A method for preparing an anti-influenza virus drug intermediate

Abstract

The present invention discloses a method for preparing an anti-influenza virus drug intermediate, comprising the following steps: a. reacting compound III with ethanolamine to obtain compound VII; b. reacting compound VII with bromoethanol dimethyl acetal to obtain compound V; c. deprotecting and cyclizing compound V to obtain compound VI. The method solves the problems of high cost, poor atom economy, long synthesis route and low efficiency in the existing method for synthesizing compound VI in formula 3 in the prior art, and it is necessary to develop an economical, effective and environmentally friendly synthesis route and method. The method of the present invention has low cost, is environmentally friendly and improves the yield of the product.

Description

[Technical field]

[0001] The invention relates to the field of pharmaceutical chemical industry, and in particular to a method for preparing an anti-influenza virus drug baloxavir intermediate. [Background Technology]

[0002] Baloxavir, trade name It is an anti-influenza virus drug developed by Shionogi Co., Ltd. of Japan. It was launched in Japan on February 23, 2018 and in the United States on October 24 of the same year. Baloxavir has shown excellent effects in the treatment of influenza diseases and has low adverse reactions. Therefore, it has attracted much attention since its launch.

[0003] The core synthesis steps of baloxavir can be found in Shionogi's patent JPWO2016175224. As shown in Formula 1, compounds VIII and IX undergo condensation reaction to obtain X, and then the benzyl group is removed to obtain XI, which is then subjected to etherification reaction to obtain baloxavir. Compounds VIII and IX are two important compounds for the synthesis of baloxavir.

[0004]

[0005] The synthesis of compound IX is based on 3,4-difluorobenzoic acid as raw material, and is obtained through aldehyde formation, cyclization and reduction reaction, as shown in Formula 2.

[0006]

[0007] The synthesis of compound VIII is based on compound I as the raw material, and is obtained through esterification, condensation, cyclization, splitting and other reactions. Compound IV is an important raw material for the synthesis of VIII, which is obtained from phthalic anhydride as the raw material through aminolysis, substitution, hydrazine deprotection reactions, as shown in Formula 3.

[0008]

[0009] The existing methods for synthesizing compound VI in formula 3 have the disadvantages of high cost, poor atom economy, long synthesis route and low efficiency. It is necessary to develop economical, effective and environmentally friendly synthesis routes and methods. [Summary of the invention]

[0010] The present invention aims to provide a method for preparing an anti-influenza virus drug intermediate, which solves the problems of long reaction route and low efficiency in the prior art. The method of the present invention has low cost, is environmentally friendly, and improves the yield of the product.

[0011] The technical solution of the present invention includes:

[0012] A method for preparing an anti-influenza virus drug intermediate comprises the following steps:

[0013] a. Compound III reacts with ethanolamine to obtain compound VII;

[0014] b. Compound VII reacts with bromoethanol dimethyl acetal to obtain compound V;

[0015] c. Compound V is deprotected and cyclized to obtain compound VI;

[0016]

[0017] The reaction conditions of step a include heating after mixing compound III, organic solvent and ethanolamine for reaction; preferably, the reaction temperature after mixing is 40-100° C., and further, the reaction temperature is 40, 50, 60, 70, 80, 90, 100° C. Preferably, the organic solvent used in step a includes tetrahydrofuran, ethanol, N,N-dimethylformamide, and toluene.

[0018] The reaction conditions of step b include mixing compound VII and an organic solvent, adding a strong base and bromoacetaldehyde dimethyl acetal after cooling, and reacting after mixing. Preferably, the organic solvent of step b includes one or a mixture of tetrahydrofuran, N-methylpyrrolidone, and alcohol. Preferably, the strong base includes potassium alkoxide, sodium alkoxide, or sodium hydrogen; further, potassium alkoxide includes one or more of potassium methoxide, potassium ethoxide, potassium propoxide, potassium butoxide, and potassium tert-butoxide. Further, sodium alkoxide includes one or more of sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, and sodium tert-butoxide. Preferably, the temperature after cooling step b is 0-10°C. Further the temperature is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10°C.

