Synthesis method of anti-aids drug amdoxovir

Abstract

This invention provides a method for synthesizing the anti-AIDS drug enovirine. This invention belongs to the field of pharmaceutical preparation technology. The synthesis method includes the following steps: (1) SM1 compound reacts with Grignard reagent and then reacts with SM2 compound to obtain compound III; (2) Compound III undergoes oxidation reaction to obtain compound II; (3) Compound II undergoes demethylation reaction under the action of demethylation reagent to obtain compound I; (4) Compound I undergoes ethylation reaction to obtain enovirine. The synthesis route of this invention effectively avoids the use of highly toxic cyanide reagents and expensive heavy metal catalysts. At the same time, the reaction conditions of this route are simple and mild, with high yield, and have excellent industrialization prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for synthesizing the anti-AIDS drug enavirin. Background Technology

[0002] Ainuovirine, chemically known as 3-{[3-ethyl-2,6-dioxo-5-(propyl-2-yl)-1,2,3,6-tetrahydropyrimidin-4-yl]carbonyl}-5-methylbenzonitrile, is considered a new generation of non-nucleoside reverse transcription inhibitors. It is often used in combination with nucleoside antiretroviral drugs in clinical practice for the prevention and treatment of HIV infection. It has the advantages of low drug interactions, manageable side effects, and a high drug resistance barrier.

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

[0004]

[0005] Numerous synthetic methods for anivirine have been reported in the literature, and most of these methods require the synthesis of the key intermediate, compound 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile, with the following structural formula:

[0006]

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

[0008] Route 1 is the synthetic route for enovalin reported in patent document WO2008 / 016522, as shown below:

[0009]

[0010] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and 3-bromo-5-methylphenylacetonitrile as starting materials, and prepares the key intermediate formula I through condensation oxidation reaction, demethylation, and palladium-catalyzed cyanoation. Subsequently, ethylation reaction is carried out to obtain enovetine.

[0011] This route uses zinc cyanide as the cyaniding reagent in the palladium-catalyzed cyanation process. Zinc cyanide is a highly toxic cyanide reagent, and safety concerns during production primarily include its high toxicity and severe environmental damage. Furthermore, this route uses tetraphenylphosphine palladium as the heavy metal palladium catalyst, which is expensive and costly. It also carries the risk of residual heavy metal palladium in the finished drug product, which only involves two steps, making it unsuitable for industrial production.

[0012] Route 2 is the synthetic route for enovalin reported in patent document CN117304118. The synthetic process is as follows:

[0013]

[0014] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and methyl 3-methyl-5-ethylcyanobenzoate as starting materials. A one-pot synthesis involving condensation, oxidation, ester hydrolysis, and demethylation yields the intermediate carboxylic acid. The remaining two steps involve amidation of the carboxylic acid and dehydration of the amide to prepare the key intermediate, Formula I. Finally, an ethyl substitution reaction is completed to obtain the active pharmaceutical ingredient, enovvirine. While this process operates under mild conditions, the synthetic route is lengthy, resulting in low yields. Furthermore, the dehydration reaction uses expensive trifluoroacetic anhydride as a dehydrating agent, leading to high costs.

[0015] Route 3 is the synthetic route for enovalin reported in patent document CN118063395. The synthetic process is shown below:

[0016]

[0017] This route uses 4-chloro-5-isopropyl-2,6-dimethoxypyrimidine and 3-methyl-5-ethylcyanobenzoamide as starting materials, and prepares the key intermediate formula I through condensation, oxidation, dehydration, and demethylation reactions, followed by ethylation to obtain enovirine. This process is simple and mild, but the yield of the starting material 3-methyl-5-ethylcyanobenzoamide is low and difficult to purify, which can affect subsequent condensation reactions.

[0018] It is evident that most of the current synthesis processes involving anifloxacin involve highly toxic cyanide reagents and expensive heavy metal catalysts, which cause serious environmental pollution, resulting in difficulties in industrialization, high environmental safety requirements, and challenges in the treatment of highly toxic hazardous waste.

