A method of preparing molipiravir
The one-pot synthesis route simplifies the operation, reduces the types of solvents and recycling, and solves the problems of cumbersome operation and high cost in the preparation of mupiravir intermediates. It achieves high purity and high yield, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- 山东诚汇双达药业有限公司
- Filing Date
- 2022-11-30
- Publication Date
- 2026-06-02
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to 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] On August 9, 2021, Merck's oral antiviral drug mupiravir was granted provisional approval by the Australian Therapeutic Goods Administration (TGA), becoming the world's first approved oral antiviral drug for COVID-19. In November 2021, oral mupiravir was approved for marketing in the UK for the treatment of mild to moderate COVID-19 patients at high risk of severe illness and hospitalization. On December 23, the US Food and Drug Administration (FDA) approved emergency use authorization for mupiravir for the treatment of mild to moderate COVID-19 in patients aged 18 years and older. On March 23, 2022, the Korean Ministry of Food and Drug Safety granted emergency use authorization for Merck's oral antiviral drug mupiravir.
[0004] ((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:
[0005]
[0006] 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) using protected cytidine as a starting material. Acetonitrile was used as the solvent and DBU was used as the base. The purity of the reaction solution was 35%. After the reaction, the intermediate was purified by column chromatography with dichloromethane and then purified with 5% methanol in chloroform to obtain an intermediate with a yield of 78%. The next 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 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 expensive DBU is used as the base in the first reaction step; (2) The purity of the reaction solution is low, only 35%, and column chromatography is required for post-processing, followed by purification with a mixed solvent; (3) The second reaction step uses an excess of hydroxylamine sulfate, requiring acetonitrile to dissolve the product and then filtration to remove insoluble salts; (4) The purity and yield of the product obtained by azeotropic dehydration with toluene are not high; (5) The excess hydroxylamine sulfate is unstable when heated, making production scale-up unsafe; (6) The reaction solvent cannot be recovered and reused.
[0007] Patent WO2019113462 (Chinese Patent Publication No. CN111372592A, Publication Date: 2020.07.03) discloses a three-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) isobutyrate using protected cytosine as a raw material. In the first step, isobutyric anhydride is used for acylation. After the reaction is completed, the mixture is concentrated, dissolved in 600 ml of ethyl acetate, washed twice with sodium bicarbonate solution, water, and brine, respectively. The organic matter is dried with sodium sulfate and concentrated to obtain a colorless oil. The second step uses acetonitrile as the reaction 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 with isopropanol, adds hydroxylamine to react, after the reaction is completed, removes some solvent at ambient temperature and high vacuum at 45℃, dissolves with ethyl acetate, washes the solution, dries with a drying agent, concentrates to obtain oil for crystallization; the filtered solid is washed with ether to obtain a white solid product. This method has several problems: (1) the first step involves concentration, dissolution and repeated washing with multiple aqueous solutions, which is cumbersome; (2) the second step requires the use of phosphorus oxychloride, and the wastewater generated is difficult to treat in an environmentally friendly biochemical manner; (3) the post-processing uses silica gel chromatography for purification; (4) the third step requires high vacuum concentration; (5) after solvent extraction and washing, it is also necessary to wash with ether to remove impurities, which is cumbersome. (6) The reaction uses a variety of solvents such as ethyl acetate, acetonitrile, dichloromethane, isopropanol, and diethyl ether, which are not conducive to recycling and reuse, resulting in high raw material costs.
[0008] Overall, the existing methods for preparing 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)isobutyrate, to some extent, limit the widespread application of this project. Summary of the Invention
[0009] The present invention aims to at least partially solve one of the technical problems in the related art.
[0010] Based on existing technologies, the inventors have addressed the aforementioned technical problems and provided a method for preparing mupiravir. This method features a simple synthetic route, streamlined post-reaction processing steps, reduced solvent usage, elimination of multi-step column chromatography purification, and solvent recycling. It also boasts low raw material and production costs, generates less mother liquor, and is more environmentally friendly. The resulting mupiravir intermediate exhibits high liquid-phase purity and yield, making it more suitable for large-scale industrial production.
[0011] This invention is achieved through the following technical solution:
[0012] A one-pot method for preparing mupiravir intermediates includes the following steps:
[0013]
[0014] 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.
