Synthesis method of inovirin key intermediate

Abstract

The invention relates to the technical field of synthesis of drug intermediates, and particularly discloses a synthesis method of an inovirin key intermediate. Orotic acid and N, O-dimethyl hydroxylamine hydrochloride are used as starting raw materials, an intermediate 1 is prepared through amidation reaction, N, N '-carbonyldiimidazole is selected as a condensing agent to activate the reaction raw material orotic acid, and the conversion rate and the yield of the reaction are remarkably improved. According to the preparation method, the intermediate 1 and halogenated silane are subjected to a silanization reaction to prepare a silanide, and by introducing a silyl ether group, the solubility of the intermediate 1 is remarkably improved, and the reaction selectivity of a subsequent Grignard reaction and an addition reaction is improved, so that the feeding amount of halogenated benzonitrile compounds with relatively high cost is reduced. And finally, preparing the key intermediate of the inovirin through a Minisci reaction which is mild in condition and high in atom economic benefit. The route not only effectively reduces the production cost, but also ensures the purity and yield of the inovirin key intermediate.

Description

Technical Field

[0001] The present invention relates to the technical field of drug intermediate synthesis, and particularly relates to a method for synthesizing a key intermediate of Ainuovirine. Background Art

[0002] Ainuovirine, chemically named 3-[[3-ethyl-2,6-dioxo-5-(propan-2-yl)-1,2,3,6-tetrahydropyrimidin-4-yl]carbonyl]-5-methylbenzonitrile, has the following structural formula and is a novel non-nucleoside reverse transcriptase inhibitor, which can be used for the prevention and treatment of human immunodeficiency virus (HIV) infection. Due to its novel mechanism of action, good efficacy and few side effects, Ainuovirine has very good clinical value and market prospects.

[0003]

[0004] So far, several synthetic routes for Ainuovirine have been reported in the literature. Route 1 (shown below), which uses diethyl malonate as the raw material, undergoes 9 steps of reactions including substitution, cyclization, chlorination, substitution, addition, oxidation, hydrolysis, cyanidation, and ethylation to obtain Ainuovirine. This route is long and the total yield is only 16.7%. In addition, highly toxic potassium cyanide and zinc cyanide are used in this process, resulting in high safety risks; moreover, a precious metal palladium catalyst is also used, leading to high production costs and being not suitable for industrial production applications.

[0005]

[0006] Route 2 (shown below), which uses 3,5-dimethylbenzoic acid as the raw material, undergoes 7 steps of reactions including ammonolysis, bromination, cyanidation, addition, hydrolysis, dehydration, and ethylation to obtain Ainuovirine. The bromination reaction in this route has poor selectivity (3:1), the third step of the reaction requires column chromatography purification, and the total yield of the two steps is only 21.7%, and the overall total yield is only 12.1%, which is not suitable for industrial production.

[0007]

[0008] Route 3 (shown below), which uses methyl 3-(cyanomethyl)-5-methylbenzoate and 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine as the raw materials, undergoes 8 steps of reactions including addition, oxidation, alkaline hydrolysis, hydrolysis, chlorination, ammoniation, dehydration, and ethylation to obtain Ainuovirine. This route has a relatively high total yield (42.1%), but the starting material methyl 3-(cyanomethyl)-5-methylbenzoate is not easily available. In addition, the one-pot process is used for synthesizing the first intermediate, which is not conducive to the removal and control of impurities and is not conducive to achieving the safety control of the drug Ainuovirine.

[0009]

[0010] Route 4 (as shown below), using orotic acid as the raw material, undergoes three steps of reaction including ethylation, addition, and Minisci reaction to obtain ivermectin. The reaction steps of this route are greatly shortened, but the yields of each step are not high, and the total yield is only 21.1%. Many impurities are generated in the second step of the reaction, resulting in a low yield. For example, the reaction of the ester group with the Grignard reagent will produce an over-addition side reaction, generating impurity A and leading to a low reaction yield, which is not conducive to the control of the finished product quality. The reaction conditions for the third step of the Minisci reaction are high temperature and high pressure reactions, which require relatively high production equipment.

[0011]

[0012] In the existing technology for synthesizing ivermectin routes, it is necessary to synthesize the key intermediate shown in formula (I). In view of the defects commonly existing in the existing preparation methods, such as low reaction yield, cumbersome operation, use of highly toxic substances or precious metal catalysts, and difficult control of drug quality, it is necessary to develop a green, environmentally friendly, higher-yield, and more suitable industrialization process.

[0013] Summary of the Invention

[0014] In view of the defects commonly existing in the existing ivermectin preparation methods in the prior art, such as low reaction yield, cumbersome operation, use of highly toxic substances or precious metal catalysts, and difficult control of drug quality, the present invention provides a method for synthesizing a key intermediate of ivermectin.

[0015] To solve the above technical problems, the technical solution provided by the present invention is:

[0016] A method for synthesizing a key intermediate of ivermectin, comprising the following steps:

[0017] S1, using orotic acid and N,O-dimethylhydroxylamine hydrochloride as raw materials, and N,N'-carbonyldiimidazole as a condensing agent, to carry out an amidation reaction to obtain intermediate 1 shown in formula (II);

[0018]

[0019] S2, intermediate 1 and a halogenated silane are subjected to a silylation reaction to obtain a silylated product shown in formula (III);

[0020]

[0021] Wherein, R1, R2, and R3 are each independently selected from C1-C6 alkyl or phenyl;

[0022] S3, after the halogenated benzonitrile compound shown in formula (IV) undergoes a Grignard reaction with a Grignard reagent, and then undergoes an addition reaction with the silylated product, to obtain intermediate 2 shown in formula (V);

[0023]

[0024] S4. Intermediate 2 undergoes a Minisci reaction with isobutyric acid to obtain the key intermediate of tenofovir disoproxil fumarate shown in formula (I).

