Preparation method of salt of 2, 4-disubstituted-5-fluoropyrimidine derivative

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a salt of a 2, 4-disubstituted-5-fluoropyrimidine derivative, which comprises the following steps: carrying out protecting group removal and salt forming reaction on a compound VI in a reaction solvent in the presence of hydrochloric acid to obtain a compound I; wherein the preparation method of the compound VI comprises the following steps: carrying out salt forming reaction on a compound V in a hydrochloric acid solution to prepare the compound VI; after the reaction is completed, post-treatment is carried out, and the post-treatment comprises the steps that an anti-solvent is added, and crystallization is carried out at a certain temperature. The invention provides the preparation method of the salt of the 2, 4-disubstituted-5-fluoropyrimidine derivative, which has the advantages of high yield, high purity, lower cost and simplicity and convenience in operation. By optimizing a plurality of preparation steps, the yield and purity of the target compound are improved, and the prepared finished product can meet the general standard requirements of bulk drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative. Background Art

[0002] 1-[5-Fluoro-4-[[4-(piperazin-1-yl)phenyl]amino]pyrimidin-2-yl]-1H-benzo[d]imidazol-2-amine is a compound with a novel structure first reported in Chinese patent application CN116514779A, and is a small molecule compound with anti-renal fibrosis effect. The prior art discloses a preparation method thereof, which specifically comprises the following steps: using p-fluoronitrobenzene and 1-Boc-piperazine as starting materials and dimethyl sulfoxide as a reaction solvent, a nucleophilic substitution reaction occurs under reflux for 5 hours to obtain compound 3; then the nitro group is reduced to an amino group using iron powder and ammonium chloride to obtain compound 4; compound 4 and 2,4-dichloro-5-fluoropyrimidine undergo a nucleophilic substitution reaction in methanol to obtain compound 5; compound 5 and 2-aminobenzimidazole undergo a Buchwald-Hartwig coupling reaction using Cs2CO3 as a base, Xantphos as a carrier, Pd2(dba)3 as a catalyst, and 1,4-dioxane as a solvent to obtain compound 6a; compound 6a undergoes a Boc removal reaction using trifluoroacetic acid at room temperature, alkali ionization, extraction, and concentration to obtain the free base of compound I.

[0003] However, this synthesis method has the following defects: 1. When the synthesis method is used to synthesize compound 5, although the product obtained has a high purity, the yield is very low. The yield is only about 20% when the preparation method is reproduced.

[0004] 2. This synthesis method uses a Buchwald-hartwig coupling reaction when synthesizing compound 6a, which requires the use of expensive ligand 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and catalyst tri(dibenzylideneacetone)dipalladium (Pd2(dba)3). On the other hand, since the reaction temperature reaches 120°C and the boiling point of dioxane is only 101°C, the reaction needs to be carried out in a closed, high-pressure environment. The post-processing after the reaction is complete also requires filtration, extraction, separation, concentration and column chromatography, which is relatively cumbersome and not suitable for large-scale industrial production, and the yield is only 47%.

[0005] 3. When the synthesis method is used to synthesize the free base of compound I, the post-treatment after the reaction is complete also requires multiple extractions, separations and concentrations, and the yield is only about 83%. In addition, the prepared compound is a free base with poor solubility, which is not conducive to the purification of the raw material drug, and its purity does not meet the general standard of the raw material drug (unknown single impurities shall not exceed 0.1%). Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, so as to provide a method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative with high yield, high purity, low cost and simple operation.

[0007] In order to achieve the above object, the present invention adopts the following technical solution: A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative comprises the following steps: using compound II and compound III as starting materials, performing a substitution reaction to obtain compound IV; performing a substitution reaction on compound IV to obtain compound V; performing a salt-forming reaction on compound V to obtain compound VI; performing a deprotection reaction and a salt-forming reaction on compound VI to obtain compound I; the reaction route is as follows: .

[0008] In one aspect, the method for preparing the salt of the 2,4-disubstituted-5-fluoropyrimidine derivative comprises the following steps: Compound VI is subjected to a deprotection reaction and a salt-forming reaction in a reaction solvent at a reaction temperature in the presence of hydrochloric acid to obtain Compound I: .

[0009] In a preferred embodiment, the reaction solvent is acetonitrile and the reaction temperature is 20°C-30°C.

