Process for the preparation of molipiravir

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of Mupiravir. The selected synthesis route is simple in operation and simplifies the post-reaction treatment steps. After the reaction is completed, the organic phase is separated from the aqueous solution of hydroxylamine sulfate and sodium acetate, the recovery rate of the solvent can be maximized due to the absence of dangerous hydroxylamine sulfate, more importantly, the decomposition of hydroxylamine sulfate is avoided, the production safety is higher, the production is green and environmentally friendly, and the method is more suitable for the popularization of industrialized safe mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for the safe production of mupiravir intermediate ((3AR,4R,6R,6AR)-6-(4-(hydroxyamino)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate (compound 1) and a method for preparing mupiravir. Background Technology

[0002] Mupiravir is a nucleoside analogue. Its plasma esterase metabolites work by interfering with RNA synthesis, causing a high mutation rate in viral gene synthesis and ultimately leading to viral death. Because RNA polymerases are structurally relatively conserved in RNA viruses, and this drug targets RNA polymerases, it is effective against various variants. Studies have shown that its activity in inhibiting SARS-CoV-2 replication is 3-10 times higher than that of remdesivir, and it has demonstrated activity in multiple preclinical models of SARS-CoV-2 infection prevention, treatment, and transmission prevention.

[0003] ((3AR,4R,6R,6AR)-6-(4-(hydroxyamino)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate is an important intermediate (compound 1) of the antiviral drug mupiravir, CAS No.: 2346620-55-9, molecular formula: C 16 H 23 N3O7, structural formula as follows:

[0004]

[0005] The literature V. Gopalsamuthiram et al. reported a two-step synthesis of methyl isobutyrate ((3AR,4R,6R,6AR)-6-(4-(hydroxyamino)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl) from protected cytidine. The second reaction step uses 70% isopropanol-water as solvent, with 3.2 eq of hydroxylamine sulfate. The reaction is carried out at 72-73℃ for 17 hours. After the reaction is completed, the solvent is removed by concentration, acetonitrile is added, and the excess hydroxylamine sulfate is removed by filtration. The filtrate is concentrated to obtain a crude product. Toluene is then added for azeotropic dehydration and crystallization to obtain a white solid with a purity of 94% and a yield of 96%. This method has several problems: (1) The second reaction step uses an excess of hydroxylamine sulfate. The theoretical reaction requires 1 eq, but the actual amount used is 3.2 eq; (2) After the reaction is completed, the solvent is removed by concentration, which produces a large amount of hydroxylamine sulfate, which is very unsafe during concentration; (3) The product is dissolved in acetonitrile, and then the excess hydroxylamine sulfate is removed by filtration. There is no treatment plan, which is also unsafe.

[0006] The Material Safety Data Sheet (MSDS) for hydroxylamine sulfate states that it is corrosive, irritating, and a strong reducing agent; it decomposes upon heating, forming a corrosive and explosive fumes. An 8% aqueous solution of hydroxylamine sulfate will explode upon heating to 90°C. The spill response section states: isolate the contaminated area and restrict access. Emergency responders should wear full-face dust masks and acid / alkali resistant clothing. Collect the spilled substance with a clean shovel into a dry, clean, covered container and transfer it to a safe location. Alternatively, flush with plenty of water; dilute the wash water and dispose of it in the wastewater system. In case of a large spill, collect and recover the spilled substance or transport it to a waste treatment facility for disposal.

[0007] Because the reaction of hydroxylamine sulfate is excessive by 2.2 eq, the problems in (2) and (3) above are very unsafe in industrial production and are not suitable for industrial production.

