Key intermediate of Leibro and synthesis method of key intermediate of Leibro

Abstract

The invention provides a high-efficiency and green preparation method of an important intermediate compound V of Lembrexant, as well as an intermediate in the method and preparation of the intermediate. A compound I is used as an initial raw material, the invention accidentally finds that a short-chain aliphatic acylation reagent is selected to protect an alcoholic hydroxyl group on one side, a sulfonylation reagent with small steric hindrance is selected to protect an alcoholic hydroxyl group on the other side, and then condensation and hydrolysis are performed to generate a target compound V, so that the reaction selectivity is high, the yield is high, protective groups are easy to remove, intermediate treatment steps are reduced, and the production cost is reduced. The method is environment-friendly, safe and simple in process and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a key intermediate of leboresen, and a novel intermediate substance in the method. Background Technology

[0002] Leemborexant, developed by Eisai Co., Ltd. of Japan, is clinically used to treat insomnia. Insomnia is a subjective experience characterized by dissatisfaction with sleep duration and / or quality, impacting daytime social functioning. According to international diagnostic criteria for insomnia and epidemiological studies, at least 6% of the world's population suffers from insomnia and sleep disorders, and this number is increasing. Leemborexant is a dual inhibitor of orexin receptors OX1 and OX2. This compound inhibits orexin by competitively binding to two subtypes of orexin receptors (orexin receptor 1 and receptor 2). Leemborexant can purposefully promote the initiation and maintenance of sleep by interfering with orexinergic neurotransmission. According to relevant literature, although many synthetic routes for leemborexant have been reported, compound V is a crucial common intermediate in its synthesis, and the synthetic process of this compound determines the economic and environmental costs of the entire process. Compound V is named ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol, and its chemical structural formula is shown below:

[0003]

[0004] Compound V is an important intermediate in the synthesis of Leborresen. Currently, the main synthetic processes for this compound are as follows:

[0005] 1. CN103153963B uses tert-butyldiphenylchlorosilane as a reagent to protect the alcohol hydroxyl group, and then adds the pyrimidine ring under the conditions of diisopropyl azodicarboxylate and triphenylphosphine. The synthetic reagents used in this process are expensive, and the reaction requires low temperature (-15℃). Finally, the product needs to be purified and separated step by step. Column chromatography separation is expensive and inefficient, and is not suitable for industrial production.

[0006] 2. In CN104114524B, lipase is used as an acrylic resin catalyst and ethylene acetate as a hydroxyl protectant. Then, the hydroxyl group is sulfonated with p-toluenesulfonic anhydride, and finally, a pyrimidine ring is added under the catalysis of cesium carbonate. The lipase in this process needs to be customized, the equipment cost is high, and the selectivity of sulfonation with p-toluenesulfonic anhydride is not high. The product is relatively impure and needs to be further purified before the next reaction. However, the product in this step is very easy to deteriorate, and the product content will decrease during the purification process.

[0007] 3. CN113727962A uses Grignard reagents and acetyl chloride as the hydroxyl protecting agent, followed by sulfonation of the hydroxyl group at another position with p-toluenesulfonyl chloride, and finally, the addition of a pyrimidine ring under the catalysis of potassium tert-butoxide. This process has a relatively high yield and a relatively mild reaction temperature. However, acetyl chloride is a highly reactive, colorless, fuming liquid with low boiling and flash points, posing a significant risk of leakage and environmental harm. Furthermore, the high reactivity of acetyl chloride as the hydroxyl protecting agent leads to low reaction selectivity and a tendency to generate disubstituted products. In addition, p-toluenesulfonyl chloride is a solid, and adding it during the reaction by opening the container can affect the reaction environment. Even when dissolved in a solvent and added dropwise, the reaction solvent has strict requirements regarding moisture content. Moreover, after sulfonation of the hydroxyl group with p-toluenesulfonyl chloride, due to steric hindrance, a strong base such as potassium tert-butoxide is required to activate the ester group and introduce the pyrimidine ring. This route is highly dangerous, has low reaction selectivity, and is unsuitable for industrial production. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing compound V, an important intermediate of leboresen. The technical solution of this invention is as follows:

[0009] As one of the objectives of this invention, a method for synthesizing compound V is provided, characterized in that compound V is synthesized from compound III via compound IV, and the synthetic route is as follows:

[0010]

[0011] Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

[0012] Preferably, in the method described above, the alkali is selected from: sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, butyllithium, sodium carbonate, and potassium carbonate.

[0013] Preferably, in the method described above, N-methylpyrrolidone is present in the reaction system for synthesizing compound IV from compound III.

[0014] As another object of the present invention, a method for synthesizing compound III is provided, characterized in that compound III is synthesized from compound I via compound II, and the synthetic route is as follows:

[0015]

[0016] Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

[0017] Preferably, in the method described above, the acylation reagent used in the acylation reaction of synthesizing compound II from compound I is propionyl chloride, n-butyryl chloride, n-valeryl chloride, propionyl bromide, n-butyryl bromide, n-valeryl bromide, propionic anhydride, or n-butyryl anhydride.