[0010] In a preferred embodiment, the preparation method of compound VI further comprises the following steps: compound V undergoes a salt-forming reaction in a hydrochloric acid solution at a reaction temperature to obtain compound VI; after the reaction is complete, post-treatment is performed, and the post-treatment comprises: adding an anti-solvent and performing crystallization at a certain temperature; wherein the hydrochloric acid solution comprises hydrochloric acid and a solvent, and the solvent comprises at least one of methanol, ethanol, isopropanol, acetone, and purified water; the anti-solvent comprises at least one of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; the temperature of the salt-forming reaction is 0°C-40°C; the temperature of the crystallization is 0°C-40°C; .

[0011] In the second aspect, the method for preparing the salt of the 2,4-disubstituted-5-fluoropyrimidine derivative, more specifically, comprises the following steps: S1, compound II and compound III undergo substitution reaction in a reaction solvent at reaction temperature in the presence of an acid-binding agent to obtain compound IV. ; S2. Under a protective atmosphere, compound IV and 2-aminobenzimidazole undergo a substitution reaction in a reaction solvent at a reaction temperature in the presence of an acid-binding agent, a ligand, and a catalyst to obtain compound V. ; S3, compound V undergoes salt formation reaction in hydrochloric acid solution at reaction temperature, and after the reaction is complete, post-treatment is performed, wherein the post-treatment comprises: adding an anti-solvent and performing crystallization at a certain temperature to obtain compound VI, ; S4, compound VI is subjected to a deprotection reaction and a salt-forming reaction in a reaction solvent at a reaction temperature in the presence of hydrochloric acid to obtain a crude product of compound I, .

[0012] In a preferred embodiment, the reaction solvent in S1 includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, ethyl acetate and acetonitrile.

[0013] In a preferred embodiment, the reaction solvent in S1 is methanol, which is beneficial to the reaction and post-treatment.

[0014] In a preferred embodiment, the reaction time in S1 is 2-4 hours. Generally, the reaction is complete after 2-4 hours.

[0015] In a preferred embodiment, in S1, the molar ratio of compound II to compound III is 1:1-1:3.

[0016] In a preferred embodiment, in S1, the molar ratio of compound II to compound III is 1:1.3-1.5, which is beneficial to the reaction and cost control.

[0017] In a preferred embodiment, in S1, the acid binding agent includes at least one of triethylamine, N,N-diisopropylethylamine, ammonia water, pyridine, tert-butylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and potassium phosphate.

[0018] In a preferred embodiment, in S1, the acid binding agent is triethylamine, which is beneficial to the reaction and post-treatment.

[0019] In a preferred embodiment, in S1, the molar ratio of the acid binding agent to the compound II is 1:1-1:3.

[0020] In a preferred embodiment, in S1, the molar ratio of the acid binding agent to the compound II is 1: 1.3-1.5, which is beneficial to the reaction and cost control.

[0021] In a preferred embodiment, in S1, the reaction temperature is 30°C-120°C depending on the solvent.

[0022] The reaction temperature is reflux temperature, which is beneficial to the reaction and cost control.

[0023] In a preferred embodiment, the post-treatment of S1 is: after the reaction is complete, crystallization, filtration and drying are performed to obtain compound IV.

[0024] In a preferred embodiment, the crystallization is performed by adding an anti-solvent for crystallization after the product is cooled to 0°C-40°C.

[0025] In a preferred embodiment, the anti-solvent is purified water.

[0026] In the examples, post-treatment is performed by adding purified water for crystallization, which is beneficial to improving the yield and controlling the cost.

[0027] In a preferred embodiment, the protective atmosphere in S2 is a nitrogen atmosphere or an argon atmosphere.

[0028] In a preferred embodiment, the reaction solvent in S2 includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, and tert-butanol.

[0029] In a preferred embodiment, the reaction solvent in S2 is dimethyl sulfoxide, which is beneficial to the reaction and post-treatment.

[0030] In a preferred embodiment, in S2, the molar ratio of compound IV to 2-aminobenzimidazole is 1:1-1:3.

[0031] In a preferred embodiment, in S2, the molar ratio of compound IV to 2-aminobenzimidazole is 1:1.5, which is beneficial to the reaction and cost control.

[0032] In a preferred embodiment, the acid binding agent in S2 includes at least one of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate.

[0033] In a preferred embodiment, the acid binding agent in S2 is cesium carbonate, which is beneficial to the reaction and post-treatment.

[0034] In a preferred embodiment, the ligand in S2 includes at least one of 8-hydroxyquinoline, L-proline, and 2-[(1-oxido-2-pyridyl)methylamino]-2-oxoacetic acid.

[0035] In a preferred embodiment, the ligand in S2 is 8-hydroxyquinoline, which is beneficial to the reaction.

