Synthetic method of anti-AIDS drug inovirin

Abstract

The invention provides a synthesis method of an anti-AIDS drug, and belongs to the technical field of drug preparation, the synthesis method comprises the following steps: (1) reacting an SM1 compound with a Grignard reagent, and then reacting with an SM2 compound to obtain a compound shown in a formula III; (2) performing oxidation reaction on the compound in the formula III to obtain a compound in a formula II; (3) performing demethylation reaction on the compound in the formula II under the action of a demethylation reagent to obtain a compound in a formula I; (4) carrying out ethylation reaction on the compound shown in the formula I to obtain enovirin; the synthesis route effectively avoids the use of a highly toxic cyaniding reagent and an expensive heavy metal catalyst, and meanwhile, the route is simple and mild in reaction condition and high in yield, and has an extremely good industrial prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and in particular relates to a method for synthesizing an anti-AIDS drug, Ainovirin. Background Art

[0002] Ainuovirine, whose chemical name is 3-{[3-ethyl-2,6-dioxo-5-(propyl-2-yl)-1,2,3,6-tetrahydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile, is regarded as a new generation of non-nucleoside reverse transcriptase inhibitors. It is usually used in combination with nucleoside antiretroviral drugs in clinical practice and can be used for the prevention and treatment of HIV infection. It has the safety and clinical advantages of few drug interactions, controllable side effects and a high barrier to drug resistance.

[0003] The following formula is the structure of Ainuovirine:

[0004]

[0005] There are many reports on the synthesis of Ainoverine in the literature. Most of the methods require the synthesis of the key intermediate Formula I compound 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile, whose structural formula is as follows:

[0006]

[0007] The synthetic routes of intermediate formula I are mainly reported in the following literature:

[0008] Route 1 is the synthetic route of Ainovirin reported in WO2008 / 016522, as shown below:

[0009]

[0010] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and 3-bromo-5-methylbenzeneacetonitrile as starting materials, and prepares the key intermediate Formula I through condensation oxidation reaction, demethylation, and palladium-catalyzed cyanation, and then undergoes ethylation reaction to obtain anovirine.

[0011] This route uses zinc cyanide as the cyanation reagent in the palladium-catalyzed cyanation process. This highly toxic cyanide reagent poses safety concerns during production, including its high toxicity and severe environmental hazards. Furthermore, this process uses tetrakistriphenylphosphine palladium as the heavy metal palladium catalyst, which is expensive and high-cost. Furthermore, the process, which only involves two steps, carries the risk of residual heavy metal palladium in the finished API, making it unsuitable for industrial production.

[0012] Route 2 is the synthetic route of Ainovirin reported in the patent document CN117304118, and the synthetic process is as follows:

[0013]

[0014] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and methyl 3-methyl-5-acetylcyanobenzoate as starting materials. A four-step, one-pot process, condensation, oxidation, ester hydrolysis, and demethylation yield the intermediate carboxylic acid. The final two steps involve carboxylic acid amidation and amide dehydration to produce the key intermediate Formula I. Finally, an ethyl substitution reaction is performed to obtain the API, anovirin. This process has mild operating conditions, but the synthetic route is long and yields are low. Furthermore, the dehydration reaction uses trifluoroacetic anhydride as a dehydrating agent, which is expensive and leads to high costs.

[0015] Route 3 is the synthetic route of Ainovirin reported in CN118063395 patent document, and the synthetic process is as follows:

[0016]

[0017] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and 3-methyl-5-ethoxycyanobenzamide as starting materials. A key intermediate, Formula I, is prepared through condensation, oxidation, dehydration, and demethylation reactions. Ethylation is then performed to obtain enovirine. This process is simple to operate and operates under mild conditions. However, the starting material, 3-methyl-5-ethoxycyanobenzamide, has a low yield and is difficult to purify, which can affect subsequent condensation reactions.

[0018] It can be seen that the current synthesis processes involving ainovirin mostly involve highly toxic cyanide reagents and expensive heavy metal catalysts, which seriously pollute the environment, leading to difficulties in industrialization, high environmental safety requirements and difficulty in handling highly toxic and hazardous wastes.

[0019] Therefore, it is necessary to seek a new synthetic process route for the anti-AIDS drug anovirine that is simple in process, environmentally friendly and low in price. Summary of the Invention

[0020] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for synthesizing the anti-AIDS drug Ainovirin and an intermediate compound for preparing Ainovirin.