[0019] The reaction conditions of step c include mixing compound V, acetonitrile and water, heating to 50-60°C, and adding methanesulfonic acid dropwise. Further, the reaction temperature of step C is 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60°C.

[0020] One reaction condition of step b includes mixing compound VII and an organic solvent, cooling by 0-10°C, adding potassium tert-butoxide or sodium tert-butoxide, and bromoacetaldehyde dimethyl acetal, and reacting after mixing; preferably, cooling by 0-10°C, adding potassium tert-butoxide or sodium tert-butoxide, and bromoacetaldehyde dimethyl acetal, and the reaction temperature after mixing is 30-60°C. Further, the reaction temperature after mixing is 30, 35, 40, 45, 50, 55, or 60°C.

[0021] Another reaction condition of step b includes mixing compound VII and an organic solvent, cooling to 0-10° C., adding sodium hydrogen sulfide and bromoacetaldehyde dimethyl acetal, and then mixing and maintaining the temperature at 0-10° C. for reaction;

[0022] The reaction conditions of step b may also include mixing compound VII and tert-butanol, cooling by 0-10° C., adding potassium tert-butoxide, and heating up before adding bromoacetaldehyde dimethyl acetal; preferably, the temperature is maintained at 70-80° C. after heating up.

[0023] Compound III can be prepared by the following method:

[0024]

[0025] i) Compound I reacts with an alkylating agent to prepare Compound II;

[0026] ii) Compound II undergoes a replacement reaction to prepare compound III.

[0027] Compound I reacts with an alkylating agent to prepare compound II, and preferred reaction conditions include reacting compound I with dimethyl sulfate.

[0028] Compound II undergoes a replacement reaction with tert-butyl carbazate to prepare compound III.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. Reduce reaction steps, shorten reaction route and save costs;

[0031] 2. Good atomic economy, reducing three wastes and further saving costs;

[0032] 3. Improve the yield of the final product compound VI. [Drawings]

[0033] Figure 1 is the HPLC spectrum of compound VII Example 3-1;

[0034] Figure 2 is the NMR spectrum of compound VII;

[0035] Figure 3 is the mass spectrum of compound VII;

[0036] Figure 4 is the HPLC spectrum of compound VII Example 3-2;

[0037] Figure 5 is the HPLC spectrum of compound VII Example 3-3;

[0038] Figure 6 is the HPLC spectrum of Compound VII Example 3-4;

[0039] Figure 7 is the NMR spectrum of compound V;

[0040] Figure 8 is the mass spectrum of compound V;

[0041] Fig. 9 is the mass spectrum of compound VI;

[0042] Fig.10 This is the NMR spectrum of compound VI. [Specific embodiment]

[0043] To further illustrate the technical means and effects of the present invention, the present invention is further described below in conjunction with the embodiments and drawings. It should be understood that the specific implementation methods described herein are only used to explain the present invention, rather than to limit the present invention.

[0044] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0045] 1. Synthesis of Compound II

[0046]

[0047] Example 1-1:

[0048] Add 100g of compound I and 300mL of N,N-dimethylformamide to the reaction bottle, stir to dissolve, then add 44.4g of sodium bicarbonate, control the temperature at 20-30°C, drop 59.0g of dimethyl sulfate, add, and continue stirring until the reaction is complete. Add 16.8g of concentrated hydrochloric acid, 300mL of water and 500mL of ethyl acetate to another reaction bottle, start stirring, and slowly pour the reaction solution into the reaction bottle to quench. After standing, separate the layers, extract the aqueous phase with ethyl acetate, combine the organic phases, wash once with 5% sodium chloride aqueous solution and water respectively, and concentrate the organic phase to obtain compound II. The product is directly used in the next step without further separation and purification.

[0049] 2. Synthesis of Compound III

[0050]

[0051] Example 2-1:

[0052] To the compound II obtained in Example 1 of the previous step, 200 mL of N, N-dimethylformamide was added, and the mixture was stirred and dissolved completely. Then, 264 g of pyridine p-toluenesulfonate was added, and the temperature was raised to 50-60° C., and a solution of 69.8 g of tert-butyl hydrazinecarboxylate dissolved in 200 mL of N, N-dimethylformamide was added dropwise. After the addition was completed, the reaction was continued until the raw material disappeared, and the temperature was lowered to 20-30° C., seed crystals were added, and ethanol aqueous solution was added dropwise for crystallization. The mixture was filtered and dried to obtain a white solid with a yield of 76.9% and a purity of 98.3%.

