A method for preparing a 3CL protease inhibitor

Abstract

This invention relates to a method for preparing a 3CL protease inhibitor, belonging to the field of medicinal chemistry. The preparation method of this invention involves reacting raw materials under acidic conditions to obtain the target compound. The method of this invention is simple, has a high yield, is environmentally friendly, and is easily scalable for large-scale commercial production.

Description

Technical Field

[0001] This invention relates to a method for preparing a 3CL protease inhibitor, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Patent applications WO2022138987A1 and WO2022138988A1 disclose a class of triazine derivatives with viral replication inhibitory effects and pharmaceutical compositions containing them. These compounds inhibit the coronavirus 3CL protease. Specifically, the patent applications disclose the compound Ensitrelvir (S-217622), CAS number 2647530-73-0, a 3CL protease inhibitor that can be used against the novel coronavirus. Its structure is shown below:

[0003]

[0004] Ensitrelvir, an antiviral drug developed by Shionogi & Co., Ltd. of Japan, has undergone Phase III clinical trials in Japan and Singapore. The published Phase IIa clinical trial results show that it has good efficacy in combating the virus, improving clinical symptoms, and preventing disease progression, with no major safety concerns. Shionogi formally submitted its clinical trial approval application to the Japanese Ministry of Health, Labour and Welfare in February 2022.

[0005] Existing technologies, such as patent applications WO2022138987A1 and WO2022138988A1, and literature J.Med.Chem.2022,65,6499-6512, all report methods for preparing compound (I). The synthetic route involves reacting 6-(ethio)-3-(1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione and 6-chloro-2-methyl-2H-indazole-5-amine as starting materials under LHMDS to obtain compound (I). This process is cumbersome, has a low yield (approximately 25%), high production costs, and is difficult to purify (e.g., recrystallization purification is required after column chromatography). Furthermore, the product requires column chromatography separation and purification, making it unsuitable for large-scale production.

[0006] Existing technologies, such as patent application CN103153968A, disclose a method for preparing 6-imino-1,3,5-triazine-2,4-dione compounds by using a condensation reaction with a tert-butanol / acetic acid system. The inventors used this method to prepare compound (I) and found that the yield was very low and the operation process was cumbersome.

[0007] On the other hand, eutectic forms of Ensitrelvir have also attracted much attention, such as the fumaric acid eutectic of Ensitrelvir. Existing technologies, such as patent applications WO2022138987A1 and WO2022138988A1, and literature J.Med.Chem.2022,65,6499-6512, all report the preparation method of compound (3). The synthetic route is as follows: 6-(ethylthio)-3-(1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione and 6-chloro-2-methyl-2H-indazole-5-amine are reacted under the action of LHMDS to obtain compound (I); compound (I) is then stirred with fumaric acid in ethyl acetate to obtain the fumaric acid cocrystal compound of Ensitrelvir, whose CAS number is 2796273-00-0, and whose structure is shown in the following formula:

[0008]

[0009] However, the above-mentioned synthesis of compound (3) requires two steps: first synthesizing compound (I) and then synthesizing compound (3). The operation is cumbersome, the product is difficult to purify, and it needs to be purified by recrystallization after column chromatography. The total yield of the two steps is only 23.75%, the production cost is high, and it is not suitable for large-scale production.

[0010] Therefore, it is essential to develop a simple, high-yield, environmentally friendly, and easily commercially viable method for the preparation of Ensitrelvir and its fumaric acid eutectic. Summary of the Invention

[0011] Through research, the inventors have developed a method for preparing Ensitrelvir compounds. This method boasts high yield, simple operation, and high product purity, avoiding column chromatography separation and purification, effectively reducing production costs and environmental pollution, and facilitating large-scale commercial production. Simultaneously, the inventors have also developed a novel method for preparing Ensitrelvir fumarate cocrystals. This method utilizes a one-pot process to obtain Ensitrelvir fumarate cocrystals with a yield exceeding 89%. It is simple to operate, environmentally friendly, produces high product purity, effectively reduces production costs, and is suitable for industrial production.

[0012] The compounds represented by formula (I) are not limited to specific isomers, but include all possible isomers (e.g., keto-ol isomers, imine-enamine isomers, disteromers, optical isomers, rotatable isomers, etc.), racemates, or mixtures thereof. For example, compound (I) comprises compound (Ia) as shown below, and compound (3) comprises compound (3-a) as shown below:

[0013]

[0014]

[0015] This invention provides a method for preparing compound (I) or its isomers, comprising: reacting compound (1) and compound (2) in an aqueous solvent in the presence of an acid to prepare compound (I) or its isomers.