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

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

[0021] To achieve this objective, the present invention adopts the following technical solution:

[0022] On one hand, the present invention provides a method for synthesizing the anti-AIDS drug enovalin, the method comprising the following steps:

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

[0024] (2) Compound III undergoes an oxidation reaction to give compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile;

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

[0026] (4) The compound of formula I undergoes an ethylation reaction to give enovirine;

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

[0028] .

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

[0030] Preferably, the Grignard reagent in step (1) is selected from one or a combination of at least two of isopropyl magnesium chloride lithium chloride, phenyl magnesium chloride, tert-butyl magnesium chloride, isopropyl magnesium bromide or 4-chlorophenyl magnesium bromide; more preferably, isopropyl magnesium 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, and 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, wherein 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, chloroform, tetrahydrofuran or 1,4-dioxane; and even more preferably, tetrahydrofuran.

[0033] Preferably, the reaction temperature 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, and more preferably -20 to 10°C.

[0034] Preferably, the reaction time of the SM1 compound with 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, and more preferably 3-6 h.

[0035] Preferably, the molar ratio of SM1 compound and SM2 compound 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, and more preferably 1:(1-1.1).

[0036] Preferably, the temperature at which the reaction with the SM2 compound occurs 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, and 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, and more preferably 12-15 h.

[0038] Preferably, the reaction with the SM2 compound in step (1) is carried out in a solvent, which 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, 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, which is selected from 2,2,6,6-tetramethylpiperidine-N-oxygen radical (TEMPO) and / or 2,2,6,6-tetramethyl-4-methoxypiperidine-N-oxygen radical (4-methoxy-TEMPO); more preferably 2,2,6,6-tetramethylpiperidine-N-oxygen 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, and more preferably 1:(0.01-0.05).

[0041] Preferably, the oxidation reaction in step (2) is carried out under the action of a co-oxidizing agent, which 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, and more preferably 1:(1-2).

[0043] Preferably, the oxidation reaction in step (2) is carried out in the presence of a pH adjuster, which 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 described in 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, and more preferably 8.0-9.5.

[0045] Preferably, the oxidation reaction in step (2) is carried out in a solvent, which 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, any one or a combination of at least two of chloroform, tetrahydrofuran, dichloromethane or water; more preferably, dichloromethane or water.

[0046] Preferably, the temperature of the oxidation reaction in step (2) is 0-80℃, for example 0℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 50℃, 60℃, 70℃ or 80℃, and more preferably 10-40℃.

[0047] Preferably, the oxidation reaction in step (2) takes 1-10 hours, for example, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours or 10 hours, and more preferably 1-4 hours.

[0048] Preferably, the demethylating agent in step (3) is selected from any one or at least a combination of 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 demethylating 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 more preferably 1:(5-6).

[0050] Preferably, the demethylation reaction in step (3) is carried out in a solvent, which 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, chloroform, tetrahydrofuran or 1,4-dioxane; and more preferably, 1,4-dioxane.

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

[0052] Preferably, the demethylation reaction in step (3) takes 1-10 h, for example 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h, and more preferably 2-5 h.

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

[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, and more preferably 1:(1-1.6).

[0055] Preferably, the ethylation reaction in step (4) is carried out in a solvent, which 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 solvents; further, it is 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, for example 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C or 100°C, and more preferably 70-80°C.

[0057] Preferably, the ethylation reaction time in step (4) is 10-30 h, for example 10 h, 15 h, 20 h, 25 h, 28 h or 30 h, and more preferably 15-20 h.

[0058] In this invention, the C1-C8 alkanes can be C1, C2, C3, C4, C5, C6, C7 or C8 alkanes, the C2-C8 ethers can be C2, C3, C4, C5, C6, C7 or C8 ethers, and the C6-C10 aromatics can be C6, C7, C8, C9 or C10 aromatics.