[0036] In a preferred embodiment, the catalyst in S2 includes at least one of cuprous iodide, cuprous chloride, cuprous bromide, cupric iodide, cupric bromide, anhydrous cupric chloride, cuprous oxide, cupric oxide, and elemental copper.

[0037] In a preferred embodiment, the catalyst in S2 is cuprous iodide, which is beneficial to the reaction.

[0038] In a preferred embodiment, the reaction temperature is 100° C.-140° C., which is beneficial to the reaction and cost control.

[0039] In a preferred embodiment, the post-treatment of S2 is: after the reaction is complete, crystallization, filtration, drying and recrystallization are performed to obtain compound V.

[0040] In a preferred embodiment, the crystallization is performed by cooling the product to 0°C-60°C and then adding an anti-solvent for crystallization.

[0041] In a preferred embodiment, the anti-solvent includes at least one of purified water, ammonia water, ethanol, isopropanol, and acetone.

[0042] In a preferred embodiment, the anti-solvent is a mixed solvent of ethanol and ammonia water, which is beneficial to improve the yield and purity.

[0043] In a preferred embodiment, the mass ratio of ethanol to aqueous ammonia in the anti-solvent is 10:1-3:1. A mixed solvent within this range is beneficial to improving the yield and purity.

[0044] In one preferred embodiment, in S2, the recrystallization is to add the solid substance to be purified into an appropriate amount of hot solvent, heat until dissolved, and form a nearly saturated solution; then add an anti-solvent dropwise, stir and cool, so that crystals precipitate from the supersaturated solution; after the crystals are completely precipitated, filter and separate the crystals from the mother liquor; wash the crystals with a small amount of cold solvent to remove impurities attached to the surface, and then dry.

[0045] In a preferred embodiment, the hot solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0046] In a preferred embodiment, the hot solvent is N-methylpyrrolidone, which is beneficial to improve the yield and purity.

[0047] In a preferred embodiment, the anti-solvent includes at least one of purified water, methanol, ethanol, isopropanol, and acetone.

[0048] In a preferred embodiment, the anti-solvent is ethanol and the crystallization temperature is room temperature, which is conducive to improving the yield and purity.

[0049] In a preferred embodiment, in S3, the hydrochloric acid solution includes hydrochloric acid and a solvent, and the solvent includes at least one of methanol, ethanol, isopropanol, acetone, and purified water.

[0050] In a preferred embodiment, the solvent is a mixture of ethanol and purified water.

[0051] In a preferred embodiment, in S3, in the hydrochloric acid solution, the mass ratio of ethanol, hydrochloric acid and purified water is 1:(1-10):(1-5).

[0052] In a preferred embodiment, in S3, the anti-solvent includes at least one of methanol, ethanol, isopropanol, acetone and tetrahydrofuran.

[0053] In a preferred embodiment, in S3, the anti-solvent is ethanol, which is beneficial to improve the yield and purity.

[0054] In a preferred embodiment, in S3, the temperature of the salt-forming reaction is 0°C-40°C; and the temperature of the crystallization is 0°C-40°C.

[0055] In a preferred embodiment, in S3, the salt-forming reaction temperature is 5°C-10°C, and the crystallization temperature is 20°C-25°C, which is conducive to improving the yield and purity.

[0056] In a preferred embodiment, the hydrochloric acid in S4 is 37% concentrated hydrochloric acid.

[0057] In a preferred embodiment, in S4, the reaction solvent is acetonitrile and the reaction temperature is 20°C-30°C.

[0058] In a preferred embodiment, after the reaction of S4 is completed, the crude product of compound I obtained in S4 is further refined, i.e., S5. S5 includes the following steps: adding purified water to the crude product, heating it until dissolved, adding activated carbon for decolorization, filtering, and collecting the filtrate; adding the solution to the filtrate, heating it again until completely dissolved, then cooling it to 0°C-30°C, filtering, and drying to obtain compound I.

[0059] In a preferred embodiment, the weight of purified water added in S5 is 3-5 times the weight of the crude product of Compound I.

[0060] In a preferred embodiment, the heating in S5 refers to heating to 40°C-80°C.

[0061] In a preferred embodiment, the solution in S5 includes at least one of methanol, ethanol, isopropanol and acetone.

