methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, glacial acetic acid, and phosphoric acid; The reaction solvent is selected from any one of ethyl acetate, isopropyl acetate, butyl acetate, methyl acetate, tert-butyl acetate, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether, toluene, benzene, mesitylene or a mixed solvent of two or more of them.

6. A method for synthesizing a baloxavir marboxil key intermediate, characterized in that The synthesis method specifically comprises the following steps: 1) 2-Mercaptobenzaldehyde reacts with S-tert-butylsulfinamide under the catalysis of a catalyst to form a compound shown in formula (10); 2) The compound shown in formula (12) reacts with the compound shown in formula (10) after hydroxyl activation to form a compound shown in formula (9); 3) The compound shown in formula (9) is cyclized after activation with a Grignard reagent to obtain a compound shown in formula (8); 4) The compound shown in formula (8) is acid hydrolyzed to obtain a compound shown in formula (7).

7. The synthesis method of the baloxavir marboxil key intermediate according to claim 6, characterized in that, The reaction solvent for steps 1) and 2) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, toluene.

8. The synthesis method of the baloxavir marboxil key intermediate according to claim 6, characterized in that, The catalyst for step 1) is selected from one or more of copper sulfate, tetraethyl titanate, tetraisopropyl titanate, cesium carbonate, diethyl tetrafluoroborate; the reaction temperature is room temperature.

9. The synthesis method of the baloxavir marboxil key intermediate according to claim 6, characterized in that, The activator used for hydroxyl activation in step 2) is selected from any one of methanesulfonyl chloride and p-toluenesulfonyl chloride; the activation is carried out under alkaline conditions at a temperature of -20 to 0 °C; the reaction temperature for reacting with the compound shown in formula (10) is 5 to 30 °C.

10. The method for synthesizing a baloxavir marboxil key intermediate according to any one of claims 6-9, characterized in that The Grignard reagent for step 3) is selected from one or more of magnesium, isopropylmagnesium chloride, isopropyllithium chloride, tert-butylmagnesium chloride, isopropylmagnesium bromide; The acid used for acid hydrolysis in step 4) is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid.

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