[0008] Patent WO2019113462 (Chinese Patent Publication No. CN111372592A, Publication Date: 2020.07.03) discloses the synthesis of methyl isobutyrate ((3AR,4R,6R,6AR)-6-(4-(hydroxyamino)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl) in three steps using protected cytidine as a raw material. The second reaction step uses acetonitrile as solvent, adds 1,2,4-triazole and N,N-diethylethylamine, stirs and dissolves, cools to 0℃ and then adds phosphorus oxychloride to react under argon conditions, adds water to terminate the reaction, concentrates, extracts and washes with dichloromethane, concentrates, etc., and obtains a solid after silica gel chromatography concentration; the third step dissolves the intermediate in isopropanol, adds hydroxylamine hydrochloride to react, after the reaction is completed, removes some solvent at ambient temperature and 45℃ high vacuum, dissolves in ethyl acetate, washes the solution, dries with a drying agent, concentrates to obtain oil for crystallization; the filtered solid is washed with diethyl ether to obtain a white solid product. This method has several problems: (1) According to the "Regulations on the Safety Management of Hazardous Chemicals", phosphorus oxychloride used in the second step is controlled by the public security department and is a highly toxic substance with toxicity similar to phosgene. (2) It must be reacted at 55℃ in a sealed pressure tube, indicating that the reaction needs to be under positive pressure conditions. (3) Hydroxylamine hydrochloride is greatly in excess in the reaction, reaching 10-30 eq. (4) Post-processing: rotary evaporation concentration, passing through silica gel column, the undissolved hydroxylamine is attached to diatomaceous earth or silica gel; only the amount of feed is small, improper handling of excessive hydroxylamine hydrochloride is equivalent to leakage, and if the production volume is increased, it will bring great safety hazards. (5) The reaction crystallization and washing use diethyl ether with a boiling point of 34.5℃. Since the boiling point is low and close to room temperature, it is not conducive to industrial production operation and solvent recovery.

[0009] In addition, the above-mentioned use of hydroxylamine hydrochloride involves an over-feeding of the reaction material by tens of times; hydroxylamine hydrochloride has reducing properties, and although the MSDS does not mention the instability of the solution at high temperatures, it clearly states that the handling procedures for leaks are the same as those for hydroxylamine sulfate; therefore, there are also significant safety hazards in production, which is not conducive to large-scale industrial production. Summary of the Invention

[0010] The technical problem solved by the present invention is to provide a method for the safe production of mupiravir intermediate ((3AR,4R,6R,6AR)-6-(4-(hydroxyamino)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate (compound 1).

[0011] This invention is achieved through the following technical solution:

[0012] A method for safely producing mupiravir intermediates includes the following steps:

[0013]

[0014] The above-mentioned method for safely producing mupiravir intermediates includes the following steps:

[0015] (1) Preparation of compound 3:

[0016] Solvent was added to the reaction vessel, and compound 2, DMAP, organic base and isobutyric anhydride were added under stirring. After the reaction was completed, water was added and stirred until homogeneous. The mixture was separated and the organic phase was concentrated to obtain compound 3.

[0017] (2) Preparation of compound 1:

[0018] Isopropanol and water were added to the reaction vessel of compound 3 and stirred to dissolve. Then hydroxylamine sulfate and anhydrous sodium acetate were added, and the reaction was heated until compound 3 was completely reacted. The mixture was separated. The upper organic phase was concentrated to recover isopropanol. After concentration, water was added and stirred to form a slurry. The mixture was cooled to crystallize, centrifuged, and the wet product was dried to obtain the intermediate ((3AR,4R,6R,6AR)-6-(4-(hydroxylamine)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate (compound 1).

[0019] Among them, the compound marked with 2 below the structural formula represents compound 2, the compound marked with 3 below the structural formula represents compound 3, and the compound marked with 1 below the structural formula represents compound 1.

[0020] The solvent in step (1) is 1,2-dichloroethane, and the mass ratio of the amount of 1,2-dichloroethane to the amount of compound 2 is 2.0-8.0:1.

[0021] The organic base mentioned in step (1) is triethylamine, and the mass ratio of the amount of triethylamine to the amount of compound 2 is 0.40-1.33:1.

[0022] The reaction temperature described in step (1) is 10-40℃.

[0023] The mass ratio of compound 2, DMAP and isobutyric anhydride used in step (1) is 350:1.14-5.69:145.7-440.0.

[0024] The mass ratio of the amount of hydroxylamine sulfate used in step (2) to the amount of compound 2 is 0.43-1.29:1.

[0025] The mass ratio of the amount of anhydrous sodium acetate used in step (2) to the amount of compound 2 is 0.11-0.32:1.

[0026] The reaction temperature of the heating reaction in step (2) is 75-85℃.

[0027] The mass ratio of the amount of isopropanol and water used in step (2) to the amount of compound 2 is 1.0-3.0:1.0-5.0:1.

