A preparation method of lemborexant intermediate

Abstract

The present invention describes a preparation method of a lemborexant intermediate, belonging to the field of preparation of pharmaceutical intermediates. In the present invention, 2,4-dimethyl-5-hydroxypyrimidine is used as a raw material, which reacts with a sulfonylation reagent to form compound II, and then reacts with compound III to remove the acetyl group, and finally forms the key intermediate compound I for the synthesis of lemborexant. The present invention has the advantages of stable properties of intermediate compound II, good reaction economy, environmental friendliness, high yield and purity of compound I, good appearance of the product, and suitability for industrial production, etc.

Description

Technical Field

[0001] The present invention relates to a preparation method of a lemborexant intermediate in the field of drug intermediate preparation. Background Art

[0002] Lemborexant is an OX1 / OX2 dual receptor antagonist of the G protein-coupled receptor orexin, used for the treatment of insomnia characterized by difficulty falling asleep and / or difficulty maintaining sleep, and is developed by Japanese pharmaceutical company Eisai. The US Food and Drug Administration (FDA) approved its listing in the United States in December 2019 under the trade name Dayvigo. Compared with traditional insomnia treatment drugs, lemborexant has the advantages of low withdrawal effect, low risk of addiction, and high safety, and is one of the orexin receptor antagonists with relatively significant curative effects at present.

[0003] {(1R,2S)-2-[[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol, the chemical formula of which is shown as follows:

[0004]

[0005] The above compound I is an important intermediate for the synthesis of lemborexant. In the prior art, the synthesis method of compound I is shown by the following reaction equation:

[0006]

[0007] Compound III is first sulfonylated with p-toluenesulfonic anhydride to form compound V, then condensed with 2,4-dimethyl-5-hydroxypyrimidine to obtain compound IV, and then deprotected to obtain compound I, with a yield of 70.4% (CN104114524B).

[0008] It should be noted that compound V generated by the above preparation method has poor stability and needs to be stored refrigerated (2-8°C). After cumbersome post-treatment such as gradient cooling and stirring with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, and n-heptane, the ee value of compound V is only 89.3%; at the same time, since compound V is a fatty sulfonate with poor stability, the use of p-toluenesulfonyl chloride as a sulfonylation reagent will cause an in-situ reaction due to the presence of chloride ions, resulting in the deterioration of compound V, and further increasing the impurities in compound I. Therefore, the sulfonylation reagent used in the above reaction is the relatively expensive p-toluenesulfonic anhydride, and the structural formula is shown as follows:

[0009]

[0010] p-Toluenesulfonic anhydride is formed by the condensation of two p-toluenesulfonic acid molecules with the elimination of one molecule of water. Therefore, it has a large molecular weight and poor atom economy, and a large amount of p-toluenesulfonic acid waste liquid will be generated after the reaction, which is not conducive to environmental protection. Moreover, after the organic layer containing Compound I is washed with saturated sodium chloride aqueous solution in the above reaction, the solvent is directly removed by concentration under reduced pressure to obtain Compound I, which has not undergone purification steps such as column chromatography or recrystallization, and the reaction intermediate Compound V has only 89.3% ee. Thus, it can be seen that the purity of the obtained Compound I is not high. Therefore, it is urgent to research and develop an economical, green and industrially scalable synthesis method for {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol. SUMMARY OF THE INVENTION

[0011] The object of the present invention is to provide a method for preparing the lemborexant intermediate {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol. This method has the characteristics of high overall reaction yield, high purity of intermediate Compound II and target product Compound I, easily available and less used reaction raw materials, less consumption of reaction solvent, mild reaction conditions, and simple post-treatment for intermediate Compound II and target product Compound I. The object of the present invention is also to provide an intermediate Compound II that can be used to prepare the target product Compound I. This compound is a solid at room temperature and has good stability, which is conducive to the preparation and post-treatment of intermediate Compound II itself, as well as the preparation and post-treatment of target product Compound I.

