Preparation method of Lescalobolifera intermediate

Abstract

The invention discloses a preparation method of a lyboxadone intermediate, and belongs to the field of preparation of drug intermediates. According to the method, 2, 4-dimethyl-5-hydroxypyrimidine is taken as a raw material, a compound II is generated under the action of a sulfonylation reagent, then the compound II reacts with a compound III to remove acetyl, and finally, a key intermediate compound I for synthesis of the Leibrexant is generated. The method has the advantages that the intermediate compound II is stable in property, good in reaction economy and environment-friendly, and the compound I is high in yield, high in purity, good in product appearance, suitable for industrial production and the like.

Description

Technical Field

[0001] The invention relates to a method for preparing a lebroxan intermediate in the field of pharmaceutical intermediate preparation. Background Art

[0002] Lebrexan is a dual OX1 / OX2 receptor antagonist of the G protein-coupled receptor orexin, used to treat insomnia characterized by difficulty falling asleep and / or maintaining sleep. It was developed by the Japanese pharmaceutical company Eisai. The U.S. Food and Drug Administration (FDA) approved its marketing in the United States in December 2019 under the trade name Dayvigo. Compared with traditional insomnia treatment drugs, Lebrexan has the advantages of low withdrawal effect, low risk of addiction, and high safety. It is one of the orexin receptor antagonists with more significant efficacy.

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

[0004]

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

[0006]

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

[0008] It should be noted that the compound V produced by the above preparation method is less stable and needs to be stored in a refrigerator (2-8°C). After tedious post-treatments such as saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, and n-heptane gradient cooling and stirring, the compound V has only 89.3% ee. At the same time, since compound V is a fatty sulfonate ester with poor stability, the presence of chloride ions in p-toluenesulfonyl chloride as the sulfonylation agent will trigger an in-situ reaction, causing compound V to deteriorate, and thus leading to an increase in impurities in compound I. Therefore, the sulfonylation agent in the above reaction uses the more expensive p-toluenesulfonic anhydride, and the structural formula is as follows:

[0009]

[0010] p-Toluenesulfonic anhydride is formed by condensation of two p-toluenesulfonic acid molecules by removing one molecule of water, so its molecular weight is large and atom economy is poor. After the reaction, a large amount of p-toluenesulfonic acid waste liquid will be produced, which is not conducive to environmental protection. Moreover, the above reaction uses a saturated sodium chloride aqueous solution to wash the organic layer containing compound I, and then directly concentrates under reduced pressure to remove the solvent to obtain compound I, without purification steps such as column chromatography or recrystallization, and its reaction intermediate compound V is only 89.3% ee, which shows that the purity of the compound I obtained is not high. Therefore, it is urgent to research and develop a kind of {(1R, 2S)-2-[[(2,4-dimethylpyrimidin-5-yl) oxygen] methyl]-2-(3-fluorophenyl) cyclopropyl} methanol economic, green, suitable for industrial production synthesis method. Summary of the invention

[0011] The purpose of the present invention is to provide a method for preparing a leborax intermediate {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol, which has the characteristics of high total reaction yield, high purity of intermediate compound II and target product compound I, easy availability of reaction raw materials and less amount used, less consumption of reaction solvent, mild reaction conditions, simple post-treatment of intermediate compound II and target product compound I, etc. The purpose of the present invention is also to provide an intermediate compound II that can be used to prepare target product compound I, which is solid at room temperature and has good stability, thereby facilitating 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 by: a method for preparing a compound represented by formula I;

[0013] ;

[0014] The preparation method comprises the following steps:

[0015] (1) in the presence of a first organic solvent, using 2,4-dimethyl-5-hydroxypyrimidine as a raw material, reacting with a sulfonylating agent and a first base to obtain a compound represented by formula II;

[0016] ;

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

[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 acetyl.

[0021] In the step (1), the sulfonylating 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 to 15° C., and the reaction time of the reaction is 2 to 3.5 hours; the mass ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the volume ratio of the first organic solvent is 20:70 to 125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 to 10; and the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1 to 3.

