Preparation method of catalyst for synthesizing macavir intermediate and preparation method of intermediate

Abstract

The invention discloses a catalyst for synthesis of a macloxvir intermediate and a preparation method of the intermediate, and belongs to the technical field of pharmaceutical chemical synthesis. The catalyst is an HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst; under the combined action with sodium hypochlorite, methyl in 3-(benzyloxy)-2-methyl-4H-pyran-4-one can be oxidized into carboxyl with high selectivity, so that a target carboxylic acid structure is efficiently constructed. The preparation method of the intermediate comprises the following steps: synchronously pumping a mixed solution of a sodium hydroxide aqueous solution of maltol and acetonitrile and a benzyl chloride solution into a first microchannel reactor for a benzylation reaction to obtain a 3-(benzyloxy)-2-methyl-4H-pyran-4-one solution; then pumping the 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid solution and a sodium hypochlorite solution into a second micro-channel reactor for oxidation reaction to generate a 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid solution; and finally, separating out the product through an acidification process, and filtering and recrystallizing to obtain the macarovir intermediate with the purity of 99.9%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a catalyst for the synthesis of mabaloxavir intermediates and a method for preparing the intermediates. Background Technology

[0002] Influenza viruses belong to the Orthomyxoviridae family and are enveloped pathogens. They can cause not only annual seasonal epidemics but also periodic global pandemics. Among the various influenza viruses, types A and B can infect the human respiratory tract, leading to acute respiratory syndromes (ARDS) with high morbidity and transmissibility. It is estimated that there are approximately 1 billion seasonal influenza infections globally each year, with 3 to 5 million severe cases and between 290,000 and 650,000 deaths due to related respiratory complications. As a pathogen that continues to cause significant health burdens and economic impacts, influenza remains a serious challenge to global public health.

[0003] Mabaloxavir, marketed as Xofluza, is an endonuclease inhibitor that acts on the acidic (PA) protein of the influenza virus polymerase. Developed by Shionogi & Co., Ltd., it was approved for adult use in Japan in February 2018 under the "pioneer review" system by the Medical Device Evaluation and Approval Agency (PMDA). In October of the same year, it received approval from the U.S. Food and Drug Administration (FDA), and in 2020, its use was expanded to include acute uncomplicated influenza in individuals aged 5 years and older. The core structure of this drug relies on the key starting material 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. Since 2022, the market price of this raw material has climbed to over $800 per kilogram. Given the burden of 3 to 5 million severe influenza cases globally each year, developing economical and scalable synthetic processes for Compound 1 has become an important direction for reducing the cost of antiviral drugs and improving drug accessibility.

[0004] Currently, there are many reported synthetic routes for 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, which can be mainly divided into the following categories: Pace et al. used benzylated maltol as a raw material, successively oxidizing the methyl group to an aldehyde group with selenium dioxide and further oxidizing it to a carboxylic acid with sodium chlorite to obtain the target product. However, this route requires the use of highly toxic selenium dioxide, and the reaction conditions are harsh, requiring a reaction at 150°C for 12 hours, accompanied by the release of malodorous gases, posing safety and environmental risks and making it difficult to scale up production. Luo Shipeng et al. used nitrogen oxides as a catalyst, reacting bromobenzene at 160°C with oxygen for 20 hours to achieve the conversion of the methyl group to an aldehyde group, followed by oxidation with ammonium persulfate to obtain a carboxylic acid. This route not only has high catalyst costs and long reaction times, but also poses a risk of combustion and explosion due to the high temperature and oxygen purging, making it unfeasible for industrial application.

[0005] Aoyama et al. synthesized the target product via a four-step reaction involving bis(trimethylsilylamine)lithium-promoted aldehyde-alcohol condensation, dehydration, oxidative cleavage, and TEMPO / NaClO oxidation. However, this method requires a low-temperature reaction of -65°C and uses expensive reagents such as rhodium trichloride and sodium periodate, as well as highly toxic methanesulfonyl chloride, making the process complex, costly, and difficult to apply practically. Similarly, the -50°C halogenation route proposed by Li Wensen et al. also suffers from the problem of stringent low-temperature requirements and lacks industrialization potential.

[0006] Sun Guangxiang et al. used benzylated maltol as a raw material, synthesized the target carboxylic acid through the formation of an enamine intermediate and subsequent oxidative cleavage with sodium periodate. While Huang, Wang Zhongqing, and others optimized the reaction conditions or used olefin-forming reagents such as trimethyl orthoformate, they still required large amounts of sodium periodate, resulting in high material costs and a lack of price competitiveness. Furthermore, Ye Weiping et al. used furfuryl alcohol as a raw material, synthesizing the target product through chlorine rearrangement, formaldehyde nucleophilic substitution, and oxidation steps, but this involved highly toxic substances such as chlorine and formaldehyde, limiting its industrial application. Li Guangxu's NaIO4 / CrO3 oxidation system also presents serious environmental pollution problems and does not meet the requirements of green chemistry.