[0012] The object of the present invention is achieved as follows: a method for preparing a compound represented by Formula I;

[0013] ;

[0014] The preparation method includes the following steps:

[0015] (1) In the presence of a first organic solvent, using 2,4-dimethyl-5-hydroxypyrimidine as a raw material, reacting under the action of a sulfonating agent and a first base to obtain a compound represented by Formula II;

[0016] ;

[0017] R is selected from a p-toluenesulfonyl group or a methanesulfonyl group;

[0018] (2) The compound represented by Formula II and the compound represented by Formula III are subjected to a condensation reaction in the presence of a second base and a second organic solvent to generate a compound represented by Formula IV, and then the acetyl group is removed to generate a compound represented by Formula I;

[0019] ;

[0020] Ac is an acetyl group.

[0021] In the step (1), the sulfonylation reagent is selected from one or more of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, and methanesulfonic anhydride; the first organic solvent is selected from one or more of ethyl acetate, methyl acetate, and toluene; the first base is selected from one or more of pyridine and triethylamine; the reaction temperature of the reaction is 5 - 15 °C, and the reaction time of the reaction is 2 - 3.5 hours; the mass ratio of 2,4-dimethyl-5-hydroxypyrimidine to the volume of the first organic solvent is 20:70 - 125, where the unit of the mass is g and the unit of the volume is mL; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 - 10; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1 - 3.

[0022] In the step (1), the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5 - 5; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1 - 2.5.

[0023] In the step (1), the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7 - 3.3; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1.2 - 2.1.

[0024] In the step (1), after the reaction under the action of the sulfonylation reagent and the first base, before obtaining the compound shown in formula II, it further includes a post-treatment step; the post-treatment step includes adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing it with water until neutral, standing for liquid separation, taking the organic phase, and concentrating it under reduced pressure; the dilute acid is selected from one or more of dilute hydrochloric acid and dilute citric acid; the concentration of the dilute acid is 0.5 - 2 mol / L; the specific step of the reaction of 2,4-dimethyl-5-hydroxypyrimidine as a raw material under the action of the sulfonylation reagent and the first base in the presence of the first organic solvent is to dissolve 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cool down after adding the first base, and then add the sulfonylation reagent in batches, and keep the temperature for reaction after the addition is completed; the temperature is cooled down to 5 - 15 °C after adding the first base.

[0025] In the step (2), the second base is selected from one or more of cesium carbonate, cesium bicarbonate, rubidium carbonate, potassium carbonate, and sodium carbonate; the second organic solvent is selected from acetonitrile; the molar ratio of the compound shown in formula II to the compound shown in formula III is 1:0.75 to 1.1; the molar ratio of the compound shown in formula II to the second base is 1:1 to 8; the mass ratio of the compound shown in formula II to the volume of the second organic solvent is 32.5:90 to 130, the unit of the mass is g, and the unit of the volume is mL; the reaction temperature of the condensation reaction is 60 to 75 °C; the reaction time of the condensation reaction is 1.7 to 3.5 h.

[0026] In the step (2), the molar ratio of the compound shown in formula II to the compound shown in formula III is 1:0.75 to 1.0; the molar ratio of the compound shown in formula II to the second base is 1:1 to 5; the reaction temperature of the condensation reaction is 60 to 70 °C.

[0027] In the step (2), the molar ratio of the compound shown in formula II to the second base is 1:1 to 4.

[0028] In the step (2), before the deacetylation, it further includes the step of cooling the reaction solution; the cooling of the reaction solution is to cool the reaction solution to 15 to 35 °C; the deacetylation is carried out in the presence of a third base; the third base is selected from one or more of sodium hydroxide and potassium hydroxide; the third base participates in the reaction in the form of an aqueous solution of the third base; the concentration of the aqueous solution of the third base is 1 to 3 mol / L; after the deacetylation, it further includes the steps of extraction with a third organic solvent and concentration under reduced pressure; the third organic solvent is selected from one or more of ethyl acetate, methyl acetate, toluene, and methyl tert-butyl ether; the mass ratio of the compound shown in formula II to the volume of the aqueous solution of the third base is 32.5:130 to 250, the unit of the mass is g, and the unit of the volume is mL; the mass ratio of the compound shown in formula II to the volume of the third organic solvent is 32.5:130 to 250, the unit of the mass is g, and the unit of the volume is mL; in the step (2), it further includes the step of recrystallizing the crude product obtained after concentration under reduced pressure; the solvent for recrystallization is a mixed solvent of a fourth organic solvent and a fifth organic solvent; the fourth organic solvent is selected from ethyl acetate; the fifth organic solvent is selected from n-heptane; the volume ratio of the fourth organic solvent to the fifth organic solvent is 1:2 to 6.