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

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

[0024] In the step (1), after the reaction under the action of the sulfonylating agent and the first base, before obtaining the compound shown in formula II, a post-treatment step is also included; the post-treatment step includes the steps of adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing with water until neutral, standing and stratifying, 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 steps of reacting in the presence of the first organic solvent with 2,4-dimethyl-5-hydroxypyrimidine as the raw material under the action of the sulfonylating agent and the first base are: dissolving 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cooling after adding the first base, then adding the sulfonylating agent in batches, and keeping the temperature for reaction after the addition is completed; cooling 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 represented by formula II to the compound represented by formula III is 1:0.75-1.1; the molar ratio of the compound represented by formula II to the second base is 1:1-8; the mass ratio of the compound represented by formula II to the volume ratio of the second organic solvent is 32.5:90-130, the unit of mass is g, and the unit of volume is mL; the reaction temperature of the condensation reaction is 60-75°C; and the reaction time of the condensation reaction is 1.7-3.5h.

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

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

[0028] In the step (2), before the acetyl group is removed, the reaction solution is cooled to 15-35°C; the acetyl group is removed by reacting 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 a third base aqueous solution; the concentration of the third base aqueous solution is 1-3 mol / L; after the acetyl group is removed, the step of extracting with a third organic solvent and concentrating under reduced pressure is also included; the third organic solvent is selected from one or more of ethyl acetate, methyl acetate, toluene, and methyl tert-butyl ether; the mass of the compound represented by formula II is The volume ratio of the mass of the compound represented by formula II to the third organic solvent is 32.5:130-250, the unit of mass is g, and the unit of volume is mL; the volume ratio of the mass of the compound represented by formula II to the third organic solvent is 32.5:130-250, the unit of mass is g, and the unit of volume is mL; in the step (2), it also includes a step of recrystallizing the crude product obtained after the reduced pressure concentration; the recrystallization solvent is selected from 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 1:2-6.

[0029] A compound represented by formula II or an acceptable salt thereof;

[0030] ;

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

[0032] Use of the compound represented by formula II or an acceptable salt thereof in preparing the compound represented by formula I;

[0033] .

[0034] A method for preparing a compound represented by formula II;

[0035] ;

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

[0037] The preparation method comprises the following steps:

[0038] In the presence of a first organic solvent, 2,4-dimethyl-5-hydroxypyrimidine is used as a raw material, and reacts with a sulfonylating agent and a first base to obtain a compound represented by formula II.

[0039] The sulfonylating 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 to 15° C., and the reaction time of the reaction is 2 to 3.5 hours; the mass ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the volume ratio of the first organic solvent is 20:70 to 125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 to 10; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1 to 3.

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

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

[0042] After the reaction under the action of the sulfonylating agent and the first base, before obtaining the compound shown in formula II, a post-treatment step is also included; the post-treatment step includes the steps of adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing it with water until it is neutral, standing and stratifying, 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 steps of reacting in the presence of the first organic solvent with 2,4-dimethyl-5-hydroxypyrimidine as the raw material under the action of the sulfonylating agent and the first base are as follows: dissolving 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cooling after adding the first base, then adding the sulfonylating agent in batches, and keeping the temperature for reaction after the addition is completed; cooling to 5-15°C after adding the first base.

[0043] The gist of the present invention is to provide a method for preparing {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol. The chemical principle is as follows: (1) The route of the present invention uses 2,4-dimethyl-5-hydroxypyrimidine as a raw material, generates compound II under the action of a sulfonylating agent (preferably p-toluenesulfonyl chloride), and then reacts with compound III to remove the acetyl group, and finally generates compound I, a key intermediate compound for the synthesis of Lebrexan, with a yield of 80.3% and a purity of 99.39%. The product has a good appearance and is an off-white solid. (2) The route of the present invention avoids the preparation of the unstable compound {(1R,2S)-2-(3-fluorophenyl)-2-[(toluenesulfonyloxy)methyl]cyclopropyl}acetic acid methyl ester (i.e., compound V) in the prior art, and the p-toluenesulfonyl chloride used in the preparation of compound II is cheaper and has better atom economy than the p-toluenesulfonic anhydride used in the reported route. At the same time, the preparation method reduces the concentration of p-toluenesulfonic acid in the waste liquid, is more environmentally friendly, and is a more economical, green, and industrially suitable preparation method. (3) The intermediate compound II is 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) The preparation of compound II is preferably carried out in the presence of low-cost, environmentally friendly ethyl acetate as a solvent, and after the reaction solution is quenched with water, the organic phase only needs to be extracted with 1M dilute hydrochloric acid, washed with water to neutrality, and concentrated under reduced pressure to obtain a light brown solid of compound II with a purity of 98.75%. (5) When compound II is used to prepare compound I, the amount of reaction materials such as reaction solvent (preferably acetonitrile) and base (preferably cesium carbonate) used is small, and an off-white solid with a purity of 99.39% can be obtained by simply recrystallizing the crude product of compound I.