[0016]

[0017] In some embodiments, a method for preparing a salt of compound (I) or an isomer thereof includes: reacting compound (1) and compound (2) in an aqueous solvent in the presence of an acid to prepare a salt of compound (I) or an isomer thereof.

[0018] The inventors unexpectedly discovered that when compounds (1) and (2) react in a water / acid system, fewer impurities are produced. In particular, water can inhibit the reaction of compound (2) with acid to generate amide impurities. Furthermore, the amount of acid and compound (2) used is small, while the reaction yield is high, the reaction cost is low, and it is environmentally friendly. Overall, the reaction is simple to operate, has a high yield, high purity, and is environmentally friendly.

[0019] In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:3. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:2. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:1.3. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:1.5. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1, or 1:1.1, or 1:1.2, or 1:1.3, or 1:1.4, or 1:1.5, or 1:1.6, or 1:1.7, or 1:1.8, or 1:1.9, or 1:2, or 1:2.5, or 1:3. Preferably, the molar ratio of compound (1) to compound (2) is approximately 1:1.3, which is beneficial for the reaction to proceed better.

[0020] In some embodiments, the weight-to-volume ratio (W / V, g / mL) of the compound (1) to water is approximately 1 g:3 mL to 1 g:20 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is 1 g:5 mL to 1 g:10 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is approximately 1 g:3 mL, or 1 g:4 mL, or 1 g:5 mL, or 1 g:6 mL, or 1 g:7 mL, or 1 g:8 mL, or 1 g:9 mL, or 1 g:10 mL, or 1 g:11 mL, or 1 g:12 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is approximately 1 g:8 mL, which is beneficial for the formation of the target product. Through extensive experimental research, the inventors have found that in this reaction, if the amount of water is too small, the reaction compound becomes viscous and difficult to stir; if the amount of water is too large, the reaction will slow down and prolong the reaction time.

[0021] In some embodiments, the acid is selected from at least one of oxalic acid, citric acid, malic acid, tartaric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. In some embodiments, the acid is preferably at least one of formic acid, acetic acid, propionic acid, butyric acid, succinic acid, malic acid, and oxalic acid.

[0022] In some embodiments, the acid is formic acid; in some embodiments, the acid is acetic acid; in some embodiments, the acid is propionic acid; in some embodiments, the acid is butyric acid; in some embodiments, the acid is succinic acid; in some embodiments, the acid is malic acid; in some embodiments, the acid is oxalic acid; using these acids facilitates a better reaction.

[0023] In some embodiments, the molar ratio of compound (1) to acid is approximately 1:0.1 to 1:30. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:1 to 1:20. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:1 to 1:10. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:1 to 1:8. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:1 to 1:5. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:1 to 1:3. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:0.5, or 1:1, or 1:1.5, or 1:2, or 1:2.5, or 1:3, or 1:5, or 1:10, or 1:15, or 1:20. In some embodiments, the molar ratio of compound (1) to acid is approximately 1:2, which is beneficial for the reaction to proceed better.

[0024] Controlling the reaction temperature within a suitable range is beneficial for the formation of the target product. In some embodiments, the reaction temperature of compound (1) and compound (2) is 80°C to 120°C. In some embodiments, the reaction temperature of compound (1) and compound (2) is 110°C to 120°C. In some embodiments, the reaction temperature of compound (1) and compound (2) is 80°C, or 85°C, or 90°C, or 95°C, or 100°C, or 105°C, or 110°C, or 115°C, or 120°C. In some embodiments, the reaction temperature is 115°C. When the reaction temperature is below 80°C, the reaction is slow, a large amount of reactants remain, and the yield is low; when the reaction temperature is above 120°C, it exceeds the boiling point of the solvent, the reaction system boils violently, and the production conditions in the workshop are difficult to achieve.

[0025] In some embodiments, optionally, the reaction of compound (1) and compound (2) is carried out in the presence of a first catalyst selected from at least one of NaBr, NaI, KI, KBr, Me4NI, Me4NBr, and NH4I. In some embodiments, the first catalyst is KI; in some embodiments, the first catalyst is NaI; in some embodiments, the first catalyst is NH4I; using these catalysts facilitates a better reaction.

[0026] In some embodiments, optionally, the reaction of compound (1) and compound (2) is carried out in the presence of a first catalyst; wherein the molar ratio of compound (1) to the first catalyst is approximately 1:0 to 1:1. In other embodiments, the molar ratio of compound (1) to the first catalyst is approximately 1:0.2 to 1:0.6. In some embodiments, the molar ratio of compound (1) to the first catalyst is approximately 1:0.1, or 1:0.2, or 1:0.3, or 1:0.4, or 1:0.5, or 1:0.6, or 1:0.7, or 1:0.8, or 1:0.9, or 1:1. In some embodiments, a molar ratio of compound (1) to the first catalyst of approximately 1:0.3 is beneficial for the formation of the target product.