[0029] A compound of formula II or a pharmaceutically acceptable salt thereof;

[0030] ;

[0031] Wherein, R is selected from p-toluenesulfonyl or methanesulfonyl.

[0032] Use of the compound shown in Formula II or its acceptable salt in the preparation of the compound shown in Formula I;

[0033] 。

[0034] A preparation method of the compound shown in Formula II;

[0035] ;

[0036] R is selected from p-toluenesulfonyl or methanesulfonyl;

[0037] The preparation method includes the following steps:

[0038] Using 2,4-dimethyl-5-hydroxypyrimidine as a raw material, in the presence of a first organic solvent, reacting under the action of a sulfonating agent and a first base to obtain the compound shown in Formula II.

[0039] The sulfonating agent is selected from one or more of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, and methanesulfonic anhydride; the first organic solvent is selected from one or more of ethyl acetate, methyl acetate, and toluene; the first base is selected from one or more of pyridine and triethylamine; the reaction temperature of the reaction is 5-15 °C, the reaction time of the reaction is 2-3.5 hours; the mass ratio of 2,4-dimethyl-5-hydroxypyrimidine to the volume of the first organic solvent is 20:70-125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1-10; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonating agent is 1:1-3.

[0040] The molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5-5; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonating agent is 1:1-2.5.

[0041] The molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7-3.3; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonating agent is 1:1.2-2.1.

[0042] After the reaction under the action of the sulfonylation reagent and the first base, before obtaining the compound shown in Formula II, a post-treatment step is further included; the post-treatment step includes adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing with water until neutral, standing for layer separation, taking the organic phase, and concentrating under reduced pressure; the dilute acid is selected from one or more of dilute hydrochloric acid and dilute citric acid; the concentration of the dilute acid is 0.5-2 mol / L; the specific step of reacting 2,4-dimethyl-5-hydroxypyrimidine as a raw material under the action of the sulfonylation reagent and the first base in the presence of the first organic solvent is to dissolve 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cool down after adding the first base, and then add the sulfonylation reagent in batches, and keep the temperature for reaction after the addition is completed; the temperature is cooled down to 5-15 °C after adding the first base.

[0043] The key point of the present invention is to provide a preparation method of {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol. Its chemical principle is: (1) The route of the present invention uses 2,4-dimethyl-5-hydroxypyrimidine as a raw material, and generates Compound II under the action of a sulfonylation reagent (preferably p-toluenesulfonyl chloride), and then reacts with Compound III to remove the acetyl group, and finally generates the key intermediate Compound I for the synthesis of lemborexant, with a yield of 80.3% and a purity of 99.39%, and the appearance of the product is good, being an off-white solid. (2) The route of the present invention avoids the preparation of the unstable compound {(1R,2S)-2-(3-fluorophenyl)-2-[(tosyloxy)methyl]cyclopropyl}methyl acetate (i.e., Compound V) in the prior art, and p-toluenesulfonyl chloride used for the preparation of Compound II is cheaper and has better atom economy than p-toluenesulfonic anhydride used in the reported routes. At the same time, this preparation method reduces the concentration of p-toluenesulfonic acid in the waste liquid, is more environmentally friendly, and is a more economical, green and industrialization-suitable preparation method. (3) The intermediate Compound II is a solid at room temperature and has good stability, which is conducive to the preparation and post-treatment of the intermediate Compound II itself, as well as the preparation and post-treatment of the target product Compound I. (4) It is preferred to react to prepare Compound II in ethyl acetate, which has low cost and is environmentally friendly, as a solvent. After the reaction solution is quenched with water, only 1M dilute hydrochloric acid is needed to extract the organic phase, wash it with water until neutral, and concentrate under reduced pressure to obtain a light brown solid of Compound II with a purity of up to 98.75%. (5) The amounts of reaction materials such as the reaction solvent (preferably acetonitrile) and the base (preferably cesium carbonate) used to prepare Compound I from Compound II are small, and only the crude product of Compound I needs to be recrystallized to obtain an off-white solid with a purity of up to 99.39%.