[0053] The obtained product was characterized by H NMR spectrum, and the detection data are as follows: 1 H-NMR (400 Hz, CDCl 3 ), δppm: 8.40(brs,1H),7.29-7.40(m,6H),6.51-6.60(m,1H),5.25(s,2H),3.78(s,3H),1.45(s,9H).

[0054] The mass spectrometry value of the obtained product was 375.1552 (M+1), which was consistent with the theoretical value of 375.1551 (M+1); the test results showed that the molecular weight was consistent with the target compound:

[0055] The results of mass spectrometry and nuclear magnetic resonance hydrogen spectrum showed that the product structure was correct and compound III was successfully synthesized.

[0056] Example 2-2:

[0057] Add 50g of compound I and N,N-dimethylacetamide to the reaction flask, stir to dissolve, add 10.6g of sodium hydroxide, control the temperature at 5-10°C, add 29.5g of dimethyl sulfate dropwise, add and continue to react until the raw materials disappear. Add 100.4g of p-toluenesulfonic acid monohydrate, 41.8g of pyridine and 100mL of N,N-dimethylacetamide to the reaction flask, heat to 40-50°C, add dropwise a solution of 34.9g of tert-butyl hydrazinecarboxylate dissolved in 100mL of N,N-dimethylacetamide, add dropwise, continue to stir until the reaction is complete, cool to 10-20°C, add seed crystals, add methanol aqueous solution dropwise for crystallization, filter, and dry to obtain an off-white solid; yield 76.3%, purity 96.3%.

[0058] Example 2-3

[0059] Add 50g of compound I and 150mL of N,N-dimethylacetamide to the reaction flask, stir and dissolve, add 22.2g of sodium bicarbonate, control the temperature at 20-30°C, drop 29.5g of dimethyl sulfate, and after the reaction is completed, add 132g of pyridine p-toluenesulfonate and 100mL of N,N-dimethylacetamide to the reaction flask, control the temperature at 60-70°C, drop 34.9g of tert-butyl carbazate dissolved in 100mL of N,N-dimethylacetamide, and continue to react at 60-70°C. After the reaction is completed, cool to 20-30°C, add seed crystals, drop ethanol aqueous solution for crystallization, filter, and dry to obtain a light yellow solid; the yield is 69.0% and the purity is 94.4%.

[0060] 3. Synthesis of Compound VII

[0061]

[0062] Example 3-1:

[0063] Under nitrogen protection, add 10g of compound III, 20mL of THF and 4.8g of ethanolamine to the reaction bottle, start stirring, heat to 50-60℃ for reaction, and cool to 20-30℃ after the reaction. Add 4.0g of acetic acid, 25mL of water and 50mL of ethyl acetate to another reaction bottle, start stirring, slowly pour the above reaction solution into the reaction bottle, continue stirring the reaction after the addition, filter and dry in turn after the reaction to obtain a crude product of compound VII, separate and purify by column chromatography to obtain a white solid; the yield is 77.9% and the purity is 99.0%. HPLC spectrum is shown in Figure 1 .

[0064] The H NMR spectrum of the obtained product is as follows (see Figure 2 ): 1 H-NMR (400 Hz, CDCl 3 ), δppm: 10.91(brs,1H),8.56(brs,1H),7.66(d,J=7.76Hz,1H),7.29-7.42(m,5H),6.21(d,J=7. 76Hz,1H),5.09(s,2H),4.68(t,J=5.6Hz,1H),3.35-3.42(m,2H),3.18-3.27(m,2H),1.43(s,9H)

[0065] The obtained product was detected by mass spectrometry (see Figure 3 ), the detected value was 404.1814 (M+1), which was consistent with the theoretical value of 404.1816 (M+1). The detection results showed that the molecular weight of the detected substance was consistent with that of the target compound.

[0066] The results of mass spectrometry and nuclear magnetic resonance hydrogen spectrum showed that the structure of the synthesized product was correct and compound VII was successfully obtained.