[0027] In some embodiments, the aforementioned method for preparing compound (I) or its isomers includes: reacting compound (1) and compound (2) in an aqueous solvent in the presence of an acid to prepare compound (I) or its isomers; wherein the acid is selected from at least one of formic acid, acetic acid, propionic acid, butyric acid, succinic acid, malic acid, and oxalic acid; the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:2; the molar ratio of compound (1) to acid is approximately 1:1 to 1:10; the reaction temperature is 80°C to 120°C; optionally, the weight-volume ratio of compound (1) to water is approximately 1 g:5 mL to 1 g:10 mL. In some embodiments, the aforementioned method for preparing compound (I) or its isomers includes: reacting compound (1) and compound (2) in an aqueous solvent in the presence of an acid to prepare compound (I) or its isomers; wherein the acid is formic acid, acetic acid, propionic acid, butyric acid, succinic acid, malic acid, or oxalic acid; the molar ratio of compound (1) to compound (2) is approximately 1:1.3; the molar ratio of compound (1) to acid is approximately 1:2; the weight-volume ratio of compound (1) to water is approximately 1 g:8 mL; and the reaction temperature is 115°C.

[0028] To further improve the purity of compound (I) or its isomers, any suitable method or method that can improve the purity of the target product may be used, including but not limited to cooling, stirring, crystallization, filtration, vacuum drying, decolorization, adsorption, washing, crystallization, recrystallization, etc.

[0029] In some embodiments, the reaction of the aforementioned method for preparing compound (I) or its isomers further includes a post-treatment to obtain compound (I) or its isomers, wherein the post-treatment may include: crystallization in a ketone solvent or an ester solvent; optionally, the ketone solvent is selected from at least one of acetone, butanone, and pentanone; optionally, the ester solvent is selected from at least one of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate.

[0030] In some embodiments, in the aforementioned method for preparing compound (I) or its isomers, the reaction of compound (1) and compound (2) may be followed by post-processing to obtain compound (I) or its isomers, wherein the post-processing may include: cooling, adding a ketone solvent or an ester solvent, crystallization, filtration, and vacuum drying to obtain the product; optionally, the ketone solvent is selected from at least one of acetone, butanone, and pentanone; optionally, the ester solvent is selected from at least one of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate.

[0031] In some embodiments, the ketone solvent is acetone; in some embodiments, the ketone solvent is butanone; in some embodiments, the ketone solvent is pentanone; in some embodiments, the ester solvent is ethyl acetate; using these solvents is more conducive to the purification of the product.

[0032] In some embodiments, the crystallization temperature is -10°C to 30°C. In some embodiments, the crystallization temperature is 0°C to 30°C. In some embodiments, the crystallization temperature is 10°C to 30°C. In some embodiments, the crystallization temperature is 20°C, 25°C, or 30°C. In some embodiments, a crystallization temperature of 25°C is beneficial for crystal precipitation.

[0033] In some embodiments, the crystallization time is 1 hour to 20 hours. In some embodiments, the crystallization time is 1 hour to 15 hours. In some embodiments, the crystallization time is 1 hour to 10 hours. In some embodiments, the crystallization time is 2 hours to 6 hours. In some embodiments, the crystallization time is 2 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours. In some embodiments, a crystallization time of 2 hours is beneficial for crystal precipitation.

[0034] In some embodiments, the vacuum drying temperature is 40°C to 80°C. In some embodiments, the vacuum drying temperature is 45°C to 70°C. In some embodiments, the vacuum drying temperature is 50°C to 60°C. In some embodiments, the vacuum drying temperature is 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 80°C. In some embodiments, a vacuum drying temperature of 50°C is beneficial for improving the quality of the product.

[0035] In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL to 1 g:15 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL to 1 g:10 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:4 mL to 1 g:8 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL, or 1 g:4 mL, or 1 g:5 mL, or 1 g:6 mL, or 1 g:7 mL, or 1 g:8 mL, or 1 g:9 mL, or 1 g:10 mL, or 1 g:11 mL, or 1 g:12 mL.