[0059] As a preferred technical solution, the method for synthesizing the anti-AIDS drug enavirin according to the present invention specifically includes the following steps:

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

[0061] (2) Compound III is oxidized with an oxidant and a co-oxidant at 0-80℃ for 1-10h in the presence of a pH adjuster to obtain compound II 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile; wherein the oxidant is selected from 2,2,6,6-tetramethylpiperidine-N-oxy radical and / or 2,2,6,6-tetramethyl-4-methoxypiperidine-N-oxy radical, and the co-oxidant is selected from any one or at least two of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, sodium hypochlorite or calcium hypochlorite, the molar ratio of compound III to oxidant is 1:(0.01-0.1), the molar ratio of compound III to 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) Compound II undergoes a demethylation reaction at 40-100℃ for 1-10 h under the action of a demethylating agent to obtain compound I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile; wherein the molar ratio of compound II to the demethylating agent is 1:(2-10).

[0063] (4) The compound of formula I and the ethylating agent are subjected to ethylation reaction at 60-100℃ for 10-30 h, and the molar ratio of the compound of formula I to the ethylating agent is 1:(1-3) to obtain enovirine.

[0064] On the other hand, the present invention provides an intermediate compound for the preparation of enovivin, said intermediate compound having the structure shown in Formula III:

[0065] .

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

[0067] On the other hand, the present invention provides a method for preparing an intermediate compound of formula I of anivirine, the preparation method comprising steps (1) to (3) of the synthesis method of anivirine as described above, which will not be repeated here.

[0068] This invention prepares an intermediate compound with the structure shown in Formula II by oxidizing an intermediate compound with the structure shown in Formula III, and then obtains a compound of Formula I by demethylation. The compound of Formula I can be ethylated to prepare enovilin, effectively avoiding the use of highly toxic cyanide reagents and expensive heavy metal catalysts. At the same time, the reaction conditions of this route are simple and mild, with high yield, and it has excellent prospects for industrialization.

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

[0070] The preparation method of this invention first obtains the intermediate compound with the structure shown in Formula III through Grignard reagent condensation reaction, and then efficiently and safely prepares the key intermediate compound of Formula I through oxidation reaction and demethylation reaction. Finally, enovirine is prepared through ethylation reaction. The route of this invention effectively avoids the use of highly toxic cyanide reagents and expensive heavy metal catalysts. At the same time, the reaction conditions of this route are simple and mild, with high yield, and have excellent industrialization prospects. Detailed Implementation

[0071] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

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

[0073] .

[0074] Example 1: Preparation of starting material SM1 compound 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine

[0075] In a 2L reaction flask, 2,4,6-trihydroxy-5-isopropylpyrimidine (200.00 g, 1.18 mol, Cas: 7391-69-7), toluene (1000 ml), and phosphorus tribromooxy (1348.00 g, 4.70 mol) were added and stirred. 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 mixture was brought back to room temperature, poured into ice water, extracted, and concentrated to obtain 416.00 g of 2,4,6-tribromo-5-isopropylpyrimidine, with a yield of 98.6%. Next, 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 a 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, and the reaction process was monitored by TLC. After the reaction was completed, the pH was adjusted to 4-5, the mixture was extracted and separated, 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 intermediate compound 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile

[0077] In a 1L reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (100.00 g, 0.38 mol) and tetrahydrofuran (200 ml) were added, and the mixture was replaced with N2. Isopropyl magnesium 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. In another 1L reaction flask, 3-cyano-5-methylbenzaldehyde (60.00 g, 0.41 mol) and tetrahydrofuran (3... 0.00 ml of N2 was used to replace the solvent. The mixture was stirred and cooled to 0°C. The Grignard reagent solution was slowly added dropwise. After the addition was complete, the mixture was stirred and cooled to 0°C. The mixture was kept at this temperature and stirred for 13 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was brought back to room temperature. Ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (94.09 g), yield 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 intermediate compound 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile

[0079] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) was added, and tetrahydrofuran (10 ml) was used for N2 replacement. 4-Chlorophenyl magnesium bromide (14.4 ml, 28.75 mmol) was 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. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (3.00 g, 20.6 mmol) was added. 5 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0°C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to 0°C and stirred for 13 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (2.63 g), with a yield of 41.9%.