[0018] Preferably, in the method described above, the acylation reaction of compound I to synthesize compound II is carried out in the presence of a Grignard reagent; preferably, the Grignard reagent is selected from phenyl magnesium chloride, propyl magnesium chloride, ethyl magnesium chloride, cyclohexyl magnesium chloride, benzyl magnesium chloride, isopropyl magnesium chloride, and isobutyl magnesium chloride.

[0019] Preferably, in the method described above, the sulfonating agent used in the sulfonation reaction for synthesizing compound III from compound II is methanesulfonyl chloride, ethylsulfonyl chloride, n-propylsulfonyl chloride, n-butylsulfonyl chloride, methanesulfonic anhydride, or ethylsulfonic anhydride.

[0020] Preferably, in the method described above, the sulfonation reaction for synthesizing compound III from compound II is carried out in the presence of an acid-binding agent; preferably, the acid-binding agent is selected from pyridine, triethylamine, sodium methoxide, diethylamine, N-ethylisopropylamine, and N-phenylaniline.

[0021] As another object of the present invention, compounds II, III or IV are also provided below.

[0022]

[0023] Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

[0024] The aforementioned compound is an intermediate for the synthesis of compound V, an important intermediate in the synthesis of Leborersen.

[0025] As another object of the present invention, a method for synthesizing Leborresen is also provided, which includes the step of synthesizing compound V, characterized in that the step of synthesizing compound V is to synthesize compound V from compound I as a starting material according to the method described above, and the synthetic route is as follows:

[0026]

[0027] R1, R2, and each step of the reaction, such as the reactants and / or reagents used in the reaction, are as described above.

[0028] The present invention does not particularly limit the process of preparing leboresen from compound V, and can follow methods existing in the art. For example, the method for synthesizing compound XI (i.e., leboresen) from compound VII (i.e., compound V corresponding to the present invention) disclosed in CN113727962A.

[0029] Compared with existing technologies, this invention unexpectedly discovers that the use of the short-chain aliphatic acylation reagent described in this invention to protect the single-sided alcohol hydroxyl group in the synthetic route effectively reduces the formation of the other isomer product due to its steric hindrance effect, significantly improving the yield of the target product. Furthermore, it is easily removed during the final product preparation process, resulting in fewer impurities and convenient and simple post-processing. In addition, this invention also uses the sterically less hindrance sulfonylation reagent described in this invention to protect the other side of the alcohol hydroxyl group of compound II, making the bimolecular nucleophilic substitution reaction easier to proceed, more complete, and under milder reaction conditions. It also facilitates removal in subsequent reactions, increasing the reaction yield. Compared with existing methods, the method of synthesizing compound V in this invention not only has mild process conditions and high yield (the total molar yield of the four steps can even reach over 75%), but the entire synthetic method is also safe, greatly reducing the risk of the synthetic route and making it more suitable for industrial production. The method of this invention has complete reaction, high reaction selectivity, fewer byproducts, and each step only requires simple post-processing, eliminating the need for purification before proceeding to the next reaction, reducing waste emissions, being environmentally friendly, and having low energy consumption, making it suitable for industrial production. In addition, the solvents and reaction reagents selected in this invention are safe to use, inexpensive, and readily available. Furthermore, the solvents can be recycled and reused, resulting in high economic benefits and providing a guarantee for industrial production.

[0030] As one of the most preferred embodiments of the present invention, the method for preparing compound V of the present invention includes the following steps:

[0031] (1) Under inert gas protection, compound I and solvent A were placed in a reaction flask and stirred to dissolve. Grignard reagent solution was added dropwise under controlled temperature. After the addition was complete, the temperature was controlled until the reaction was finished. The above reaction system solution was added dropwise to a mixed solution of acylation reagent and solvent B under controlled temperature. The reaction was controlled until the reaction was finished. Water was added to quench the reaction. The organic phase was separated, dried, and rotary evaporated to obtain compound II, which was used directly in the next reaction without purification.

[0032] (2) Add compound II obtained in the previous step, solvent C, and acid-binding agent to the reaction flask, stir, and add sulfonating reagent dropwise under controlled temperature until the reaction is complete. Quench the reaction with water, separate the organic phase, dry and rotary evaporate to obtain compound III, which can be used directly in the next step without purification.

[0033] (3) Add solvent D, N-methylpyrrolidone, and base to the reaction flask, stir to dissolve, and then add 2,4-dimethyl-5-hydroxypyrimidine under controlled temperature. After adding the base, continue the reaction under controlled temperature. Add compound III and continue the reaction under controlled temperature until the reaction is complete. Add water and stir. Separate the liquid and collect the organic phase. Extract the aqueous phase with organic solvent E and combine the organic phases. Wash the organic phase with an aqueous sodium carbonate solution and remove the solvent by rotary evaporation to obtain compound IV.

[0034] (4) Add compound IV, purified water, solvent F, and base to a reaction flask, stir, and control the temperature until the reaction is complete. Add solvent G, stir, separate the layers, take the organic layer, wash with saturated sodium chloride solution, concentrate the solvent, and obtain compound V.

[0035] According to the above method for preparing compound V, the inert gas mentioned in step (1) can be nitrogen or argon.

[0036] According to the above method for preparing compound V, the solvent A mentioned in step (1) is one of toluene, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, and ethanol.