[0036] In some embodiments, the post-treatment in the aforementioned method for preparing compound (I) or its isomers includes: cooling to 10°C–30°C, adding acetone, butanone, pentanone, or ethyl acetate, crystallizing at 10°C–30°C, filtering, and vacuum drying at 45°C–70°C to obtain the product. In some embodiments, the post-treatment includes: cooling to 25°C, adding acetone, butanone, pentanone, or ethyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product. In some embodiments, the post-treatment includes: cooling to 25°C, adding acetone, butanone, pentanone, or ethyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product; wherein the weight-to-volume ratio of compound (1) to acetone, butanone, pentanone, or ethyl acetate is approximately 1 g: 3 mL; and the crystallization time is 2 h–10 h. In some embodiments, the post-processing includes: cooling to 25°C, adding acetone, butanone, pentanone or ethyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product; wherein the weight-volume ratio of compound (1) to acetone, butanone, pentanone or ethyl acetate is approximately 1 g: 5 mL or 1 g: 8 mL; and the crystallization time is 4 h.

[0037] Another aspect of the present invention provides a method for preparing compound (3) or its isomers, comprising: reacting compound (1), compound (2) and fumaric acid in an aqueous solvent in a one-pot reaction to prepare compound (3) or its isomers.

[0038]

[0039] In some embodiments, x in the compound (3) or its isomers is 0.1 to 10. In some embodiments, x in the compound (3) or its isomers is 0.5 to 5. In some embodiments, x in the compound (3) or its isomers is 1 to 3. In some embodiments, x in the compound (3) or its isomers is 2. In some embodiments, x in the compound (3) or its isomers is 1.

[0040] In some embodiments, a method for preparing compound (4) or its isomers includes: reacting compound (1), compound (2), and fumaric acid in an aqueous solvent in a one-pot reaction to prepare compound (4) or its isomers.

[0041]

[0042] In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:3. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:2. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:1.3. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1 to 1:1.5. In some embodiments, the molar ratio of compound (1) to compound (2) is approximately 1:1, or 1:1.1, or 1:1.2, or 1:1.3, or 1:1.4, or 1:1.5, or 1:1.6, or 1:1.7, or 1:1.8, or 1:1.9, or 1:2, or 1:2.5, or 1:3. Preferably, the molar ratio of compound (1) to compound (2) is approximately 1:1.2, which is beneficial for the reaction to proceed better.

[0043] In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:0.1 to 1:10. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:10. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:8. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:5. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:3. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:0.5 to 1:2. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:0.5, or 1:1, or 1:1.5, or 1:2, or 1:2.5, or 1:3, or 1:5, or 1:10, or 1:15, or 1:20. In some embodiments, the molar ratio of compound (1) to fumaric acid is approximately 1:1.1, which is beneficial for the reaction to proceed better.

[0044] In some embodiments, the weight-to-volume ratio (W / V, g / mL) of the compound (1) to water is approximately 1 g:3 mL to 1 g:20 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is 1 g:3 mL to 1 g:10 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is 1 g:5 mL to 1 g:10 mL. In some embodiments, the weight-to-volume ratio of the compound (1) to water is approximately 1 g:3 mL, or 1 g:4 mL, or 1 g:5 mL, or 1 g:6 mL, or 1 g:7 mL, or 1 g:8 mL, or 1 g:9 mL, or 1 g:10 mL, or 1 g:11 mL, or 1 g:12 mL. In some embodiments, a weight-to-volume ratio of the compound (1) to water of approximately 1 g:8 mL is beneficial for the formation of the target product. Through extensive experimental research, the inventors discovered that in this reaction, if the amount of water is too small, the reaction compound becomes viscous and difficult to stir; if the amount of water is too large, the reaction will slow down and prolong the reaction time.

[0045] Controlling the one-pot reaction temperature within a suitable range is beneficial for the formation of the target product. In some embodiments, the reaction temperature of the one-pot reaction is 80℃~120℃. In some embodiments, the reaction temperature of the one-pot reaction is 110℃~120℃. In some embodiments, the reaction temperature of the one-pot reaction is 80℃, or 85℃, or 90℃, or 95℃, or 100℃, or 105℃, or 110℃, or 115℃, or 120℃. In some embodiments, the temperature of the one-pot reaction is 115℃. If the reaction temperature is below 80℃, the reaction is slow, a large amount of reactant remains, and the yield is low; if the reaction temperature is above 120℃, it exceeds the boiling point of the solvent, the reaction system boils violently, and the workshop production conditions are difficult to achieve.

[0046] In some embodiments, optionally, the one-pot reaction is carried out in the presence of a second catalyst selected from at least one of NaBr, NaI, KI, KBr, Me4NI, Me4NBr, NH4I, and tetrabutylammonium iodide. In some embodiments, the second catalyst is KI; in some embodiments, the second catalyst is KBr; in some embodiments, the second catalyst is NH4I; using these catalysts facilitates a better reaction.