[0021] To achieve this object, the present invention adopts the following technical solutions:

[0022] In one aspect, the present invention provides a method for synthesizing the anti-AIDS drug Ainovirin, comprising the following steps:

[0023] (1) SM1 compound 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine reacts with a Grignard reagent, and then reacts with SM2 compound 3-cyano-5-methylbenzaldehyde to obtain a compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile;

[0024] (2) The compound of formula III undergoes oxidation reaction to obtain the compound of formula II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile;

[0025] (3) The compound of formula II undergoes a demethylation reaction under the action of a demethylating agent to obtain the compound of formula I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile;

[0026] (4) The compound of formula I undergoes ethylation reaction to obtain anoverine;

[0027] The reaction process of the method is as follows:

[0028] .

[0029] The preparation method of the present invention efficiently and safely prepares the key intermediate Formula I through Grignard reagent condensation reaction, oxidation reaction, and demethylation reaction, and then prepares anovirine through ethylation reaction, thereby effectively avoiding the use of highly toxic cyaniding reagents and expensive heavy metal catalysts. At the same time, the reaction conditions of this route are simple and mild, the yield is high, and it has excellent industrial prospects.

[0030] Preferably, the Grignard reagent in step (1) is selected from one or a combination of at least two of isopropylmagnesium chloride lithium chloride, phenylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium bromide or 4-chlorophenylmagnesium bromide; more preferably, isopropylmagnesium chloride lithium chloride.

[0031] Preferably, the molar ratio of the SM1 compound to the Grignard reagent in step (1) is 1:(1-3); for example, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, more preferably 1:(1-1.5).

[0032] Preferably, the reaction of the SM1 compound with the Grignard reagent in step (1) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of a C1-C8 alkane solvent, a C2-C8 ether solvent or a C6-C10 aromatic solvent; more preferably, any one or a combination of at least two of chloroform, tetrahydrofuran or 1,4-dioxane; and even more preferably, tetrahydrofuran.

[0033] Preferably, the temperature of the reaction of the SM1 compound with the Grignard reagent in step (1) is -50 to 30°C, for example, -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C, further -20 to 10°C.

[0034] Preferably, the reaction time of the SM1 compound and the Grignard reagent in step (1) is 1-15 h, for example, 1 h, 3 h, 5 h, 8 h, 10 h, 12 h, 14 h or 15 h, further 3-6 h.

[0035] Preferably, the molar ratio of the SM1 compound to the SM2 compound in step (1) is 1:(1-3), such as 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, more preferably 1:(1-1.1).

[0036] Preferably, the temperature of the reaction with the SM2 compound in step (1) is -50 to 30°C, for example, -50°C, -40°C, -30°C, -20°C, -10°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C, more preferably -20 to 10°C.

[0037] Preferably, the reaction time with the SM2 compound in step (1) is 5-24 h, for example, 5 h, 9 h, 12 h, 15 h, 18 h, 21 h or 24 h, more preferably 12-15 h.

[0038] Preferably, the reaction with the SM2 compound in step (1) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents or C6-C10 aromatic solvents; more preferably, any one or a combination of at least two of chloroform, tetrahydrofuran or 1,4-dioxane; and even more preferably, tetrahydrofuran.

[0039] Preferably, the oxidation reaction in step (2) is carried out under the action of an oxidant, and the oxidant is selected from 2,2,6,6-tetramethylpiperidinyl-N-oxyl free radical (TEMPO) and / or 2,2,6,6-tetramethyl-4-methoxypiperidinyl-N-oxyl free radical (4-methoxy-TEMPO); more preferably, 2,2,6,6-tetramethylpiperidinyl-N-oxyl free radical.

[0040] Preferably, the molar ratio of the compound of formula III to the oxidant is 1:(0.01-0.1); for example, 1:0.01, 1:0.03, 1:0.05, 1:0.07, 1:0.09 or 1:0.1, more preferably 1:(0.01-0.05).

[0041] Preferably, the oxidation reaction in step (2) is carried out under the action of a co-oxidant, and the co-oxidant is selected from any one or a combination of at least two of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), sodium hypochlorite or calcium hypochlorite; more preferably, N-bromosuccinimide.

[0042] Preferably, the molar ratio of the compound of formula III to the co-oxidant is 1:(1-4), for example, 1:1, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5, 1:2.8, 1:3, 1:3.3, 1:3.5, 1:3.8 or 1:4, more preferably 1:(1-2).

[0043] Preferably, the oxidation reaction in step (2) is carried out in the presence of a pH regulator, and the pH regulator is selected from any one or a combination of at least two of sodium bicarbonate, sodium dihydrogen phosphate or potassium carbonate; more preferably sodium bicarbonate.

[0044] Preferably, in the oxidation reaction of step (2), the pH of the system is adjusted to 7.0-11.0, for example, 7.0, 7.2, 7.4, 7.8, 8.0, 8.5, 8.8, 9.0, 9.5, 9.8, 10.0, 10.5, 10.8 or 11.0, more preferably 8.0-9.5.