[0037] According to the above method for preparing compound V, the temperature of the Grignard reagent solution added in step (1) is -5℃ to 25℃, and the reaction time after the addition is 1 to 8 hours.

[0038] According to the above method for preparing compound V, the Grignard reagent solution mentioned in step (1) can be one of phenyl magnesium chloride, propyl magnesium chloride, ethyl magnesium chloride, cyclohexyl magnesium chloride, benzyl magnesium chloride, isopropyl magnesium chloride, and isobutyl magnesium chloride.

[0039] Further, the molar ratio of the Grignard reagent solution to compound I in step (1) is 0.5:1 to 1.5:1.

[0040] According to the above method for preparing compound V, the acylation reagent mentioned in step (1) is one of propionyl chloride, n-butyryl chloride, n-valeryl chloride, propionyl bromide, n-butyryl bromide, n-valeryl bromide, propionic anhydride, and n-butyryl anhydride.

[0041] Further, the molar ratio of the acylation reagent in step (1) to compound I is 0.8:1 to 1.5:1.

[0042] According to the above method for preparing compound V, the temperature of the reaction system solution added in step (1) is -5℃ to 30℃, and the reaction time after the addition is 1 to 12 hours.

[0043] According to the above method for preparing compound V, the solvent B mentioned in step (1) is one of toluene, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, DMF, and diethyl ether.

[0044] According to the above method for preparing compound V, the solvent C mentioned in step (2) is one of toluene, ethyl acetate, dichloromethane, chloroform, and tetrahydrofuran.

[0045] According to the above method for preparing compound V, the acid-binding agent mentioned in step (2) is one of pyridine, triethylamine, sodium methoxide, diethylamine, N-ethylisopropylamine, and N-phenylaniline.

[0046] Furthermore, the molar ratio of the acid-binding agent to compound II in step (2) is 1:1 to 3:1.

[0047] According to the above method for preparing compound V, the sulfonating agent mentioned in step (2) is one of methanesulfonyl chloride, ethylsulfonyl chloride, n-propylsulfonyl chloride, n-butylsulfonyl chloride, methanesulfonic anhydride, and ethylsulfonic anhydride.

[0048] Furthermore, the molar ratio of the sulfonating agent to compound II in step (2) is 0.8:1 to 3:1.

[0049] According to the above method for preparing compound V, the temperature of adding the sulfonating agent in step (2) is -5℃ to 20℃, the reaction temperature after the addition is completed is 0℃ to 30℃, and the reaction time is 1 to 8 hours.

[0050] According to the above method for preparing compound V, the solvent D mentioned in step (3) is one of benzene, toluene, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform, and dimethyl sulfoxide.

[0051] According to the above method for preparing compound V, the base mentioned in step (3) is one of sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, lithium butylene, sodium carbonate, and potassium carbonate.

[0052] Furthermore, the molar ratio of the base to compound III in step (3) is 0.5:1 to 5:1.

[0053] According to the above method for preparing compound V, the temperature during the addition of 2,4-dimethyl-5-hydroxypyrimidine in step (3) is -5℃ to 60℃.

[0054] According to the above method for preparing compound V, the reaction temperature after adding 2,4-dimethyl-5-hydroxypyrimidine in step (3) is 30℃-80℃, and the reaction time is 1-4 hours.

[0055] Further, the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to compound III in step (3) is 0.8:1 to 1.5:1.

[0056] According to the above method for preparing compound V, the reaction temperature after adding compound III in step (3) is 20℃-80℃ and the reaction time is 1-12 hours.

[0057] According to the above method for preparing compound V, the organic solvent E mentioned in step (3) is one of tetrahydrofuran, toluene, ethyl acetate, diethyl ether, petroleum ether, dichloromethane, chloroform, and xylene.

[0058] According to the above method for preparing compound V, the solvent F mentioned in step (4) is one of methanol, ethanol, acetonitrile, N,N-dimethylformamide, isopropanol, acetone, and dimethyl ether.

[0059] According to the above method for preparing compound V, the base mentioned in step (4) is one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

[0060] Furthermore, the hydrolysis reaction temperature in step (4) is 30-80℃, and the reaction time is 1-8 hours.

[0061] According to the above method for preparing compound V, the solvent G mentioned in step (4) is one of toluene, diethyl ether, ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, and xylene.

[0062] Furthermore, the molar ratio of the base to compound IV in step (4) is 0.5:1 to 5:1. Attached Figure Description

[0063] Figure 1 MS spectrum of compound II in Example 1

[0064] Figure 2 MS spectrum of compound III in Example 1

[0065] Figure 3 MS spectrum of compound IV in Example 1

[0066] Figure 4 MS spectrum of compound V in Example 1 Specific Implementation

[0067] The present invention will be further explained or illustrated by the following examples.

[0068] The chemical reactions in the examples were confirmed by liquid chromatography-mass spectrometry (LC-MS). LC conditions: mobile phase 0.15% phosphoric acid-water solution: acetonitrile = 30:70 (v / v); flow rate 1.0 mL / min; injection volume 1 μL; column temperature 35℃; detection wavelength 254 nm; chromatographic column: Shimadzu ODS, 4.6*250 mm, 5 μm.