[0067] Example 3-2:

[0068] Under nitrogen protection, add 30g of compound III, 150mL of ethanol and 15g of ethanolamine to the reaction bottle, start stirring, heat to 40-50℃ for reaction, and cool to 20-30℃ after the reaction. Add 6.0g of citric acid and 180mL of water to another reaction bottle, start stirring, control the temperature at 20-35℃, slowly pour the above reaction solution into the reaction bottle, add, continue stirring for 1-2 hours, filter, and dry to obtain a crude compound VII with a yield of 86.3% and a purity of 87.5%. HPLC spectrum is shown in Figure 4 .

[0069] Example 3-3:

[0070] Under nitrogen protection, 30g of compound III, 25mL of N,N-dimethylformamide and 15g of ethanolamine were added to the reaction bottle, stirring was started, and the temperature was raised to 50-60°C for reaction. After the reaction was complete, the temperature was lowered to 20-30°C. 6.0g of citric acid and 180mL of water were added to another reaction bottle, stirring was started, and the above reaction solution was slowly poured into the reaction bottle. After the addition was completed, stirring was continued for 1-2 hours, filtered, and dried to obtain a crude compound VII with a yield of 87.2% and a purity of 92.07%. HPLC spectrum is shown in Figure 5 .

[0071] Embodiment 3-4:

[0072] Under nitrogen protection, 30g of compound III, 150mL of toluene and 18g of ethanolamine were added to the reaction bottle, stirring was started, and the temperature was raised to 90-100°C for reaction. After the reaction was completed, the temperature was lowered to 20-30°C. 6.0g of citric acid and 180mL of water were added to another reaction bottle, stirring was started, and the temperature was controlled at 0-10°C. The above reaction solution was slowly poured into the reaction bottle. After the addition was completed, the temperature was controlled at 0-10°C and stirred for 1-2 hours, filtered, and dried to obtain a crude compound VII with a yield of 57.2% and a purity of 85.46%. HPLC spectrum is shown in Figure 6 .

[0073] 4. Synthesis of Compound V

[0074]

[0075] Example 4-1.

[0076] Under nitrogen protection, 20g of compound VII and 100mL of NMP were added to the reaction bottle. Stirring was started, the temperature was lowered to 0-10°C, 28.6g of sodium tert-butoxide and 25.1g of bromoacetaldehyde dimethyl acetal were added to the reactor in batches, and the temperature was raised to 30-40°C for reaction. After the reaction was completed, the temperature was lowered to room temperature, 45mL of water and 11.9g of acetic acid were added dropwise to quench the reaction, and the reaction was extracted twice with ethyl acetate, the aqueous phase was separated, the organic phase was combined, and the organic phase was washed with 8% sodium bicarbonate aqueous solution and water, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure until there was no fraction, ethyl acetate was added, stirred and dissolved, n-heptane was added dropwise for crystallization, filtered, and dried to obtain compound V, which was an off-white solid with a yield of 62.3% and a purity of 98.4%.

[0077] The product's nuclear magnetic hydrogen spectrum test data are as follows (see the spectrum Figure 7 ): 1 H-NMR (400 Hz, CDCl 3 ), δppm:8.54(brs,1H),7.28-7.71(m,6H),7.24(m,1H),6.39-6.48(m,1H),5.29(s,2 H), 4.41 (t, J = 5.2Hz, 1H), 3.38-3.46 (m, 6H), 3.35 (s, 6H), 3.27 (m, 2H), 1.44 (s, 9H).

[0078] The mass spectrometry value of the product is 492.2338 (M+1) (see Figure 8 ), which is consistent with the theoretical value 492.2340(M+1).

[0079] The results of mass spectrometry and nuclear magnetic resonance hydrogen spectrum showed that the product structure was correct.