[0045] Preferably, the oxidation reaction in step (2) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic solvents or water; more preferably, it is any one or a combination of at least two of chloroform, tetrahydrofuran, dichloromethane or water; more preferably, it is dichloromethane or water.

[0046] Preferably, the temperature of the oxidation reaction in step (2) is 0-80°C, such as 0°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50°C, 60°C, 70°C or 80°C, further 10-40°C.

[0047] Preferably, the oxidation reaction time in step (2) is 1-10 h, such as 1 h, 2 h, 3 h, 5 h, 8 h or 10 h, further 1-4 h.

[0048] Preferably, the demethylation agent in step (3) is selected from any one or a combination of at least two of lithium hydroxide, lithium bromide or hydrobromic acid; more preferably, hydrobromic acid.

[0049] Preferably, the molar ratio of the compound of formula II to the demethylation agent in step (3) is 1:(2-10), for example, 1:2, 1:2.3, 1:2.5, 1:2.8, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, and further 1:(5-6).

[0050] Preferably, the demethylation reaction in step (3) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of C1-C8 alkane solvents, C2-C8 ether solvents or C6-C10 aromatic solvents; more preferably, it is any one or a combination of at least two of chloroform, tetrahydrofuran or 1,4-dioxane; more preferably, it is 1,4-dioxane.

[0051] Preferably, the temperature of the demethylation reaction in step (3) is 40-100°C, for example, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C or 100°C, further 60-90°C.

[0052] Preferably, the demethylation reaction time in step (3) is 1-10 h, such as 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h, more preferably 2-5 h.

[0053] Preferably, the ethylating agent used in the ethylation reaction in step (4) is selected from ethyl iodide and / or diethyl sulfate, more preferably ethyl iodide.

[0054] Preferably, the molar ratio of the compound of formula I to the ethylating agent is 1:(1-3), for example 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8 or 1:3, further 1:(1-1.6).

[0055] Preferably, the ethylation reaction in step (4) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of C2-C8 nitrile solvents, C2-C8 ether solvents or C6-C10 aromatic hydrocarbon solvents; further, any one or a combination of at least two of acetonitrile, tetrahydrofuran, 1,4-dioxane or toluene, and more preferably acetonitrile.

[0056] Preferably, the temperature of the ethylation reaction in step (4) is 60-100°C, such as 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C or 100°C, further 70-80°C.

[0057] Preferably, the ethylation reaction time in step (4) is 10-30 h, such as 10 h, 15 h, 20 h, 25 h, 28 h or 30 h, further 15-20 h.

[0058] In the present invention, the C1-C8 alkane may be C1, C2, C3, C4, C5, C6, C7 or C8 alkane, the C2-C8 ether may be C2, C3, C4, C5, C6, C7 or C8 ether, and the C6-C10 aromatic hydrocarbons may be C6, C7, C8, C9 or C10 aromatic hydrocarbons.

[0059] As a preferred technical solution, the synthesis method of the anti-AIDS drug Ai Nuowei Lin described in the present invention specifically comprises the following steps:

[0060] (1) The SM1 compound reacts with the Grignard reagent at a molar ratio of 1:(1-3), the reaction temperature is -50 to 30°C, and the reaction time is 1 to 15 h. The reaction product reacts with the SM2 compound at a molar ratio of 1:(1-3), the reaction temperature is -50 to 30°C, and the reaction time is 5 to 24 h to obtain the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile;

[0061] (2) The compound of formula III is subjected to an oxidation reaction with an oxidant and a co-oxidant in the presence of a pH regulator at 0-80° C. for 1-10 hours to obtain the compound of formula II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile; wherein the oxidant is selected from 2,2,6,6-tetramethylpiperidin-N-oxyl radical and / or 2,2,6,6-tetramethyl-4-methoxypiperidin-N-oxyl radical, and the co-oxidant is selected from any one or a combination of at least two of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, sodium hypochlorite or calcium hypochlorite, the molar ratio of the compound of formula III to the oxidant is 1:(0.01-0.1), and the molar ratio of the compound of formula III to the co-oxidant is 1:(1-4), and the pH of the system is adjusted to 7.0-11.0 during the oxidation reaction;

[0062] (3) The compound of formula II is subjected to a demethylation reaction at 40-100°C for 1-10 h to obtain the compound of formula I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile; wherein the molar ratio of the compound of formula II to the demethylation reagent is 1:(2-10).

[0063] (4) The compound of formula I is subjected to an ethylation reaction with an ethylating agent at 60-100° C. for 10-30 h, wherein the molar ratio of the compound of formula I to the ethylating agent is 1:(1-3), to obtain anovirine.

[0064] On the other hand, the present invention provides an intermediate compound for preparing ainovirin, wherein the intermediate compound has a structure shown in Formula III:

[0065] .