[0069] Example 1:

[0070] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 mL of tetrahydrofuran were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. Then, 200 mL (259.91 mmol) of cyclohexyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 1 hour. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 26.1 g (280.31 mmol) of propionyl chloride and 200 mL of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 0 °C. The mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 4 hours. After the reaction was complete, 150 mL of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is ethyl), a yellow liquid, 63.1 g (250.23 mmol), with a molar yield of 98.2%. The MS spectrum of compound II is shown below. Figure 1 [M+1]: 252.90.

[0071] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 63.1 g of compound II prepared in the previous step, 300 mL of acetonitrile, and 30.4 g (300.28 mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 0°C. 31.5 g (275.25 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 10°C, and the reaction was allowed to proceed for 1 hour. After the reaction was complete, 260 mL of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 81.4 g (246.48 mmol), with a molar yield of 98.5%. The MS spectrum of compound III is shown below. Figure 2 , [M+I]: 331.10.

[0072] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of acetonitrile, 200ml of N-methylpyrrolidone, and 33.2g (295.78mmol) of potassium tert-butoxide. Stir and heat to 30℃. Add 36.7g (295.78mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 1 hour. Add 81.4g of compound III prepared in the previous step and react at 50℃ for 4 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain compound IV (R1 is ethyl), a brown liquid, 83.9g (234.16mmol), with a molar yield of 95.0%. The MS chromatogram of compound IV is shown below. Figure 3 [M+I]: 359.65.

[0073] In a 1L four-necked flask equipped with a thermometer and stirrer, add 83.9g of compound IV prepared in the previous step, 100ml of purified water, 100ml of methanol, and 18.7g (468.32mmol) of sodium hydroxide. Stir and heat to 50℃, reacting for 5 hours. After the reaction is complete, cool to room temperature, add 250ml of toluene, stir for 30 minutes, allow to stand, separate the layers, and collect the organic layer. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 65.2g (215.67mmol), with a molar yield of 92.1%. The MS spectrum of compound V is shown below. Figure 4 [M+1]: 303.45.

[0074] Example 2:

[0075] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 ml of ethyl acetate were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred to dissolve the compound, and the temperature was lowered to 10 °C. 180 ml (254.82 mmol) of cyclohexylmagnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 3 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 34.8 g (267.56 mmol) of propionic anhydride and 200 ml of toluene were added. The mixture was stirred, and the temperature was lowered to 0 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 10 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain 61.5 g (243.64 mmol) of compound II (R1 is ethyl) as a yellow liquid, with a molar yield of 95.6%.

[0076] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 61.5g of compound II prepared in the previous step, 300ml of tetrahydrofuran, and 67.2g (664.5mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 20°C. 28.5g (221.49mmol) of ethylsulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 30°C, and the reaction was allowed to proceed for 5 hours. After the reaction was completed, 260ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is ethyl), a brown liquid, 76.0g (229.75mmol), with a molar yield of 94.3%.

[0077] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of dichloromethane, 200ml of N-methylpyrrolidone, and 36.2g (376.54mmol) of sodium tert-butoxide. Stir and heat to 30°C. Add 25.7g (207.10mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 2 hours. Add 76.0g of compound III prepared in the previous step and react at 30°C for 3 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain 77.1g (215.05mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 93.6%.

[0078] In a 1L four-necked flask equipped with a thermometer and stirrer, add 77.1g of compound IV prepared in the previous step, 100ml of purified water, 100ml of methanol, and 69.1g (615.65mmol) of potassium tert-butoxide. Stir and heat to 80°C, reacting for 3 hours. After the reaction is complete, cool to room temperature, add 250ml of toluene, stir for 30 minutes, allow to stand, and separate the layers. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 61.8g (204.29mmol), with a molar yield of 95%.

[0079] Example 3:

[0080] Under argon protection, 50 g (254.82 mmol) of compound I and 250 ml of toluene were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to -5 °C. 200 ml (254.82 mmol) of magnesium phenyl chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 5 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 36.7 g (267.6 mmol) of propionyl bromide and 200 ml of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 20 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 10 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is ethyl), a yellow liquid, 61.1 g (242.33 mmol), with a molar yield of 95.1%.

[0081] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 61.1g of compound II prepared in the previous step, 300ml of chloroform, and 24.5g (242.33mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 20°C. 30.5g (266.56mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 30°C, and the reaction was allowed to proceed for 2 hours. After the reaction was completed, 260ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 75.8g (229.24mmol), with a molar yield of 94.6%.

[0082] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of tetrahydrofuran, 200ml of N-methylpyrrolidone, and 14.2g (208.40mmol) of sodium ethoxide. Stir and heat to 60℃. Add 28.5g (229.24mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 4 hours. Add 75.8g of compound III prepared in the previous step and react at 80℃ for 2 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of ethyl acetate and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution with stirring for 20 minutes. Separate the layers, dry, and rotary evaporate to obtain compound IV (R1 is ethyl), a brown liquid, 78.1g (217.78mmol), with a molar yield of 95.1%.