[0047] In some embodiments, optionally, the reaction is carried out in the presence of a second catalyst; wherein the molar ratio of the compound (1) to the second catalyst is approximately 1:0 to 1:2. In some embodiments, the molar ratio of the compound (1) to the second catalyst is approximately 1:0 to 1:1. In other embodiments, the molar ratio of the compound (1) to the second catalyst is approximately 1:0.2 to 1:0.6. In some embodiments, the molar ratio of the compound (1) to the second catalyst is approximately 1:0.1, or 1:0.2, or 1:0.3, or 1:0.4, or 1:0.5, or 1:0.6, or 1:0.7, or 1:0.8, or 1:0.9, or 1:1. In some embodiments, a molar ratio of the compound (1) to the second catalyst of approximately 1:0.5 is beneficial for the formation of the target product.

[0048] In some embodiments, the aforementioned method for preparing compound (3) or its isomers includes: reacting compound (1), compound (2) and fumaric acid in an aqueous solvent to prepare compound (3) or its isomers; wherein the molar ratio of compound (1) and compound (2) is approximately 1:1 to 1:2; the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:10; the weight-volume ratio of compound (1) to water is 1g:3mL to 1g:10mL; optionally, the reaction temperature is 80°C to 120°C. In some embodiments, the aforementioned method for preparing compound (3) or its isomers includes: reacting compound (1), compound (2) and fumaric acid in an aqueous solvent to prepare compound (3) or its isomers; wherein the molar ratio of compound (1) and compound (2) is approximately 1:1.2; the molar ratio of compound (1) to fumaric acid is approximately 1:1.1; the weight-volume ratio of compound (1) to water is 1 g:6 mL; optionally, the reaction temperature is 115 °C.

[0049] In some embodiments, the method for preparing compound (4) or its isomers includes: reacting compound (1), compound (2) and fumaric acid in an aqueous solvent to prepare compound (4) or its isomers; wherein the molar ratio of compound (1) and compound (2) is approximately 1:1 to 1:2; the molar ratio of compound (1) to fumaric acid is approximately 1:1 to 1:10; the weight-volume ratio of compound (1) to water is 1g:3mL to 1g:10mL; optionally, the reaction temperature is 80℃ to 120℃.

[0050] To further improve the purity of compound (I), any suitable method or method that can improve the purity of the target product may be used, including but not limited to cooling, stirring, crystallization, filtration, vacuum drying, decolorization, adsorption, washing, crystallization, recrystallization, etc.

[0051] In some embodiments, the one-pot reaction further includes a post-treatment to obtain the compound (3) or its isomers, wherein the post-treatment may include crystallization in a ketone solvent or an ester solvent; optionally, the ketone solvent is selected from at least one of acetone, butanone, and pentanone; optionally, the ester solvent is selected from at least one of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate.

[0052] In some embodiments, in the aforementioned method for preparing compound (4) or its isomers, the one-pot reaction may be post-processed to obtain compound (3) or its isomers, wherein the post-processing may include: cooling, adding a ketone solvent or an ester solvent, crystallization, filtration, and vacuum drying to obtain the product; optionally, the ketone solvent is selected from at least one of acetone, butanone, and pentanone; optionally, the ester solvent is selected from at least one of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate.

[0053] In some embodiments, the ketone solvent is acetone; in some embodiments, the ketone solvent is butanone; in some embodiments, the ketone solvent is pentanone; in some embodiments, the ester solvent is ethyl acetate; in some embodiments, the ester solvent is isopropyl acetate; using these solvents is more conducive to the purification of the product.

[0054] In some embodiments, the crystallization temperature is -10°C to 30°C. In some embodiments, the crystallization temperature is 0°C to 30°C. In some embodiments, the crystallization temperature is 10°C to 30°C. In some embodiments, the crystallization temperature is 20°C, 25°C, or 30°C. In some embodiments, a crystallization temperature of 25°C is beneficial for crystal precipitation.

[0055] In some embodiments, the crystallization time is 1 hour to 20 hours. In some embodiments, the crystallization time is 1 hour to 15 hours. In some embodiments, the crystallization time is 1 hour to 10 hours. In some embodiments, the crystallization time is 2 hours to 6 hours. In some embodiments, the crystallization time is 2 hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours. In some embodiments, a crystallization time of 2 hours is beneficial for crystal precipitation.