[0025]

[0026] Compared with the prior art, the present invention provides a new method for synthesizing the key intermediate of tenofovir disoproxil fumarate by designing a new synthetic route. This method uses orotic acid and N,O-dimethylhydroxylamine hydrochloride as starting materials, and prepares intermediate 1 through an amidation reaction. By selecting N,N'-carbonyldiimidazole as a condensing agent to activate the starting material orotic acid, the conversion rate and yield of this reaction are significantly improved. Then, intermediate 1 and a halogenated silane are subjected to a silylation reaction to obtain a silylated product. By introducing a silyl ether group, the solubility of intermediate 1 is significantly improved, and the reaction selectivity of the subsequent Grignard reaction and addition reaction is improved, thereby reducing the feeding amount of the relatively expensive halogenated benzonitrile compounds and achieving the purpose of reducing costs and increasing efficiency. Finally, the key intermediate of tenofovir disoproxil fumarate is prepared through a Minisci reaction with mild conditions and high atom economy.

[0027] The preparation method of the key intermediate of tenofovir disoproxil fumarate provided by the present invention has the advantages of reasonable process design, mild reaction conditions, no need for high-temperature and high-pressure equipment, high product yield and purity, and low production cost. It is beneficial to realize the large-scale production of tenofovir disoproxil fumarate and has very important significance for promoting the wide application of tenofovir disoproxil fumarate in the prevention and treatment of human immunodeficiency virus (HIV) infection. In addition, starting materials such as orotic acid and N,O-dimethylhydroxylamine hydrochloride are usually easily available in the market, with wide sources, which can ensure the stability of raw material supply and is beneficial to the raw material reserve for large-scale production, and has good industrialization prospects.

[0028] As a specific embodiment of the present invention, the synthesis method of the key intermediate of tenofovir disoproxil fumarate specifically includes the following steps:

[0029] Step 1. In a polar solvent, orotic acid and N,N'-carbonyldiimidazole are activated at 0°C to 50°C, and then N,O-dimethylhydroxylamine hydrochloride is added to continue the amidation reaction to obtain intermediate 1.

[0030] Step 2. Under an inert atmosphere and in the presence of an organic base, intermediate 1 and a halogenated silane are subjected to a silylation reaction in an organic solvent at 20°C to 30°C to obtain a silylated product.

[0031] Step 3: Under an inert atmosphere, the halogenated benzonitrile compound and the Grignard reagent are subjected to a Grignard reaction in an organic solvent at 0 °C to 20 °C, and then an addition reaction with the silane compound is carried out at -10 °C to 10 °C to obtain Intermediate 2;

[0032] Step 4: Intermediate 2 and isobutyric acid undergo a Minisci reaction in an organic solvent-aqueous solvent at 10 °C to 30 °C under the conditions of a catalyst and an oxidant to obtain the key intermediate of tenofovir alafenamide.

[0033] The reaction equations for the above preparation process are as follows:

[0034]

[0035] The preparation method of the key intermediate of tenofovir alafenamide provided by the present invention has mild reaction conditions, does not require high-temperature and high-pressure equipment, improves the safety of the process and equipment investment, and has high reaction efficiency, simple operation, the product yield can reach more than 42%, and the purity can reach more than 99%. According to the conventional process, the total yield of preparing tenofovir alafenamide with this key intermediate as the raw material can reach more than 33%, laying a foundation for realizing large-scale and continuous production of tenofovir alafenamide, and having broad application prospects.

[0036] Further, in Step 1, the polar solvent is at least one of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide or N,N-dimethylacetamide.

[0037] Preferably, in Step 1, the polar solvent is N,N-dimethylformamide.

[0038] The preferred reaction solvent can promote the full dissolution of orotic acid, N,N'-carbonyldiimidazole and N,O-dimethylhydroxylamine, and is beneficial to improving the selectivity of the reaction and the reaction efficiency.

[0039] Further, in Step 1, the molar ratio of orotic acid, N,N'-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride is 1:(1-3):(1-3).

[0040] Preferably, in Step 1, the molar ratio of orotic acid, N,N'-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride is 1:(1-2):(1-2).

[0041] More preferably, in Step 1, the molar ratio of orotic acid, N,N'-carbonyldiimidazole and N,O-dimethylhydroxylamine hydrochloride is 1:1.5:1.5.

[0042] Preferably, in Step 1, the reaction temperature is 15 °C to 30 °C.

[0043] Further, in Step 1, the activation time is 12 h to 16 h.

[0044] Further, in Step 1, the time of the amidation reaction is 2 h to 3 h.

[0045] It should be noted that after the reaction in Step 1, a post-treatment process is further included: adding water and isopropanol to the reaction solution, mixing evenly, keeping warm for 1 h to 2 h, continuing to cool down to 0 °C to 10 °C, performing solid-liquid separation, washing, and drying to obtain Intermediate 1.

[0046] Further, the organic base is at least one of trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, pyridine, or triethylenediamine.

[0047] Preferably, the organic base is triethylamine.

[0048] Further, in Step 2, the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or toluene.

[0049] Preferably, in Step 2, the organic solvent is tetrahydrofuran.

[0050] Further, in Step 2, the molar ratio of Intermediate 1, the halogenated silane, and the organic base is 1:(2.0 - 2.5):(2.0 - 2.5).

[0051] Further, in Step 2, the time of the silylation reaction is 8 h to 12 h.

[0052] The preferred reaction conditions in Step 2 can promote the full progress of the silylation reaction and improve the yield and purity of the silylated product.

[0053] It should be noted that after the reaction in Step 2, a post-treatment process is further included: filtering the reaction solution, washing with tetrahydrofuran, and concentrating under reduced pressure to obtain the silylated product.

[0054] Further, in Step 3, the structural formula of the halogenated silane is as follows:

[0055]

[0056] Among them, R1, R2, and R3 are each independently selected from C1 - C6 alkyl or phenyl; X is chlorine, bromine, or iodine.

[0057] Further, in Step 3, the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or toluene.

[0058] Preferably, in Step 3, the organic solvent is tetrahydrofuran.

[0059] Further, in Step 3, the Grignard reagent is at least one of isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride, or methylmagnesium chloride.

[0060] Preferably, in Step 3, the Grignard reagent is isopropylmagnesium chloride-lithium chloride.

[0061] Further, in Step 3, the molar ratio of the halogenated benzonitrile compound, the Grignard reagent, and the silane compound is 1:(1-1.5):(1-3).