[0083] In a 1L four-necked flask equipped with a thermometer and stirrer, add 78.1g of compound IV prepared in the previous step, 100ml of purified water, 100ml of N,N-dimethylformamide, and 22.5g (562.68mmol) of sodium hydroxide. Stir and heat to 80°C, reacting for 4 hours. After the reaction is complete, cool to room temperature, add 250ml of chloroform, stir for 30 minutes, allow to stand, and separate the layers. Collect the organic layer. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain 60g (198.40mmol) of compound V, a viscous yellow liquid, with a molar yield of 91.1%.

[0084] Example 4:

[0085] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 ml of ethyl acetate were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred to dissolve the compound, and the temperature was lowered to 10 °C. 220 ml (305.8 mmol) of isopropyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 3 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 38.3 g (305.8 mmol) of propionyl chloride and 200 ml of tetrahydrofuran were added. The mixture was stirred, and the temperature was lowered to 0 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 8 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is ethyl), a yellow liquid, 62.1 g (246.1 mmol), with a molar yield of 96.6%.

[0086] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 62.1 g of compound II prepared in the previous step, 300 mL of toluene, and 38.9 g (491.8 mmol) of pyridine were added. The mixture was stirred, and the temperature was maintained at 10°C. 56.4 g (492.3 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 25°C, and the reaction was allowed to proceed for 8 hours. After the reaction was completed, 260 mL of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 76.4 g (231.26 mmol), with a molar yield of 93.9%.

[0087] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of chloroform, 200ml of N-methylpyrrolidone, and 19.4g (346.5mmol) of potassium hydroxide. Stir and heat to 60℃. Add 34.4g (227.3mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 3 hours. Add 76.4g of compound III prepared in the previous step and react at 60℃ for 12 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution with stirring for 20 minutes. Separate the layers, dry, and rotary evaporate to obtain 78.5g (219.70mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 95.1%.

[0088] In a 1L four-necked flask equipped with a thermometer and stirrer, add 78.5g of compound IV prepared in the previous step, 100ml of purified water, 100ml of ethanol, and 21.5g (537.78mmol) of sodium hydroxide. Stir and heat to 70°C, reacting for 6 hours. After the reaction is complete, cool to room temperature, add 250ml of chloroform, stir for 30 minutes, allow to stand, and separate the layers. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 62.4g (206.30mmol), with a molar yield of 93.9%.

[0089] Example 5:

[0090] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 mL of acetonitrile were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. Then, 280 mL (382.23 mmol) of ethyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 12 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 36.5 g (280.31 mmol) of propionic anhydride and 200 mL of acetonitrile were added. The mixture was stirred, and the temperature was lowered to 8 °C. The mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 7 hours. After the reaction was complete, 150 mL of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain 59.8 g (237.14 mmol) of compound II (R1 is ethyl), a yellow liquid, with a molar yield of 93.1%.

[0091] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 59.8 g of compound II prepared in the previous step, 300 ml of dichloromethane, and 28.2 g (323.37 mmol) of N-ethylisopropylamine were added. The mixture was stirred, and the temperature was maintained at 20°C. 61.5 g (431.16 mmol) of propylsulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 30°C, and the reaction was allowed to proceed for 8 hours. After the reaction was completed, 260 ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is n-propyl), a brown liquid, yielding 73.18 g (221.48 mmol), with a molar yield of 93.4%.

[0092] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of tetrahydrofuran, 200ml of N-methylpyrrolidone, and 14.1g (125.90mmol) of potassium tert-butoxide. Stir and heat to 40℃. Add 23.4g (188.85mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 2 hours. Add 73.18g of compound III prepared in the previous step and react at 70℃ for 8 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain 71.8g (200.22mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 90.4%.

[0093] In a 1L four-necked flask equipped with a thermometer and stirrer, 71.8 g of compound IV prepared in the previous step, 100 ml of purified water, 100 ml of isopropanol, and 60.3 g (569.05 mmol) of sodium carbonate were added. The mixture was stirred and heated to 80°C, and reacted for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, and 250 ml of ethyl acetate was added and stirred for 30 minutes. The mixture was allowed to stand and separated, and the organic layer was collected. The organic layer was washed with 300 ml of saturated sodium chloride solution for 20 minutes, allowed to stand and separated, and the organic phase was dried and rotary evaporated to give compound V, a viscous yellow liquid, 56.6 g (187.21 mmol), with a molar yield of 93.5%.

[0094] Example 6:

[0095] Under nitrogen protection, 25 g (127.41 mmol) of compound I and 100 ml of tetrahydrofuran were added to a 500 ml four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. 100 ml (130 mmol) of cyclohexyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 1 hour. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 14.94 g (140.16 mmol) of n-butyryl chloride and 160 ml of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 0 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 4 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is n-propyl), a yellow liquid, 33.1 g (124.22 mmol), with a molar yield of 97.5%.

[0096] In a 500 ml four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 33.1 g of compound II prepared in the previous step, 150 ml of acetonitrile, and 25.1 g (248.44 mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 0 °C. 28.5 g (248.44 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 10 °C, and the reaction was allowed to proceed for 2 hours. After the reaction was completed, 200 ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is n-propyl, R2 is methyl), a brown liquid, 39.2 g (118.51 mmol), with a molar yield of 95.4%.

