Synthesis method of macavir diastereoisomer

Abstract

The invention relates to the technical field of preparation of drugs and isomers thereof, and discloses a chemical synthesis method of a macloxvir diastereoisomer, which comprises the following steps: (A) condensing a compound shown as a formula I and a compound shown as a formula II to obtain a compound shown as a formula III; (B) removing an n-hexyl protecting group from the compound shown in the formula III under the action of lithium chloride to obtain a compound shown in a formula IV; and (C) carrying out substitution on the compound shown in the formula IV and chloromethyl methyl carbonate under an alkaline condition to obtain the macavir diastereoisomer. By adopting the synthesis method disclosed by the invention, large-batch preparation of the mabaloxvir diastereoisomers can be quickly realized, and the prepared product can be used as a reference substance for quality control of mabaloxvir bulk drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of drugs and isomers thereof, and in particular to a chemical synthesis method of mabaloxavir diastereoisomers. Background Art

[0002] Baloxavir acid is the first Cap-dependent endonuclease inhibitor, jointly developed by Roche and Shionogi Pharmaceuticals of Japan. Its prodrug, Mabaloxavir (trade name: Sufoda), was first approved in Japan in February 2018 for the treatment of influenza A or B virus infection. Subsequently, on October 24, 2018, Mabaloxavir was approved by the U.S. Food and Drug Administration. As the first and only single-dose oral anti-influenza drug at this stage, Mabaloxavir can significantly shorten the infection cycle and relieve influenza symptoms in the treatment of influenza, providing patients with a simpler treatment plan.

[0003] Mabaloxavir molecular formula is: C 27 H 23 F2N3O7S, chemical structure is as follows:

[0004]

[0005] There are many different stereoisomers that will appear in the production process of Mabaloxavir. Shi Kai et al. reported the detection method of several isomers in Mabaloxavir API ("Simultaneous determination of the content of three stereoisomers in Mabaloxavir API by reversed-phase high performance liquid chromatography", Engineering Science and Technology, Volume I; Medical and Health Science and Technology, (accepted and finalized) Network first release time: 2024-03-28). The article discloses the structures of the following three isomers and their detection methods:

[0006]

[0007] However, the article does not provide the preparation methods of the above-mentioned isomers. Since the content of mabaloxavir isomers is related to the quality of mabaloxavir finished products, the use of pure mabaloxavir isomers as reference substances can be used to conduct qualitative and quantitative analysis of related isomers in mabaloxavir raw materials, help control the content of the isomers in the production process, and thus improve the quality of mabaloxavir finished products.

[0008] The first isomer mentioned above is an isomer of mabaloxavir. The difference between them is that the CN bond connecting the two rings is in different spatial positions. Its molecular formula is: C 27 H 23 F2N3O7S has a similar chemical structure to Mabaloxavir API and similar physical and chemical properties. In addition, its content is relatively low, so it is extremely difficult to separate. At present, there is no relevant preparation method for this diastereoisomer. Therefore, it is of great significance to prepare a pure product of this isomer. Summary of the invention

[0009] In order to solve the technical problem that it is difficult to realize mass production of mabaloxavir diastereomers, the present invention provides a method for synthesizing mabaloxavir diastereomers. The method can realize mass preparation of mabaloxavir diastereomers, and the prepared product can be used for quality control of mabaloxavir raw materials.

[0010] The specific technical scheme of the present invention is:

[0011] A chemical synthesis method of mabaloxavir diastereoisomers comprises the following steps:

[0012] (A) without adding additional acid, condensing the compound of formula I with the compound of formula II to obtain the compound of formula III, the reaction process is as follows:

[0013]

[0014] (B) removing the n-hexyl protecting group from the compound of formula III under the action of an alkali metal halide to obtain a compound of formula IV; the reaction process is as follows:

[0015]

[0016] (C) substituting the compound of formula IV and chloromethyl methyl carbonate under alkaline conditions to obtain diastereoisomers of mabaloxavir;

[0017]

[0018] In step (A) of the preparation method of the present invention, no additional acid additive (such as methanesulfonic acid) is added, so that the content of the target isomer is greatly increased, and nearly 1:1 diastereoselective control can be achieved, so that mabaloxavir diastereomers can be quickly prepared in large quantities. Compared with directly separating a small amount of isomers from the product, this method does not require preparative chromatography separation, can be quickly prepared in large quantities, has low requirements for instruments and equipment, is simple to post-process, and has a large diastereoisomer yield and high purity.