[0015] The one-pot method for preparing mupiravir intermediates described above includes the following steps:
[0016] S1: Add solvent to the reaction vessel, add compound 2, DMAP and organic base under stirring, add isobutyric anhydride while controlling the temperature at 10-50℃, add water after the reaction is complete, and stir evenly to obtain a solution of compound 3.
[0017] S2: Add hydroxylamine sulfate and anhydrous sodium acetate to the solution of compound 3, heat to 20-90℃ and react until compound 3 has reacted completely, cool down to crystallize, centrifuge and dry the wet product to obtain 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).
[0018] In the above-described one-pot method for preparing mupiravir intermediates, the solvent is one or more of dichloromethane, 1,2-dichloroethane, n-hexane, and cyclohexane.
[0019] Preferably, the solvent is dichloromethane, and the mass ratio of dichloromethane to compound 2 is 2.0-8.0:1; more preferably 3.0-6.0:1.
[0020] The organic base is one or more of diethylamine, triethylamine, and diisopropylethylamine.
[0021] Preferably, the organic base is triethylamine. The mass ratio of triethylamine to compound 2 is 0.40-1.33:1, preferably 0.5-0.9:1.
[0022] The temperature at which isobutyric anhydride is added is 20-40℃, and the temperature at which the reaction is raised until compound 3 is completely reacted is 30-85℃.
[0023] The mass ratio of the added hydroxylamine sulfate to compound 2 is 0.43-1.29:1, and the mass ratio of the added anhydrous sodium acetate to compound 2 is 0.11-0.32:1.
[0024] The mass ratio of water to compound 2 is 3.0-8.0:1; preferably 4.0-6.0:1.
[0025] A method for preparing mupiravir includes the following steps:
[0026]
[0027]
[0028] The above-mentioned method for preparing mupiravir includes the following steps:
[0029] (1) Preparation of 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);
[0030] S1: Add solvent to the reaction vessel, add compound 2, DMAP and organic base under stirring, add isobutyric anhydride at 10-50℃, add water after the reaction is complete, stir evenly to obtain a solution of compound 3; S2: Add hydroxylamine sulfate and anhydrous sodium acetate to the solution of compound 3, heat to 20-90℃ and react until compound 3 is completely reacted, cool down to crystallize, centrifuge and dry the wet product to obtain 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);
[0031] (2) Preparation of mupiravir
[0032] 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.
[0033] In the above-mentioned method for preparing mupiravir, the mass ratio of dichloromethane to compound 1 is 3.0-8.0:1.
[0034] The mass ratio of water to compound 1 is 2.0-5.0:1.
[0035] When the ethyl acetate was extracted twice, the amount of ethyl acetate used in the first extraction was 6 times the mass of compound 1, and the amount of ethyl acetate used in the second extraction was 4 times the mass of compound 1.
[0036] In the technical solution of this invention, the concentrated hydrochloric acid is a hydrochloric acid solution with a mass percentage concentration of 36%-38%. DMAP is an abbreviation for 4-dimethylaminopyridine.
[0037] Beneficial technical effects:
[0038] (1) The one-pot method for preparing mupiravir intermediates of the present invention has a simple synthetic route, simplifies post-reaction processing steps, reduces the types of solvents used, lowers raw material and production costs, produces less mother liquor, and is more environmentally friendly. The obtained 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)isobutyrate methyl ester has high liquid phase purity and yield, making it more suitable for large-scale industrial production. The resulting mupiravir intermediate has a liquid phase purity of over 99.9% and a yield of 78.9%.
[0039] (2) The one-pot method for preparing mupiravir intermediates of the present invention uses an organic solvent that is immiscible with water in step S1, which solves the problem of the high water content of the solvent acetonitrile, making it difficult to recover and reuse. After the reaction is completed, water is added directly to carry out the next reaction, eliminating the need for organic phase concentration of solvent and washing to remove organic salts.
[0040] (3) In the one-pot method for preparing mupiravir intermediate of the present invention, compound 3 does not need to be concentrated and separated separately. In the subsequent heating reaction, the organic solvent can be almost completely removed by distillation. At the same time, after the organic solvent is removed by distillation, the added water is used as the reaction solvent, which directly eliminates the use of solvents such as isopropanol or acetonitrile in the literature.