[0028] The lower liquid obtained in step (2) is an excess of hydroxylamine sulfate and sodium acetate solution, which is combined with the centrifuged mother liquor from step (2) and then transferred to the environmental protection station for treatment.

[0029] A method for preparing mupiravir includes the following steps:

[0030]

[0031] The above-mentioned method for preparing mupiravir includes the following steps:

[0032] (1) Preparation of compound 3:

[0033] Solvent was added to the reaction vessel, and compound 2, DMAP, organic base and isobutyric anhydride were added under stirring. After the reaction was completed, water was added and stirred until homogeneous. The mixture was separated and the organic phase was concentrated to obtain compound 3.

[0034] (2) Preparation of compound 1:

[0035] Isopropanol and water were added to the reaction vessel of compound 3 and stirred to dissolve. Then hydroxylamine sulfate and anhydrous sodium acetate were added, and the reaction was heated until compound 3 was completely reacted. The mixture was separated. The upper organic phase was concentrated to recover isopropanol. After concentration, water was added and stirred to form a slurry. The mixture was cooled to crystallize, centrifuged, and the wet product was dried to obtain the intermediate ((3AR,4R,6R,6AR)-6-(4-(hydroxylamine)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate (compound 1).

[0036] (3) Preparation of mupiravir

[0037] Dichloromethane was added to the reaction vessel, followed by compound 1. The temperature was lowered to -5 to 0°C, and concentrated hydrochloric acid was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction of compound 1 was completed, deionized water was added at a controlled temperature of 0 to 5°C, followed by slow dropwise addition of 26% ammonia solution. The pH of the solution was adjusted to approximately 7.5. After confirming that the pH remained unchanged, the stirring was stopped, and the solution was allowed to stand for half an hour. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, separated, and concentrated. Deionized water was added, and the solution was heated to dissolve, decolorized with activated carbon, filtered, and then slowly cooled to 0 to 10°C to crystallize. The crystals were centrifuged, and the wet product was dried to obtain mupiravir.

[0038] In the above method for preparing mupiravir, the mass ratio of dichloromethane used in step (3) to compound 1 is 3.0-8.0:1.

[0039] The mass ratio of water used in step (3) to compound 1 is 2.0-5.0:1.

[0040] When the ethyl acetate is extracted twice in step (3), the amount of ethyl acetate used in the first extraction is 6 times the mass of compound 1, and the amount of ethyl acetate used in the second extraction is 4 times the mass of compound 1.

[0041] Solution treatment scheme for hydroxylamine sulfate and sodium acetate:

[0042] The hydroxylamine sulfate and sodium acetate brine layers from Examples 1-4 were combined with the centrifuged mother liquor from step (2) and transferred to the environmental protection station reactor. After adding anhydrous ferric chloride, the solution was heated and 27% hydrogen peroxide was added dropwise. After the addition was complete, a sample was taken to test the hydroxylamine sulfate content, which was less than 0.5%. After stirring for 30 minutes, another sample was taken to test the content, which remained unchanged. The solution with a hydroxylamine sulfate content of less than 0.5% was no longer dangerous. The solution was then transferred to electrocoagulation and triple-effect treatment before entering the wastewater biochemical treatment plant, and then transferred to the wastewater treatment plant.

[0043] In the technical solution of this invention, DMAP is an abbreviation for 4-dimethylaminopyridine. The concentrated hydrochloric acid is a hydrochloric acid solution with a mass percentage concentration of 36%-38%. The concentrated ammonia solution is an ammonia solution with a mass percentage concentration of 25%-28%. The hydrogen peroxide solution has a mass percentage concentration of 26-28%.

[0044] Beneficial technical effects:

[0045] The synthetic route selected in this invention is simple to operate and simplifies the post-reaction processing steps. After the reaction is completed, the organic phase is separated to remove hydroxylamine sulfate and sodium acetate aqueous solution, which is free of hazardous hydroxylamine sulfate. This maximizes the solvent recovery rate and, more importantly, avoids the decomposition of hydroxylamine sulfate, making the production safer and more environmentally friendly, and more suitable for the promotion of safe large-scale industrial production.