[0056] In some embodiments, the vacuum drying temperature is 40°C to 80°C. In some embodiments, the vacuum drying temperature is 45°C to 70°C. In some embodiments, the vacuum drying temperature is 50°C to 60°C. In some embodiments, the vacuum drying temperature is 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 80°C. In some embodiments, a vacuum drying temperature of 50°C is beneficial for improving the quality of the product.

[0057] In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL to 1 g:20 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL to 1 g:15 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL to 1 g:10 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:4 mL to 1 g:8 mL. In some embodiments, the weight-to-volume ratio of compound (1) to the ketone or ester solvent is approximately 1 g:3 mL, or 1 g:4 mL, or 1 g:5 mL, or 1 g:6 mL, or 1 g:7 mL, or 1 g:8 mL, or 1 g:9 mL, or 1 g:10 mL, or 1 g:11 mL, or 1 g:12 mL.

[0058] In some embodiments, the post-treatment in the aforementioned method for preparing compound (3) or its isomers includes: cooling to 10°C–30°C, adding acetone, ethyl acetate, or isopropyl acetate, crystallizing at 10°C–30°C, filtering, and vacuum drying at 45°C–70°C to obtain the product. In some embodiments, the post-treatment includes: cooling to 25°C, adding acetone, ethyl acetate, or isopropyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product. In some embodiments, the post-treatment includes: cooling to 25°C, adding acetone, ethyl acetate, or isopropyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product; wherein the weight ratio of compound (1) to the volume ratio of acetone, ethyl acetate, or isopropyl acetate is approximately 1:3–1:10; and the crystallization time is 2 h–10 h. In some embodiments, the post-processing includes: cooling to 25°C, adding acetone, ethyl acetate or isopropyl acetate, crystallizing at 25°C, filtering, and vacuum drying at 50°C to obtain the product; wherein the weight ratio of compound (1) to the volume ratio of acetone, ethyl acetate or isopropyl acetate is approximately 1:6; and the crystallization time is 2 hours.

[0059] The method provided by this invention is simple to operate, has a high yield, is environmentally friendly, and is easy to scale up for industrial production. Attached Figure Description

[0060] Figure 1 X-ray powder diffraction (XRPD) pattern of the Ensitrelvir fumarate eutectic compound. Detailed Implementation

[0061] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0062] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0063] In this invention, the compound (3) is a fumaric acid eutectic of compound (I) or an Ensitrelvir fumaric acid eutectic, which are equivalent and can be substituted for each other.

[0064] In this invention, g: gram; mL: milliliter; mmol: millimole; ℃: degree Celsius; h: hour;

[0065] LHMDS: Lithium hexamethyldisilamide; NH4Cl: Ammonium chloride; MgSO4: Magnesium sulfate;

[0066] NaBr: Sodium bromide; NaI: Sodium iodide; KI: Potassium iodide; KBr: Potassium bromide;

[0067] Me4NI: Tetramethylammonium iodide; Me4NBr: Tetramethylammonium bromide; NH4I: Ammonium iodide.

[0068]

[0069] Example 1

[0070] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and formic acid (1.12 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h to obtain 5.75 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.92% and a yield of 89.16%.

[0071] Example 2

[0072] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and acetic acid (1.46 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h to obtain 5.83 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.84% and a yield of 90.40%.

[0073] Example 3

[0074] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and propionic acid (1.80 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h to obtain 5.86 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.98% and a yield of 90.87%.

[0075] Example 4

[0076] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and butyric acid (2.14 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h to obtain 5.69 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.86% and a yield of 88.23%.

[0077] Example 5

[0078] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), NH4I (0.53 g, 3.66 mmol), water (40 mL), and propionic acid (1.80 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of butanone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of butanone and dried under vacuum at 50 °C for 16 h to obtain 5.8 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.98% and a yield of 89.94%.

[0079] Example 6

[0080] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), NH4I (0.53 g, 3.66 mmol), water (40 mL), and propionic acid (1.80 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of pentanone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The crystals were filtered, and the solid was washed with 5 mL of pentanone. The solid was dried under vacuum at 50 °C for 16 h to obtain 5.66 g of solid. NMR analysis confirmed that the solid was compound (I) or its isomer, with a purity of 99.92% and a yield of 87.77%.

[0081] Comparative Example 1 (S-217622 synthesized according to the method disclosed in patent CN103153968A)

[0082] Compound (1) (5.0 g, 12.12 mmol), compound (2) (3.30 g, 18.19 mmol), acetic acid (10.92 g, 181.87 mmol), and tert-butanol (100 mL) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 24 h. After the reaction was complete, the reaction mixture was cooled to 25 °C and added to a saturated sodium bicarbonate solution (400 mL), and extracted with ethyl acetate (300 mL). The extract was washed with a saturated sodium bicarbonate solution (100 mL) and a saturated brine solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chloroform / methanol) to obtain a crude solid compound (I). This crude compound (I) was recrystallized from acetone / H₂O to obtain 2.5 g of solid. NMR analysis confirmed that the solid was compound I with a purity of 99.63% and a yield of 38.77%.