[0007] In summary, existing synthetic routes generally suffer from problems such as high material costs, high toxicity, heavy pollution, harsh reaction conditions, poor safety, and difficulty in scale-up. Therefore, developing a low-cost, safe, environmentally friendly process for the preparation of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid suitable for industrial production is of great practical significance. Summary of the Invention

[0008] The purpose of this invention is to provide a catalyst for the synthesis of mabaloxavir intermediates, in order to solve the problems of high price, toxicity, harsh operating conditions and low reaction selectivity of catalysts used in the prior art.

[0009] The present invention also aims to provide a method for preparing an intermediate of the antiviral drug mabaloxavir, in order to solve the problems of high material cost, high toxicity, heavy pollution, and inability to scale up production in the existing synthetic route of mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0010] In a first aspect, the present invention provides a catalyst for the synthesis of mabaloxavir intermediates, wherein the catalyst is an iron / tungsten-based catalyst supported on HZSM-5 spherical molecular sieves. The raw materials for the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst include HZSM-5 spherical molecular sieve and iron / tungsten salt in a mass ratio of (20-50):1. The loading amount of the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst is not less than 30% of the maltol mass.

[0011] By adopting the above technical solution, the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst for the synthesis of mabaloxavir intermediates is prepared by using HZSM-5 spherical molecular sieves and iron / tungsten salts. Loading iron / tungsten salts onto the HZSM-5 spherical molecular sieve significantly increases the specific surface area of ​​active sites, improving catalytic efficiency and stability. Simultaneously, utilizing the shape selectivity of the molecular sieve, it effectively promotes the efficient and selective conversion of methyl groups to carboxyl groups in benzylated maltol, avoiding over-oxidation or the formation of byproducts. Using a mass ratio of (20–50):1 for HZSM-5 spherical molecular sieves and iron / tungsten salts ensures high dispersion of the active metal components on the support, avoiding insufficient activity due to low loading and preventing aggregation of active sites due to excessive loading. This achieves effective cost control while maintaining high catalytic activity.

[0012] Preferably, the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst is prepared by the following method: HZSM-5 spherical molecular sieves are added to a hot aqueous solution of iron / tungsten salt at 70-100℃, shaken, concentrated to remove the solvent, and the solid is obtained. After calcination, it is sieved to obtain the final product.

[0013] Preferably, the iron salt is ferric ammonium oxalate and the tungsten salt is ammonium paratungstate; the mass ratio of the iron salt to the tungsten salt is 1:(3-6).

[0014] More preferably, the mass ratio of HZSM-5 spherical molecular sieve to iron salt / tungsten salt is 30:1; the mass ratio of iron salt to tungsten salt is 1:5.

[0015] Preferably, the calcination temperature is 600–800℃.

[0016] More preferably, the calcination temperature is 700°C.

[0017] Preferably, the sieve mesh size is 12 mesh.

[0018] Secondly, the present invention also provides a method for preparing a mabaloxavir intermediate, comprising the following steps: S1. Maltol and the first solvent are added to an alkaline sodium hydroxide solution to obtain reaction solution A. Benzyl chloride is dissolved in the second solvent to obtain reaction solution B. Reaction solutions A and B are pumped into the first microchannel reactor to react and obtain benzylated maltol reaction solution. S2. The sodium hypochlorite solution and benzylated maltol reaction solution are pumped into the second microchannel reactor to react and obtain the crude effluent of intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. S3. After removing sodium hypochlorite, the solution is obtained by vacuum concentration, extraction, acidification of the aqueous phase, filtration, and recrystallization. The second microchannel reactor is loaded with an iron / tungsten-based catalyst supported by HZSM-5 spherical molecular sieves.

[0019] By adopting the above technical solution, the specific process for synthesizing the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to the present invention is as follows: Under alkaline conditions, maltol and benzyl chloride undergo a nucleophilic substitution reaction to obtain a benzylated maltol (intermediate 2) reaction solution, and the reaction process is shown below:

[0020] Subsequently, under the action of HZSM-5 supported iron / tungsten-based catalyst and sodium hypochlorite oxidant, the methyl group in intermediate 2 is oxidized to a carboxyl group, yielding crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The reaction process is shown below:

[0021] Preferably, in step S1, the concentration of maltol is 0.1-0.3 mol / L, the concentration of benzyl chloride is 0.1-0.3 mol / L, and the molar ratio of alkaline solution to maltol is (1.2-1.5):1.

[0022] More preferably, in step S1, the concentration of maltol is 0.2 mol / L; the concentration of benzyl chloride is 0.2 mol / L; and the molar ratio of sodium hydroxide alkaline solution to maltol is 1.3:1.

[0023] Preferably, in step S1, the first solvent is a mixture of acetonitrile and water in a volume ratio of (1-2):1; the second solvent includes one of tetrahydrofuran, acetonitrile, 1,4-dioxane or acetone.

