A three-step method for synthesizing monoravir
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-06-02
- Publication Date
- 2026-08-14
AI Technical Summary
[0004]莫诺拉韦作为核苷类药物，其在RNA病毒复制时会模拟RNA病毒所需要的胞嘧啶和尿嘧啶核苷，从而导致RNA聚合酶（RdRp）合成出错误的RNA分子链，最终使病毒丧失活性
[0018]本发明实现了三步反应合成莫诺拉韦，并最终得到了纯度为95%的产品，为莫诺拉韦药物的合成提供了一种新的合成路线，并且每一步反应都有较高的转化率，这将会极大地缩短莫诺拉韦的合成步骤，对其合成成本的降级有很大的促进作用。
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Figure CN122562853A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the fields of organic synthesis and drug preparation, and specifically to a three-step method for synthesizing monoravir. Background Technology
[0002] Monopravir was first announced by Emory University for the treatment of Venezuelan equine encephalitis virus. In 2019, the National Institute of Allergy and Infectious Diseases (NIAID) approved monopravir for a Phase I clinical trial of influenza. Subsequently, the drug was acquired by Merck and Remdesivir and used as a treatment for COVID-19. The synthetic route disclosed by Emory University involved five steps, including not only protecting and deprotecting groups, but also using expensive uridine as a starting material, resulting in a final yield of only 17%. In recent years, synthetic routes using the less expensive cytidine as a starting material have been developed.
[0003] Because cytidine molecules have four esterification sites, highly selective esterification reagents are needed to avoid the introduction of protecting groups and shorten the reaction pathway. The challenge lies in the fact that the hydroxyl group at site 5 has lower esterification activity than the hydroxyl and amino groups at sites 3 and 4. Therefore, highly selective acylation reagents are crucial for shortening the reaction route and reducing reaction costs. Venkatanarayana et al. disclosed a two-step chemical synthesis method starting from cytidine. For example... Figure 6 As shown, the first step involves selectively acylating the 5-hydroxyl group of cytidine in the presence of isobutyryl chloride, triethylamine, and DMF to obtain 5'-O-methylpropylcytidine nucleoside in 89.3% yield. The 5'-O-methylpropylcytidine nucleoside is then reacted with hydroxylamine sulfate in water at 70°C for 5 hours to obtain the final product monoravir in 96% yield.
[0004] Monopravir, a nucleoside analogue, mimics the cytosine and uracil nucleosides required by RNA viruses during replication, causing the RNA polymerase (RdRp) to synthesize incorrect RNA molecular chains, ultimately rendering the virus inactive. Besides its activity against SARS-CoV-2 (the novel coronavirus), it also retains activity against variant strains of the SARS-CoV-2 virus. Therefore, improvements in the synthetic route of monopravir have a positive impact on human resistance to RNA retroviruses. Summary of the Invention
[0005] The purpose of this invention is to synthesize monoravir by selectively introducing a methacryloyl group at the 5-position of cytidine, reducing the isopropenyl group to isobutyryl group through a hydrogenation reaction, and then converting the amino group of cytidine to a hydroxylamine group. Finally, a monoravir product with a purity greater than 95% is obtained through separation and purification.
[0006] To achieve the above objectives, the present invention adopts the following technical solution:
[0007] Using cytidine as a raw material, cytidine is dissolved in a reaction solvent, and an acylation reagent is added to selectively acylate it at the fifth site of cytidine to obtain 5'-O-methylpropenylcytidine nucleoside. Through extraction and pH adjustment, the solvent is replaced with water to obtain an aqueous solution of 5'-O-methylisopropylcytidine nucleoside. The reaction solvent is then replaced with water again to obtain another aqueous solution of 5'-O-methylpropenylcytidine nucleoside. A catalyst is added to this solution, and under a specified pressure of H2 atmosphere, the introduced isopropenyl group is reduced to isopropyl, yielding an aqueous solution of 5'-O-methylisopropylcytidine nucleoside. Finally, a hydroxylamine group is used to convert the amino group of cytidine to a hydroxylamine group to obtain the monoravir product.
[0008] Preferably, the acylation reagent includes methacryloyl chloride and isobutyryl chloride.
[0009] Preferred catalysts for hydrogenation reactions include Pd / Al2O3, Pd / CaCO3, and Pd / C.
[0010] Preferably, the hydroxylamine reagent includes one or more of aqueous hydroxylamine, aqueous hydroxylamine hydrochloride, and aqueous hydroxylamine sulfate.
[0011] Preferably, the reaction solvent used for acylation is a mixture of DMPU and dioxane chloride.
[0012] Preferably, the volume percentage of dioxane chloride in the reaction solvent is 30%–60%.
[0013] Preferably, the solvents used in the hydrogenation and hydroxylation reactions include water, methanol, ethanol, and isopropanol.