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

[0081] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) was added, 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 mixture was stirred and cooled to 5 °C. After 4 hours of reaction, TLC showed that SM1 had disappeared. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (3.00 g, 20.65 mmol) was added. 1 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0 °C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to 0 °C and stirred for 13 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (1.90 g), with a yield of 30.4%.

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

[0083] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added, and the mixture was replaced with N2. Isopropyl magnesium chloride and lithium chloride (10 ml, 19.15 mmol) were slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred and cooled to 5 °C. After reacting for 4 hours, TLC showed that SM1 had disappeared. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (3.00 g, 20.6 mmol) was added. 5 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0 °C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to 0 °C and stirred for 13 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (2.93 g), with a yield of 46.7%.

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

[0085] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added, and the mixture was replaced with N2. Isopropyl magnesium 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 reacting for 6 hours, TLC showed that SM1 had disappeared. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (3.00 g, 20 ml) was added. 65 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0 °C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to 10 °C and kept at this temperature for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.40 g), with a yield of 70.3%.

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

[0087] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added, and N2 was used for replacement. Isopropyl magnesium 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 reacting for 4 hours, TLC showed that SM1 had disappeared. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (2.78 g, 19.15 mmol) was added. 15 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0 °C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to 0 °C and stirred for 13 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (3.04 g), with a yield of 48.5%.

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

[0089] In a 25 ml reaction flask, 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine (5.00 g, 19.15 mmol) and tetrahydrofuran (10 ml) were added, and N2 was used for replacement. Isopropyl magnesium 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 10 °C. After reacting for 3 hours, TLC showed that SM1 had disappeared. In another 50 ml reaction flask, 3-cyano-5-methylbenzaldehyde (8.34 g, 57.5 mmol) was added. 45 mmol) and tetrahydrofuran (15 ml) were added, replaced with N2, and stirred until the temperature dropped to 0 °C. The Grignard reagent solution was then slowly added dropwise. After the addition was complete, the temperature was lowered to -20 °C and kept at this temperature for 15 hours. The reaction was monitored by TLC. After the reaction was completed, the temperature was restored to room temperature, and ammonium chloride solution and ethyl acetate were added for extraction and separation. The mixture was washed with water and dried to obtain a pale yellow solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.57 g), with a yield of 72.9%.

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

[0091] In a 2L reaction flask, sodium bicarbonate (37.00 g, 0.44 mol) and water (500 ml) were added. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (90.00 g, 0.28 mol), dissolved in dichloromethane (1000 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was adjusted to 9.0. The catalyst TEMPO (2.00 g, 12.80 mmol) and oxidizing agent were then added sequentially. NBS (98.00 g, 0.55 mol) was added, and the temperature was controlled <25℃. After the addition was complete, the reaction was carried out at 25℃ 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 57.00 g of a white solid 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 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 intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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 compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH was adjusted to 9.0. Catalyst 4-methoxyTEMPO (0.12 g, 0.70 mmol) and oxidant NBS (4.90 g, 27.50 mol) were added sequentially, maintaining the temperature below 25 °C. After the additions were complete, the reaction was carried out at 25 °C for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 2.49 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 50.2%.

[0094] Example 11: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 9.0. The catalyst TEMPO (0.10 g, 0.64 mmol) and the oxidant NCS (3.67 g, 27.50 mmol) were added sequentially, and the temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.85 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 41.3%.