[0024] More preferably, the first solvent is a mixture of acetonitrile and water in a volume ratio of 1:1; the second solvent is tetrahydrofuran.

[0025] Preferably, in step S2, the concentration of sodium hypochlorite is 0.3–0.9 mol / L.

[0026] More preferably, in step S2, the concentration of sodium hypochlorite is 0.6 mol / L.

[0027] Preferably, in step S3, the solvent for recrystallization includes isopropanol, n-butanol, and ethanol.

[0028] More preferably, isopropanol is used as the solvent for recrystallization.

[0029] Preferably, step S3 is as follows: quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with a reducing agent selected from sodium sulfite aqueous solution, sodium bisulfite aqueous solution, and sodium thiosulfate aqueous solution; remove the organic solvent by vacuum distillation at 40-60°C; extract the aqueous phase with ethyl acetate or methyl tert-butyl ether; after separating and removing the organic phase, adjust the pH of the aqueous phase to 2-4 with 1-3 M hydrochloric acid; filter out the solid; dissolve the solid by heating it to reflux with 6-20 times its weight of isopropanol, n-propanol, or ethanol; stop stirring; allow it to cool naturally to crystallize, thus obtaining pure 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0030] More preferably, step S3 is as follows: quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with an aqueous sodium sulfite solution, remove the organic solvent by vacuum distillation at 50°C, extract the aqueous phase with ethyl acetate, separate and remove the organic phase, adjust the pH of the aqueous phase to 3 with 2 M hydrochloric acid, filter out the solid, dissolve the solid by heating it to reflux with 10 times its weight of isopropanol, stop stirring, allow it to cool naturally and crystallize, thus obtaining pure 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0031] Preferably, the pumping rate of both the maltol solution and the benzyl chloride solution is 1.0–5.0 mL / min; and the pumping rate of both the benzylated maltol reaction solution and the sodium hypochlorite solution is 1.2–5.5 mL / min.

[0032] More preferably, the pumping rate of both maltol solution and benzyl chloride solution is 2.0 mL / min; and the pumping rate of sodium hypochlorite solution is 3.0 mL / min.

[0033] Preferably, the temperature of the first microchannel reactor is 10–40°C; and the temperature of the second microchannel reactor is 70–90°C.

[0034] More preferably, the temperature of the first microchannel reactor is 30°C; and the temperature of the second microchannel reactor is 80°C.

[0035] Preferably, the pressure of the first microchannel reactor is 1.0–3.0 MPa; and the pressure of the second microchannel reactor is 1.0–5.0 MPa.

[0036] More preferably, the pressure of the first microchannel reactor is 2.0 MPa; and the pressure of the second microchannel reactor is 5.0 MPa.

[0037] The beneficial effects of this invention are: 1. This invention provides a catalyst for the synthesis of mabaloxavir intermediates, which can efficiently oxidize the methyl group in benzylated maltol to a carboxyl group. This novel catalyst is reported for the first time both domestically and internationally, solving the problem of limited methods for selectively oxidizing allyl methyl groups to carboxyl groups, and providing a reliable guarantee for the industrial production of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0038] 2. This invention provides a method for synthesizing an intermediate of the antiviral drug mabaloxavir using a microfluidic reactor, filling a gap in existing technologies for the synthesis of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. This method significantly simplifies the reaction process, effectively reduces production costs, significantly improves reaction efficiency, shortens reaction time, and yields a high-purity 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid product with a high liquid phase purity (HPLC) of 99.9%, meeting the requirements of green and modern production. Attached Figure Description

[0039] Figure 1 This is a schematic diagram of the process for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid using a microfluidic reactor according to the present invention. Figure 2 The proton nuclear magnetic resonance spectrum of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in this invention ( 1 H-NMR); Figure 3 The high-performance liquid chromatography (HPLC) chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 1; Figure 4 List of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 1; Figure 5 HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 2; Figure 6 List of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 2; Figure 7 The HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 3; Figure 8 List of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 3; Figure 9 The HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 4; Figure 10 List of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 4; Figure 11 The HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 5; Figure 12 List of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 5; Figure 13 The HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in comparison; Figure 14 A list of peaks from the HPLC chromatogram of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in comparison. Figure 15 The infrared spectrum of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared in Example 1. Detailed Implementation

[0040] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below.

[0041] A catalyst for the synthesis of mabaloxavir intermediates, wherein the catalyst is an iron / tungsten-based catalyst supported on HZSM-5 spherical molecular sieves; The raw materials for the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst include HZSM-5 spherical molecular sieve and iron / tungsten salt in a mass ratio of (20-50):1.