[0014] Preferably, the acylation reaction temperature is controlled at 40-60 °C, and the reaction time is 8-16 h. The hydrogenation reaction temperature is controlled at 40-60 °C, and the reaction time is 2-16 h. The hydroxylation reaction temperature is controlled at 50-80 °C, and the reaction time is 1-8 h.
[0015] Preferably, the reaction is carried out in a single reaction system, which is a one-pot reaction.
[0016] Preferably, the reaction vessel is one or more of the following: a high-pressure reactor, a flask, and a storage bottle.
[0017] The beneficial effects of this invention are as follows:
[0018] This invention enables the three-step synthesis of monoravir, ultimately yielding a product with a purity of 95%. It provides a new synthetic route for the synthesis of monoravir, and each step of the reaction has a high conversion rate, which will greatly shorten the synthesis steps of monoravir and significantly promote the reduction of its synthesis cost. Attached Figure Description
[0019] Figure 1 This is a three-step synthesis route diagram for one-pot famonoravir according to the present invention.
[0020] Figure 2 This is a schematic diagram of the nuclear magnetic resonance imaging of monoravir of the present invention. 1 H-NMR).
[0021] Figure 3 This is a schematic diagram of the nuclear magnetic resonance imaging of monoravir of the present invention. 13 C-NMR).
[0022] Figure 4 This is a high-performance liquid chromatogram of the monoravir sample of the present invention.
[0023] Figure 5 This is the liquid chromatogram of a monoravir blank sample from the present invention.
[0024] Figure 6 There is a two-step chemical synthesis method roadmap. Detailed Implementation
[0025] The following description is merely a preferred embodiment of the present invention and does not limit the invention. Various changes and modifications can be made by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
[0026] like Figure 1 As shown, this invention discloses a three-step method for synthesizing monoravir. Using cytidine as a starting material, the method involves dissolving cytidine in a reaction solvent, adding an acylation reagent to selectively acylate it at the fifth site, yielding 5'-O-methylpropenylcytidine nucleoside; by extraction and pH adjustment, the solvent is replaced with water to obtain an aqueous solution of 5'-O-methylisopropylcytidine nucleoside; the reaction solvent is then replaced with water again to obtain another aqueous solution of 5'-O-methylpropenylcytidine nucleoside; a catalyst is added to this aqueous solution, and under a specified pressure H2 atmosphere, the introduced isopropenyl group is reduced to isopropyl, yielding another aqueous solution of 5'-O-methylisopropylcytidine nucleoside; finally, a hydroxylaminer is used to convert the amino group of cytidine to a hydroxylamine group, yielding the monoravir product.
[0027] Example 1
[0028] In a dry reaction vessel, cytidine (5.005 g, 20.56 mmol), methacryloyl chloride (3 mL, 31.00 mmol), DMPU (18 mL), and 4 M dioxane (18 mL) hydrochloride were added sequentially. After thorough mixing, the mixture was stirred at 40 °C for 16 h. After extraction and pH adjustment, an aqueous solution of 5'-O-methylpropenylcytidine was obtained. According to the liquid chromatography results, the conversion rate was 78% and the selectivity was 99%.
[0029] Example 2
[0030] In a dry reaction vessel, cytidine (4.005 g, 16.49 mmol), methacryloyl chloride (3 mL, 31.00 mmol), DMPU (18 mL), and 4 M dioxane hydrochloride (18 mL) were added sequentially. After thorough mixing, the mixture was stirred at 40 °C for 16 h. After extraction and pH adjustment, an aqueous solution of 5'-O-methylpropenylcytidine was obtained. According to the liquid chromatography results, the conversion rate was 92% and the selectivity was 98%.
[0031] Example 3
[0032] In a dry reaction vessel, cytidine (4.005 g, 16.49 mmol), methacryloyl chloride (3 mL, 31.00 mmol), DMPU (10 mL), and 4 M dioxane hydrochloride (5 mL) were added sequentially. After thorough mixing, the mixture was stirred at 40 °C for 16 h. After extraction and pH adjustment, an aqueous solution of 5'-O-methylpropenylcytidine was obtained. According to the liquid chromatography results, the conversion rate was 96% and the selectivity was 99%.
[0033] Example 4
[0034] In a dry, high-pressure reactor, 50 mL of an aqueous solution of 5'-O-methacryloylcytosine nucleoside and 50 mg of 2 wt% Pd / CaCO3 powder were added sequentially. After thorough mixing, the mixture was reacted at 50 °C and 1 MPa H2 for 8 h. After filtration, an aqueous solution of 5'-O-methylisopropylcytosine nucleoside was obtained. According to the liquid chromatography results, the conversion rate was 51% and the selectivity was 99%.
[0035] Example 5
[0036] In a dry, high-pressure reactor, 50 mL of an aqueous solution of 5'-O-methacryloylcytosine nucleoside and 50 mg of 2 wt% Pd / Al₂O₃ powder were added sequentially. After thorough mixing, the mixture was reacted at 50 °C and 1 MPa H₂ for 8 h. After filtration, an aqueous solution of 5'-O-methylisopropylcytosine nucleoside was obtained. According to the liquid chromatography results, the conversion rate was 99% and the selectivity was 99%.