[0096] Example 12: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 9.0. The catalyst TEMPO (0.10 g, 0.64 mmol) and the oxidant 10% sodium hypochlorite solution (20.47 g, 27.50 mmol) were added sequentially. The temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.65 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 37.5%. Example 13: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 9.0. The catalyst TEMPO (0.022 g, 0.14 mmol) and the oxidant NBS (4.89 g, 27.50 mol) were added sequentially, and the temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 0.56 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 12.6%.

[0099] Example 14: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 8.0. The catalyst TEMPO (0.22 g, 1.38 mmol) and the oxidant NBS (4.89 g, 27.50 mol) were added sequentially, and the temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 10 °C for 4 hours. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 2.69 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 60.1%.

[0101] Example 15: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 9.0. The catalyst TEMPO (0.10 g, 0.64 mmol) and the oxidant NBS (2.45 g, 13.75 mol) were added sequentially, and the temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 1.78 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 39.7%.

[0103] Example 16: Preparation of intermediate compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidin-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. Then, a solution of compound III, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-hydroxy)-5-methylbenzonitrile (4.50 g, 13.75 mmol), dissolved in dichloromethane (50 ml) was added. The mixture was cooled in an ice-water bath, and the pH of the reaction flask was controlled to 9.5. The catalyst TEMPO (0.10 g, 0.64 mmol) and the oxidant NBS (9.79 g, 55.00 mol) were added sequentially, and the temperature was controlled to be <25 °C. After the addition was complete, the reaction was carried out at 40 °C for 2 hours. The reaction process was monitored by TLC. After the reaction was completed, the mixture was extracted with dichloromethane, concentrated, and dried to obtain 2.80 g of a white solid, 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 62.5%.

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

[0106] 3-(5-isopropyl-2,6-dimethoxypyrimidin-4-carbonyl)-5-methylbenzonitrile (50.00 g, 0.15 mol), 40% hydrobromic acid (151.71 g, 0.75 mol), and 1,4-dioxane (100 ml) were added to a 500 ml reaction flask. The mixture was heated to 75 °C and reacted for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed with water, and dried to obtain 44.00 g of a white solid 3-(5-isopropyl-2,6-dioxane-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile, yield 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 intermediate compound 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile

[0108] 3-(5-isopropyl-2,6-dimethoxypyrimidin-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 mixture was heated to 80 °C and reacted for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed with water, and dried to obtain 2.60 g of a white solid 3-(5-isopropyl-2,6-dioxane-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 57.1%.

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

[0110] 3-(5-isopropyl-2,6-dimethoxypyrimidin-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 mixture was heated to 80 °C and reacted for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed with water, and dried to obtain 2.30 g of a white solid, 3-(5-isopropyl-2,6-dioxane-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 50.3%.

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

[0112] 3-(5-isopropyl-2,6-dimethoxypyrimidin-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 mixture was heated to 60 °C and reacted for 5 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed with water, and dried to obtain 4.39 g of a white solid 3-(5-isopropyl-2,6-dioxane-1,2,3,6-tetrahydropyrimidin-4-carbonyl)-5-methylbenzonitrile, with a yield of 96.0%.

[0113] Example 21: Preparation of enovalin

[0114] In a 1 L reaction flask, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-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. The mixture was heated to 70 °C and reacted for 17 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 4, and purified water (400 mL) was added. The mixture was stirred for 1 hour, filtered, washed with water, recrystallized from anhydrous ethanol, filtered, and dried to obtain 38.44 g of enovirine, 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 enovalin

[0116] 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-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 flask. The mixture was heated to 70 °C and reacted for 17 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled 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, filtered, and dried to obtain 3.44 g of enovirine, with a yield of 62.8%.

[0117] Example 23: Preparation of enovalin

[0118] In a 50 mL reaction flask, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-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. The mixture was heated to 90 °C and reacted for 15 hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 4, and purified water (50 mL) was added. The mixture was stirred for 1 hour, filtered, washed with water, recrystallized from anhydrous ethanol, filtered, and dried to obtain 2.90 g of enovirine, with a yield of 53.0%.