[0019] Preferably, the specific process of step (A) comprises: mixing the compound of formula I, the compound of formula II, n-propyl phosphoric anhydride and a reaction solvent, carrying out a condensation reaction, and after the reaction is completed, post-treating to obtain a compound of formula III.

[0020] The reaction solvent in step (A) is one or a mixture of ethyl acetate, 1,4-dioxane, cyclohexane, butyl acetate, isopropyl acetate, and more preferably a mixture of ethyl acetate and cyclohexane.

[0021] Preferably, in step (A), the molar ratio of the compound of formula I to the compound of formula II is 1:1.2 to 1.8, more preferably 1:1.5.

[0022] Preferably, in step (A), the reaction temperature is 30-80°C, and the reaction time is 3-48 hours. Further preferably, the reaction temperature is 70°C, and the reaction time is 28 hours.

[0023] In the present invention, by not adding an acid additive, the content of the target isomer is increased and the difficulty of separating the target isomer is reduced. Preferably, in step (A), the separation step is: filtering to remove insoluble matter, adjusting the pH to neutral with a 20-40% sodium hydroxide aqueous solution, washing the organic phase with saturated sodium chloride, adding an ethyl methanesulfonic acid solution, filtering to remove insoluble matter, and concentrating the mother liquor under reduced pressure to remove the solvent to obtain an oily substance for column chromatography separation.

[0024] Preferably, the specific process in step (B) comprises: mixing the compound of formula III, anhydrous lithium chloride and a reaction solvent, and separating the product after the reaction conversion is complete to obtain the compound of formula IV.

[0025] Preferably, in step (B), the alkali metal halide is selected from anhydrous lithium chloride.

[0026] Preferably, in step (B), the molar ratio of the compound of formula III to anhydrous lithium chloride is 1:8-11, more preferably 1:9.

[0027] Preferably, in step (B), the reaction solvent is N-methylpyrrolidone.

[0028] Preferably, in step (B), the reaction temperature is 70-90° C. and the reaction time is 24-30 hours.

[0029] Preferably, in step (B), the separation method is: cooling the reaction solution to room temperature, quickly adding ice water, stirring for 1 hour, and filtering to obtain the compound of formula IV.

[0030] Preferably, the specific process in step (C) comprises: mixing the compound of formula IV, a base, potassium iodide, chloromethyl methyl carbonate and a reaction solvent, and separating the products after the reaction conversion is complete to obtain mabaloxavir diastereoisomers.

[0031] The alkali is potassium carbonate, sodium carbonate or sodium hydroxide, preferably potassium carbonate.

[0032] Preferably, in step (C), the molar ratio of potassium carbonate, potassium iodide and the compound of formula IV is 2:1:1.

[0033] Preferably, the reaction temperature in step (C) is 50-70°C, and the reaction time is 6-12 hours. More preferably, the reaction temperature is 60°C, and the reaction time is 6 hours.

[0034] The separation method of the compound in step (C) is as follows: filtering the reaction solution, adding ethyl acetate and water to extract and separate the phases, evaporating and concentrating the organic phase, and separating the obtained oil by column chromatography. The eluent can be n-heptane and ethyl acetate in a volume ratio of 1:1.

[0035] In steps (A)-(C), the amount of each reaction solvent is not strictly limited and can be adjusted according to the amount of the reaction raw materials: if the reaction raw materials are more, the amount of the reaction solvent and the reaction reagent can be increased; if the reaction raw materials are less, the amount of the reaction solvent and the reaction reagent can be reduced; each reaction solvent can be selected according to the common sense of those skilled in the art, such as alcohols, ketones, ethers, etc.