[0062] Preferably, in Step 3, the molar ratio of the halogenated benzonitrile compound, the Grignard reagent, and the silane compound is 1:(1.0-1.2):(1.5-2.0).

[0063] Further, in Step 3, the temperature of the addition reaction is 0°C to 10°C.

[0064] The preferred reaction conditions in Step 3 can promote the full progress of the Grignard reaction and the addition reaction, and improve the yield and purity of Intermediate 2.

[0065] It should be noted that after the reaction in Step 3, there is also a post-treatment process: concentrated hydrochloric acid and water are added to the reaction solution, the reaction solvent is removed by reduced pressure concentration, filtered, the obtained filter cake is slurried in saturated sodium bicarbonate solution, filtered, washed with water and toluene respectively, and dried to obtain Intermediate 2.

[0066] Further, in Step 4, the catalyst is a soluble silver salt.

[0067] Specifically, in Step 4, the catalyst is one or both of silver nitrate and silver acetate.

[0068] Further, in Step 4, the oxidant is at least one of ammonium persulfate, sodium persulfate, or potassium persulfate.

[0069] Preferably, in Step 4, the oxidant is ammonium persulfate.

[0070] Further, in Step 4, the organic solvent is at least one of tetrahydrofuran, ethyl acetate, dichloromethane, or chloroform.

[0071] Preferably, in Step 4, the organic solvent is dichloromethane.

[0072] Using the above organic solvent as the reaction solvent for the Minisci reaction can promote the full dissolution of each material, improve the reaction rate, enable the Minisci reaction to proceed efficiently under mild conditions, and avoid the use of high-temperature and high-pressure equipment.

[0073] Further, in Step 4, the molar ratio of Intermediate 2, catalyst, oxidant, and isobutyric acid is 1:(0.05 - 0.1):(2 - 4):(2 - 4).

[0074] Preferably, in Step 4, the molar ratio of Intermediate 2, catalyst, oxidant, and isobutyric acid is 1:(0.05 - 0.1):(3 - 4):(3 - 4).

[0075] More preferably, in Step 4, the molar ratio of Intermediate 2, catalyst, oxidant, and isobutyric acid is 1:0.05:4:3.

[0076] Further, in Step 4, the volume ratio of the organic solvent to water is 1:(0.5 - 1.5).

[0077] Preferably, in Step 4, the volume ratio of the organic solvent to water is 1:1.

[0078] Further, in Step 4, the time of the Minisci reaction is 5 h - 7 h.

[0079] Further, after the Minisci reaction in Step 4, it further includes: adding water to the reaction solution, adjusting the pH to neutral, then adding the first solvent, performing solid-liquid separation, washing, pulping the obtained filter cake in a mixed solution of the first solvent and the second solvent, performing solid-liquid separation, washing, and drying to obtain the key intermediate of ainovir.

[0080] The first solvent is at least one of n-heptane, cyclohexane, n-hexane, methyl tert-butyl ether, toluene, cyclopentyl methyl ether, methyl cyclohexane, or xylene; and / or

[0081] The second solvent is at least one of dichloromethane, tetrahydrofuran, ethyl acetate, or chloroform.

[0082] Preferably, the first solvent is n-heptane and the second solvent is dichloromethane.

[0083] Further, in Step 4, the volume ratio of the first solvent to the second solvent is (0.1 - 1):1.

[0084] Preferably, in Step 4, the volume ratio of the first solvent to the second solvent is 0.5:1.

[0085] Further, in Step 4, the pulping time is 1 h - 2 h.

[0086] It should be noted that in Step 4, the above washing processes are all carried out using a mixed solvent of the first solvent and the second solvent for washing.

[0087] As a specific embodiment of the present invention, the above-prepared key intermediate of alnovudine can be used to prepare alnovudine products with reference to existing conventional processes. Specifically, the process of 202410227735.1 can be used to prepare alnovudine products from the above key intermediate, or other processes in the prior art can also be used. The present invention does not make special limitations.

[0088] It should be noted that the addition ratio of the reaction solvent in each step of the present invention can be adjusted by those skilled in the art through conventional tests to ensure that all reaction materials are fully dissolved. The present invention does not make special limitations.

[0089] The synthesis method of the key intermediate of alnovudine provided by the present invention has a simple process route and mild reaction conditions. It not only effectively reduces the production cost, but also ensures the purity and yield of the key intermediate of alnovudine, providing a new process route for the preparation of alnovudine. The development of this method provides strong support for the wide application of alnovudine and also brings new hope to the field of prevention and treatment of human immunodeficiency virus (HIV) infection, with high promotion and application value. Specific Embodiments

[0090] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0091] Example 1

[0092] This example provides a method for preparing intermediate 3 of alnovudine, and the specific steps are as follows:

[0093] Step 1: Prepare intermediate 1 (N-methoxy-N-methyl-2,6-dioxo-1,3-dihydropyrimidine-4-carboxamide):

[0094] Add N,N-dimethylformamide (28 L) and orotic acid (3.5 kg, 22.4 mol) into a 100 L reaction kettle, slowly add N,N'-carbonyldiimidazole (5.45 kg, 33.6 mol), react at a temperature of 20-30 °C for 12 h, slowly add N,O-dimethylhydroxylamine hydrochloride (3.28 kg, 33.6 mol), continue to react for 2 h, add water (0.6 kg), then add isopropanol (56 L), keep the temperature for 2 h, continue to cool down to 0-10 °C, filter, wash with isopropanol, and dry to obtain intermediate 1 (4.10 kg, yield 91.8%, purity 99.96%); the reaction equation is as follows:

[0095]

[0096] MS(ESI)[M+H+ =200.2。

[0097] 1 1H-NMR(600 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.23 (s, 1H), 5.67 (d, J = 1.8 Hz, 1H), 3.68 (s, 3H), 3.22 (s, 3H) ppm。

[0098] 13 13C-NMR(150 MHz, DMSO-d6) δ 164.28, 151.35, 147.66, 98.71, 62.05, 32.67 ppm。

[0099] Step 2: Preparation of the silylated compound (N-methoxy-N-methyl-2,6-bis((trimethylsilyl)oxy)pyrimidine-4-carboxamide):