[0062] In a preferred embodiment, the preparation method of compound I more specifically comprises the following steps: S1, mixing compound II, compound III, a reaction solvent and an acid binding agent uniformly, and subjecting the mixture to reflux reaction; after the reaction is complete, crystallizing, filtering and drying to obtain compound IV; S2. Under a protective atmosphere, compound IV, 2-aminobenzimidazole, a reaction solvent, an acid-binding agent, a ligand and a catalyst are uniformly mixed, and reacted at 100-140° C. After the reaction is complete, crystallization, filtration, drying and recrystallization are performed to obtain compound V; S3, adding compound V to a hydrochloric acid solution for reaction, and then adding an anti-solvent to crystallize into a salt after the reaction is completed to obtain compound VI; S4, adding compound VI to acetonitrile, adding hydrochloric acid dropwise for reaction, filtering and drying after the reaction is complete to obtain a crude product; S5. Add purified water to the crude product, heat it until dissolved, then add activated carbon for decolorization, filter, and collect the filtrate; add the solution to the filtrate, heat it again until completely dissolved, then cool it to 0°C-30°C, filter, and dry to obtain compound I.

[0063] In a preferred embodiment, the synthesis route of the salt of the 2,4-disubstituted-5-fluoropyrimidine derivative is as follows: . Among them, the last step is to purify the crude product of compound I to obtain the pure product of compound I.

[0064] The present invention is further explained below: The present invention removes water in the original reaction of the prior art in step S1, thereby preventing the salt formed by HCl and compound IV generated during the reaction from dissolving in water, further reducing the generation of the impurity of compound IV hydrochloride, and improving the yield of compound IV; at the same time, removing water during the reaction can also prevent compound IV from hydrolyzing, further improving the yield of compound IV.

[0065] In the present invention, an acid-binding agent is added in step S1 to inhibit the salt formation between HCl generated by the reaction and compound IV, thereby greatly improving the yield of compound IV.

[0066] The present invention reduces the economic cost by replacing the original ligand, catalyst and solvent in step S2 on the one hand; on the other hand, simplifies the equipment, simplifies the post-processing, and improves the yield and purity. The post-processing methods in the prior art are filtration, extraction, liquid separation, concentration, and column chromatography. Filtration is to remove the catalyst, and after liquid separation, concentration is performed to remove the organic solvent. Column chromatography is used for purification, and the purity after purification is only 50%. However, the present invention washes the product with an ammonia solution after crystallization, and then recrystallizes it. The crystallization step removes the solvent and impurities and ligands dissolved in the solvent, and the ammonia washing step removes the catalyst; then recrystallization is performed, and the purity exceeds 90%. The present invention reduces cumbersome operations by directly precipitating the product from the reaction solution; purification by recrystallization avoids column chromatography, so that the process can be suitable for industrial production.

[0067] In the present invention, compound V is subjected to a salt-forming treatment in step S3, so that most impurities are removed from the mother liquor, the purity is greatly improved, and the problem of poor properties of compound I due to low purity is avoided.

[0068] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention has high selectivity of the reaction site of the starting materials, and is cheap and readily available; 2. The present invention can avoid the use of special equipment, is easy to operate and has a stable process; 3. The economic and time costs of the present invention are relatively low, and the yield and purity are greatly improved compared with the prior art; 4. The finished product prepared by the present invention can meet the general standard requirements of raw materials; 5. The free base of compound I is insoluble in water, while the finished product prepared by the present invention is easily soluble in water and is more suitable as a raw material for preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 HPLC spectrum of compound IV prepared in Example 1; Figure 2 The HNMR spectrum of compound IV prepared in Example 1; Figure 3 HPLC spectrum of compound IV prepared in Comparative Example 1; Figure 4 HPLC spectrum of compound V prepared in Example 1; Figure 5 is the HNMR spectrum of compound V prepared in Example 1; Figure 6 HPLC spectrum of compound V prepared in Comparative Example 5; Figure 7 HPLC spectrum of the hydrochloride salt of compound V prepared in Example 1; Figure 8 HPLC spectrum of the crude compound I prepared in Example 1; Fig. 9 The HNMR spectrum of the crude compound I prepared in Example 1; Fig.10 HPLC spectrum of the refined compound I prepared in Example 1; Fig.11 This is a property diagram of the refined compound I prepared in Example 1; Fig.12 HPLC spectrum of the free base of Compound I prepared in Comparative Example 10; Fig.13 This is a property diagram of Compound I prepared in Comparative Example 10. DETAILED DESCRIPTION

[0070] The present invention is not limited to the following specific embodiments. A person skilled in the art can implement the present invention in various other specific embodiments according to the contents disclosed in the present invention, or any simple changes or modifications made to the design structure and ideas of the present invention fall within the protection scope of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention can be combined with each other without conflict.

[0071] The concentrated hydrochloric acid described in the examples is 37% by mass. eq. is the abbreviation of "equivalent", which is used to indicate the relative amount or proportional relationship of substances in a chemical reaction. RRT is the abbreviation of "relative retention time", which is used to describe the ratio of the retention time of the target compound to the reference compound in chromatographic analysis (such as high performance liquid chromatography, HPLC).