[0044] Compared with the prior art, the preparation method of {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol has the advantages of high overall reaction yield, high purity of intermediate compound II and target product compound I, easy availability and less consumption of reaction raw materials, less consumption of reaction solvent, mild reaction conditions, simple post-treatment of intermediate compound II and target product compound I, solid state of intermediate compound II at room temperature, good stability, overall economic, green and environmental protection, and suitability for industrial production, etc., and will be widely applied to the field of preparation of the intermediate of the drug lemborexant. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is the structural formula diagram of compound I of the present application.

[0046] Figure 2 It is the structural formula diagram of compound II-1 of the present application.

[0047] Figure 3 It is the reaction equation diagram for preparing compound I of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0048] The following examples will help to understand the present invention, but these examples are only for illustrating the present invention, and the present invention is not limited to these contents.

[0049] Example 1

[0050] Dissolve 20 g of 2,4-dimethyl-5-hydroxypyrimidine (0.16 mol, 1 eq) in 80 mL of ethyl acetate, cool to 10 °C after adding 25 g of pyridine (0.32 mol, 2 eq), and then add 46 g of p-toluenesulfonyl chloride (0.24 mol, 1.5 eq) in batches. After the addition is completed, keep the temperature at 10-15 °C and react for 3 h. After the reaction is completed, add 50 mL of water to quench the reaction. The reaction solution is extracted with 25 mL of 1 M dilute hydrochloric acid and washed with water until neutral, then left to stand and separated. The upper organic phase is taken and concentrated under reduced pressure to obtain 38.1 g of light brown solid compound II-1, with a yield of 86.8% and a purity of 98.75%.

[0051] 1 H NMR(600 MHz, DMSO-d6) δ: 7.78-7.74(m, 1H), 7.75-7.71(m, 1H), 7.51-7.48(m, 2H), 7.46(d, J=6.0 Hz, 1H), 2.42(s, 6H), 2.39(s, 3H). 1313C NMR (150 MHz, DMSO-d6) δ: 164.40, 158.76, 142.52, 141.97, 135.94, 134.37, 129.60, 129.11, 23.92, 21.18, 19.25. [M+H] + 279.1

[0052] 32.5 g of compound II-1 (0.12 mol, 1 eq), 25 g of compound III (0.105 mol, 0.9 eq), and 35 g of cesium carbonate (0.12 mol, 1 eq) were dispersed in 100 mL of acetonitrile and heated to reflux at 65 - 70 °C. After a condensation reaction for 2 h, compound IV was obtained. The reaction solution was cooled to 20 - 25 °C, and 200 mL of sodium hydroxide aqueous solution (2 M) was added to remove the acetyl group. After all of compound IV was converted to compound I, 200 mL of methyl tert-butyl ether was added for extraction. The upper organic phase was taken and concentrated under reduced pressure to obtain the crude product of compound I. The crude product was recrystallized from ethyl acetate / n-heptane (30 mL:90 mL) to obtain 29.3 g of a white solid of compound I, with a yield of 92.5% and a purity of 99.39%.

[0053] 1 1H NMR (600 MHz, DMSO-d6) δ: 8.22 (s, 1H), 7.33 - 7.35 (m, 1H), 7.15 - 7.21 (m, 2H), 7.01 - 7.04 (m, 1H), 4.63 (t, J = 9.6 Hz, 1H), 4.33 - 4.40 (m, 2H), 3.64 - 3.66 (m, 2H), 2.46 (s, 3H), 2.23 (s, 3H), 1.44 - 1.47 (m, 1H), 1.16 - 1.25 (m, 1H), 1.00 - 1.02 (t, J = 5.2 Hz, 1H). [M - H] - 301.4

[0054] The total yield of the preparation of compound I was 80.3%.