[0036] Compared with the prior art, the present invention has the following advantages:

[0037] (1) The present invention realizes the chemical synthesis and separation of diastereoisomers of mabaloxavir for the first time, which is simple to operate and easy to scale up, and can realize the large-scale preparation of diastereoisomers of mabaloxavir, which has obvious advantages over the separation scheme from raw materials.

[0038] (2) The chemical synthesis method of mabaloxavir diastereomers of the present invention can achieve a higher yield and product purity. Compared with the direct separation of diastereomers from API, no advanced equipment such as preparative liquid phase is required, and it can be obtained by column chromatography separation. The source of raw materials and auxiliary materials is wide, and the post-processing is simple.

[0039] (3) In the process of synthesizing the diastereoisomers of mabaloxavir, the present invention increases the proportion of the compound of formula III in the product by controlling the conditions, and purifies the compound of formula III, i.e., the stereoisomer mixture. This method can significantly improve the purity of the subsequent target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the liquid phase spectrum of the compound of formula III obtained in Example 1;

[0041] Figure 2 This is the liquid phase spectrum of the compound of formula IV obtained in Example 1;

[0042] Figure 3 This is the liquid phase spectrum of mabaloxavir diastereoisomers obtained in Example 1;

[0043] Figure 4 This is the liquid chromatography spectrum of crude Mabaloxavir;

[0044] Figure 5 This is the liquid chromatography spectrum of Mabaloxavir;

[0045] Figure 6 The spiked HPLC spectra of mabaloxavir and mabaloxavir diastereoisomers are shown;

[0046] Figure 7 A compound of formula III 1 H NMR spectrum;

[0047] Figure 8 A compound of formula III 13 C NMR spectrum;

[0048] Fig. 9 A compound of formula IV 1 H NMR spectrum;

[0049] Fig.10 A compound of formula IV 13 C NMR spectrum;

[0050] Fig.11 Mabaloxavir diastereoisomers 1 H NMR spectrum;

[0051] Fig.12 Mabaloxavir diastereoisomers 13 C NMR spectrum. DETAILED DESCRIPTION

[0052] The present invention will be further described below in conjunction with the embodiments.

[0053] The present invention is described below by specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims and any equivalents thereof are the protection scope of the present invention.

[0054] Example 1: Synthesis of Mabaloxavir Diastereoisomers

[0055] (A) condensing the compound of formula I with the compound of formula II to obtain the compound of formula III, the reaction process is as follows:

[0056]

[0057] The specific steps are as follows:

[0058] (A) Add 5.00g of the compound of formula I, 11.83g of T3P (n-propyl phosphoric anhydride), 4.02g of the compound of formula II to a 100mL three-necked flask, add 15.00mL of ethyl acetate, and stir at 80°C for 3 hours. Cool to room temperature, filter out insoluble matter, adjust pH to 7 with 30% sodium hydroxide aqueous solution, wash the organic phase with saturated sodium chloride, add 1.17g of methanesulfonic acid 25.00mL of ethyl acetate solution, filter out insoluble matter, adjust pH to 7 for the mother liquor, concentrate under reduced pressure to remove the solvent, and obtain an oily substance for column chromatography separation. The eluent can be n-heptane and ethyl acetate in a volume ratio of 1:1-1:3 for gradient elution. 1.30g of white solid is obtained, with a yield of 19.3%. The liquid phase spectrum is shown in Figure 1 .