[0042] By adopting the above technical solution, the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst for the synthesis of mabaloxavir intermediates is prepared by using HZSM-5 spherical molecular sieves and iron / tungsten salts. Loading iron / tungsten salts onto the HZSM-5 spherical molecular sieve significantly increases the specific surface area of ​​active sites, improving catalytic efficiency and stability. Simultaneously, utilizing the shape selectivity of the molecular sieve, it effectively promotes the efficient and selective conversion of methyl groups to carboxyl groups in benzylated maltol, avoiding over-oxidation or the formation of byproducts. Using a mass ratio of (20–50):1 for HZSM-5 spherical molecular sieves and iron / tungsten salts ensures high dispersion of the active metal components on the support, avoiding insufficient activity due to low loading and preventing aggregation of active sites due to excessive loading. This achieves effective cost control while maintaining high catalytic activity.

[0043] More preferably, the mass ratio of HZSM-5 spherical molecular sieve to iron salt / tungsten salt is 30:1, which can achieve the optimal dispersion state and catalytic performance balance of iron / tungsten active components.

[0044] In some embodiments, the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst is prepared by the following method: HZSM-5 spherical molecular sieves are added to a hot aqueous solution of iron / tungsten salt at 70-100℃, shaken, concentrated to remove the solvent, and the solid is obtained. After calcination, it is sieved to obtain the final product.

[0045] By loading iron / tungsten salts onto HZSM-5 spherical molecular sieves through calcination, the iron and tungsten precursors can be transformed into highly active metal oxide forms, which can synergize with the acidic sites of the molecular sieve. At the same time, the calcination process can remove organic matter and moisture from the surface of the support, enhance the mechanical strength and thermal stability of the catalyst, and make it suitable for continuous reaction environments in microchannel reactors.

[0046] In some embodiments, the iron salt is ferric ammonium oxalate and the tungsten salt is ammonium paratungstate; the mass ratio of iron salt to tungsten salt is 1:(3-6); the mass ratio of iron salt to tungsten salt is 1:5; the iron / tungsten combination in this ratio has a synergistic catalytic effect in the catalytic oxidation reaction. Ferric ammonium oxalate and ammonium paratungstate, as precursors, have thermal decomposition products that can efficiently activate sodium hypochlorite oxidant to achieve specific oxidation of methyl groups.

[0047] In some embodiments, the calcination temperature is 600–800°C; more preferably, the calcination temperature is 700°C. This temperature range ensures complete decomposition of the precursor salts and the formation of a stable active oxide phase, while preventing damage to the molecular sieve framework structure due to excessively high temperatures. 700°C is the temperature at which the catalyst achieves its highest specific surface area and optimal surface acidity.

[0048] In some embodiments, the sieve mesh size is 12 mesh; sieving fine particles through a 12-mesh filter can ensure the uniformity of catalyst particles, avoid clogging in the microchannel reactor, and improve the mechanical strength of the catalyst, thereby improving catalytic activity.

[0049] A method for preparing a mabaloxavir intermediate includes the following steps: S1. Maltol and the first solvent are added to an alkaline sodium hydroxide solution to obtain reaction solution A. Benzyl chloride is dissolved in the second solvent to obtain reaction solution B. Reaction solutions A and B are pumped into the first microchannel reactor to react and obtain benzylated maltol reaction solution. S2. The sodium hypochlorite solution and benzylated maltol reaction solution are pumped into the second microchannel reactor to react and obtain the crude effluent of intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. S3. After removing sodium hypochlorite, the solution is obtained by vacuum concentration, extraction, acidification of the aqueous phase, filtration, and recrystallization. The second microchannel reactor is loaded with an iron / tungsten-based catalyst supported by HZSM-5 spherical molecular sieves.

[0050] By adopting the above technical solution, the specific process for synthesizing the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid according to the present invention is as follows: Under alkaline conditions, maltol and benzyl chloride undergo a nucleophilic substitution reaction to obtain a benzylated maltol (intermediate 2) reaction solution, and the reaction process is shown below:

[0051] Subsequently, under the action of HZSM-5 supported iron / tungsten-based catalyst and sodium hypochlorite oxidant, the methyl group in intermediate 2 is oxidized to a carboxyl group, yielding crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The reaction process is shown below:

[0052] Finally, the crude effluent of the intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid was purified to obtain high-purity 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The synthesis method of this invention not only avoids the use of highly toxic and expensive reagents in existing technologies, optimizing reaction conditions from high temperature and high pressure or ultra-low temperature to a milder range, but also achieves continuous and automated operation of the reaction through the combination of a microchannel reactor and a dedicated catalyst, significantly improving production efficiency and process safety, and laying a solid foundation for large-scale industrial production.

[0053] In some embodiments, in step S1, the concentration of maltol is 0.1–0.3 mol / L, the concentration of benzyl chloride is 0.1–0.3 mol / L, and the molar ratio of sodium hydroxide alkaline solution to maltol is (1.2–1.5):1; more preferably, in step S1, the concentration of maltol is 0.2 mol / L, the concentration of benzyl chloride is 0.2 mol / L, and the molar ratio of alkaline solution to maltol is 1.3:1.