[0055]

[0056] Example 2

[0057] Dissolve 20 g of 2,4-dimethyl-5-hydroxypyrimidine (0.16 mol, 1 eq) in 90 mL of methyl acetate. After adding 49 g of triethylamine (0.49 mol, 3.1 eq), cool the temperature to 10 °C, and then add 105.2 g of p-toluenesulfonic anhydride (0.32 mol, 2 eq) in batches. After the addition is completed, keep the temperature at 10 - 15 °C for reaction for 3 h. After the reaction is completed, add 50 mL of water to quench the reaction. The reaction solution is extracted with 25 mL of 1 M dilute hydrochloric acid and then washed with water until neutral. After standing and separating layers, take the upper organic phase and concentrate it under reduced pressure to obtain 37.2 g of a light brown solid compound II-1, with a yield of 83.1% and a purity of 97.91%.

[0058] Disperse 32.5 g of compound II-1 (0.12 mol, 1 eq), 28.6 g of compound III (0.120 mol, 1 eq), and 32.2 g of potassium carbonate (0.23 mol, 2 eq) in 120 mL of acetonitrile. Heat it to reflux at 65 - 70 °C and carry out a condensation reaction for 3 h to obtain compound IV. After the reaction solution is cooled to 20 - 25 °C, add 200 mL of sodium hydroxide aqueous solution (2 M) to remove the acetyl group. After all of compound IV is converted into compound I, add 150 mL of ethyl acetate for extraction. Take the upper organic phase and concentrate it under reduced pressure to obtain the crude product of compound I. Recrystallize it with ethyl acetate / n-heptane (30 mL:150 mL) to obtain 32.1 g of a white-like solid of compound I, with a yield of 88.4% and a purity of 99.10%.

[0059] The total yield of the preparation of compound I is 73.5%.

[0060]

[0061] Example 3

[0062] Dissolve 20 g of 2,4-dimethyl-5-hydroxypyrimidine (0.16 mol, 1 eq) in 120 mL of toluene. After adding 38 g of pyridine (0.49 mol, 3.1 eq), cool the temperature to 10 °C, and then add 46 g of p-toluenesulfonyl chloride (0.24 mol, 1.5 eq) in batches. After the addition is completed, keep the temperature at 10 - 15 °C for reaction for 3 h. After the reaction is completed, add 50 mL of water to quench the reaction. The reaction solution is extracted with 40 mL of 1 M dilute hydrochloric acid and then washed with water until neutral. After standing and separating layers, take the upper organic phase and concentrate it under reduced pressure to obtain 37.7 g of a light brown solid compound II-1, with a yield of 84.2% and a purity of 98.03%.

[0063] Disperse 32.5 g of Compound II-1 (0.12 mol, 1 eq), 22.9 g of Compound III (0.096 mol, 0.8 eq), and 81.1 g of rubidium carbonate (0.35 mol, 2.9 eq) in 120 mL of acetonitrile, heat to reflux at 65 - 70 °C, and obtain Compound IV through a condensation reaction for 2 h. After the reaction solution is cooled to 20 - 25 °C, add 150 mL of potassium hydroxide aqueous solution (2 M) to remove the acetyl group. After all of Compound IV is converted to Compound I, add 150 mL of toluene for extraction, take the upper organic phase, and concentrate it under reduced pressure to obtain the crude product of Compound I. Recrystallize it with ethyl acetate / n-heptane (30 mL:100 mL) to obtain 26.1 g of a white solid of Compound I, with a yield of 89.9% and a purity of 98.82%.

[0064] The total yield of the preparation of Compound I is 75.7%.

[0065]

[0066] Unless otherwise specified, in the figures of this application, Ts is p-toluenesulfonyl; Py is pyridine; Et3N is triethylamine; Ac is acetyl.