[0041] (4) In the one-pot method for preparing mupiravir intermediate of the present invention, in the step of synthesizing compound 1 from compound 3, the reaction is started by heating, and at the same time, as the temperature of the reaction solution increases, the low-boiling-point organic solvent is distilled; the reaction time is shortened and the production cycle of this step is shortened; the number of operation steps is reduced and the production cost is reduced.
[0042] (5) In the one-pot method for preparing mupiravir intermediate of the present invention, in the step of synthesizing compound 1 from compound 3, the organic solvent and water used in the step of synthesizing compound 3 are used as reaction solvents. The organic solvent distilled in the reaction is washed with deionized water and dried to remove water, and can be applied to the next batch in step S1; the raw material cost of the product is reduced, which is conducive to the industrial-scale production and promotion.
[0043] (6) In the one-pot method for preparing mupiravir intermediates of the present invention, the synthesis of compound 1 from compound 3 requires increasing the amount of water and reducing the content of hydroxylamine sulfate in the solution due to the instability of hydroxylamine sulfate. In the present application, the amount of water is hardly reduced when the organic solvent is evaporated in the compound 3 step; therefore, the safety of the reaction solution is ensured. At the same time, compared with the water-miscible solvents such as acetonitrile or isopropanol selected in the literature, the recovery rate of organic solvents is improved.
[0044] (7) The one-pot method for preparing mupiravir intermediates of the present invention uses inexpensive triethylamine as a base; it also eliminates the use of solvents such as acetonitrile, ethyl acetate, and diethyl ether in existing literature, as well as the multi-step aqueous solution washing operations; it also eliminates column chromatography and the purification step of 5% methanol with chloroform solution as described in the literature. This significantly reduces the cost of raw materials and the discharge of waste liquid, making it environmentally friendly; it also solves the problem of cumbersome operation.
[0045] (8) The one-pot method for preparing mupiravir intermediate of the present invention has a liquid phase purity of more than 99.1%; and lays the foundation for producing high-quality mupiravir in the next step. In the example, the liquid phase purity of the mupiravir produced in the next step reaches more than 99.9%, which meets the quality requirement of less than 0.1% single impurity. Detailed Implementation
[0046] 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.
[0047] Example 1:
[0048] Under nitrogen protection, 105 kg of n-hexane was added to a 500 L reactor, followed by 35 kg of compound 2, 0.2 kg of DMAP, and 23.5 kg of triethylamine, and the mixture was stirred until homogeneous. The temperature was controlled at 10-40 °C, and 22 kg of isobutyric anhydride was added. The reaction of compound 2 was then monitored for complete reaction. 150 kg of deionized water was added, and 6.2 kg of anhydrous sodium acetate and 23.7 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased until the n-hexane was completely distilled, and then further increased to 70-80 °C and maintained until compound 3 was completely reacted. The mixture was then cooled to 20-30 °C and centrifuged. The wet product was washed with 30 kg of deionized water, centrifuged again, and dried to obtain 28.5 kg of dry compound 1, with a molar yield of 83.6% and a liquid phase purity of 99.14%.
[0049] Solvent recovery solution:
[0050] The hexane recovered by distillation in S2 is washed with water, separated, and the organic phase is dried before being reused in the next batch of compound 2 reaction.
[0051] Example 2:
[0052] Under nitrogen protection, 1050 kg of dichloromethane was added to a 5000 L reactor, followed by 350 kg of compound 2, 2.2 kg of DMAP, and 235 kg of triethylamine, and the mixture was stirred thoroughly. The temperature was controlled at 10-40 °C, and 220 kg of isobutyric anhydride was added. The reaction of compound 2 was checked for completeness. 1500 kg of deionized water was added, and 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased until the dichloromethane was completely distilled, and then further increased to 70-80 °C and maintained until compound 3 was completely reacted. The mixture was then cooled to 20-30 °C and centrifuged. The wet product was rinsed with 300 kg of deionized water, centrifuged again, and dried to obtain 291.7 kg of dry compound 1, with a molar yield of 85.6% and a liquid phase purity of 99.35%.
[0053] Solvent recovery solution:
[0054] The dichloromethane recovered by distillation in S2 is washed with water, separated, and the organic phase is dried before being reused in the next batch of compound 2 reaction.