[0097] In a 500 ml four-necked flask equipped with a thermometer and stirrer, add 100 ml of acetonitrile, 100 ml of N-methylpyrrolidone, and 26.6 g (237.02 mmol) of potassium tert-butoxide. Stir and heat to 30 °C. Add 17.7 g (142.21 mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 1 hour. Add compound III 39.2 prepared in the previous step and react at 50 °C for 4 hours. After the reaction is complete, add 200 ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 150 ml of toluene and combine the organic phases. Wash the organic phase with 300 ml of 7% sodium carbonate aqueous solution for 20 minutes with stirring. Separate the layers, dry, and rotary evaporate to obtain compound IV (R1 is n-propyl), a brown liquid, 39.0 g (108.79 mmol), with a molar yield of 91.8%.

[0098] In a 500 ml four-necked flask equipped with a thermometer and stirrer, add 39.0 g of compound IV prepared in the previous step, 80 ml of purified water, 80 ml of methanol, and 13.1 g (326.37 mmol) of sodium hydroxide. Stir and heat to 50 °C, reacting for 5 hours. After the reaction is complete, cool to room temperature, add 150 ml of toluene, stir for 30 minutes, allow to stand, and separate the layers. Collect the organic layer. Wash the organic layer with 200 ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 30.5 g (100.96 mmol), with a molar yield of 92.8%.

[0099] Example 7:

[0100] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 mL of ethanol were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred to dissolve the compound, and the temperature was lowered to 0 °C. 210 mL (259.91 mmol) of isobutylmagnesium chloride solution was slowly added dropwise, and the reaction continued for 2 hours after the addition was complete. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 26.1 g (280.31 mmol) of propionyl chloride and 200 mL of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 5 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask, and the reaction continued for 3 hours after the addition was complete. After the reaction was complete, 150 mL of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain 61.1 g (241.82 mmol) of compound II (R1 is ethyl) as a yellow liquid, with a molar yield of 94.9%.

[0101] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 61.1g of compound II prepared in the previous step, 300ml of chloroform, and 32.3g (190.86mmol) of N-phenylaniline were added. The mixture was stirred, and the temperature was maintained at 5°C. 31.5g (229.0326.2mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 10°C, and the reaction was allowed to proceed for 3 hours. After the reaction was completed, 260ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 72.7g (220.06mmol), with a molar yield of 91%.

[0102] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml toluene, 200ml N-methylpyrrolidone, and 33.4g (347.37mmol) sodium tert-butoxide. Stir and heat to 50°C. Add 25.9g (208.42mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 3 hours. Add 72.7g of compound III prepared in the previous step and react at 80°C for 2 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain 71.7g (200.25mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 91%.

[0103] In a 1L four-necked flask equipped with a thermometer and stirrer, 71.7g of compound IV prepared in the previous step, 100ml of purified water, 100ml of isopropanol, and 19.4g (140.68mmol) of potassium carbonate were added. The mixture was stirred and heated to 80°C, and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and 250ml of xylene was added and stirred for 30 minutes. The mixture was allowed to stand and separated, and the organic layer was collected. The organic layer was washed with 300ml of saturated sodium chloride solution for 20 minutes, allowed to stand and separated, and the organic phase was dried and rotary evaporated to give compound V, a viscous yellow liquid, 55.6g (183.83mmol), with a molar yield of 91.8%.

[0104] Example 8:

[0105] Under argon protection, 50 g (254.82 mmol) of compound I and 250 ml of tetrahydrofuran were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was maintained at 25 °C. 200 ml (259.91 mmol) of cyclohexyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 2 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 26.1 g (280.31 mmol) of propionyl chloride and 200 ml of tetrahydrofuran were added. The mixture was stirred, cooled to 5 °C, and the reaction mixture from the previous step was added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 12 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is ethyl), a yellow liquid, 58.1 g (230.10 mmol), with a molar yield of 90.3%.

[0106] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 58.1 g of compound II prepared in the previous step, 300 ml of tetrahydrofuran, and 69.9 g (690.3 mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 10°C. 31.5 g (275.25 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 20°C, and the reaction was allowed to proceed for 2 hours. After the reaction was complete, 260 ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 72.8 g (219.98 mmol), with a molar yield of 95.6%.

[0107] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of acetone, 200ml of N-methylpyrrolidone, and 33.2g (295.78mmol) of potassium tert-butoxide. Stir and heat to 40℃. Add 36.7g (295.78mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 2 hours. Add 72.8g of compound III prepared in the previous step and react at 40℃ for 7 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of ethyl acetate and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain 72.6g (202.62mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 92.1%.

[0108] In a 1L four-necked flask equipped with a thermometer and stirrer, add 72.6g of compound IV prepared in the previous step, 100ml of purified water, 100ml of isopropanol, and 9.8g (181.41mmol) of sodium methoxide. Stir and heat to 70°C, reacting for 3 hours. After the reaction is complete, cool to room temperature, add 250ml of toluene, stir for 30 minutes, allow to stand, and separate the layers. Collect the organic layer. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 57.3g (189.45mmol), with a molar yield of 93.5%.