[0066] The preparation method of the intermediate compound of the structure shown in Formula III is as described in step (1) of the synthesis method of Anovirin above, and will not be repeated here.

[0067] On the other hand, the present invention provides a method for preparing a compound of formula I, an intermediate of enovirine. The preparation method comprises steps (1) to (3) of the above-mentioned method for synthesizing enovirine, which will not be described in detail here.

[0068] The present invention prepares an intermediate compound of the structure shown in formula II through an oxidation reaction of an intermediate compound of the structure shown in formula III, and then obtains a compound of formula I through a demethylation reaction. The compound of formula I can be subjected to an ethylation reaction to prepare ainovirin, effectively avoiding the use of highly toxic cyaniding reagents and expensive heavy metal catalysts. At the same time, this route has simple and mild reaction conditions, high yield, and excellent industrial prospects.

[0069] Compared with the prior art, the present invention has the following beneficial effects:

[0070] The preparation method of the present invention first obtains an intermediate compound with a structure shown in formula III through a Grignard reagent condensation reaction, and then efficiently and safely prepares the key intermediate compound of formula I through an oxidation reaction and a demethylation reaction, and then prepares anovirine through an ethylation reaction. The route of the present invention effectively avoids the use of highly toxic cyaniding reagents and expensive heavy metal catalysts. At the same time, the reaction conditions of this route are simple and mild, the yield is high, and it has excellent industrial prospects. DETAILED DESCRIPTION

[0071] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0072] The overall preparation routes of the compounds involved in the following examples are as follows:

[0073] .

[0074] Example 1: Preparation of Starting Material SM1 Compound 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine

[0075] 2,4,6-trihydroxy-5-isopropylpyrimidine (200.00 g, 1.18 mol, Cas: 7391-69-7), toluene (1000 ml) and phosphorus oxybromide (1348.00 g, 4.70 mol) were added to a 2 L reaction flask. After stirring, N,N-diethylaniline (316.00 g, 2.12 mol) was slowly added dropwise. The temperature was raised to 100-110°C and the reaction was carried out for 4 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was returned to room temperature. The reaction solution was poured into ice water, extracted and separated, and concentrated to obtain 416.00 g of 2,4,6-tribromo-5-isopropylpyrimidine (yield 98.6%). Then, 2,4,6-tribromo-5-isopropylpyrimidine (200.00 g, 0.56 mol) and methanol (800 ml) were added to a 2 L reaction flask. The temperature was controlled at 0°C, and the prepared 28% sodium methoxide methanol solution (66.00 g, 1.22 mol) was slowly added dropwise. The reaction was carried out at 0°C for 20 hours. The reaction process was monitored by TLC. After the reaction was completed, the pH was adjusted to 4-5, and the liquid was extracted and concentrated to obtain 144.00 g of 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine, with a yield of 98.9%. HRMS: 261.02316 [M+H] + , 1 H-NMR: (400 MHz, DMSO-d6) δ 3.95 (s, 3H), 3.87 (s, 3H), 3.32 (s, 1H), 1.22 (d, J = 7.0 Hz, 6H).

[0076] Example 2: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0077] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (100.00 g, 0.38 mol) and tetrahydrofuran (200 ml) were added to a 1 L reaction flask. The mixture was replaced with N2. Isopropylmagnesium chloride and lithium chloride (285 ml, 0.57 mol) were slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred and cooled to 5 °C. After 4 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (60.00 g, 0.41 mol) and tetrahydrofuran (3 00ml), N2 was replaced, and the mixture was stirred and cooled to 0℃. The Grignard reagent solution was slowly added dropwise after the reaction was completed. After stirring, the mixture was cooled to 0℃ and kept stirring for 13 hours. The reaction process was monitored by TLC. After the reaction was completed, the mixture was returned to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction. The mixture was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (94.09g). The yield was 74.9%. HRMS: 328.16498[M+H] + , 1 H-NMR: (400 MHz, DMSO-d6) δ 7.60 – 7.43 (m, 3H), 6.23 (d, J = 5.9 Hz, 1H), 5.86 (d, J = 5.3 Hz, 1H), 3.89 (d, J = 15.5 Hz, 6H), 3.30 (s, 1H), 2.32 (s, 3H), 1.08 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H).

[0078] Example 3: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0079] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) was added to a 25 ml reaction bottle, and tetrahydrofuran (10 ml) was replaced with N2. 4-Chlorophenylmagnesium bromide (14.4 ml, 28.75 mmol) was slowly added dropwise at 0 ° C. After the addition was complete, the temperature was stirred and cooled to 5 ° C. After 4 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (3.00 g, 20.6 The reaction mixture was stirred at 0 °C and the reaction mixture was cooled to 0 °C. The reaction mixture was stirred and cooled to 0 °C for 13 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was returned to room temperature. Ammonium chloride solution and ethyl acetate were added to extract the separated liquid. The liquid was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (2.63 g) with a yield of 41.9%.