[0059] 1 H NMR(600MHz,DMSO-d6)δ7.52(dd,J=7.8,1.6Hz,1H),7.36–7.31(m,1H),7.26–7.14(m,4H),7.04(dd,J=8.7,4.5Hz,1H), 5.71(dd,J=7.8,1.9Hz,1H),5.67(s,1H),5.52(dd,J=14.6,2.3Hz,1H),4.44(dd,J=13.6,2.7Hz,1H),4.23–4.12(m,2H) ,4.08(d,J=14.6Hz,1H),3.97–3.90(m,2H),3.64(dd,J=11.7,3.4Hz,1H),3.49(t,J=10.4Hz,1H),3.27(td,J=11.8,2.7 Hz,1H),2.63–2.56(m,1H),1.71(dt,J=8.5,6.5Hz,2H),1.43(t,J=7.5Hz,2H),1.31(q,J=3.8Hz,4H),0.92–0.83(m,3H). 13 CNMR(151MHz,DMSO)δ174.87,155.09,152.69,150.95(dd,J C-F =246.7,13.3Hz),146.89(dd,J C-F =246.7,13.3Hz),140.74,136.98,135.07,132.43,130.54,129.25,128.91,128.15,127.05,126.57(d,J C-F =12.9Hz),125.84,116.33(d,J C-F=16.6Hz),113.76,74.99,72.68,69.88,68.74,66.03,45.79,31.65,30.13,25.49,23.10,22.59,14.43.Calcd for C 30 H 32 F2N3O4S([M+H] + )=568.2076,found([M+H] + )=568.2089

[0060] (B) removing the n-hexyl protecting group from the compound of formula III under the action of lithium chloride to obtain the compound of formula IV; the reaction process is as follows:

[0061]

[0062] The specific steps are as follows:

[0063] In a 50mL three-necked flask, add 1.10g of the compound of formula III obtained above, 4.16mL of N-methylpyrrolidone, and 0.85g of anhydrous lithium chloride. After heating at 80°C for 30 hours, cool to room temperature, quickly add 16.12g of ice-water mixture to the system, stir for 15 minutes, filter, and dry the filter cake at 50°C with air blast to obtain 0.81g of white solid with a yield of 85.7%. The liquid phase spectrum is shown in FIG. Figure 2 .

[0064] 1 H NMR (600MHz, DMSO-d6) δ12.48–11.27(m,1H),7.45(dd,J=7.9,1.5Hz,1H),7.30–7.21(m,1H),7.20–7.07(m,3 H),7.03(d,J=7.7Hz,1H),6.97(dd,J=8.8,4.8Hz,1H),5.63(s,1H),5.55(d,J=7.7Hz,1H),5.45(dd,J=14.6,2 .1Hz,1H),4.35(dd,J=13.5,2.6Hz,1H),4.13(dd,J=10.0,3.0Hz,1H),4.01(d,J=14.5Hz,1H),3.88(dd,J=10. 9,3.0Hz,1H),3.60(d,J=10.7Hz,1H),3.34(td,J=11.8,2.8Hz,2H),2.67–2.55(m,1H),2.43(p,J=1.8Hz,2H). 13C NMR(151MHz,DMSO-d6)δ171.69,162.00,153.86,151.69,150.05,147.80,147.71,146.16,146.08,139.11,136.92,134.86,132.66, 130.58,129.27,129.01,126.24,126.15,125.91,116.41,116.30,115.98,111.11,74.78,70.47,68.61,65.86,45.80,23.09.Calcd for C 24 H 20 F2N3O4S([M+H] + )=484.1137,found([M+H] + )=484.1144

[0065] (C) Substituting the compound of formula IV and chloromethyl carbonate under alkaline conditions to obtain the diastereoisomer of mabaloxavir

[0066]

[0067] The specific steps are as follows:

[0068] In a 10 mL pressure-resistant sealed tube, add 0.80 g of the compound IV obtained above, 0.34 g of potassium carbonate, 0.27 g of potassium iodide, 0.41 g of chloromethyl methyl carbonate, and 8.00 mL of N,N-dimethylacetamide. Heat the system at 50°C for 12 hours, cool to room temperature, add 16.00 mL of ethyl acetate, wash twice with 16.00 mL of purified water, evaporate and concentrate the organic phase, and separate the crude product by column chromatography, with the eluent being n-heptane and ethyl acetate in a volume ratio of 1:1, to obtain 0.90 g of a white solid with a yield of 95.0%. The liquid phase spectrum is shown in FIG. Figure 3 , the chromatographic purity was 97.66%.