[0054] In some embodiments, in step S1, the first solvent is a mixed solvent of acetonitrile and water in a volume ratio of (1-2):1; the second solvent includes one of tetrahydrofuran, acetonitrile, 1,4-dioxane or acetone; more preferably, the first solvent is a mixed solvent of acetonitrile and water in a volume ratio of 1:1; the second solvent is tetrahydrofuran; this mixed solvent system can effectively dissolve the reactants, ensure the homogeneity of the reaction system, and facilitate rapid liquid-liquid mixing and reaction in the microchannel.

[0055] In some embodiments, in step S2, the concentration of sodium hypochlorite is 0.3 to 0.9 mol / L; more preferably, in step S2, the concentration of sodium hypochlorite is 0.6 mol / L; the above-mentioned range of oxidant concentration can provide sufficient oxidative equivalent while avoiding excessive oxidation of the product or side reactions caused by excessively high local concentration, and 0.6 mol / L is the optimal balance point between oxidation efficiency and selectivity.

[0056] In some embodiments, in step S3, the recrystallization solvent includes isopropanol, n-butanol, and ethanol; more preferably, the recrystallization solvent is isopropanol; by using, for example, isopropanol as the recrystallization solution, impurities in the crude product can be effectively dissolved, and the target product has good solubility at high temperatures, and can be efficiently precipitated when cooled, thereby obtaining a product with high purity and ideal crystal form.

[0057] In some embodiments, step S3 is as follows: quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with a reducing agent selected from sodium sulfite aqueous solution, sodium bisulfite aqueous solution, and sodium thiosulfate aqueous solution; remove the organic solvent by vacuum distillation at 40-60°C; extract the aqueous phase with ethyl acetate or methyl tert-butyl ether; after separating and removing the organic phase, adjust the pH of the aqueous phase to 2-4 with 1-3 M hydrochloric acid; filter out the solid; dissolve the solid by heating it to reflux with 6-20 times its weight of isopropanol, n-propanol, or ethanol; stop stirring; allow it to cool naturally to crystallize, thus obtaining pure 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. More preferably, step S3 is as follows: quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with an aqueous sodium sulfite solution, remove the organic solvent by vacuum distillation at 50°C, extract the aqueous phase with ethyl acetate, separate and remove the organic phase, adjust the pH of the aqueous phase to 3 with 2 M hydrochloric acid, filter out the solid, dissolve the solid by heating it to reflux with 10 times its weight of isopropanol, stop stirring, allow it to cool naturally and crystallize, thus obtaining pure 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0058] By adopting the above purification method, residual oxidants, inorganic salts, and trace organic impurities that may be generated during the reaction can be completely removed. By precisely controlling the acidification pH value, the product is ensured to precipitate completely in the form of free acid. Then, it is further purified by recrystallization with isopropanol, and finally a high-quality product with a liquid phase purity of over 99.9% is obtained.

[0059] In some embodiments, the pumping rates of the maltol solution and benzyl chloride solution are both 1.0–5.0 mL / min; the pumping rates of the benzylated maltol reaction solution and sodium hypochlorite solution are both 1.2–5.5 mL / min; more preferably, the pumping rates of the maltol solution and benzyl chloride solution are both 2.0 mL / min; and the pumping rate of the sodium hypochlorite solution is both 3.0 mL / min. The optimized pumping rates ensure that the reactants have a precise stoichiometric ratio and sufficient residence time in the microchannel, thereby guaranteeing high conversion and high selectivity of each step of the reaction.

[0060] In some embodiments, the temperature of the first microchannel reactor is 10–40°C; the temperature of the second microchannel reactor is 70–90°C; more preferably, the temperature of the first microchannel reactor is 30°C; the temperature of the second microchannel reactor is 80°C; the S1 reaction is carried out at 30°C, which can ensure a sufficient reaction rate and effectively control side reactions; the S2 oxidation reaction is carried out at 80°C, which provides the best energy conditions for catalyst activation of oxidant and deep oxidation of methyl groups, and significantly shortens the reaction time.

[0061] In some embodiments, the pressure of the first microchannel reactor is 1.0 to 3.0 MPa; the pressure of the second microchannel reactor is 1.0 to 5.0 MPa, more preferably, the pressure of the first microchannel reactor is 2.0 MPa; the pressure of the second microchannel reactor is 5.0 MPa. Applying a certain system pressure helps to suppress the vaporization of the solvent at higher temperatures, maintain the reaction system in a stable liquid phase state, ensure the smooth progress of continuous production, and at the same time, the high-pressure environment is also conducive to promoting gas-liquid mass transfer.

[0062] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0063] Preparation Example

[0064] Preparation Example 1: A catalyst for the synthesis of mabaloxavir intermediates was obtained by the following preparation method: 0.5 g of ferric ammonium oxalate and 2.5 g of ammonium paratungstate were weighed and dissolved in 200 mL of hot water at 80 °C. 90 g of HZSM-5 spherical molecular sieve was added, and after shaking and concentration to remove the solvent, a solid molecular sieve was obtained. Next, the solid molecular sieve was calcined in a muffle furnace at 700 °C for 20 hours, cooled to room temperature under argon protection, and fine particles were removed by sieving through a 12-mesh filter to obtain the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst.