[0044] Compared with the prior art, a method for preparing {(1R,2S)-2-[[(2,4-dimethylpyrimidin-5-yl)oxy]methyl]-2-(3-fluorophenyl)cyclopropyl}methanol has the advantages of high total reaction yield, high purity of intermediate compound II and target product compound I, easy availability of reaction raw materials and small amount of reaction solvent, low reaction condition, simple post-treatment of intermediate compound II and target product compound I, intermediate compound II is solid at room temperature and has good stability, the method is overall economical, green and environmentally friendly, suitable for industrial production, etc., and will be widely used in the field of preparation of drug leborax intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is the structural formula diagram of Compound I of the present application.

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

[0047] Figure 3 A reaction equation diagram for preparing compound I in this application. DETAILED DESCRIPTION

[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] Embodiment 1

[0050] Dissolve 20g of 2,4-dimethyl-5-hydroxypyrimidine (0.16mol, 1eq) in 80mL of ethyl acetate, add 25g of pyridine (0.32mol, 2eq) and cool to 10°C, then add 46g of p-toluenesulfonyl chloride (0.24mol, 1.5eq) in batches, and keep at 10-15°C for 3h after the addition. After the reaction, add 50mL of water to quench the reaction. The reaction solution is extracted with 25mL of 1M dilute hydrochloric acid and washed with water until neutral, stand and stratify, take the upper organic phase, and concentrate under reduced pressure to obtain 38.1g 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). 13C 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, heated to 65-70 ° C and refluxed, and compound IV was obtained after condensation reaction for 2 h. The reaction solution was cooled to 20-25 ° C and 200 mL of sodium hydroxide aqueous solution (2M) was added to remove the acetyl group. After compound IV was completely converted into compound I, 200 mL of methyl tert-butyl ether was added for extraction, and the upper organic phase was taken and concentrated under reduced pressure to obtain a crude compound I. It was recrystallized from ethyl acetate / n-heptane (30 mL:90 mL) to obtain 29.3 g of an off-white solid compound I with a yield of 92.5% and a purity of 99.39%.

[0053] 1 H 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).[MH] - 301.4.

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

[0055]

[0056] Embodiment 2

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

[0058] 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) were dispersed in 120 mL of acetonitrile, heated to 65-70 ° C and refluxed, and condensed for 3 h to obtain compound IV. After the reaction solution was cooled to 20-25 ° C, 200 mL of sodium hydroxide aqueous solution (2M) was added to remove the acetyl group. After compound IV was completely converted into compound I, 150 mL of ethyl acetate was added for extraction, and the upper organic phase was taken and concentrated under reduced pressure to obtain a crude compound I. It was recrystallized from ethyl acetate / n-heptane (30 mL: 150 mL) to obtain 32.1 g of an off-white compound I solid with a yield of 88.4% and a purity of 99.10%.

[0059] The total yield of compound I was 73.5%.

[0060]

[0061] Embodiment 3

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

[0063] 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) were dispersed in 120 mL of acetonitrile, heated to 65-70 ° C and refluxed, and subjected to condensation reaction for 2 h to obtain compound IV. After the reaction solution was cooled to 20-25 ° C, 150 mL of potassium hydroxide aqueous solution (2 M) was added to remove the acetyl group. After compound IV was completely converted into compound I, 150 mL of toluene was added for extraction, and the upper organic phase was taken and concentrated under reduced pressure to obtain a crude compound I. It was recrystallized from ethyl acetate / n-heptane (30 mL: 100 mL) to obtain 26.1 g of an off-white compound I solid with a yield of 89.9% and a purity of 98.82%.

[0064] The total yield of compound I was 75.7%.

[0065]

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

[0067] The HPLC detection conditions for compound II-1 and compound I in the examples of the present application are as follows (see CN104114524B

[0579] ):

[0068] Column: Waters SunFire C18;

[0069] Column temperature: 40°C;

[0070] Mobile phase gradient elution:

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

[0072] Mobile phase B: 1000 mL acetonitrile and 1 mL 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 was 12.535 min, and the retention time of compound II-1 was 26.637 min.

Claims

1. A method for preparing a compound of formula I, ， It is characterized in that The preparation method comprises the following steps: (1) In the presence of a first organic solvent, 2,4-dimethyl-5-hydroxypyrimidine is used as a raw material, reacted with a sulfonylating agent and a first base to obtain a compound represented by formula II, ， R is selected from p-toluenesulfonyl or methanesulfonyl; (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; ， Ac is acetyl.