[0100] Under nitrogen protection, add tetrahydrofuran (19 L) and Intermediate 1 (1.90 kg, 9.54 mol) to a 100 L reaction kettle. Add trimethylchlorosilane (2.19 kg, 20.2 mol) at a temperature of 0 - 10 °C, then continue to add triethylamine (2.04 kg, 20.2 mol). Heat up to 20 - 25 °C and keep warm overnight. After the reaction is completed, filter to remove insoluble substances, wash the filter cake with tetrahydrofuran, and concentrate under reduced pressure until the feed liquid is about 14 L to obtain a tetrahydrofuran solution of the silylated compound, which is directly fed into the next reaction; the reaction equation is as follows:

[0101]

[0102] Step 3: Preparation of Intermediate 2 (3-[(2,6-dioxo-1,3-dihydropyrimidin-4-yl)carbonyl]-5-methylbenzonitrile):

[0103] Under nitrogen protection, add tetrahydrofuran (1.5 L) and 3-bromo-5-methylbenzonitrile (1.0 kg, 5.1 mol) to a 100 L reaction kettle. Cool down to 0 - 10 °C, add 1.3 M isopropylmagnesium chloride-lithium chloride (4.32 L, 5.62 mol), and react at a temperature of 10 - 20 °C. After the reaction is completed, at a temperature of 0 - 10 °C, add the tetrahydrofuran solution of the silylated compound prepared above. The molar ratio of the silylated compound to 3-bromo-5-methylbenzonitrile is 1.2:1. Keep warm and react for 2 h. After the reaction is completed, add concentrated hydrochloric acid (1.29 kg, 12.75 mol) and water (12 L), concentrate under reduced pressure to remove tetrahydrofuran, filter, slurry the filter cake in saturated sodium bicarbonate solution (10 L), filter, wash with water and toluene respectively, and dry to obtain Intermediate 2 (1.17 kg, yield 90%, purity 99.95%); the reaction equation is as follows:

[0104]

[0105] MS(ESI)[M+H + = 256.2。

[0106] 1 H-NMR(600 MHz, d6-DMSO) δ 11.39 (s, 1H), 11.20 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 5.79 (s, 1H), 2.45 (s, 3H)。

[0107] 13 C-NMR(150 MHz, DMSO-d6) δ 188.14, 164.37, 151.46, 147.08, 140.85, 138.05, 135.63, 134.79, 131.35, 118.39, 112.43, 105.08, 20.85 ppm。

[0108] Step 4. Preparation of Intermediate 3 (3-{[2,6-dioxo-5-(propan-2-yl)-1,3-dihydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile):

[0109] Add water (10 L) and dichloromethane (10 L) to a 100 L reactor. Sequentially add silver acetate (33 g, 0.20 mol), ammonium persulfate (3.58 kg, 15.69 mol), and Intermediate 2 (1.0 kg, 3.92 mol). At a temperature of 20 - 30 °C, add isobutyric acid (1.04 kg, 11.75 mol), keep the temperature for reaction for 6 h, add water (6 L), then add sodium bicarbonate to adjust the pH to neutral, add n-heptane (5 L), stir for 1 h, filter, wash the filter cake with dichloromethane and n-heptane in a volume ratio of 1:0.5, wash with water, slurry the filter cake in dichloromethane (10 L) and n-heptane (5 L), filter, wash the filter cake with dichloromethane and n-heptane in a volume ratio of 1:0.5, wash with water, and dry to obtain Intermediate 3 (0.82 kg, yield 70.5%, purity 99.6%); The reaction equation is as follows:

[0110]

[0111] MS(ESI)[M+H + = 298.2。

[0112] 1H-NMR (600 MHz, d6-DMSO) δ 11.18 (s, 1H), 11.01 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 2.47 (s, 3H), 2.23 - 2.30 (m, 1H), 1.06 (d, J = 7.2 Hz, 6H).

[0113] 13 C-NMR (150 MHz, DMSO-d6) δ 189.89, 164.07, 150.92, 144.45, 141.41, 139.07, 135.59, 134.32, 131.37, 118.22, 114.62, 112.97, 27.82, 20.75, 20.55 ppm.

[0114] Example 2

[0115] This example provides a method for preparing intermediate 3 of ainovirine, and the specific steps are as follows:

[0116] Step 1: Prepare intermediate 1 (N-methoxy-N-methyl-2,6-dioxo-1,3-dihydropyrimidine-4-carboxamide):

[0117] Add N,N-dimethylacetamide (25 L) and orotic acid (3.5 kg, 22.4 mol) to a 100 L reaction kettle, slowly add N,N'-carbonyldiimidazole (3.64 kg, 22.4 mol), react at a temperature of 10 - 20 °C for 14 h, slowly add N,O-dimethylhydroxylamine hydrochloride (2.19 kg, 22.4 mol), continue to react for 3 h, add water (0.4 kg), then continue to add isopropanol (50 L), keep warm for 1 h, then continue to cool to 0 - 10 °C, filter, wash with isopropanol, and dry to obtain intermediate 1 (4.11 kg, yield 92.1%, purity 99.90%); the reaction equation is as follows:

[0118]

[0119] MS (ESI) [M + H + = 200.2.

[0120] 1 H-NMR (600 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.23 (s, 1H), 5.67 (d, J = 1.8 Hz, 1H), 3.68 (s, 3H), 3.22 (s, 3H) ppm.

[0121] 1313C-NMR (150 MHz, DMSO-d6) δ 164.28, 151.35, 147.66, 98.71, 62.05, 32.67 ppm.