[0069] 1H NMR(600MHz,DMSO-d6)δ7.48(d,J=7.8Hz,1H),7.37–7.31(m,1H),7.26–7.18(m,4H),7.07(dd,J=8.9,4 .8Hz,1H),5.80(d,J=7.7Hz,1H),5.74(d,J=6.7Hz,1H),5.71–5.64(m,2H),5.54–5.46(m,1H),4.38(dd, J=13.6,2.6Hz,1H),4.16(dd,J=9.9,2.9Hz,1H),4.09(d,J=14.6Hz,1H),4.05–3.96(m,1H),3.72(s,3H) ,3.68(dd,J=11.7,3.3Hz,1H),3.45(t,J=10.4Hz,1H),3.27(td,J=11.7,2.9Hz,1H),2.66–2.56(m,1H). 13 C NMR(151MHz,DMSO-d6)δ173.51,155.12,154.78,150.03,141.39,137.05,134.90,132.26,130.63,129.32,128.72,128.30 ,127.23,126.62,126.54,125.92,116.47,116.36,114.28,91.50,75.21,69.92,68.74,66.02,55.14,46.03,23.08.Calcd for C 27 H 24 F2N3O7S([M+H] + )=572.1298,found([M+H] + )=572.1306.

[0070] Example 2: Synthesis of Mabaloxavir Diastereoisomers

[0071] (A) condensing the compound of formula I with the compound of formula II to obtain the compound of formula III, the reaction process is as follows:

[0072]

[0073] The specific steps are as follows:

[0074] In a 100mL three-necked flask, add 5.00g of compound I, 11.83g of T3P, 4.02g of compound II, 15.00mL of ethyl acetate, 5.00mL of cyclohexane, and stir at 30°C for 48 hours. Cool to room temperature, filter to remove insoluble matter, adjust pH=7 with 30% sodium hydroxide aqueous solution, wash the organic phase with saturated sodium chloride, add 1.17g of methanesulfonic acid ethyl acetate 25.00mL solution, filter to remove insoluble matter, neutralize the mother liquor to pH=7, concentrate under reduced pressure to remove solvent, and obtain an oily substance for column chromatography separation. The eluent can be n-heptane and ethyl acetate in a volume ratio of 1:1-1:3 for gradient elution. 2.96g of white solid is obtained, with a yield of 40.0%.

[0075] (B) removing the n-hexyl protecting group from the compound of formula III under the action of lithium chloride to obtain the compound of formula IV; the reaction process is as follows:

[0076]

[0077] The specific steps are as follows:

[0078] In a 50mL three-necked flask, add 2.50g of the compound of formula III obtained above, 8.00mL of N-methylpyrrolidone, and 1.44g of anhydrous lithium chloride. After heating at 80°C for 24 hours, cool to room temperature, quickly add 31.00g of ice-water mixture to the system, stir for 15 minutes, filter, and dry the filter cake at 50°C with air blast to obtain 1.73g of white solid, with a yield of 91.1%.

[0079] (C) Substituting the compound of formula IV and chloromethyl carbonate under alkaline conditions to obtain the diastereoisomer of mabaloxavir

[0080]

[0081] The specific steps are as follows:

[0082] In a 50mL three-necked flask, add 1.70g of the compound IV obtained above, 0.73g of potassium carbonate, 1.16g of potassium iodide, 0.88g of chloromethyl methyl carbonate, and 17.00mL of N,N-dimethylacetamide. Heat the system at 70°C for 6 hours, cool to room temperature, add 34.00mL of ethyl acetate, wash twice with 34.00mL of purified water, evaporate and concentrate the organic phase, and separate the crude product by column chromatography, with the eluent being n-heptane and ethyl acetate in a volume ratio of 1:1, to obtain 1.88g of a white solid with a yield of 93.5%.