[0046] 1. The present invention provides a method for the safe production of mupiravir intermediates. The selected synthetic route eliminates the need for the use of highly toxic phosphorus oxychloride and avoids the generation of phosphorus-containing mother liquor, thereby greatly reducing the cost of subsequent environmental treatment.

[0047] 2. The present invention provides a method for the safe production of mupiravir intermediates, which only requires about 1.5 times the theoretical amount of hydroxylamine sulfate to completely convert the raw materials, avoiding the use of dozens of times the amount of hydroxylamine hydrochloride as described in the literature. It also eliminates the dangerous concentration and filtration steps in the presence of large amounts of hydroxylamine sulfate, making it more conducive to safe industrial production.

[0048] 3. The present invention provides a method for the safe production of mupiravir intermediates that does not require the use of sealed pressure tubes for the reaction, but can be carried out at atmospheric pressure, which reduces the requirements for equipment and is more suitable for safe industrial production.

[0049] 4. The present invention provides a safe method for producing mupiravir intermediates, eliminating the step of removing hydroxylamine hydrochloride using diatomaceous earth or silica gel columns after concentration. Simultaneously, it eliminates the use of diethyl ether and rinsing steps in the crystallization process, avoiding the volatilization of low-boiling-point solvents, making production safer and more controllable.

[0050] 5. The present invention provides a method for the safe production of mupiravir intermediates. In step (1), the recovered solvent can be reused in the next batch of production, which improves the solvent recovery and reuse rate and makes the production process more green and environmentally friendly.

[0051] 6. A method for the safe production of mupiravir intermediate according to the present invention, wherein after the reaction in step (2) is completed, the liquid is separated; the upper organic layer can recover the organic solvent to the greatest extent because of the non-hazardous hydroxylamine sulfate, and the recovered solvent can be recycled in the next batch of production without purification. The lower layer is a brine layer of hydroxylamine sulfate and sodium acetate; it is transferred to the environmental protection station for treatment, and after meeting the standards, it is transferred to the sewage treatment plant.

[0052] 7. The present invention provides a method for the safe production of mupiravir intermediates, with a liquid phase purity greater than 99.2% and a molar yield of over 82.1%; the obtained mupiravir intermediates have high liquid phase purity and yield; due to solvent recovery and recycling, raw material costs and production costs are lower, and the safety of production and post-processing operations is improved, making it more suitable for large-scale industrial safe production. Detailed Implementation

[0053] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention, but it is not intended to limit the present invention.

[0054] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. It can also be implemented or applied through other different specific embodiments. Various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0055] Furthermore, it should be understood that the one or more method steps mentioned in this invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise stated. Moreover, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not intended to limit the order of the method steps or to limit the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the invention.

[0056] Example 1:

[0057] Under nitrogen protection, 1050 kg of 1,2-dichloroethane was injected into a 3000 L reactor, followed by 350 kg of compound 2, 2 kg of DMAP, and 235 kg of triethylamine. The mixture was stirred until homogeneous. 220 kg of isobutyric anhydride was added while maintaining the temperature at 10-40 °C, and the reaction of compound 2 was monitored until complete. 300 kg of deionized water was added, and the mixture was stirred at 20-30 °C for half an hour. The mixture was separated, and the organic phase was concentrated to recover 1,2-dichloroethane, yielding compound 3. 700 kg of deionized water and 700 kg of 95% ethanol were added to the reactor containing compound 3. While stirring, 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added. The temperature was slowly increased to 75-80 °C until the reaction of compound 3 was complete. The mixture was separated into liquid and liquid layers. The lower layer was a brine layer of hydroxylamine sulfate and sodium acetate. The upper alcohol layer was concentrated under reduced pressure at 50-60℃ to recover 800-900 kg of solvent. Then, 800 kg of deionized water was added to the reactor, and the mixture was stirred and slurried for 2 hours. After cooling to 20-30℃, the mixture was centrifuged. After drying the wet product, 279.8 kg of compound 1 was obtained as a dry product, with a molar yield of 82.1% and a liquid phase purity of 99.61%.

[0058] Solvent recovery and reuse:

[0059] 1. The recovered 1,2-dichloroethane was dried with sodium sulfate, filtered, and directly reused in the next batch of compound 3 production.