[0122] Step 2. Preparation of the silylated compound (N-methoxy-N-methyl-2,6-bis((trimethylsilyl)oxy)pyrimidine-4-carboxamide):

[0123] Under nitrogen protection, add isopropyl ether (25 L) and Intermediate 1 (1.90 kg, 9.54 mol) to a 100 L reaction kettle. Add trimethylchlorosilane (2.60 kg, 23.9 mol) at a temperature of 0 - 10 °C, then continue to add pyridine (1.89 kg, 23.9 mol). Heat up to 20 - 25 °C and keep warm overnight. After the reaction is completed, filter to remove insoluble substances, wash the filter cake with isopropyl ether, and concentrate under reduced pressure until the feed liquid is about 14 L to obtain an isopropyl ether solution of the silylated compound, which is directly fed into the next reaction; the reaction equation is as follows:

[0124]

[0125] Step 3. Preparation of Intermediate 2 (3-[(2,6-dioxo-1,3-dihydropyrimidin-4-yl)carbonyl]-5-methylbenzonitrile):

[0126] Under nitrogen protection, add isopropyl ether (1.5 L) and 3-bromo-5-methylbenzonitrile (1.0 kg, 5.1 mol) to a 100 L reaction kettle. Cool down to 0 - 10 °C and add 2M isopropylmagnesium chloride (2.6 L, 5.2 mol). React at a temperature of 10 - 20 °C. After the reaction is completed, at a temperature of 0 - 10 °C, add the above-prepared isopropyl ether solution of the silylated compound. The molar ratio of the silylated compound to 3-bromo-5-methylbenzonitrile is 1.5:1. Keep warm and react for 3 h. After the reaction is completed, add concentrated hydrochloric acid (1.17 kg, 11.58 mol) and water (12 L), concentrate under reduced pressure to remove isopropyl ether, filter, slurry the filter cake in saturated sodium bicarbonate solution (10 L), filter, wash with water and toluene respectively, and dry to obtain Intermediate 2 (1.06 kg, yield 81.2%, purity 99.1%); the reaction equation is as follows:

[0127]

[0128] MS (ESI) [M + H + = 256.2.

[0129] 1H-NMR (600 MHz, d6-DMSO) δ 11.39 (s, 1H), 11.20 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 5.79 (s, 1H), 2.45 (s, 3H).

[0130] 13 C-NMR (150 MHz, DMSO-d6) δ 188.14, 164.37, 151.46, 147.08, 140.85, 138.05, 135.63, 134.79, 131.35, 118.39, 112.43, 105.08, 20.85 ppm.

[0131] Step 4: Preparation of Intermediate 3 (3-{[2,6-Dioxo-5-(propan-2-yl)-1,3-dihydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile):

[0132] Add water (10 L) and tetrahydrofuran (10 L) to a 100 L reaction kettle. Add silver nitrate (40 g, 0.24 mol), sodium persulfate (2.86 kg, 12.01 mol) and Intermediate 2 (1.0 kg, 3.92 mol) in sequence. At a temperature of 20 - 30 °C, add isobutyric acid (1.39 kg, 15.78 mol), keep the temperature for reaction for 6 h, add water (10 L), then add sodium bicarbonate to adjust the pH to neutral, add cyclohexane (5 L), stir for 1 h, filter, wash the filter cake with tetrahydrofuran and cyclohexane with a volume ratio of 1:0.5, wash with water, slurry the filter cake in tetrahydrofuran (10 L) and cyclohexane (5 L), filter, wash the filter cake with tetrahydrofuran and cyclohexane with a volume ratio of 1:0.5, wash with water, and dry to obtain Intermediate 3 (0.70 kg, yield 60.4%, purity 99.0%); The reaction equation is as follows:

[0133]

[0134] MS (ESI) [M + H + = 298.2.

[0135] 1 H-NMR (600 MHz, d6-DMSO) δ 11.18 (s, 1H), 11.01 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 2.47 (s, 3H), 2.23 - 2.30 (m, 1H), 1.06 (d, J = 7.2 Hz, 6H).

[0136] 1313C-NMR (150 MHz, DMSO-d6) δ 189.89, 164.07, 150.92, 144.45, 141.41, 139.07, 135.59, 134.32, 131.37, 118.22, 114.62, 112.97, 27.82, 20.75, 20.55 ppm.

[0137] Example 3

[0138] This example provides a method for preparing intermediate 3 of ainovirine, and the specific steps are as follows:

[0139] Step 1: Prepare intermediate 1 (N-methoxy-N-methyl-2,6-dioxo-1,3-dihydropyrimidine-4-carboxamide):

[0140] Dimethyl sulfoxide (21 L) and orotic acid (3.5 kg, 22.4 mol) were added to a 100 L reaction kettle, and N,N'-carbonyldiimidazole (7.27 kg, 44.8 mol) was slowly added. The reaction was carried out at a temperature of 0 - 10 °C for 15 h. N,O-dimethylhydroxylamine hydrochloride (4.37 kg, 44.8 mol) was slowly added, and the reaction was continued for 2 h. Water (0.81 kg) was added, and then isopropanol (52.5 L) was added. The mixture was kept warm for 1 h, then cooled to 0 - 10 °C, filtered, washed with isopropanol, and dried to obtain intermediate 1 (3.81 kg, yield 85.4%, purity 99.95%); the reaction equation is as follows:

[0141]

[0142] MS (ESI) [M + H + = 200.2.

[0143] 1 1H-NMR (600 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.23 (s, 1H), 5.67 (d, J = 1.8 Hz, 1H), 3.68 (s, 3H), 3.22 (s, 3H) ppm.

[0144] 13 13C-NMR (150 MHz, DMSO-d6) δ 164.28, 151.35, 147.66, 98.71, 62.05, 32.67 ppm.