[0065] Preparation Example 2: A catalyst for the synthesis of mabaloxavir intermediates was obtained by the following preparation method: 0.5 g of ferric ammonium oxalate and 3.0 g of ammonium paratungstate were weighed and dissolved in 200 mL of 80 °C hot water. 175 g of HZSM-5 spherical molecular sieve was added, and after shaking and concentration to remove the solvent, a solid molecular sieve was obtained. Next, the solid molecular sieve was calcined in a muffle furnace at 800 °C for 20 hours, cooled to room temperature under argon protection, and fine particles were removed by sieving through a 12-mesh filter to obtain the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst.

[0066] Preparation Example 3: A catalyst for the synthesis of mabaloxavir intermediates was obtained by the following preparation method: 0.5 g of ferric ammonium oxalate and 1.5 g of ammonium paratungstate were weighed and dissolved in 200 mL of 80 °C hot water. 40 g of HZSM-5 spherical molecular sieve was added, and after shaking and concentration to remove the solvent, a solid molecular sieve was obtained. Next, the solid molecular sieve was calcined in a muffle furnace at 600 °C for 20 hours, cooled to room temperature under argon protection, and fine particles were removed by sieving through a 12-mesh filter to obtain the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst. Example Example 1: A mabaloxavir intermediate was obtained by the following preparation method: S1. Dissolve 0.65 mol sodium hydroxide in 1.25 L water, then add 1.25 L acetonitrile and 0.5 mol maltol sequentially, and stir thoroughly to obtain reaction solution A; dissolve 0.5 mol benzyl chloride in 2.5 L tetrahydrofuran to obtain reaction solution B. Pump reaction solutions A and B simultaneously into the first microchannel reactor at the same rate of 2.0 mL / min to carry out the benzylation reaction. The temperature of the first microchannel reactor is 30℃ and the pressure is 2.0 MPa, to obtain the benzylated maltol reaction solution, i.e., the solution of intermediate 2. S2. A 10% sodium hypochlorite solution was diluted with water to 0.6 mol / L to obtain reaction solution C. Reaction solution C and the reaction solution of intermediate 2 were simultaneously pumped into the second microchannel reactor at the same rate of 3.0 mL / min for oxidation reaction. The packing material of the second microchannel reactor was the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst prepared in Preparation Example 1, and the packing amount was 40% of the maltol mass. The temperature of the second microchannel reactor was 80℃ and the pressure was 3.0 MPa, and crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid was obtained, which is the crude solution of target molecule 3. S3. Quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with saturated sodium sulfite aqueous solution. Recover acetonitrile and tetrahydrofuran by vacuum distillation at 50°C. Extract the aqueous phase with 10 kg of ethyl acetate. After separating and removing the organic phase, adjust the pH of the aqueous phase to 3 with 2M hydrochloric acid. Stir at 20°C for 30 minutes, filter out the solid, and dissolve the solid in 1.2 kg of isopropanol by heating to reflux. Stop stirring and allow it to cool naturally to 20°C to crystallize. Filter out the solid and dry it in a forced-air oven at 60°C for 12 hours to obtain 102 g of pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0067] Detected by high performance liquid chromatography, from Figure 3 and Figure 4 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 99.98%, the overall yield of the two-step reaction is 83%, and the maximum single impurity content is 0.02%.

[0068] Example 2, a mabaloxavir intermediate, was obtained by the following preparation method: S1. Dissolve 0.75 mol sodium hydroxide in 1.25 L water, then add 1.25 L acetonitrile and 0.5 mol maltol sequentially, and stir thoroughly to obtain reaction solution A; dissolve 0.5 mol benzyl chloride in 1.66 L tetrahydrofuran to obtain reaction solution B. Pump reaction solutions A and B simultaneously into the first microchannel reactor at the same rate of 5.0 mL / min to carry out the benzylation reaction. The temperature of the first microchannel reactor is 40 °C and the pressure is 3.0 MPa, to obtain the benzylated maltol reaction solution, i.e., the solution of intermediate 2. S2. A 10% sodium hypochlorite solution was diluted with water to 0.9 mol / L to obtain reaction solution C. Reaction solution C and the reaction solution of intermediate 2 were simultaneously pumped into the second microchannel reactor at the same rate of 5.5 mL / min for oxidation reaction. The packing material of the second microchannel reactor was the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst prepared in Preparation Example 1, and the packing amount was 40% of the maltol mass. The temperature of the second microchannel reactor was 90℃ and the pressure was 5.0 MPa, and crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid was obtained, which is the crude solution of target molecule 3. S3. Quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with saturated sodium sulfite aqueous solution. Recover acetonitrile and tetrahydrofuran by vacuum distillation at 60℃. Extract the aqueous phase with 10 kg of ethyl acetate. After separating and removing the organic phase, adjust the pH of the aqueous phase to 4 with 3M hydrochloric acid. Stir at 20℃ for 30 minutes, filter out the solid, and dissolve the solid in 2.0 kg of isopropanol by heating to reflux. Stop stirring and allow it to cool naturally to 20℃ to crystallize. Filter out the solid and dry it in a forced-air oven at 60℃ for 12 hours to obtain 80 g of pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0069] Detected by high performance liquid chromatography, from Figure 5 and Figure 6 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 99.97%, the overall yield of the two-step reaction is 65%, and the maximum single impurity content is 0.026%.