[0067] The HPLC detection conditions for Compound II-1 and Compound I in the examples of this application are (see CN104114524B

[0579] ):

[0068] Chromatographic column: Waters SunFire C18;

[0069] Column temperature: 40 °C;

[0070] Mobile phase gradient elution:

[0071] Mobile phase A: 1000 mL of water and 1 mL of trifluoroacetic acid;

[0072] Mobile phase B: 1000 mL of acetonitrile and 1 mL of trifluoroacetic acid;

[0073] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5 70 30 9 60 40 17 0 100 20 0 100 20.1 95 5 30 95 5

[0074] The retention time of Compound I is 12.535 min, and the retention time of Compound II-1 is 26.637 min.

Claims

1. A method for preparing a compound represented by formula I, ， It is characterized in that The preparation method includes the following steps: (1) In the presence of a first organic solvent, using 2,4-dimethyl-5-hydroxypyrimidine as a raw material, reacting under the action of a sulfonylation reagent and a first base to obtain a compound represented by formula II, ， R is selected from a p-toluenesulfonyl group or a methanesulfonyl group; (2) The compound represented by formula II and the compound represented by formula III are subjected to a condensation reaction in the presence of a second base and a second organic solvent to generate a compound represented by formula IV, and then after removing the acetyl group, a compound represented by formula I is generated; ， Ac is an acetyl group.

2. The preparation method of a compound represented by Formula I according to claim 1, characterized in that In the step (1), the sulfonylation reagent is selected from one or more of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, and methanesulfonic anhydride; the first organic solvent is selected from one or more of ethyl acetate, methyl acetate, and toluene; the first base is selected from one or more of pyridine and triethylamine; the reaction temperature of the reaction is 5 - 15°C, and the reaction time of the reaction is 2 - 3.5 hours; the mass ratio of 2,4-dimethyl-5-hydroxypyrimidine to the volume of the first organic solvent is 20:70 - 125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 - 10; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1 - 3.

3. The preparation method of a compound represented by Formula I according to claim 2, wherein In the step (1), the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5 - 5; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1 - 2.

5.

4. The preparation method of a compound represented by Formula I according to claim 3, characterized in that, In the step (1), the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7 - 3.3; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1.2 - 2.

1.

5. The preparation method of a compound represented by Formula I according to claim 1, wherein, In the step (1), after the reaction under the action of the sulfonylation reagent and the first base and before obtaining the compound represented by formula II, it also includes a post-treatment step; the post-treatment step includes adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing it to neutral, standing for liquid separation, taking the organic phase, and concentrating it under reduced pressure; the dilute acid is selected from one or more of dilute hydrochloric acid and dilute citric acid; the concentration of the dilute acid is 0.5 - 2 mol / L; the specific step of reacting using 2,4-dimethyl-5-hydroxypyrimidine as a raw material under the action of a sulfonylation reagent and a first base in the presence of a first organic solvent is to dissolve 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cool down after adding the first base, and then add the sulfonylation reagent in batches, and keep the reaction warm after the addition is completed; the temperature is cooled down to 5 - 15°C after adding the first base.

6. The preparation method of a compound represented by Formula I according to claim 1, characterized in that, In the step (2), the second base is selected from one or more of cesium carbonate, cesium bicarbonate, rubidium carbonate, potassium carbonate, and sodium carbonate; the second organic solvent is selected from acetonitrile; the molar ratio of the compound shown in formula II to the compound shown in formula III is 1:0.75 to 1.1; the molar ratio of the compound shown in formula II to the second base is 1:1 to 8; the mass ratio of the compound shown in formula II to the volume of the second organic solvent is 32.5:90 to 130, the unit of the mass is g, and the unit of the volume is mL; the reaction temperature of the condensation reaction is 60 to 75 °C; the reaction time of the condensation reaction is 1.7 to 3.5 h.

7. The preparation method of a compound represented by Formula I according to claim 6, characterized in that, In the step (2), the molar ratio of the compound shown in formula II to the compound shown in formula III is 1:0.75 to 1.0; the molar ratio of the compound shown in formula II to the second base is 1:1 to 5; the reaction temperature of the condensation reaction is 60 to 70 °C.