[0060] 2. The recovered ethanol, containing approximately 20% water, can be directly reused in the next batch of compound 1 production.

[0061] 3. The separated lower layer of hydroxylamine sulfate and sodium acetate brine contains a slight excess of hydroxylamine sulfate, which is then combined with the centrifuged mother liquor of compound 1; and then transferred to the environmental protection station for treatment according to Example 6. After meeting the standards, it is transferred to the sewage treatment plant.

[0062] Example 2:

[0063] Under nitrogen protection, 1050 kg of 1,2-dichloroethane was injected into a 3000 L reactor, followed by 350 kg of compound 2, 2 kg of DMAP, and 235 kg of triethylamine. The mixture was stirred until homogeneous. 220 kg of isobutyric anhydride was added at a controlled temperature of 10-40 °C, and the reaction of compound 2 was monitored until complete. 300 kg of deionized water was added, and the mixture was stirred at a controlled temperature of 20-30 °C for half an hour. The mixture was separated, and the organic phase was concentrated to recover 1,2-dichloroethane, yielding compound 3. 700 kg of deionized water and 700 kg of isopropanol were added to the reactor containing compound 3. 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased to 80-85 °C until the reaction of compound 3 was complete. The mixture was separated into liquid and liquid layers. The lower layer was a brine layer of hydroxylamine sulfate and sodium acetate. The upper alcohol layer was concentrated under reduced pressure at 50-60℃ to recover 800-900 kg of solvent. Then, 800 kg of deionized water was added to the reactor, and the mixture was stirred and slurried for 2 hours. After cooling to 20-30℃, the mixture was centrifuged. After drying the wet product, 284.5 kg of compound 1 was obtained as dry product, with a molar yield of 83.5% and a liquid phase purity of 99.52%.

[0064] Solvent recovery and reuse:

[0065] 1. The recovered 1,2-dichloroethane was dried with sodium sulfate, filtered, and directly reused in the next batch of compound 3 production.

[0066] 2. The recovered isopropanol, containing approximately 20% water, was directly reused in the next batch of compound 1 production.

[0067] 3. The separated lower layer of hydroxylamine sulfate and sodium acetate brine contains a slight excess of hydroxylamine sulfate, which is then combined with the centrifuged mother liquor of compound 1; and then transferred to the environmental protection station for treatment according to Example 6. After meeting the standards, it is transferred to the sewage treatment plant.

[0068] Example 3:

[0069] Under nitrogen protection, 1050 kg of 1,2-dichloroethane was injected into a 3000 L reactor, followed by 350 kg of compound 2, 2 kg of DMAP, and 235 kg of triethylamine. The mixture was stirred until homogeneous. 220 kg of isobutyric anhydride was added at a controlled temperature of 10-40 °C, and the reaction of compound 2 was monitored until complete. 300 kg of deionized water was added, and the mixture was stirred at a controlled temperature of 20-30 °C for half an hour. The mixture was separated, and the organic phase was concentrated to recover 1,2-dichloroethane, yielding compound 3. 700 kg of deionized water and 700 kg of isopropanol were added to the reactor containing compound 3. 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased to 80-85 °C until the reaction of compound 3 was complete. The mixture was separated into liquid and liquid layers. The lower layer was a brine layer of hydroxylamine sulfate and sodium acetate. The upper alcohol layer was concentrated under reduced pressure at 60-70℃ to recover 900-1000 kg of solvent. Then, 900 kg of deionized water was added to the reactor, and the mixture was stirred and slurried for 2 hours. After cooling to 20-30℃, the mixture was centrifuged. After drying the wet product, 290.7 kg of compound 1 was obtained as a dry product, with a molar yield of 85.3% and a liquid phase purity of 99.26%.

[0070] Solvent recovery and reuse:

[0071] 1. The recovered 1,2-dichloroethane was dried with sodium sulfate, filtered, and directly reused in the next batch of compound 3 production.

[0072] 2. The recovered isopropanol, containing approximately 25% water, was directly reused in the next batch of compound 1 production.

[0073] 3. The separated lower layer of hydroxylamine sulfate and sodium acetate brine contains a slight excess of hydroxylamine sulfate, which is then combined with the centrifuged mother liquor of compound 1; and then transferred to the environmental protection station for treatment according to Example 6. After meeting the standards, it is transferred to the sewage treatment plant.