[0070] Example 3, a mabaloxavir intermediate, was obtained by the following preparation method: S1. Dissolve 0.60 mol sodium hydroxide in 2.5 L of water, then add 2.5 L of acetonitrile and 0.5 mol maltol sequentially, and stir thoroughly to obtain reaction solution A; dissolve 0.5 mol benzyl chloride in 5 L of tetrahydrofuran to obtain reaction solution B. Pump reaction solutions A and B into the first microchannel reactor at the same rate of 1.0 mL / min simultaneously to carry out the benzylation reaction. The temperature of the first microchannel reactor is 10 °C and the pressure is 1.0 MPa, to obtain the benzylated maltol reaction solution, i.e., the solution of intermediate 2. S2. A 10% sodium hypochlorite solution was diluted with water to 0.3 mol / L to obtain reaction solution C. Reaction solution C and the reaction solution of intermediate 2 were simultaneously pumped into the second microchannel reactor at the same rate of 1.2 mL / min for oxidation reaction. The packing material of the second microchannel reactor was the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst prepared in Preparation Example 1, and the packing amount was 40% of the maltol mass. The temperature of the second microchannel reactor was 70℃ and the pressure was 1.0 MPa, and crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid was obtained, which is the crude solution of target molecule 3. S3. Quench the residual sodium hypochlorite in the crude effluent of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid with saturated sodium sulfite aqueous solution. Recover acetonitrile and tetrahydrofuran by vacuum distillation at 40°C. Extract the aqueous phase with 20 kg of ethyl acetate. After separating and removing the organic phase, adjust the pH of the aqueous phase to 2 with 1 M hydrochloric acid. Stir at 20°C for 30 minutes, filter out the solid, and dissolve the solid in 0.6 kg of isopropanol by heating to reflux. Stop stirring and allow it to cool naturally to 20°C to crystallize. Filter out the solid and dry it in a forced-air oven at 60°C for 12 hours to obtain 73 g of pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0071] Detected by high performance liquid chromatography, from Figure 7 and Figure 8 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 99.94%, the overall yield of the two-step reaction is 59%, and the maximum single impurity content is 0.027%.

[0072] Example 4, a mabaloxavir intermediate, differs from Example 1 only in that the catalyst prepared in Example 2 is used instead of the catalyst in Example 1, yielding 87 g of pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0073] Detected by high performance liquid chromatography, from Figure 9 and Figure 10 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 99.83%, the overall yield of the two-step reaction is 71%, and the maximum single impurity content is 0.05%.

[0074] Example 5, a mabaloxavir intermediate, differs from Example 1 only in that the catalyst prepared in Example 3 is replaced with the same amount of catalyst prepared in Example 3, yielding 93 g of pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0075] Detected by high performance liquid chromatography, from Figure 11 and Figure 12 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 99.59%, the overall yield of the two-step reaction is 77%, and the maximum single impurity content is 0.41%.

[0076] Comparative Example

[0077] Comparative Example 1, a mabaloxavir intermediate, was obtained by the following preparation method: 0.65 mol sodium hydroxide was dissolved in 1.25 L of water, followed by the addition of 1.25 L of acetonitrile and 0.5 mol maltol. The mixture was stirred thoroughly, and then 2.5 L of tetrahydrofuran solution containing 0.5 mol benzyl chloride was slowly added dropwise. The reaction was carried out at an internal temperature of 30 °C for 3 hours. Next, 20 g of the HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst prepared in Example 1 and 5 L of a 0.6 mol / L sodium chlorate aqueous solution were added sequentially, and the reaction was carried out at an internal temperature of 80 °C for 72 hours. The solution was cooled to 10°C, and the residual sodium hypochlorite in the reaction solution was quenched with a saturated sodium sulfite aqueous solution. Acetonitrile and tetrahydrofuran were recovered by vacuum distillation at 50°C. The aqueous phase was extracted with 10 kg of ethyl acetate. After separating and removing the organic phase, the pH of the aqueous phase was adjusted to 3 with 2 M hydrochloric acid. After stirring at room temperature for 30 minutes, the solid was filtered off. The solid was dissolved by heating with 1.2 kg of isopropanol to reflux. Stirring was stopped, and the solution was allowed to cool naturally to 20°C to crystallize. The solid was filtered off and dried in a forced-air oven at 60°C for 12 hours to obtain pure mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid.

[0078] Detected by high performance liquid chromatography, from Figure 13 and Figure 14 It can be seen that the purity of the mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is 95.26%, the overall yield of the two-step reaction is 24%, and the maximum single impurity content is 2.16%.