[0109] Example 9:

[0110] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 ml of tetrahydrofuran were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. 200 ml (259.91 mmol) of isobutyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 3 hours. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 26.1 g (280.31 mmol) of propionyl chloride and 200 ml of acetonitrile were added. The mixture was stirred, and the temperature was lowered to 10 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 6 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain 59.6 g (236.22 mmol) of compound II (R1 is ethyl), a yellow liquid, with a molar yield of 92.7%.

[0111] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 59.6 g of compound II prepared in the previous step, 300 ml of toluene, and 50.7 g (693.36 mmol) of diethylamine were added. The mixture was stirred, and the temperature was maintained at -5°C. 108.6 g (693.36 mmol) of n-butylsulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 5°C, and the reaction was allowed to proceed for 3 hours. After the reaction was completed, 260 ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is n-butyl), a brown liquid, yielding 72.9 g (220.63 mmol), with a molar yield of 93.4%.

[0112] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of dimethyl sulfoxide, 200ml of N-methylpyrrolidone, and 41.8g (413.24mmol) of diisopropylamine. Stir and heat to 50°C. Add 30.8g (247.94mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 2 hours. Add 72.9g of compound III prepared in the previous step and react at 50°C for 8 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of ethyl acetate and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain 75.1g (209.16mmol) of compound IV (R1 is ethyl), a brown liquid, with a molar yield of 94.8%.

[0113] In a 1L four-necked flask equipped with a thermometer and stirrer, 75.1g of compound IV prepared in the previous step, 100ml of purified water, 100ml of acetone, and 26.3g (656.5mmol) of sodium hydroxide were added. The mixture was stirred and heated to 60°C, and reacted for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, and 250ml of toluene was added and stirred for 30 minutes. The mixture was allowed to stand and separated, and the organic layer was collected. The organic layer was washed with 300ml of saturated sodium chloride solution for 20 minutes, allowed to stand and separated, and the organic phase was dried and rotary evaporated to give compound V, a viscous yellow liquid, 58.3g (193.05mmol), with a molar yield of 92.3%.

[0114] Example 10:

[0115] Under nitrogen protection, 250 g (1274.1 mmol) of compound I and 1 mmol of tetrahydrofuran were added to a 5 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. 1 L (1300 mmol) of cyclohexyl magnesium chloride solution was slowly added dropwise, and the reaction continued for 1 hour after the addition was complete. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 131 g (1400 mmol) of propionyl chloride and 1 L of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 0 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask, and the reaction continued for 4 hours after the addition was complete. After the reaction was complete, 800 mL of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain 314.4 g (1246.07 mmol) of compound II (R1 is ethyl) as a yellow liquid, with a molar yield of 97.8%.

[0116] In a 5L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 314.4 g of compound II prepared in the previous step, 1.5 L of acetonitrile, and 151.3 g (1495.4 mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 0°C. 157 g (1370.68 mmol) of methanesulfonyl chloride was added dropwise. After the addition was complete, the temperature was raised to 10°C, and the reaction was allowed to proceed for 1 hour. After the reaction was completed, 1500 mL of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is ethyl, R2 is methyl), a brown liquid, 398.1 g (1204.95 mmol), with a molar yield of 96.7%.

[0117] In a 3L four-necked flask equipped with a thermometer and stirrer, add 500ml of acetonitrile, 500ml of N-methylpyrrolidone, and 162.2g (1445.94mmol) of potassium tert-butoxide. Stir and heat to 30°C. Add 179.5g (1445.94mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 1 hour. Add 398.1g of compound III prepared in the previous step and react at 50°C for 4 hours. After the reaction is complete, add 1.5L of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 1.5L of toluene and combine the organic phases. Wash the organic phase with 1.5L of 7% sodium carbonate aqueous solution for 20 minutes, separate the layers, dry, and rotary evaporate to obtain compound IV (R1 is ethyl), a brown liquid, 400.3g (1116.99mmol), with a molar yield of 92.7%.

[0118] In a 3L four-necked flask equipped with a thermometer and stirrer, add 400.3g of compound IV prepared in the previous step, 500ml of purified water, 500ml of methanol, and 89.4g (2233.98mmol) of sodium hydroxide. Stir and heat to 50°C, reacting for 5 hours. After the reaction is complete, cool to room temperature, add 1.2L of toluene, stir for 30 minutes, allow to stand, and separate the layers. Collect the organic layer. Wash the organic layer with 1.5L of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 316.1g (1045.50mmol), with a molar yield of 93.6%.

[0119] Example 11:

[0120] Under nitrogen protection, 50 g (254.82 mmol) of compound I and 250 ml of tetrahydrofuran were added to a 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer. The mixture was stirred until dissolved, and the temperature was lowered to 5 °C. 100 ml (127.41 mmol) of cyclohexyl magnesium chloride solution was slowly added dropwise. After the addition was complete, the reaction continued for 1 hour. In another 1 L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 32.3 g (203.9 mmol) of n-butyric anhydride and 180 ml of ethyl acetate were added. The mixture was stirred, and the temperature was lowered to 0 °C. The reaction mixture from the previous step was then added dropwise to the four-necked flask. After the addition was complete, the reaction continued for 4 hours. After the reaction was complete, 150 ml of purified water was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound II (R1 is n-propyl), a yellow liquid, yielding 64.2 g (240.80 mmol), with a molar yield of 94.6%.