[0083] Comparative Example 2 (S-217622 synthesized according to the method disclosed in patent WO2022138988A1)

[0084] Compound (1) (300 mg, 0.727 mmol) and compound (2) (172 mg, 0.946 mmol) were placed in THF (6 mL) solvent, cooled to 0 °C, and LHMDS (1 M in THF; 1.46 mL, 1.46 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 2.5 h, then stirred at room temperature for 40 min. The reaction was then quenched with NH4Cl solution, extracted with EA, washed with organic phase salt, dried with MgSO4, concentrated under reduced pressure, and purified by column chromatography (chloroform / methanol, 0–20% methanol) to obtain crude compound (I). The crude compound (I) was then recrystallized from acetone / H2O to obtain brown solid I (95.3 mg, yield 25%).

[0085] Comparative Example 3 (the reaction system contains a relatively large proportion of water)

[0086] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (125 mL), and acetic acid (1.46 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 36 h. The reaction mixture was then cooled to 40 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 4 h to allow crystals to crystallize. The crystals were filtered, and the wet solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h. 5.46 g of solid was obtained. NMR analysis confirmed that the solid was compound (I) with a purity of 99.86% and a yield of 84.67%.

[0087] Comparative Example 4 (reaction temperature below 80℃)

[0088] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and acetic acid (1.46 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was then cooled to 25 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 4 h to allow crystals to crystallize. The crystals were filtered, and the wet solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h. 3.23 g of solid was obtained. NMR analysis confirmed that the solid was compound (I) with a purity of 98.76% and a yield of 50.09%.

[0089] Comparative Example 5 (crystallization temperature above 30℃)

[0090] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and acetic acid (1.46 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 40 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 4 h to allow crystals to crystallize. The crystals were filtered, and the wet solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h. 3.66 g of solid was obtained. NMR analysis confirmed that the solid was compound (I) with a purity of 99.96% and a yield of 56.75%.

[0091] Comparative Example 6 (crystallization temperature above 30℃)

[0092] Compound (1) (5.0 g, 12.12 mmol), compound (2) (2.86 g, 15.76 mmol), KI (0.6 g, 3.64 mmol), water (40 mL), and acetic acid (1.46 g, 24.25 mmol) were added sequentially to a 100 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was then cooled to 50 °C, and 40 mL of acetone was added. The mixture was kept at this temperature for 4 h to allow crystals to crystallize. The crystals were filtered, and the wet solid was washed with 5 mL of acetone and dried under vacuum at 50 °C for 16 h. 3.28 g of solid was obtained. NMR analysis confirmed that the solid was compound (I) with a purity of 99.98% and a yield of 50.86%.

[0093]

[0094] Example 7

[0095] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), water (60 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. The reaction mixture was cooled to 25 °C, and 60 ml of acetone was added. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The mixture was then filtered, and the wet solid was washed with 10 ml of acetone and dried under vacuum at 50 °C for 16 h. 14.66 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.92% and the yield is 93.30%.

[0096] Example 8

[0097] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), water (60 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. After the reaction was complete, the temperature was lowered to 25 °C, and 60 ml of ethyl acetate was added to each flask. The mixture was kept at this temperature for 2 h to allow crystallization. The mixture was then filtered, and the solid wet product was washed with 10 ml of ethyl acetate and dried under vacuum at 50 °C for 16 h. 14.80 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.96% and the yield is 94.19%.

[0098] Example 9

[0099] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), water (60 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. After the reaction was complete, the temperature was lowered to 25 °C, and 60 ml of isopropyl acetate was added to each flask. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The solid wet product was filtered, washed with 10 ml of isopropyl acetate, dried under vacuum, and then dried at 50 °C under vacuum for 16 h. 14.2 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.95% and the yield is 90.38%.

[0100] Example 10

[0101] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), tert-butanol (60 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. After the reaction was complete, the temperature was lowered to 25 °C, and 60 ml of acetone was added to each flask. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The solid wet product was filtered, washed with 10 ml of acetone, dried under vacuum, and then dried at 50 °C under vacuum for 16 h. 14.52 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.90% and the yield is 92.41%.