[0080] Example 4: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0081] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) was added to a 25 ml reaction bottle, and tetrahydrofuran (10 ml) was replaced with N2. Tert-butylmagnesium chloride (14.4 ml, 28.75 mmol) was slowly added dropwise at 0 ° C. After the addition was complete, the temperature was stirred and cooled to 5 ° C. After 4 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (3.00 g, 20.65 The reaction mixture was stirred at 0 °C and the Grignard reagent solution was slowly added dropwise. After the addition was complete, the temperature was cooled to 0 °C with stirring. The mixture was kept warm and stirred for 13 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was returned to room temperature. Ammonium chloride solution and ethyl acetate were added to extract the liquid. The liquid was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (1.90 g) with a yield of 30.4%.

[0082] Example 5: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0083] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added to a 25 ml reaction bottle. After N2 replacement, isopropylmagnesium chloride and lithium chloride (10 ml, 19.15 mmol) were slowly added dropwise at 0 ° C. After the addition was complete, the temperature was stirred and cooled to 5 ° C. After 4 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (3.00 g, 20.6 The reaction mixture was stirred at 0 °C and the reaction mixture was cooled to 0 °C. The reaction mixture was stirred and cooled to 0 °C for 13 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was returned to room temperature. Ammonium chloride solution and ethyl acetate were added to extract the separated liquid. The liquid was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (2.93 g) with a yield of 46.7%.

[0084] Example 6: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0085] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added to a 25 ml reaction flask. After N2 substitution, isopropylmagnesium chloride and lithium chloride (29 ml, 57.45 mmol) were slowly added dropwise at 0°C. After the addition was complete, the mixture was stirred and cooled to -15°C. After 6 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (3.00 g, 20. The reaction mixture was stirred at 0 °C and the reaction mixture was cooled to 10 °C. The mixture was stirred for 12 hours and the reaction process was monitored by TLC. After the reaction was completed, the mixture was returned to room temperature and extracted with ammonium chloride solution and ethyl acetate. The mixture was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.40 g) with a yield of 70.3%.

[0086] Example 7: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0087] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added to a 25 ml reaction flask. After N2 substitution, isopropylmagnesium chloride and lithium chloride (14.4 ml, 28.73 mmol) were slowly added dropwise at 0°C. After the addition was complete, the mixture was stirred and cooled to 5°C. After 4 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (2.78 g, 19.15 mmol) was added to another 50 ml reaction flask. The reaction mixture was stirred at 0 °C and the reaction mixture was cooled to 0 °C. The reaction mixture was stirred and cooled to 0 °C. The reaction mixture was kept stirring for 13 hours. The reaction process was monitored by TLC. After the reaction was completed, the reaction mixture was returned to room temperature. Ammonium chloride solution and ethyl acetate were added to extract the separated liquid. The liquid was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (3.04 g) with a yield of 48.5%.

[0088] Example 8: Preparation of the intermediate compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile

[0089] 4-Bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added to a 25 ml reaction flask. After N2 displacement, isopropylmagnesium chloride and lithium chloride (14.4 ml, 28.73 mmol) were slowly added dropwise at 0°C. After the addition was complete, the temperature was lowered to 10°C with stirring. After 3 hours of reaction, TLC showed that SM1 had disappeared. 3-Cyano-5-methylbenzaldehyde (8.34 g, 57. The reaction mixture was stirred at 0 °C and the reaction mixture was cooled to -20 °C. The mixture was stirred for 15 hours and the reaction process was monitored by TLC. After the reaction was completed, the temperature was returned to room temperature, and ammonium chloride solution and ethyl acetate were added to extract the separated liquid. The mixture was washed with water and dried to obtain a light yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.57 g) with a yield of 72.9%.

[0090] Example 9: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0091] Sodium bicarbonate (37.00 g, 0.44 mol) and water (500 ml) were added to a 2 L reaction flask, followed by a solution of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (90.00 g, 0.28 mol) of the compound of formula III dissolved in dichloromethane (1000 ml). The reaction was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. The catalyst TEMPO (2.00 g, 12.80 mmol), the oxidizing agent, and the like were added in sequence. The reaction mixture was added with NBS (98.00 g, 0.55 mol), and the temperature was controlled to be less than 25 ° C. After the addition was completed, the reaction was placed at 25 ° C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, it was extracted with dichloromethane, concentrated, and dried to obtain 57.00 g of off-white solid 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile. The yield was 63.3%, HRMS: 326.1495 [M+H] +, 1H-NMR: (600 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.03 (d, J =10.4 Hz, 2H), 4.02 (s, 3H), 3.84 (s, 3H), 2.75 (p, J = 7.0 Hz, 1H), 2.44 (s,3H), 1.14 (d, J = 7.0 Hz, 6H).