[0055] Example 3:
[0056] Under nitrogen protection, 1050 kg of 1,2-dichloroethane was added to a 5000 L reactor, followed by 350 kg of compound 2, 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 checked for complete reaction. 1500 kg of deionized water was added, and 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased until the solvent was completely distilled and compound 3 had reacted completely. The mixture was then cooled to 20-30 °C and centrifuged. The wet product was washed with 300 kg of deionized water, centrifuged again, and dried to obtain 277.7 kg of dry compound 1, with a molar yield of 81.5% and a liquid phase purity of 99.52%.
[0057] Solvent recovery solution:
[0058] The 1,2-dichloroethane recovered by distillation in S2 was washed with water, separated, and the organic phase was dried before being reused in the next batch of compound 2 reaction.
[0059] Example 4 (Reuse of Recycled Solvent):
[0060] Under nitrogen protection, 900 kg of dichloromethane recovered in Example 2 and 150 kg of fresh dichloromethane were added to a 5000 L reactor. Then, 350 kg of Compound 2, 2.2 kg of DMAP, and 235 kg of triethylamine were added and 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. 1500 kg of deionized water was added, and 62 kg of anhydrous sodium acetate and 237 kg of hydroxylamine sulfate were added with stirring. The temperature was slowly increased until the dichloromethane was completely distilled, and then further increased to 70-80 °C and maintained until Compound 3 was completely reacted. The mixture was then cooled to 20-30 °C and centrifuged. The wet product was washed with 300 kg of deionized water, centrifuged again, and dried to obtain 290.0 kg of dry Compound 1, with a molar yield of 85.1% and a liquid phase purity of 99.38%.
[0061] Solvent recovery solution:
[0062] The dichloromethane recovered by distillation in S2 is washed with water, separated, and the organic phase is dried before being reused in the next batch of compound 2 reaction.
[0063] Example 5: Preparation of mupiravir:
[0064] 1. Reaction formula:
[0065]
[0066] 2. Reaction procedure:
[0067] 2000 kg of dichloromethane was added to a reaction vessel, followed by 400 kg of compound 1. The mixture was stirred and cooled to -5 to 0°C. 216 kg of concentrated hydrochloric acid was added dropwise, and the reaction was maintained at this temperature for 3 hours after the addition was complete. After the reaction of compound 1 was complete, 400 kg of deionized water was added at 0 to 5°C, followed by 170 kg of 26% ammonia solution. The pH of the solution was adjusted 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, filtered, 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%.
[0068] 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 the methods and compositions of the invention, will be apparent to those skilled in the art without departing from the scope and spirit of the 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 intermediate compound 1: S1: Add solvent to the reaction vessel, add compound 2, DMAP and organic base under stirring, add isobutyric anhydride while controlling the temperature at 10-40℃, add water after the reaction is complete, and stir evenly to obtain a solution of compound 3; the solvent is one or more of dichloromethane, 1,2-dichloroethane, n-hexane and cyclohexane; S2: Add hydroxylamine sulfate and anhydrous sodium acetate to the solution of compound 3, heat to 20-90℃ and react until compound 3 has reacted completely, cool to allow crystallization, centrifuge, and dry the wet product to obtain intermediate compound 1; the mass ratio of the amount of hydroxylamine sulfate added to compound 2 is 0.43-1.29:1, and the mass ratio of the amount of anhydrous sodium acetate added to compound 2 is 0.11-0.32:1; (2) 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 for preparing mupiravir according to claim 1, characterized in that, The mass ratio of dichloromethane to compound 2 is 3.0-6.0:
1.
3. The method for preparing mupiravir according to claim 1, characterized in that, The organic base is one or more of diethylamine, triethylamine, and diisopropylethylamine.
4. The method for preparing mupiravir according to claim 3, characterized in that, The organic base is triethylamine.
5. The method for preparing mupiravir according to claim 4, characterized in that, The mass ratio of triethylamine to compound 2 is 0.40-1.33:
1.
6. The method for preparing mupiravir according to claim 5, characterized in that, The mass ratio of triethylamine to compound 2 is 0.5-0.9:
1.
7. The method for preparing mupiravir according to claim 1, characterized in that, The temperature at which isobutyric anhydride is added is 20-40℃, and the temperature at which the reaction is raised until compound 3 is completely reacted is 30-85℃.