[0102] Example 11

[0103] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), water (60 ml), tert-butanol (20 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. After the reaction was complete, the temperature was lowered to 25 °C, and 60 ml of acetone was added to each flask. The mixture was kept at this temperature for 2 h to allow crystals to crystallize. The solid wet product was filtered, washed with 10 ml of acetone, dried under vacuum, and then dried at 50 °C under vacuum for 16 h. 14.3 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.95% and the yield is 91.01%.

[0104] Example 12

[0105] Compound (1) (10.0 g, 24.25 mmol), compound (2) (5.28 g, 29.10 mmol), KI (2.01 g, 12.12 mmol), water (60 ml), isopropanol (20 ml), and fumaric acid (3.10 g, 26.67 mmol) were added sequentially to a 250 mL reaction flask. The mixture was heated to 115 °C and stirred for 16 h. After the reaction was complete, the temperature was lowered to 25 °C, and 60 ml of acetone was added to each flask. The mixture was kept at this temperature for 2 h to allow crystallization. The mixture was then filtered, and the wet solid was washed with 10 ml of acetone and dried under vacuum at 50 °C for 16 h. 14.0 g of solid was obtained. Nuclear magnetic resonance (NMR) analysis showed that the obtained solid was compound (3) or its isomer. Its X-ray powder diffraction pattern is shown below. Figure 1 As shown, the purity is 99.88% and the yield is 89.10%.

[0106] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A process for the preparation of compound (I) comprising: Compound (1) and compound (2) are reacted in an aqueous solvent in the presence of an acid to prepare compound (I), The reaction of the compound (1) and the compound (2) is carried out in the presence of a first catalyst selected from at least one of NaI, KI and NH4I.

2. The method according to claim 1, wherein the weight volume ratio of compound (1) and water is 1 g:3 mL to 1 g:20 mL.

3. The method according to claim 1 or 2, wherein the acid is at least one selected from oxalic acid, citric acid, malic acid, tartaric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and / or the molar ratio of compound (1) and acid is 1:0.1 to 1:

30.

4. The method according to claim 3, wherein the molar ratio of compound (1) and acid is 1:1 to 1:

10.

5. The method according to claim 1 or 2, wherein the reaction temperature of compound (1) and compound (2) is 80℃ to 120℃.

6. The method according to claim 1 or 2, wherein the molar ratio of compound (1) and first catalyst is 1:0 to 1:

1.

7. The method of claim 1 or 2, the reaction of compound (1) and compound (2) further comprising work-up to yield compound (I), wherein, The post-treatment comprises: crystallization in a ketone solvent or an ester solvent; and / or the crystallization temperature is -10℃ to 30℃; and / or the weight volume ratio of compound (1) and the ketone solvent or the ester solvent is 1 g:3 mL to 1 g:15 mL.

8. The method according to claim 7, wherein the ketone solvent is at least one selected from acetone, butanone and pentanone.

9. The method according to claim 7, wherein the ester solvent is at least one selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and tert-butyl acetate.

10. A method of preparing compound (3) comprising: Compound (1), compound (2) and fumaric acid are one-pot reacted in an aqueous solvent to prepare compound (3): The one-pot reaction is carried out in the presence of a second catalyst, and the second catalyst is at least one selected from NaI and KI; and x is 0.1 to 10.

11. The method according to claim 10, wherein the molar ratio of compound (1) and fumaric acid is 1:0.1 to 1:

10.

12. The method according to claim 10, wherein the molar ratio of compound (1) and fumaric acid is 1:1 to 1:

10.

13. The method according to any one of claims 10 to 12, wherein the weight volume ratio of compound (1) and water is 1 g:3 mL to 1 g:20 mL.

14. The method according to any one of claims 10 to 12, wherein the weight volume ratio of compound (1) and water is 1 g:3 mL to 1 g:10 mL.

15. The method according to any one of claims 10 to 12, wherein the molar ratio of compound (1) and second catalyst is 1:0 to 1:

2.

16. The method according to any one of claims 10 to 12, wherein the reaction temperature of the one-pot reaction is 80℃ to 120℃.

17. The process according to any one of claims 10-12, wherein the one-pot reaction further comprises a work-up to obtain compound (3), wherein, The post-treatment comprises: crystallization in a ketone solvent or an ester solvent to obtain compound (3); and / or the crystallization temperature is -10℃ to 30℃; and / or the weight-to-volume ratio of the compound (1) to the ketone solvent or the ester solvent is 1 g:3 mL to 1 g:20 mL.

18. The method according to claim 17, wherein the ketone solvent is at least one selected from the group consisting of acetone, butanone, and pentanone.

19. The method according to claim 17, wherein the ester solvent is at least one selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, and tert-butyl acetate.

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