[0080] Example 4-2:

[0081] Under nitrogen protection, 100g of compound VII, 500mL of THF and 3mL of NMP were added to the reaction flask. Stirring was started, the temperature was lowered to 0-10°C, 142.9g of sodium tert-butoxide was added to the reactor in batches, and then 104.2g of bromoacetaldehyde dimethyl acetal was added. The temperature was raised to 50-60°C for reaction. After the reaction was completed, the temperature was lowered to room temperature; 59.5g of acetic acid, 300mL of water and 500mL of ethyl acetate were added to another reaction flask, stirring was started, and the reaction solution was slowly poured into the reaction flask. After addition, the layers were separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, and the organic phases were washed with 8% sodium bicarbonate aqueous solution and water, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Ethyl acetate was added to the obtained crude product, stirred to dissolve, and then n-heptane was added dropwise for crystallization, filtered, and dried to obtain compound V with a yield of 86.2% and a purity of 99.1%.

[0082] Embodiment 4-3:

[0083] Under nitrogen protection, 100g of compound VII, 400mL of THF and 30mL of NMP were added to the reaction bottle. Stirring was started, the temperature was lowered to 0-10°C, 170g of potassium tert-butoxide was added to the reaction bottle in batches, and then 136.6g of bromoacetaldehyde dimethyl acetal was added. The temperature was raised to 40-50°C for reaction. After the reaction was completed, the temperature was lowered to room temperature; 59.5g of acetic acid, 300mL of water and 500mL of ethyl acetate were added to another reaction bottle, stirring was started, the temperature was controlled at 20-35°C, and the reaction solution was slowly poured into the reaction bottle. After addition, the layers were separated, and the ethyl acetate was extracted once. The organic phases were combined, and the organic phases were washed with 8% sodium bicarbonate aqueous solution and water, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to no fraction, ethyl acetate was added, stirred and dissolved, toluene was added dropwise for crystallization, filtered, and dried to obtain compound V as an off-white solid. The yield was 86.2% and the purity was 89.5%.

[0084] Embodiment 4-4:

[0085] Under nitrogen protection, add 100g of compound VII and 600mL of THF to the reaction bottle. Start stirring, cool to 0-10°C, add 60g of 60% NaH to the reactor in batches, then add 125.7g of bromoacetaldehyde dimethyl acetal, and keep warm until the reaction is complete. Add 59.5g of acetic acid, 300mL of water and 500mL of ethyl acetate to another reaction bottle, start stirring, control the temperature at 20-35°C, slowly pour the reaction solution into the reaction bottle, add it, separate the layers, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with 8% sodium bicarbonate aqueous solution and water, dry it with anhydrous sodium sulfate, filter it, and concentrate the filtrate to obtain a yellow solid with a purity of 69.7%.

[0086] Embodiment 4-5:

[0087] Under nitrogen protection, add 100g of compound VII and 1000mL of tert-butanol to the reaction bottle. Start stirring, cool to 0-10°C, add 170g of potassium tert-butoxide to the reaction bottle in batches, heat to 70-80°C for reaction, then slowly drop 125.7g of bromoacetaldehyde dimethyl acetal, after the reaction is completed, cool to 20-30°C. Add 59.5g of acetic acid, 300mL of water and 500mL of ethyl acetate to another reaction bottle, start stirring, slowly pour the reaction solution into the reaction bottle, add, separate, extract with ethyl acetate, combine the organic phases, wash the organic phases with 8% sodium bicarbonate aqueous solution and water, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a yellow solid with a purity of 80.8%.

[0088] 5. Synthesis of Compound VI

[0089]

[0090] 77g of compound V, 655mL of acetonitrile and 115mL of water were added to the reaction bottle. Stirring was started, the temperature was raised to 50-60°C, and 45.2g of methanesulfonic acid was added dropwise at 50-60°C. After the reaction was completed, the temperature was lowered to 0-10°C, and 30% sodium hydroxide was added dropwise for neutralization. After neutralization, the mixture was concentrated under reduced pressure, cooled for crystallization, filtered, and dried to obtain an off-white solid with a yield of 83.4% and a purity of 97.3%.

[0091] The obtained compound was detected by mass spectrometer, and the detection value was 328.1294 (M+1) (see Fig. 9 ), which is consistent with the theoretical value of 328.1292(M+1).