[0037] Example 6
[0038] In a dry reaction vessel, 100 mL of an aqueous solution of 5'-O-methylisopropylcytosine nucleoside and hydroxylamine sulfate (4.004 g, 24.39 mmol) were added sequentially, and the mixture was stirred at room temperature for 8 h. Monopravir aqueous solution was obtained, with a conversion rate of 75% and a selectivity of 99% as determined by liquid chromatography.
[0039] Example 7
[0040] In a dry reaction vessel, 100 mL of aqueous solution of 5'-O-methylisopropylcytosine nucleoside, hydroxylamine sulfate (4.004 g, 24.39 mmol), and sodium bicarbonate (1.002 g, 9.46 mmol) were added sequentially, and the mixture was stirred at room temperature for 8 h. Monopravir aqueous solution was obtained, and the conversion rate and selectivity were 98% as determined by liquid chromatography. Figure 4 and Figure 5 The images show the high-performance liquid chromatograms of the monorapir sample and the monorapir blank sample, respectively.
[0041] Example 8
[0042] In a dry reaction vessel, 100 mL of aqueous solution of 5'-O-methylisopropylcytosine nucleoside, hydroxylamine sulfate (4.004 g, 24.39 mmol), and sodium bicarbonate (1.002 g, 9.46 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 h. Monopravir aqueous solution was obtained, and the conversion rate was 98% and the selectivity was 99% according to the liquid chromatography results.
[0043] Compound verification
[0044] like Figure 2 and 3 The image shows the nuclear magnetic resonance (NMR) image of the monoravir product purified in Example 7. Specific parameters are shown below. 1 H NMR (500 MHz, D2O): δ 6.95 (d, J = 8.3 Hz, 1H), 5.85 (d, J = 5.0 Hz, 1H), 5.75 (d, J = 8.3 Hz, 1H), 4.39 – 4.28 (m, 3H), 4.25 (dd, J = 6.6, 3.4Hz, 2H), 2.67 (hept, J = 7.0 Hz, 1H), 1.16 (d, J = 2.8 Hz, 3H), 1.15 (d, J =2.8 Hz, 3H). 13C NMR (126 MHz, D2O): δ 18.1, 18.2, 33.9, 63.6, 69.6, 72.6, 81.0, 88.5, 98.7, 131.0, 146.4, 151.0, 179.8.
[0045] The technical solutions of this invention are not limited to the contents listed in the specific embodiments / examples above. Any conventional adjustments and optimizations made by those skilled in the art based on the disclosure of this invention and according to actual needs, such adjustments, are all within the scope of protection of this invention. The scope of protection of this invention is defined by the claims.
Claims
1. A three-step method for synthesizing monoravir, characterized in that, This method uses cytidine as a raw material. Cytidine is dissolved in a reaction solvent, and then an acylation reagent is added to selectively acylate it at the fifth site to obtain 5'-O-methylpropenylcytidine nucleoside. After extraction and pH adjustment, the reaction solvent is replaced with water to obtain an aqueous solution of 5'-O-methylpropenylcytidine nucleoside. A catalyst is added to the solution, and the introduced isopropenyl group is reduced to isopropyl group under a specified pressure H2 atmosphere to obtain an aqueous solution of 5'-O-methylisopropylcytidine nucleoside. Finally, a hydroxylaminer is used to convert the amino group of cytidine to a hydroxylamine group to obtain monoravir product.
2. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, Acylation reagents include methacryloyl chloride and isobutyryl chloride.
3. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, Catalysts for hydrogenation reactions include Pd / Al2O3, Pd / CaCO3, and Pd / C.
4. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, Hydroxylating agents include one of the following: aqueous solution of hydroxylamine, aqueous solution of hydroxylamine hydrochloride, and aqueous solution of hydroxylamine sulfate.
5. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, The reaction solvent used for acylation refers to a mixture of DMPU and dioxane chloride.
6. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, The volume percentage of dioxane chloride in the reaction solvent is 30%–60%.
7. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, Solvents used in hydrogenation and hydroxylamine reactions include water, methanol, ethanol, and isopropanol.
8. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, The acylation reaction temperature was controlled at 40-60 °C, and the reaction time was 8-16 h. The hydrogenation reaction temperature was controlled at 40-60 °C, and the reaction time was 2-16 h. The hydroxylation reaction temperature was controlled at 50-80 °C, and the reaction time was 1-8 h.
9. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, The reaction is carried out in a single reaction system; it is a one-pot reaction.
10. The method for synthesizing monoravir in three steps according to claim 1, characterized in that, The reaction vessel is one of the following: a high-pressure reactor, a flask, or a storage bottle.