[0083] Example 3: Synthesis of Mabaloxavir Diastereoisomers

[0084] (A) condensing the compound of formula I with the compound of formula II to obtain the compound of formula III, the reaction process is as follows:

[0085]

[0086] The specific steps are as follows:

[0087] In a 100mL three-necked flask, add 5.00g of compound I, 11.83g of T3P, 4.02g of compound II, 15.00mL of ethyl acetate, 5.00mL of cyclohexane, and stir at 70°C for 28 hours. Cool to room temperature, filter to remove insoluble matter, adjust pH=7 with 30% sodium hydroxide aqueous solution, wash the organic phase with saturated sodium chloride, add 1.17g of methanesulfonic acid ethyl acetate 25.00mL solution, filter to remove insoluble matter, neutralize the mother liquor to pH=7, concentrate under reduced pressure to remove solvent, and obtain an oily substance for column chromatography separation. The eluent can be n-heptane and ethyl acetate in a volume ratio of 1:1-1:3 for gradient elution. 3.16g of white solid is obtained, with a yield of 43.8%.

[0088] (B) removing the n-hexyl protecting group from the compound of formula III under the action of lithium chloride to obtain the compound of formula IV; the reaction process is as follows:

[0089]

[0090] The specific steps are as follows:

[0091] In a 50mL three-necked flask, add 2.50g of the compound of formula III obtained above, 8.00mL of N-methylpyrrolidone, and 1.44g of anhydrous lithium chloride. After heating at 80°C for 28 hours, cool to room temperature, quickly add 31.00g of ice-water mixture to the system, stir for 15 minutes, filter, and dry the filter cake at 50°C with air blast to obtain 1.85g of white solid, with a yield of 93.5%.

[0092] (C) Substituting the compound of formula IV and chloromethyl carbonate under alkaline conditions to obtain the diastereoisomer of mabaloxavir

[0093]

[0094] The specific steps are as follows:

[0095] In a 50mL three-necked flask, add 1.70g of the compound IV obtained above, 0.73g of potassium carbonate, 0.51g of potassium iodide, 0.88g of chloromethyl methyl carbonate, and 17.00mL of N,N-dimethylacetamide. Heat the system at 60°C for 8 hours, cool to room temperature, add 34.00mL of ethyl acetate, wash twice with 34.00mL of purified water, evaporate and concentrate the organic phase, and separate the crude product by column chromatography, with the eluent being n-heptane and ethyl acetate in a volume ratio of 1:1, to obtain 1.76g of a white solid with a yield of 87.5%.

[0096] Comparative Example 1

[0097] In a 100mL three-necked flask, add 5.00g of the compound of formula I, 11.83g of T3P, 4.02g of the compound of formula II, 1.75g ​​of methanesulfonic acid, 15.00mL of ethyl acetate, and 5.00mL of cyclohexane, and stir at 70°C for 28 hours. Cool to room temperature, filter to remove insoluble matter, adjust pH=7 with 30% sodium hydroxide aqueous solution, wash the organic phase with saturated sodium chloride, add 1.17g of methanesulfonic acid ethyl acetate 25.00mL solution, filter to remove insoluble matter, neutralize the mother liquor to pH=7, concentrate under reduced pressure to remove the solvent, and obtain an oily substance. Column chromatography separation is performed with a volume ratio of n-heptane and ethyl acetate of 1:1-1:3 for gradient elution. The solvent was removed by concentration under reduced pressure, and a yellow oil was obtained by the first column chromatography. The content of compound III in the oil was about 50%. The yellow oil was then dissolved in a small amount of ethyl acetate and separated by a second column chromatography. The eluent was n-heptane and ethyl acetate in a volume ratio of 1:1-1:3 for gradient elution. Finally, the solvent was removed by concentration under reduced pressure to obtain 0.17 g of a yellow viscous solid with a yield of 2.5%.