[0145] Step 2: Prepare the silylated compound (N-methoxy-N-methyl-2,6-bis((trimethylsilyl)oxy)pyrimidine-4-carboxamide):

[0146] Under nitrogen protection, methyl tert-butyl ether (22 L) and intermediate 1 (1.90 kg, 9.54 mol) were added to a 100 L reactor. Trimethylchlorosilane (2.1 kg, 19.1 mol) was added at a temperature of 0 - 10 °C, and then N-methylmorpholine (1.93 kg, 19.1 mol) was added continuously. The temperature was raised to 25 - 30 °C and kept overnight. After the reaction was completed, the insoluble matter was removed by filtration, and the filter cake was washed with methyl tert-butyl ether. The mixture was concentrated under reduced pressure to about 15 L of the feed liquid to obtain a solution of the silylated product in methyl tert-butyl ether, which was directly fed into the next reaction; the reaction equation is as follows:

[0147]

[0148] Step 3: Preparation of intermediate 2 (3-[(2,6-dioxo-1,3-dihydropyrimidin-4-yl)carbonyl]-5-methylbenzonitrile):

[0149] Under nitrogen protection, methyl tert-butyl ether (1.5 L) and 3-bromo-5-methylbenzonitrile (1.0 kg, 5.1 mol) were added to a 100 L reactor. The temperature was lowered to 0 - 10 °C, and 3M methylmagnesium chloride (2.55 L, 7.65 mol) was added. The reaction was carried out at a temperature of 10 - 20 °C. After the reaction was completed, at a temperature of 0 - 10 °C, the above-prepared solution of the silylated product in methyl tert-butyl ether was added. The molar ratio of the silylated product to 3-bromo-5-methylbenzonitrile was 2.0:1. The reaction was kept at a constant temperature for 1 h. After the reaction was completed, concentrated hydrochloric acid (1.50 kg, 14.78 mol) and water (12 L) were added. Methyl tert-butyl ether was removed by concentration under reduced pressure. The mixture was filtered, and the filter cake was slurried in saturated sodium bicarbonate solution (15 L), filtered, washed with water and toluene respectively, and dried to obtain intermediate 2 (0.98 kg, yield 75.1%, purity 99.3%); the reaction equation is as follows:

[0150]

[0151] MS(ESI)[M + H + = 256.2.

[0152] 1 1H-NMR(600 MHz, d6-DMSO) δ 11.39 (s, 1H), 11.20 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 5.79 (s, 1H), 2.45 (s, 3H).

[0153] 1313C-NMR (150 MHz, DMSO-d6) δ 188.14, 164.37, 151.46, 147.08, 140.85, 138.05, 135.63, 134.79, 131.35, 118.39, 112.43, 105.08, 20.85 ppm.

[0154] Step 4: Preparation of Intermediate 3 (3-{[2,6-dioxo-5-(propan-2-yl)-1,3-dihydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile):

[0155] Add water (10 L) and ethyl acetate (10 L) to a 100 L reaction kettle, successively add silver acetate (66 g, 0.40 mol), potassium persulfate (3.40 kg, 12.58 mol) and Intermediate 2 (1.0 kg, 3.92 mol). At a temperature of 20 - 30 °C, add isobutyric acid (1.25 kg, 14.19 mol), keep the temperature for reaction for 6 h, add water (6 L), then add sodium bicarbonate to adjust the pH to neutral, add methyl tert-butyl ether (5 L), stir for 1 h, filter, wash the filter cake with ethyl acetate and methyl tert-butyl ether in a volume ratio of 1:0.5, wash with water, slurry the filter cake in ethyl acetate (10 L) and methyl tert-butyl ether (5 L), filter, wash the filter cake with ethyl acetate and methyl tert-butyl ether in a volume ratio of 1:0.5, wash with water, and dry to obtain Intermediate 3 (0.76 kg, yield 65.2%, purity 98.9%); The reaction equation is as follows:

[0156]

[0157] MS (ESI) [M + H + = 298.2.

[0158] 1 1H-NMR (600 MHz, d6-DMSO) δ 11.18 (s, 1H), 11.01 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 2.47 (s, 3H), 2.23 - 2.30 (m, 1H), 1.06 (d, J = 7.2 Hz, 6H).

[0159] 13 13C-NMR (150 MHz, DMSO-d6) δ 189.89, 164.07, 150.92, 144.45, 141.41, 139.07, 135.59, 134.32, 131.37, 118.22, 114.62, 112.97, 27.82, 20.75, 20.55 ppm.

[0160] Example 4

[0161] This embodiment provides a method for preparing intermediate 3 of ainovirine, and the specific steps are as follows:

[0162] Step 1: Prepare intermediate 1 (N-methoxy-N-methyl-2,6-dioxo-1,3-dihydropyrimidine-4-carboxamide):

[0163] Add N-methylpyrrolidone (35 L) and orotic acid (3.5 kg, 22.4 mol) to a 100 L reaction kettle, slowly add N,N'-carbonyldiimidazole (10.9 kg, 67.2 mol), react at a temperature of 40 - 50 °C for 12 h, slowly add N,O-dimethylhydroxylamine hydrochloride (6.55 kg, 67.2 mol), continue to react for 3 h, add water (1.2 kg), then add isopropanol (70 L), keep the temperature for 2 h, continue to cool down to 0 - 10 °C, filter, wash with isopropanol, and dry to obtain intermediate 1 (3.73 kg, yield 83.5%, purity 99.98%); the reaction equation is as follows:

[0164]

[0165] MS(ESI)[M + H + = 200.2.

[0166] 1 1H-NMR(600 MHz, DMSO-d6) δ11.26(s, 1H), 11.23(s, 1H), 5.67(d, J = 1.8 Hz, 1H), 3.68(s, 3H), 3.22(s, 3H) ppm.

[0167] 13 13C-NMR(150 MHz, DMSO-d6) δ164.28, 151.35, 147.66, 98.71, 62.05, 32.67 ppm.

[0168] Step 2: Prepare the silylated product (N-methoxy-N-methyl-2,6-bis((trimethylsilyl)oxy)pyrimidine-4-carboxamide):

[0169] Under nitrogen protection, add toluene (28 L) and intermediate 1 (1.90 kg, 9.54 mol) to a 100 L reaction kettle, add trimethylchlorosilane (2.40 kg, 22.1 mol) at a temperature of 0 - 10 °C, then add diisopropylethylamine (2.85 kg, 22.1 mol), heat up to 20 - 25 °C, keep the temperature overnight, after the reaction is completed, filter to remove the insoluble matter, wash the filter cake with tetrahydrofuran, and concentrate under reduced pressure to about 15 L of the feed liquid to obtain the toluene solution of the silylated product, which is directly fed into the next step of the reaction; the reaction equation is as follows:

[0170]

[0171] Step 3. Preparation of Intermediate 2 (3-[(2,6-dioxo-1,3-dihydropyrimidin-4-yl)carbonyl]-5-methylbenzonitrile):