8. The preparation method of a compound shown by Formula I according to claim 7, characterized in that, In the step (2), the molar ratio of the compound shown in formula II to the second base is 1:1 to 4.

9. The preparation method of a compound represented by Formula I according to claim 1, characterized in that, In the step (2), before removing the acetyl group, it further includes the step of cooling the reaction solution; cooling the reaction solution means cooling the reaction solution to 15 to 35 °C; removing the acetyl group is carried out in the presence of a third base; the third base is selected from one or more of sodium hydroxide and potassium hydroxide; the third base participates in the reaction in the form of an aqueous solution of the third base; the concentration of the aqueous solution of the third base is 1 to 3 mol / L; after removing the acetyl group, it further includes the steps of extraction with a third organic solvent and concentration under reduced pressure; the third organic solvent is selected from one or more of ethyl acetate, methyl acetate, toluene, and methyl tert-butyl ether; the mass ratio of the compound shown in formula II to the volume of the aqueous solution of the third base is 32.5:130 to 250, the unit of the mass is g, and the unit of the volume is mL; the mass ratio of the compound shown in formula II to the volume of the third organic solvent is 32.5:130 to 250, the unit of the mass is g, and the unit of the volume is mL; in the step (2), it further includes the step of recrystallizing the crude product obtained after concentration under reduced pressure; the solvent for recrystallization is a mixed solvent of a fourth organic solvent and a fifth organic solvent; the fourth organic solvent is selected from ethyl acetate; the fifth organic solvent is selected from n-heptane; the volume ratio of the fourth organic solvent to the fifth organic solvent is 1:2 to 6.

10. A compound of formula II or an acceptable salt thereof, ， Among them, R is selected from p-toluenesulfonyl or methanesulfonyl.

11. Use of the compound of formula II or an acceptable salt thereof according to claim 10 in the preparation of the compound of formula I, 。 12. A method for preparing a compound of formula II, ， R is selected from p-toluenesulfonyl or methanesulfonyl, It is characterized in that The preparation method includes the following steps: In the presence of a first organic solvent, using 2,4-dimethyl-5-hydroxypyrimidine as a raw material, reacting under the action of a sulfonylation reagent and a first base to obtain the compound shown in formula II.

13. The preparation method of a compound represented by Formula II according to claim 12, characterized in that, The sulfonylation reagent is selected from one or more of p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, and methanesulfonic anhydride; the first organic solvent is selected from one or more of ethyl acetate, methyl acetate, and toluene; the first base is selected from one or more of pyridine and triethylamine; the reaction temperature of the reaction is 5-15 °C, and the reaction time of the reaction is 2-3.5 hours; the mass ratio of 2,4-dimethyl-5-hydroxypyrimidine to the volume of the first organic solvent is 20:70-125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1-10; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1-3.

14. The preparation method of a compound represented by Formula II according to claim 13, characterized in that, The molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5-5; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1-2.

5.

15. The preparation method of a compound represented by Formula II according to claim 14, wherein, The molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7-3.3; the molar ratio of 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylation reagent is 1:1.2-2.

1.

16. The preparation method of a compound shown in Formula II according to claim 12, wherein Before obtaining the compound shown in Formula II after the reaction under the action of the sulfonylation reagent and the first base, a post-treatment step is further included; the post-treatment step includes adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing it with water until neutral, standing for liquid separation, taking the organic phase, and concentrating it under reduced pressure; the dilute acid is selected from one or more of dilute hydrochloric acid and dilute citric acid; the concentration of the dilute acid is 0.5-2 mol / L; the specific steps of the reaction of 2,4-dimethyl-5-hydroxypyrimidine as a raw material under the action of the sulfonylation reagent and the first base in the presence of the first organic solvent are to dissolve 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cool down after adding the first base, and then add the sulfonylation reagent in batches, and keep the reaction warm after the addition is completed; the temperature is cooled down to 5-15 °C after adding the first base.

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