[0119] The applicant declares that the preparation process of this invention is illustrated by the above embodiments, but this invention is not limited to the above preparation process, that is, it does not mean that this invention must rely on the above preparation process to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials of this invention, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection scope and disclosure scope of this invention.

Claims

1. A method for synthesizing the anti-AIDS drug enovalin, characterized in that, The method includes the following steps: (1) SM1 compound 4-bromo-5-isopropyl-2,6-dimethoxypyrimidine reacts with Grignard reagent, and then reacts with SM2 compound 3-cyano-5-methylbenzaldehyde to give compound III 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-hydroxy)-5-methylbenzonitrile; (2) Compound III undergoes an oxidation reaction to give compound II, 3-(5-isopropyl-2,6-dimethoxypyrimidine-4-carbonyl)-5-methylbenzonitrile; (3) Compound II undergoes a demethylation reaction under the action of a demethylating agent to give compound I, 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile; (4) The compound of formula I undergoes an ethylation reaction to give enovirine; 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 isopropyl magnesium chloride, lithium chloride, phenyl magnesium chloride, tert-butyl magnesium chloride, isopropyl magnesium bromide or 4-chlorophenyl magnesium 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, characterized in that, The Grignard reagent mentioned in step (1) is isopropyl magnesium 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 with the Grignard reagent in step (1) is carried out in a solvent, wherein the solvent is selected from any one or a combination of at least two of the following: C1-C8 alkane solvents, C2-C8 ether solvents or C6-C10 aromatic solvents; The reaction temperature of the SM1 compound with the Grignard reagent in step (1) is -50 to 30°C; The reaction time of the SM1 compound with the Grignard reagent in step (1) is 1-15 h; The molar ratio of SM1 compound and SM2 compound in step (1) is 1:(1-3); The reaction temperature with the SM2 compound in step (1) is -50 to 30°C; The reaction time with the SM2 compound in step (1) is 5-24 h; The reaction with the SM2 compound in step (1) is carried out in a solvent selected from any one or a combination of at least two of the following: C1-C8 alkane solvents, C2-C8 ether solvents, or C6-C10 aromatic solvents.

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, which is selected from 2,2,6,6-tetramethylpiperidine-N-oxy radical and / or 2,2,6,6-tetramethyl-4-methoxypiperidine-N-oxy 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-oxidizing agent, which 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 co-oxidant is 1:(1-4); The oxidation reaction in step (2) is carried out in the presence of a pH adjuster, which is selected from any one or a combination of at least two of sodium bicarbonate, sodium dihydrogen phosphate, or potassium carbonate. In step (2), the pH of the system is adjusted to 7.0-11.0 during the oxidation reaction. The oxidation reaction in step (2) is carried out in a solvent, which is selected from any one or a combination of at least two of the following: C1-C8 alkane solvents, C2-C8 ether solvents, C6-C10 aromatic solvents, or water; The oxidation reaction in step (2) is carried out at a temperature of 0-80℃; The oxidation reaction in step (2) takes 1-10 hours.

6. The synthesis method according to claim 1, characterized in that, The demethylating agent in step (3) is selected from any one or at least a combination of two of lithium hydroxide, lithium bromide, or hydrobromic acid; The molar ratio of the compound of formula II to the demethylating agent in step (3) is 1:(2-10); The demethylation reaction in step (3) is carried out in a solvent, which 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; The temperature for the demethylation reaction in step (3) is 40-100℃; The demethylation reaction in step (3) takes 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 iodoethane 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, which is selected from any one or a combination of at least two of the following: C2-C8 nitrile solvents, C2-C8 ether solvents, or C6-C10 aromatic solvents. The ethylation reaction in step (4) is carried out at a temperature of 60-100℃; The ethylation reaction in step (4) takes 10-30 h.

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

10. An intermediate compound for the preparation of enovivin, characterized in that, The intermediate compound has the structure shown in Formula III: 。

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