[0092] Example 10: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0093] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 2 L reaction flask. Then, a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml) was added. The temperature was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. Catalyst 4-methoxyTEMPO (0.12 g, 0.70 mmol) and oxidant NBS (4.90 g, 27.50 mol) were added in sequence. The temperature was controlled to <25°C. After the addition was complete, the reaction was kept at 25°C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, the product was extracted with dichloromethane, concentrated, and dried to obtain 2.49 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid with a yield of 50.2%.

[0094] Example 11: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0095] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 50 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The mixture was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. Catalyst TEMPO (0.10 g, 0.64 mmol) and oxidant NCS (3.67 g, 27.50 mmol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was allowed to proceed at 25°C for 1 hour. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.85 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 41.3%.

[0096] Example 12: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0097] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 50 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The temperature was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. Catalyst TEMPO (0.10 g, 0.64 mmol) and oxidant 10% sodium hypochlorite solution (20.47 g, 27.50 mmol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was allowed to proceed at 25°C for 1 hour. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.65 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 37.5%. Example 13: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0098] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 200 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The temperature was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. Catalyst TEMPO (0.022 g, 0.14 mmol) and oxidant NBS (4.89 g, 27.50 mol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was kept at 25°C for 1 hour. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 0.56 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 12.6%.

[0099] Example 14: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0100] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 200 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The reaction was cooled in an ice-water bath to control the pH in the reaction flask to 8.0. Catalyst TEMPO (0.22 g, 1.38 mmol) and oxidant NBS (4.89 g, 27.50 mol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was kept at 10°C for 4 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 2.69 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 60.1%.

[0101] Example 15: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0102] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 200 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The reaction was cooled in an ice-water bath to control the pH in the reaction flask to 9.0. Catalyst TEMPO (0.10 g, 0.64 mmol) and oxidant NBS (2.45 g, 13.75 mol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was kept at 25°C for 1 hour. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.78 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 39.7%.

[0103] Example 16: Preparation of the intermediate compound of formula II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile

[0104] Sodium bicarbonate (1.85 g, 22.00 mmol) and water (25 ml) were added to a 200 ml reaction flask, followed by a solution of the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol) dissolved in dichloromethane (50 ml). The temperature was cooled in an ice-water bath to control the pH in the reaction flask to 9.5. Catalyst TEMPO (0.10 g, 0.64 mmol) and oxidant NBS (9.79 g, 55.00 mol) were added in sequence, and the temperature was controlled to <25°C. After the addition was complete, the reaction was kept at 40°C for 2 hours. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 2.80 g of 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile as an off-white solid in a yield of 62.5%.

[0105] Example 17: Preparation of the intermediate compound of formula I 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile

[0106] 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile (50.00 g, 0.15 mol), 40% hydrobromic acid (151.71.00 g, 0.75 mol) and 1,4-dioxane (100 ml) were added to a 500 ml reaction flask. The temperature was raised to 75°C and the reaction was allowed to proceed for 2 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, filtered, washed with water, and dried to obtain 44.00 g of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile as a white solid. The yield was 96.12%. HRMS: 298.11844 [M+H] + , 1 H-NMR: (500Hz, DMSO-d6), δ(ppm), 11.14(s, 1H), 10.98(s,1H), 8.36(s, 1H), 8.14(s, 1H), 8.07(s, 1H), 2.47(s, 3H), 2.28(m, 1H, J=6.7Hz), 1.06(d, 6H, J=6.7Hz).

[0107] Example 18: Preparation of the intermediate compound of formula I 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile

[0108] 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile (5.00 g, 15.35 mmol), lithium bromide (6.67 g, 76.75 mmol) and 1,4-dioxane (10 ml) were added to a 25 ml reaction flask. The temperature was raised to 80°C and the reaction was carried out for 3 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, filtered, washed with water, and dried to obtain 2.60 g of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile as a white solid with a yield of 57.1%.

[0109] Example 19: Preparation of the intermediate compound of formula I 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile

[0110] 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile (5.00 g, 15.35 mmol), 40% hydrobromic acid (6.2 g, 30.70 mmol) and 1,4-dioxane (10 ml) were added to a 500 ml reaction flask. The temperature was raised to 80°C and the reaction was carried out for 3 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, filtered, washed with water, and dried to obtain 2.30 g of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile as a white solid with a yield of 50.3%.

[0111] Example 20: Preparation of the intermediate compound of formula I 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile

[0112] 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile (5.00 g, 15.35 mmol), 40% hydrobromic acid (31.05 g, 153.50 mmol) and 1,4-dioxane (10 ml) were added to a 500 ml reaction flask. The temperature was raised to 60°C and the reaction was carried out for 5 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, filtered, washed with water, and dried to obtain 4.39 g of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile as a white solid with a yield of 96.0%.