[0121] In a 1L four-necked flask equipped with a thermometer, dropping funnel, and stirrer, 64.5g of compound II prepared in the previous step, 300ml of acetonitrile, and 30.4g (300.28mmol) of triethylamine were added. The mixture was stirred, and the temperature was maintained at 0℃. 28.2g (139.64mmol) of ethylsulfonic anhydride was added dropwise. After the addition was complete, the temperature was raised to 10℃, and the reaction was allowed to proceed for 1 hour. After the reaction was completed, 260ml of purified water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand, and the liquid was separated. The organic phase was collected, dried, and rotary evaporated to obtain compound III (R1 is n-propyl, R2 is ethyl), a brown liquid, yielding 80.6g (224.91mmol), with a molar yield of 93.5%.

[0122] In a 1L four-necked flask equipped with a thermometer and stirrer, add 100ml of acetonitrile, 200ml of N-methylpyrrolidone, and 33.2g (295.78mmol) of potassium tert-butoxide. Stir and heat to 30°C. Add 13.6g (109.6mmol) of 2,4-dimethyl-5-hydroxypyrimidine in portions. After the addition is complete, continue the reaction for 1 hour. Add 80.6g of compound III prepared in the previous step and react at 50°C for 4 hours. After the reaction is complete, add 500ml of purified water, stir for 30 minutes, allow to stand, separate the layers, and collect the organic phase. Extract the aqueous phase with 200ml of toluene and combine the organic phases. Wash the organic phase with 300ml of 7% sodium carbonate aqueous solution with stirring for 20 minutes. Separate the layers, dry, and rotary evaporate to obtain compound IV (R1 is n-propyl), a brown liquid, 79.7g (213.89mmol), with a molar yield of 95.3%.

[0123] In a 1L four-necked flask equipped with a thermometer and stirrer, add 38.27g of compound IV prepared in the previous step, 100ml of purified water, 100ml of methanol, and 18.7g (468.32mmol) of sodium hydroxide. Stir and heat to 50°C, reacting for 5 hours. After the reaction is complete, cool to room temperature, add 250ml of toluene, stir for 30 minutes, allow to stand, and separate the layers. Collect the organic layer. Wash the organic layer with 300ml of saturated sodium chloride solution for 20 minutes, allow to stand, separate the layers, dry the organic phase, and rotary evaporate to obtain compound V, a viscous yellow liquid, 61.3g (202.55mmol), with a molar yield of 94.7%.

[0124] It should be understood that the specific embodiments described above are only for explaining the present invention and are not intended to limit the present invention. Obvious variations or modifications derived from the spirit of the present invention are still within the protection scope of the present invention.

Claims

1. A method for synthesizing compound V, characterized in that... Compound V was synthesized from compound III via compound IV, and the synthetic route is as follows: Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

2. The method according to claim 1, wherein the alkali is selected from: sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamino, butyllithium, sodium carbonate, and potassium carbonate.

3. The method according to claims 1-2, wherein N-methylpyrrolidone is present in the reaction system for the synthesis of compound IV from compound III.

4. A method for synthesizing compound III, characterized in that... Compound III was synthesized from compound I via compound II, and the synthetic route is as follows: Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

5. The method according to claim 4, wherein the acylation reagent used in the acylation reaction of synthesizing compound II from compound I is propionyl chloride, n-butyryl chloride, n-valeryl chloride, propionyl bromide, n-butyryl bromide, n-valeryl bromide, propionic anhydride, or n-butyryl anhydride.

6. The method according to claims 4-5, wherein the acylation reaction of compound I to synthesize compound II is carried out in the presence of a Grignard reagent; preferably, the Grignard reagent is selected from phenyl magnesium chloride, propyl magnesium chloride, ethyl magnesium chloride, cyclohexyl magnesium chloride, benzyl magnesium chloride, isopropyl magnesium chloride, and isobutyl magnesium chloride.

7. The method according to claims 4-6, wherein the sulfonating agent used in the sulfonation reaction for synthesizing compound III from compound II is methanesulfonyl chloride, ethylsulfonyl chloride, n-propylsulfonyl chloride, n-butylsulfonyl chloride, methanesulfonic anhydride, or ethylsulfonic anhydride.

8. The method according to claims 4-7, wherein the sulfonation reaction for synthesizing compound III from compound II is carried out in the presence of an acid-binding agent; preferably, the acid-binding agent is selected from pyridine, triethylamine, sodium methoxide, diethylamine, N-ethylisopropylamine, and N-phenylaniline.

9. A compound, characterized in that... Selected from compound II, compound III, or compound IV as shown below, Wherein, R1 is ethyl, n-propyl, or n-butyl, and R2 is methyl, ethyl, n-propyl, or n-butyl.

10. A method for synthesizing Leborresen, comprising a method for synthesizing compound V, characterized in that... The method for synthesizing compound V is as follows: R1, R2, and the reagents used in the reaction are as described in claims 1-8.

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