[0172] Under nitrogen protection, toluene (1.5 L) and 3-bromo-5-methylbenzonitrile (1.0 kg, 5.1 mol) were added to a 100 L reaction kettle, and the temperature was lowered to 0 - 10 °C. 1.3 M isopropylmagnesium chloride-lithium chloride (5.88 L, 7.65 mol) was added, and the reaction was carried out at a temperature of 10 - 20 °C. After the reaction was completed, at a temperature of 0 - 10 °C, the toluene solution of the above-prepared silylated product was added. The molar ratio of the silylated product to 3-bromo-5-methylbenzonitrile was 3:1, and the reaction was kept warm for 2 h. After the reaction was completed, concentrated hydrochloric acid (1.50 kg, 14.78 mol) and water (12 L) were added, and toluene was removed by reduced pressure concentration. After filtration, the filter cake was slurried in saturated sodium bicarbonate solution (20 L), filtered, washed with water and toluene respectively, and dried to obtain Intermediate 2 (1.04 kg, yield 80.0%, purity 99.5%); the reaction equation is as follows:

[0173]

[0174] MS(ESI)[M+H + = 256.2.

[0175] 1 1H-NMR(600 MHz, d6-DMSO) δ11.39(s, 1H), 11.20(s, 1H), 8.21(s, 1H), 8.04(s, 1H), 8.03(s, 1H), 5.79(s, 1H), 2.45(s, 3H).

[0176] 13 13C-NMR(150 MHz, DMSO-d6) δ188.14, 164.37, 151.46, 147.08, 140.85, 138.05, 135.63, 134.79, 131.35, 118.39, 112.43, 105.08, 20.85 ppm.

[0177] Step 4. Preparation of Intermediate 3 (3-{[2,6-dioxo-5-(propan-2-yl)-1,3-dihydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile):

[0178] Add water (10 L) and chloroform (10 L) to a 100 L reactor. Then, add silver acetate (33 g, 0.20 mol), ammonium persulfate (3.58 kg, 15.69 mol), and intermediate 2 (1.0 kg, 3.92 mol) in sequence. At a temperature of 20 - 30 °C, add isobutyric acid (1.04 kg, 11.75 mol), and keep the temperature for reaction for 6 h. Add water (6 L), then add sodium bicarbonate to adjust the pH to neutral. Add toluene (5 L), stir for 1 h, filter, wash the filter cake with a 1:0.5 volume ratio of chloroform and toluene, wash with water, slurry the filter cake in chloroform (10 L) and toluene (5 L), filter, wash the filter cake with a 1:0.5 volume ratio of chloroform and toluene, wash with water, and dry to obtain intermediate 3 (0.79 kg, yield 67.8%, purity 99.2%); the reaction equation is as follows:

[0179]

[0180] MS(ESI)[M+H + = 298.2.

[0181] 1 1H-NMR(600 MHz, d6-DMSO) δ 11.18 (s, 1H), 11.01 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 2.47 (s, 3H), 2.23 - 2.30 (m, 1H), 1.06 (d, J = 7.2 Hz, 6H).

[0182] 13 13C-NMR(150 MHz, DMSO-d6) δ 189.89, 164.07, 150.92, 144.45, 141.41, 139.07, 135.59, 134.32, 131.37, 118.22, 114.62, 112.97, 27.82, 20.75, 20.55 ppm.

[0183] Example 5

[0184] This example provides a preparation method for a key intermediate of ainovirine. The only difference from Example 1 is the change in the addition ratio of isobutyric acid and ammonium persulfate in Step 4, and the rest are exactly the same:

[0185] Steps 1 to 3 are exactly the same as in Example 1;

[0186] Step 4: Add water (10 L) and dichloromethane (10 L) into a 100 L reaction kettle. Sequentially add silver acetate (33 g, 0.20 mol), ammonium persulfate (4.47 kg, 19.59 mol), and intermediate 2 (1.0 kg, 3.92 mol). At a temperature of 20 - 30 °C, add isobutyric acid (0.69 kg, 7.84 mol), keep the temperature for reaction for 6 h, add water (6 L), then add sodium bicarbonate to adjust the pH to neutral. Add n - heptane (5 L), stir for 1 h, filter. Wash the filter cake with a 1:0.5 volume ratio of dichloromethane and n - heptane, and then wash with water. Pulverize the filter cake in dichloromethane (10 L) and n - heptane (5 L), filter, wash the filter cake with a 1:0.5 volume ratio of dichloromethane and n - heptane, and then wash with water. Dry to obtain intermediate 3 (0.74 kg, yield 63.5%, purity 99.1%).

[0187] Example 6

[0188] Prepare tenofovir intermediate prepared in the above Example 1 into tenofovir according to Patent CN202410227735.1. The specific steps are as follows:

[0189] In a 100 mL three - necked flask, add intermediate 3 (5.0 g, 0.017 mol), acetonitrile (50 mL), N,N - diisopropylethylamine (3.47 g, 0.027 mol), and iodoethane (4.2 g, 0.027 mol). Heat up to 70 - 80 °C, keep the temperature and stir for 18 hours. After the reaction is completed and cooled to room temperature, adjust the pH of the reaction solution to 4 - 5. Add purified water (84 mL) and stir for 1 h, filter, wash with water, recrystallize with absolute ethanol (120 mL), filter, and dry to obtain tenofovir (4.29 g, purity 99.8%, yield 78.4%). The reaction equation is as follows:

[0190]

[0191] Comparative Example 1

[0192] This comparative example provides a preparation method of a key intermediate of tenofovir. The only difference from Example 1 is that N,N'-carbonyldiimidazole in Step 1 is replaced with 1 - ethyl - (3 - dimethylaminopropyl)carbodiimide hydrochloride, and the rest are exactly the same. The specific steps of Step 1 are as follows:

[0193] In a 500 mL reaction flask, add N,N-dimethylformamide (160 mL) and orotic acid (20 g, 0.128 mol), then add N,O-dimethylhydroxylamine hydrochloride (15 g, 0.154 mol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.4 g, 0.154 mol), 1-hydroxybenzotriazole (20.7 g, 0.154 mol) and diisopropylethylamine (39.7 g, 0.307 mol). Under nitrogen protection, react at 20 - 30 °C for 16 h, and sample for detection with the residual orotic acid being 62.3%.