[0113] Example 21: Preparation of Ainovirin

[0114] 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (40.00 g, 0.13 mol), acetonitrile (400 ml), N,N-diisopropylethylamine (28.00 g, 0.21 mol) and iodoethane (29.06 g, 0.21 mol) were added to a 1 L reaction flask. The temperature was raised to 70°C and the reaction was carried out for 17 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, the pH was adjusted to 4, purified water (400 ml) was added, and the mixture was stirred for 1 hour. The mixture was filtered, washed with water, and recrystallized from anhydrous ethanol. The mixture was filtered and dried to obtain 38.44 g of anovirine with a yield of 87.9%. HRMS: 326.15031 [M+H] + , 1H-NMR: (500Hz, DMSO-d6), δ(ppm),11.42(s, 1H), 8.50(s, 1H), 8.26(s, 1H), 8.12(s, 1H), 3.73(m, 1H), 3.06(m,1H), 2.48(s, 3H), 2.12(m, 1H, J=6.9Hz), 1.10(d, 3H, J=6.9Hz), 1.03(d, 3H, J=6.9Hz), 1.00(t, 3H, J=7.2Hz).

[0115] Example 22: Preparation of Ainovirin

[0116] 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (5.00 g, 16.80 mmol), acetonitrile (50 ml), N,N-diisopropylethylamine (3.47 g, 26.88 mol) and iodoethane (2.62 g, 16.80 mmol) were added to a 50 ml reaction bottle, and the temperature was raised to 70 ° C. The reaction was allowed to react for 17 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, the pH was adjusted to 4, purified water (50 ml) was added, and the mixture was stirred for 1 hour. The mixture was filtered, washed with water, recrystallized from anhydrous ethanol, and filtered and dried to obtain 3.44 g of anovirine with a yield of 62.8%.

[0117] Example 23: Preparation of Ainovirin

[0118] 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (5.00 g, 16.80 mmol), acetonitrile (50 ml), N,N-diisopropylethylamine (3.47 g, 26.88 mol) and iodoethane (7.86 g, 50.40 mmol) were added to a 50 ml reaction bottle, and the temperature was raised to 90 ° C. The reaction was reacted for 15 hours. The reaction process was monitored by TLC. After the reaction was completed, the temperature was lowered to room temperature, the pH was adjusted to 4, purified water (50 ml) was added, and the mixture was stirred for 1 hour. Filtered, washed with water, recrystallized with anhydrous ethanol, and filtered and dried to obtain 2.90 g of anovirine with a yield of 53.0%.

[0119] The applicant declares that while the above-described embodiments illustrate the preparation process of the present invention, the present invention is not limited to the above-described preparation process, and does not imply that the present invention must rely on the above-described preparation process for implementation. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. A method for synthesizing an anti-AIDS drug, Ai Nuowei Lin, characterized in that: The method comprises the following steps: (1) SM1 compound 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine reacts with a Grignard reagent, and then reacts with SM2 compound 3-cyano-5-methylbenzaldehyde to obtain a compound of formula III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile; (2) The compound of formula III undergoes oxidation reaction to obtain the compound of formula II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile; (3) The compound of formula II undergoes a demethylation reaction under the action of a demethylating agent to obtain the compound of formula I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile; (4) The compound of formula I undergoes ethylation reaction to obtain anoverine; The reaction process of the method is as follows: 。 2. The synthesis method according to claim 1, characterized in that The Grignard reagent in step (1) is selected from one or a combination of at least two of isopropylmagnesium chloride, lithium chloride, phenylmagnesium chloride, tert-butylmagnesium chloride, isopropylmagnesium bromide or 4-chlorophenylmagnesium bromide; The molar ratio of the SM1 compound to the Grignard reagent in step (1) is 1:(1-3).

3. The synthesis method according to claim 1, wherein The Grignard reagent in step (1) is isopropylmagnesium chloride and lithium chloride; The molar ratio of the SM1 compound to the Grignard reagent in step (1) is 1:(1-1.5).

4. The synthesis method according to claim 1, characterized in that The reaction of the SM1 compound and the Grignard reagent in step (1) is carried out in a solvent selected from any one or a combination of at least two of a C1-C8 alkane solvent, a C2-C8 ether solvent or a C6-C10 aromatic solvent; The temperature of the reaction between the SM1 compound and the Grignard reagent in step (1) is -50 to 30°C; The reaction time of the SM1 compound and the Grignard reagent in step (1) is 1-15 h; The molar ratio of the SM1 compound to the SM2 compound in step (1) is 1:(1-3); The temperature of the reaction with the SM2 compound in step (1) is -50 to 30°C; The reaction time of step (1) with the SM2 compound is 5-24 h; The reaction with the SM2 compound in step (1) is carried out in a solvent, and the solvent is selected from any one or a combination of at least two of a C1-C8 alkane solvent, a C2-C8 ether solvent or a C6-C10 aromatic solvent.