[0079] Performance testing

[0080] 1. 1 ¹H-NMR analysis was performed on the purified 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid from Example 1. 1 H-NMR detection, spectrum as shown in Figure 2 As shown; 2. Purity and yield determination: The purity and yield of Examples 1 to 5 and Comparative Example 1 were calculated using HPLC; the results are shown in Table 1. 3. Fourier transform infrared spectroscopy detection: The purified 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid from Example 1 was detected by infrared spectroscopy using the potassium bromide pellet method. The results are as follows: Figure 15 As shown.

[0081] Table 1. Calculation results of purity and yield

[0082] from Figure 2 and Figure 15 It is known that the substance synthesized in this invention is 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, and the specific peaks in its NMR spectrum are as follows: δ 8.20 (d, J = 5.6 Hz, 1H), 7.48–7.42 (m, 2H), 7.39–7.30 (m, 3H), 6.54 (d, J = 5.6 Hz, 1H), 5.11 (s, 2H).

[0083] Figure 1 This is a schematic diagram of the process for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid using a microfluidic reactor according to the present invention.

[0084] Combining Table 1 and Figures 3 to 14 It can be seen that the purity of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared by the present invention can reach 99.98%, and the total yield can reach 83%; while the purity of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid prepared by the conventional batch synthesis method in the comparative example is only 95.26%, and the total yield is only 24%.

[0085] The results above show that the method for synthesizing mabaloxavir intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid using the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst and microfluidic reactor provided by this invention can significantly improve the reaction efficiency of mabaloxavir intermediate synthesis. Compared with the traditional batch synthesis method, this method not only significantly improves the yield and reduces the amount of by-products, but also yields 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid product with higher purity.

[0086] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A catalyst for the synthesis of mabaloxavir intermediates, characterized in that, The catalyst is an iron / tungsten-based catalyst supported by HZSM-5 spherical molecular sieves. The raw materials for the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst include HZSM-5 spherical molecular sieve and iron / tungsten salt in a mass ratio of (20-50):

1.

2. The catalyst for the synthesis of mabaloxavir intermediates according to claim 1, characterized in that, The HZSM-5 spherical molecular sieve-supported iron / tungsten-based catalyst was prepared by the following method: HZSM-5 spherical molecular sieves are added to a hot aqueous solution of iron / tungsten salt at 70-100℃, shaken, concentrated to remove the solvent, and the solid is obtained. After calcination, it is sieved to obtain the final product.

3. The catalyst for the synthesis of mabaloxavir intermediates according to claim 1, characterized in that, The iron salt is ferric ammonium oxalate, and the tungsten salt is ammonium paratungstate; the mass ratio of the iron salt to the tungsten salt is 1:(3-6).

4. A method for preparing a mabaloxavir intermediate, using the catalyst for the synthesis of mabaloxavir intermediates as described in any one of claims 1-3, characterized in that, Includes the following steps: S1. Maltol and the first solvent are added to an alkaline sodium hydroxide solution to obtain reaction solution A. Benzyl chloride is dissolved in the second solvent to obtain reaction solution B. Reaction solutions A and B are pumped into the first microchannel reactor to react and obtain benzylated maltol reaction solution. S2. The sodium hypochlorite solution and benzylated maltol reaction solution are pumped into the second microchannel reactor to react and obtain the crude effluent of intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. S3. After removing sodium hypochlorite, the solution is obtained by vacuum concentration, extraction, acidification of the aqueous phase, filtration, and recrystallization. The second microchannel reactor is loaded with an iron / tungsten-based catalyst supported by HZSM-5 spherical molecular sieves. The loading amount of the HZSM-5 spherical molecular sieve supported iron / tungsten-based catalyst is not less than 30% of the maltol mass.

5. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, In step S1, the concentration of maltol is 0.1–0.3 mol / L; the concentration of benzyl chloride is 0.1–0.3 mol / L; and the molar ratio of the sodium hydroxide alkaline solution to maltol is (1.2–1.5):

1.

6. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, In step S1, the first solvent is a mixture of acetonitrile and water in a volume ratio of (1-2):1; the second solvent includes one of tetrahydrofuran, acetonitrile, 1,4-dioxane or acetone.

7. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, In step S2, the concentration of sodium hypochlorite is 0.3–0.9 mol / L.

8. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, The pumping rates of the maltol solution and benzyl chloride solution are both 1.0–5.0 mL / min; the pumping rates of the benzylated maltol reaction solution and sodium hypochlorite solution are both 1.2–5.5 mL / min.

9. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, The temperature of the first microchannel reactor is 10–40°C; the temperature of the second microchannel reactor is 70–90°C.

10. The method for preparing a mabaloxavir intermediate according to claim 4, characterized in that, The pressure of the first microchannel reactor is 1.0–3.0 MPa; the pressure of the second microchannel reactor is 1.0–5.0 MPa.

Images