2. The method for preparing the compound of formula (I) according to claim 1, characterized in that: In the step (1), the sulfonylating 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 to 15° C., and the reaction time of the reaction is 2 to 3.5 hours; the mass ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the volume ratio of the first organic solvent is 20:70 to 125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 to 10; and the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1 to 3.

3. The method for preparing the compound of formula I according to claim 2, characterized in that: In the step (1), the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5-5; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1-2.

5.

4. The method for preparing the compound of formula I according to claim 3, characterized in that: In the step (1), the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7-3.3; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1.2-2.

1.

5. The method for preparing the compound of formula I according to claim 1, characterized in that: In the step (1), after the reaction under the action of the sulfonylating agent and the first base, before obtaining the compound shown in formula II, a post-treatment step is also included; the post-treatment step includes the steps of adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing with water until neutral, standing and stratifying, 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 steps of reacting in the presence of the first organic solvent with 2,4-dimethyl-5-hydroxypyrimidine as the raw material under the action of the sulfonylating agent and the first base are: dissolving 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cooling after adding the first base, then adding the sulfonylating agent in batches, and keeping the temperature for reaction after the addition is completed; cooling to 5-15°C after adding the first base.

6. The method for preparing the compound of 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 represented by formula II to the compound represented by formula III is 1:0.75-1.1; the molar ratio of the compound represented by formula II to the second base is 1:1-8; the mass ratio of the compound represented by formula II to the volume ratio of the second organic solvent is 32.5:90-130, the unit of mass is g, and the unit of volume is mL; the reaction temperature of the condensation reaction is 60-75°C; and the reaction time of the condensation reaction is 1.7-3.5h.

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

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

9. The method for preparing the compound of formula I according to claim 1, characterized in that: In the step (2), before the acetyl group is removed, the reaction solution is cooled to 15-35°C; the acetyl group is removed by reacting 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 a third base aqueous solution; the concentration of the third base aqueous solution is 1-3 mol / L; after the acetyl group is removed, the step of extracting with a third organic solvent and concentrating under reduced pressure is also included; the third organic solvent is selected from one or more of ethyl acetate, methyl acetate, toluene, and methyl tert-butyl ether; the mass of the compound represented by formula II is The volume ratio of the mass of the compound represented by formula II to the third organic solvent is 32.5:130-250, the unit of mass is g, and the unit of volume is mL; the volume ratio of the mass of the compound represented by formula II to the third organic solvent is 32.5:130-250, the unit of mass is g, and the unit of volume is mL; in the step (2), it also includes a step of recrystallizing the crude product obtained after the reduced pressure concentration; the recrystallization solvent is selected from 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 1:2-6.

10. A compound of formula II or an acceptable salt thereof, ， in, 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 preparing 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 comprises the following steps: In the presence of a first organic solvent, 2,4-dimethyl-5-hydroxypyrimidine is used as a raw material, and reacts with a sulfonylating agent and a first base to obtain a compound represented by formula II.

13. The method for preparing a compound of formula II according to claim 12, characterized in that: The sulfonylating 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 to 15° C., and the reaction time of the reaction is 2 to 3.5 hours; the mass ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the volume ratio of the first organic solvent is 20:70 to 125, the unit of the mass is g, and the unit of the volume is mL; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1 to 10; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1 to 3.

14. The method for preparing a compound of formula II according to claim 13, characterized in that: The molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.5-5; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1-2.

5.

15. The method for preparing a compound of formula II according to claim 14, characterized in that: The molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the first base is 1:1.7-3.3; the molar ratio of the 2,4-dimethyl-5-hydroxypyrimidine to the sulfonylating agent is 1:1.2-2.

1.

16. The method for preparing a compound of formula II according to claim 12, characterized in that: After the reaction under the action of the sulfonylating agent and the first base, before obtaining the compound shown in formula II, a post-treatment step is also included; the post-treatment step includes the steps of adding water to quench the reaction, extracting the reaction solution with dilute acid and then washing it with water until it is neutral, standing and stratifying, 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 steps of reacting in the presence of the first organic solvent with 2,4-dimethyl-5-hydroxypyrimidine as the raw material under the action of the sulfonylating agent and the first base are as follows: dissolving 2,4-dimethyl-5-hydroxypyrimidine in the first organic solvent, cooling after adding the first base, then adding the sulfonylating agent in batches, and keeping the temperature for reaction after the addition is completed; cooling to 5-15°C after adding the first base.

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