5. The synthesis method according to claim 1, characterized in that The oxidation reaction in step (2) is carried out under the action of an oxidant, wherein the oxidant is selected from 2,2,6,6-tetramethylpiperidinyl-N-oxyl free radical and / or 2,2,6,6-tetramethyl-4-methoxypiperidinyl-N-oxyl free radical; The molar ratio of the compound of formula III to the oxidant is 1:(0.01-0.1); The oxidation reaction in step (2) is carried out under the action of a co-oxidant, wherein the co-oxidant is selected from any one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, sodium hypochlorite or calcium hypochlorite, or a combination of at least two thereof; The molar ratio of the compound of formula III to the co-oxidant is 1:(1-4); The oxidation reaction in step (2) is carried out in the presence of a pH regulator, wherein the pH regulator is selected from any one of sodium bicarbonate, sodium dihydrogen phosphate or potassium carbonate, or a combination of at least two thereof; In the oxidation reaction of step (2), the pH of the system is adjusted to 7.0-11.0; The oxidation reaction in step (2) is carried out in a solvent, wherein the solvent is selected from any one or a combination of at least two of a C1-C8 alkane solvent, a C2-C8 ether solvent, a C6-C10 aromatic hydrocarbon solvent or water; The temperature of the oxidation reaction in step (2) is 0-80°C; The oxidation reaction time in step (2) is 1-10 hours.

6. The synthesis method according to claim 1, characterized in that The demethylation reagent in step (3) is selected from any one or a combination of at least two of lithium hydroxide, lithium bromide or hydrobromic acid; In step (3), the molar ratio of the compound of formula II to the demethylation agent is 1:(2-10); The demethylation reaction in step (3) is carried out in a solvent selected from any one or a combination of at least two of a C1-C8 alkane solvent, a C2-C8 ether solvent, or a C6-C10 aromatic solvent; The temperature of the demethylation reaction in step (3) is 40-100°C; The demethylation reaction time in step (3) is 1-10 h.

7. The synthesis method according to claim 1, characterized in that The ethylating agent used in the ethylation reaction in step (4) is selected from ethyl iodide and / or diethyl sulfate; The molar ratio of the compound of formula I to the ethylating agent is 1:(1-3).

8. The synthesis method according to claim 1, characterized in that The ethylation reaction in step (4) is carried out in a solvent selected from any one or a combination of at least two of a C2-C8 nitrile solvent, a C2-C8 ether solvent, or a C6-C10 aromatic hydrocarbon solvent; The temperature of the ethylation reaction in step (4) is 60-100°C; The ethylation reaction time in step (4) is 10-30 h.

9. The synthesis method according to claim 1, characterized in that The synthesis method comprises the following steps: (1) SM1 compound reacts with Grignard reagent at a molar ratio of 1:(1-3), the reaction temperature is -50 to 30°C, and the reaction time is 1 to 15 h. The reaction product reacts with SM2 compound at a molar ratio of SM1 compound to SM2 compound of 1:(1-3), the reaction temperature is -50 to 30°C, and the reaction time is 5 to 24 h to obtain the compound of formula III, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile; (2) The compound of formula III is subjected to an oxidation reaction with an oxidant and a co-oxidant in the presence of a pH regulator at 0-80° C. for 1-10 hours to obtain the compound of formula II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile; wherein the oxidant is selected from 2,2,6,6-tetramethylpiperidin-N-oxyl radical and / or 2,2,6,6-tetramethyl-4-methoxypiperidin-N-oxyl radical, and the co-oxidant is selected from any one or a combination of at least two of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, sodium hypochlorite or calcium hypochlorite, the molar ratio of the compound of formula III to the oxidant is 1:(0.01-0.1), and the molar ratio of the compound of formula III to the co-oxidant is 1:(1-4), and the pH of the system is adjusted to 7.0-11.0 during the oxidation reaction; (3) The compound of formula II is subjected to a demethylation reaction at 40-100°C for 1-10 hours to obtain the compound of formula I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile; wherein the molar ratio of the compound of formula II to the demethylation reagent is 1:(2-10); (4) The compound of formula I is subjected to an ethylation reaction with an ethylating agent at 60-100° C. for 10-30 h, wherein the molar ratio of the compound of formula I to the ethylating agent is 1:(1-3), to obtain anovirine.

10. An intermediate compound for preparing ainovirin, characterized in that: The intermediate compound has the structure shown in Formula III: 。

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