[0092] The obtained compound was detected by nuclear magnetic resonance, and the test results are as follows (see Fig.10 ): 1 H-NMR (400 Hz, d 6 -DMSO), δppm:7.70(d,J=7.64Hz,1H),7.56(m,2H),7.27-7.38(m,4H),7.22(d,J=7.68Hz,1H),5.07(s,2H),4.76-4.84( m,1H),4.14(dd,J=14Hz,2.4Hz,1H),3.99-4.05(m,2H),3.40-3.45(m,1H),3.13(t,J=,10.4Hz,1H),2.91-2.99(m,1H).

[0093] The results of mass spectrometry and nuclear magnetic resonance detection showed that compound VI was successfully synthesized.

[0094] The applicant declares that the present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing an anti-influenza virus drug intermediate, characterized in that: The following steps are included: a. Compound III reacts with ethanolamine to obtain compound VII; b. Compound VII reacts with bromoethanol dimethyl acetal to obtain compound V; c. Compound V in H + The reaction was carried out under the following conditions to obtain compound VI; 2. A method for preparing an anti-influenza virus drug intermediate according to claim 1, characterized in that: The reaction conditions of step a include mixing compound III, an organic solvent and ethanolamine and then heating to react.

3. A method for preparing an anti-influenza virus drug intermediate according to claim 2, characterized in that: The reaction temperature after mixing is 40-100°C.

4. A method for preparing an anti-influenza virus drug intermediate according to claim 3, characterized in that: The organic solvent used in step a includes tetrahydrofuran, ethanol, N,N-dimethylformamide or toluene.

5. A method for preparing an anti-influenza virus drug intermediate according to claim 4, characterized in that: The reaction conditions of step b include mixing compound VII and an organic solvent, adding a strong base and bromoacetaldehyde dimethyl acetal after cooling, and reacting after mixing.

6. A method for preparing an anti-influenza virus drug intermediate according to claim 5, characterized in that: The organic solvent in step b includes one or a mixture of tetrahydrofuran, N-methylpyrrolidone, and alcohol.

7. A method for preparing an anti-influenza virus drug intermediate according to claim 6, characterized in that: Strong bases include potassium tert-butoxide, sodium tert-butoxide, or sodium hydrogen.

8. A method for preparing an anti-influenza virus drug intermediate according to claim 7, characterized in that: The temperature after cooling in step b is 0-10°C.

9. A method for preparing an anti-influenza virus drug intermediate according to claim 8, characterized in that: The reaction conditions of step c include mixing compound V, acetonitrile and water, heating to 50-60° C., and adding methanesulfonic acid dropwise.

10. A method for preparing an anti-influenza virus drug intermediate according to claim 9, characterized in that: The reaction conditions of step b include mixing compound VII and an organic solvent, cooling to 0-10° C., adding potassium tert-butoxide or sodium tert-butoxide and bromoacetaldehyde dimethyl acetal, and reacting after mixing.

11. A method for preparing an anti-influenza virus drug intermediate according to claim 10, characterized in that: Cool down by 0-10℃, add potassium tert-butoxide or sodium tert-butoxide and bromoacetaldehyde dimethyl acetal, and after mixing, the reaction temperature is 30-60℃.

12. A method for preparing an anti-influenza virus drug intermediate according to claim 11, characterized in that: The reaction conditions of step b include mixing compound VII and an organic solvent, cooling to 0-10° C., adding sodium hydrogen sulfide and bromoacetaldehyde dimethyl acetal, and then mixing and maintaining the temperature at 0-10° C. for reaction.

13. A method for preparing an anti-influenza virus drug intermediate according to claim 12, characterized in that: The reaction conditions of step b are as follows: Compound VII and tert-butanol are mixed, potassium tert-butoxide is added after the temperature is lowered by 0-10° C., and bromoacetaldehyde dimethyl acetal is added after the temperature is raised.

14. A method for preparing an anti-influenza virus drug intermediate according to claim 13, characterized in that: After heating, the temperature is maintained at 70-80℃.

15. A method for preparing an anti-influenza virus drug intermediate according to any one of claims 1 to 14, characterized in that: The preparation method of compound III comprises: i) Compound I reacts with an alkylating agent to prepare Compound II; ii) Compound II reacts with BocNHNH2 under PPTS conditions to prepare compound III.

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