[0194] Comparative Example 2

[0195] This comparative example provides a preparation method of an intermediate key to ainovirine. The only difference from Example 1 is that N,N'-carbonyldiimidazole in Step 1 is replaced with pivaloyl chloride, and the rest is exactly the same. The specific steps of Step 1 are as follows:

[0196] In a 500 mL reaction flask, add N,N-dimethylformamide (160 mL) and orotic acid (20 g, 0.128 mol), then add triethylamine (19.4 g, 0.192 mol), stir at 20 - 30 °C for 1 h. At 0 - 10 °C, slowly add pivaloyl chloride (23.2 g, 0.192 mol), stir at 20 - 30 °C for 16 h, add triethylamine (32.4 g, 0.32 mol) and N,O-dimethylhydroxylamine hydrochloride (18.7 g, 0.192 mol), and react at 20 - 30 °C for 16 h. Sample for detection with the residual orotic acid being 28.5%.

[0197] In the above examples, when using other reaction conditions defined in the present invention, such as reaction solvents, reaction temperatures and other reaction materials, as long as they are within the scope defined in the present invention, technical effects equivalent to those of Examples 2 - 4 can be achieved.

[0198] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements or improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a key intermediate of ainovirine, characterized in that, It includes the following steps: S1. Using orotic acid and N,O-dimethylhydroxylamine hydrochloride as raw materials and N,N'-carbonyldiimidazole as a condensing agent, an amidation reaction is carried out to obtain intermediate 1 shown in formula (Ⅱ). S2. Intermediate 1 and a halogenated silane are subjected to a silylation reaction to obtain a silylated product shown in formula (Ⅲ). Wherein, R1, R2, and R3 are each independently selected from C1-C6 alkyl or phenyl; S3. After a Grignard reaction between a halogenated benzonitrile compound shown in formula (Ⅳ) and a Grignard reagent, an addition reaction is carried out with the silylated product to obtain intermediate 2 shown in formula (Ⅴ). S4. Intermediate 2 and isobutyric acid are subjected to a Minisci reaction to obtain the key intermediate of alnovil shown in formula (Ⅰ).

2. The synthesis method of the key intermediate of ainuvir as described in claim 1, characterized in that, Specifically, it includes the following steps: Step 1. In a polar solvent, orotic acid and N,N'-carbonyldiimidazole are activated at 0°C to 50°C, and then N,O-dimethylhydroxylamine hydrochloride is added to continue the amidation reaction to obtain intermediate 1. Step 2. Under an inert atmosphere and in the presence of an organic base, intermediate 1 and a halogenated silane are subjected to a silylation reaction in an organic solvent at 20°C to 30°C to obtain a silylated product. Step 3. Under an inert atmosphere, a halogenated benzonitrile compound and a Grignard reagent are subjected to a Grignard reaction in an organic solvent at 0°C to 20°C, and then an addition reaction is carried out with the silylated product at -10°C to 10°C to obtain intermediate 2. Step 4. Intermediate 2 and isobutyric acid are subjected to a Minisci reaction in an organic solvent-aqueous solvent at 10°C to 30°C in the presence of a catalyst and an oxidant to obtain the key intermediate of alnovil.

3. The synthesis method of the key intermediate of ainovirine as described in claim 2, characterized in that, In step 1, the polar solvent is at least one of N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, or N,N-dimethylacetamide; and / or In step 1, the molar ratio of orotic acid, N,N'-carbonyldiimidazole, and N,O-dimethylhydroxylamine hydrochloride is 1:(1-3):(1-3).

4. The synthesis method of the key intermediate of ainuvir as claimed in claim 2, wherein, In step 2, the organic base is at least one of trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, pyridine, or triethylenediamine; and / or In step 2, the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or toluene; and / or In step 2, the molar ratio of intermediate 1, halogenated silane, and organic base is 1:(2.0-2.5):(2.0-2.5).

5. The synthesis method of the key intermediate of ainuvir as claimed in claim 2, wherein, In step 3, the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, or toluene; and / or In step 3, the Grignard reagent is at least one of isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride, or methylmagnesium chloride.

6. The synthesis method of the key intermediate of ainuvir as claimed in claim 2 or 5, characterized in that, In step 3, the molar ratio of the halogenated benzonitrile compound, Grignard reagent, and silylated product is 1:(1-1.5):(1-3).

7. The synthesis method of the key intermediate of ainuvirine according to claim 2, wherein, In step 4, the catalyst is a soluble silver salt; and / or In step 4, the oxidant is at least one of ammonium persulfate, sodium persulfate, or potassium persulfate; and / or In step 4, the organic solvent is at least one of tetrahydrofuran, ethyl acetate, dichloromethane, or chloroform.

8. The synthesis method of the key intermediate of ainovirine according to claim 2 or 7, characterized in that, In Step 4, the molar ratio of Intermediate 2, the catalyst, the oxidant, and isobutyric acid is 1:(0.05 - 0.1):(2 - 4):(2 - 4); and / or In Step 4, the volume ratio of the organic solvent to water is 1:(0.5 - 1.5).

9. The synthesis method of the key intermediate of ainuvir as claimed in claim 2, wherein, In Step 4, after the Minisci reaction is completed, it further includes: adding water to the reaction solution, adjusting the pH to neutral, then adding a first solvent, performing solid-liquid separation, washing, slurrying the obtained filter cake in a mixed solution of the first solvent and a second solvent, performing solid-liquid separation, washing, and drying to obtain the key intermediate of Tenofovir Alafenamide; The first solvent is at least one of n-heptane, cyclohexane, n-hexane, methyl tert-butyl ether, toluene, cyclopentyl methyl ether, methyl cyclohexane, or xylene; and / or The second solvent is at least one of dichloromethane, tetrahydrofuran, ethyl acetate, or chloroform.

10. The synthesis method of the key intermediate of ainuvirine as described in claim 9, characterized in that, In Step 4, the volume ratio of the first solvent to the second solvent is (0.1 - 1):1.

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