[0098] It can be seen that when methanesulfonic acid is added to the reaction in step (A), the content of the target isomer is greatly reduced, and only a small amount of yellow viscous solid can be obtained after at least two column chromatography steps, and the yield and purity are difficult to meet the requirements of mass production.

[0099] Application example: Qualitative analysis of mabaloxavir diastereoisomers

[0100] The mabaloxavir isomers prepared in Example 1 were monitored and analyzed by high performance liquid chromatography (HPLC). The obtained spectrum is shown in Figure 3 .

[0101] The crude sample of mabaloxavir was prepared by the method of patent CN109311911B, and the sample was detected and analyzed by HPLC. The obtained spectrum is shown in Figure 4 .

[0102] The diastereoisomer of mabaloxavir prepared in Example 1 (addition amount 50%) was added to the pure mabaloxavir, and the mixed sample was detected and analyzed by HPLC after mixing. The obtained spectrum is shown in FIG. Figure 5 and Figure 6 .

[0103] from Figure 3-Figure 6 It can be seen that the peak position of the diastereoisomer of mabaloxavir is approximately at 28.3 min, and the crude mabaloxavir contains a small amount of this isomer.

[0104] The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art.

[0105] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing diastereoisomers of mabaloxavir, characterized in that: The following steps are involved: (A) without adding additional acid, the compound of formula I and the compound of formula II are subjected to condensation reaction to obtain the compound of formula III, and the reaction process is as follows: (B) removing the n-hexyl protecting group from the compound of formula III under the action of an alkali metal halide to obtain a compound of formula IV; the reaction process is as follows: (C) subjecting the compound of formula IV and chloromethyl methyl carbonate to a substitution reaction under alkaline conditions to obtain mabaloxavir diastereomers; 2. The synthesis method according to claim 1, characterized in that The specific process of step (A) comprises: mixing the compound of formula I, the compound of formula II, n-propyl phosphoric anhydride and a reaction solvent, carrying out a condensation reaction, and after the reaction is completed, performing post-treatment to obtain a compound of formula III.

3. The synthesis method according to claim 2, characterized in that The reaction solvent in step (A) is one or a mixture of ethyl acetate, 1,4-dioxane, cyclohexane, butyl acetate, and isopropyl acetate.

4. The synthesis method according to any one of claims 1 to 3, characterized in that The temperature of the condensation reaction in step (A) is 30-80° C., and the reaction time is 3-48 hours.

5. The synthesis method according to any one of claims 1 to 3, characterized in that: In step (A), after the condensation reaction is completed, the product is separated to obtain a compound of formula III; The process of separating the product comprises the following steps: filtering to remove insoluble matter, adjusting the pH to neutral with a 20-40% sodium hydroxide aqueous solution, washing the organic phase with saturated sodium chloride, adding a methanesulfonic acid ethyl acetate solution, filtering to remove insoluble matter, concentrating the mother liquor under reduced pressure to remove the solvent, and obtaining an oily substance for column chromatography separation.

6. The synthesis method according to claim 1, characterized in that The specific process of step (B) comprises: mixing the compound of formula III, alkali metal halide and reaction solvent, separating the product after the reaction is complete, and obtaining the compound of formula IV.

7. The synthesis method according to claim 1 or 6, characterized in that: In step (B), the alkali metal halide is lithium chloride; The amount of lithium chloride used is 8-11 times the molar equivalent of the compound of formula III, and the reaction solvent is N-methylpyrrolidone or N,N-dimethylacetamide.

8. The synthesis method according to claim 1 or 6, characterized in that: In step (B), the reaction temperature is 70-90° C. and the reaction time is 24-30 hours.

9. The synthesis method according to claim 1, characterized in that The alkaline conditions described in step (C) are added with a base and an additive, the base is potassium carbonate, sodium carbonate or sodium hydroxide, and the additive is potassium iodide.

10. The synthesis method according to claim 1, characterized in that In step (C), the reaction is carried out in a solvent, and the solvent is N,N-dimethylacetamide; The reaction temperature is 50-70°C and the reaction time is 6-12 hours.

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