[0074] Example 4 (Reuse of Recycled Solvent):

[0075] Under nitrogen protection, 950 kg of 1,2-dichloroethane recovered in Example 1 and 100 kg of fresh 1,2-dichloroethane were added to a 3000 L reactor. Then, 350 kg of Compound 2, 2 kg of DMAP, and 235 kg of triethylamine were added and stirred until homogeneous. At a controlled temperature of 10-40 °C, 220 kg of isobutyric anhydride was added, and the reaction of Compound 2 was monitored until complete. 300 kg of deionized water was added, and the mixture was stirred at 20-30 °C for half an hour. The mixture was separated, and the organic phase was concentrated to recover 1,2-dichloroethane, yielding Compound 3. 600 kg of deionized water and 860 kg of isopropanol recovered in Example 2 were added to the reactor containing Compound 3. While stirring, 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added. The temperature was slowly increased to 80-85 °C until the reaction of Compound 3 was complete. The mixture was separated into liquid and liquid layers. The lower layer was a brine layer of hydroxylamine sulfate and sodium acetate. The upper alcohol layer was concentrated under reduced pressure at 50-60℃ to recover 800-900 kg of solvent. Then, 800 kg of deionized water was added to the reactor, and the mixture was stirred and slurried for 2 hours. After cooling to 20-30℃, the mixture was centrifuged. After drying the wet product, 288.3 kg of compound 1 was obtained as dry product, with a molar yield of 84.6% and a liquid phase purity of 99.45%.

[0076] Solvent recovery and reuse:

[0077] 1. The recovered 1,2-dichloroethane was dried with sodium sulfate, filtered, and directly reused in the next batch of compound 3 production.

[0078] 2. The recovered isopropanol, containing approximately 20% water, was directly reused in the next batch of compound 1 production.

[0079] 3. The separated lower layer of hydroxylamine sulfate and sodium acetate brine contains a slight excess of hydroxylamine sulfate, which is then combined with the centrifuged mother liquor of compound 1; and then transferred to the environmental protection station for treatment according to Example 6. After meeting the standards, it is transferred to the sewage treatment plant.

[0080] Example 5: Preparation of mupiravir:

[0081] 1. Reaction formula:

[0082]

[0083] 2. Reaction procedure:

[0084] 2000 kg of dichloromethane was added to a reactor, followed by 400 kg of compound 1. The mixture was cooled to -5 to 0°C, and 216 kg of concentrated hydrochloric acid was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction of compound 1 was complete, 400 kg of deionized water was added while maintaining the temperature at 0 to 5°C. Then, 170 kg of 26% ammonia solution was slowly added dropwise to adjust the pH of the solution to approximately 7.5. After confirming that the pH remained unchanged, stirring was stopped, and the mixture was allowed to stand for half an hour. The aqueous phase was extracted twice with 2400 kg and 1600 kg of ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phase was then separated, concentrated, and 800 kg of deionized water was added. The mixture was heated to dissolve, decolorized with activated carbon, and then slowly cooled to 0 to 10°C to crystallize for 2 hours. After centrifugation, the wet product was dried to obtain 281.4 kg of mupiravir with a purity of 99.92% and a molar yield of 78.9%.

[0085] Example 6: Treatment scheme for hydroxylamine sulfate and sodium acetate solution:

[0086] The hydroxylamine sulfate and sodium acetate brine layers from Examples 1-4 were combined with the centrifuged mother liquor of Compound 1 and transferred to the environmental protection station's reactor. 4.5 kg of anhydrous ferric chloride was added to the reactor with stirring. After dissolving, the solution was heated to 40°C, and 27% hydrogen peroxide was added dropwise. The rate of addition of 27% hydrogen peroxide was controlled to maintain the solution temperature at 40-60°C. After the addition was complete, the reaction was stirred for 2 hours. A sample was taken to test the hydroxylamine sulfate content, which was less than 0.5%. After stirring for 30 minutes, another sample was taken, and the content remained unchanged. Approximately 160 kg of 27% hydrogen peroxide was used in total. The solution with a hydroxylamine sulfate content of less than 0.5% was deemed non-hazardous. The solution was then transferred to electrocoagulation and triple-effect treatment before entering the wastewater biological treatment plant, and finally to the wastewater treatment plant.

[0087] The above embodiments are for illustrating the implementation schemes disclosed in this invention and should not be construed as limiting the invention. Furthermore, various modifications listed herein, as well as variations in methods and compositions, will be apparent to those skilled in the art without departing from the scope and spirit of this invention. Although the invention has been specifically described in conjunction with various specific preferred embodiments, it should be understood that the invention should not be limited to these specific embodiments. In fact, various modifications as described above that are obvious to those skilled in the art to obtain the invention should be included within the scope of this invention.

Claims

1. A method for preparing mupiravir, comprising the following steps: ； (1) Preparation of compound 3: Solvent is added to the reaction vessel, and compound 2, DMAP and organic base are added under stirring. Isobutyric anhydride is added while the temperature is controlled at 10-40℃. After the reaction is completed, water is added and stirred evenly. The liquid is separated and the organic phase is concentrated to obtain compound 3. The solvent mentioned in step (1) is 1,2-dichloroethane, and the mass ratio of the amount of 1,2-dichloroethane to the amount of compound 2 is 2.0-8.0:

1. (2) Preparation of compound 1: Isopropanol and water were added to the reaction vessel of compound 3 and stirred to dissolve. Then hydroxylamine sulfate and anhydrous sodium acetate were added, and the reaction was heated until compound 3 was completely reacted. The mixture was separated. The upper organic phase was concentrated to recover isopropanol. After concentration, water was added and stirred to form a slurry. The mixture was cooled to crystallize, centrifuged, and the wet product was dried to obtain the intermediate ((3AR,4R,6R,6AR)-6-(4-(hydroxylamine)-2-oxadiazine-1(2H)-methyl)-2,2-dimethyltetrahydrofuran[3,4-D][1,3]dioxo-4-yl)methyl isobutyrate. The mass ratio of the amount of hydroxylamine sulfate used in step (2) to the amount of compound 2 used was 0.43-1.29:

1. (3) Preparation of mupiravir Dichloromethane was added to the reaction vessel, followed by compound 1. The temperature was lowered to -5 to 0°C, and concentrated hydrochloric acid was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After the reaction of compound 1 was completed, deionized water was added at a controlled temperature of 0 to 5°C, followed by slow dropwise addition of 26% ammonia solution. The pH of the solution was adjusted to 7.

5. After confirming that the pH remained unchanged, the stirring was stopped, and the solution was allowed to stand for half an hour. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, separated, and concentrated. Deionized water was added, and the solution was heated to dissolve, decolorized with activated carbon, filtered, and then slowly cooled to 0 to 10°C to crystallize. The crystals were centrifuged, and the wet product was dried to obtain mupiravir.

2. The method of preparing of Mupirivir according to claim 1, wherein, The organic base mentioned in step (1) is triethylamine, and the mass ratio of the amount of triethylamine to the amount of compound 2 is 0.40-1.33:

1.

3. The method of preparing of Mupirivir according to claim 1, wherein, The reaction temperature in step (1) is 10-40℃.

4. The method of preparing of Mupirivir according to claim 1, wherein, The mass ratio of compound 2, DMAP and isobutyric anhydride used in step (1) is 350:1.14-5.69:145.7-440.

0.

5. The method of preparing of Mupirivir according to claim 1, wherein, The mass ratio of the amount of anhydrous sodium acetate used in step (2) to the amount of compound 2 is 0.11-0.32:

1.

6. The method of preparing of Mupirivir according to claim 1, wherein, The reaction temperature of the heating reaction in step (2) is 75-85℃.

7. The method of preparing Mplavif according to claim 1, wherein The mass ratio of dichloromethane used in step (3) to compound 1 is 3.0-8.0:

1.

8. The method of preparing Mplavil according to claim 1, wherein, The mass ratio of water used in step (3) to compound 1 is 2.0-5.0:

1.

9. The method of preparing Mplavif according to claim 1, wherein, When the ethyl acetate is extracted twice in step (3), the amount of ethyl acetate used in the first extraction is 6 times the mass of compound 1, and the amount of ethyl acetate used in the second extraction is 4 times the mass of compound 1.

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