[0072] Example 1 According to the general synthetic route, compound I was synthesized. The general synthetic route is as follows: .

[0073] Step 1 Preparation of tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound IV) In a 100mL three-necked flask, add 30mL methanol, 3.0g (1.00eq.) 1-Boc-4-(4-aminophenyl)piperazine (Compound II), 2.5g (1.40eq.) 2,4-dichloro-5-fluoropyrimidine (Compound III), heat to 60°C, add 1.5g (1.40eq.) triethylamine, react for 4h, add 30mL purified water after the reaction is complete, cool to room temperature, filter, collect the filter cake and dry to obtain 4.3g gray powder with a yield of 96.73% and a purity of 96.74%.

[0074] MS determined value: [MH]- 406.14.

[0075] HPLC spectrum Figure 1 As shown, the HNMR spectrum is as Figure 2 shown. Figure 1 The corresponding data are shown in the following table:

[0076] Step 2 Preparation of tert-butyl 4-(4-((2-(2-amino-1H-benzo(imidazol-1-yl)-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound V) In a 100mL three-necked flask, add 20mL of dimethyl sulfoxide, 5.0g (1.00eq.) tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound IV), 2.5g (1.50eq.) 2-aminobenzimidazole, 6.8g (1.70eq.) cesium carbonate, 0.2g (0.15eq.) 8-hydroxyquinoline, 0.2g (0.12eq.) cuprous iodide, N2 replacement three times and continuous protection, heat to 120℃, keep stirring until the reaction is complete, cool to 50℃, add 20mL of anhydrous ethanol + 5mL of ammonia water, add after addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL The mixture was slurried with 25% ammonia water for three times, and 20 mL of N-methylpyrrolidone was added to the wet product after filtration. The temperature was raised until the solution was clear, and 50 mL of ethanol was added dropwise at about 80 °C. After the addition was complete, the temperature was lowered to 25 °C, and stirred for crystallization for 12 h. The mixture was filtered, and the filter cake was collected and dried to obtain 4.1 g of a gray solid with a yield of 65.48% and a purity of 95.57%.

[0077] MS found [MH]-: 503.23.

[0078] HPLC spectrum Figure 4 As shown, the HNMR spectrum is as Figure 5 shown. Figure 4 The corresponding data are shown in the following table:

[0079] Step 3 Preparation of tert-butyl 4-(4-((2-(2-amino-1H-benzo(imidazol-1-yl)-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate hydrochloride (Compound V hydrochloride) In a 100mL three-necked flask, add 10.0g purified water, 5.0g anhydrous ethanol, and 5.0g concentrated hydrochloric acid, stir, cool to about 5°C, add 5.0g compound V, raise the temperature to 25°C, add 40.0g anhydrous ethanol dropwise, and after the addition is complete, keep warm for 3h for crystallization, filter, collect the filter cake and dry it to obtain 5.2g of off-white solid, with a yield of 97.83% and a purity of 99.23%. The HPLC spectrum (the impurity at RT=10.151 is compound I, and the purity is calculated by combining) is as follows: Figure 7 shown.

[0080] Step 4 Preparation of 1-[5-fluoro-4-[[4-(piperazin-1-yl)phenyl]amino]pyrimidin-2-yl]-1H-benzo[d]imidazol-2-amine dihydrochloride (Compound I) In a 250mL three-necked flask, add 1.1g (1.00eq.) of compound V hydrochloride and 17.5g of acetonitrile, stir, cool to about 10°C, add 1.0g of concentrated hydrochloric acid dropwise, and after the addition is complete, warm to room temperature to react, control the reaction of the raw materials to be complete, filter with suction, collect the filter cake and dry it to obtain 0.8g of off-white solid with a purity of 99.42% and a yield of 99.43%.

[0081] MS found [MH]-: 403.18.

[0082] HPLC spectrum Figure 8 As shown, the HNMR spectrum is as Fig. 9 shown. Figure 8 The corresponding data are shown in the following table:

[0083] Step 5 Purification of 1-[5-fluoro-4-[[4-(piperazin-1-yl)phenyl]amino]pyrimidin-2-yl]-1H-benzo[d]imidazol-2-amine dihydrochloride (Compound I) In a 100mL three-necked flask, add 10.0g of crude compound I and 30.0g of purified water, stir to dissolve, add activated carbon for decolorization, filter with suction, collect the filtrate, add 200.0g of anhydrous ethanol, raise the temperature to 60°C until the solution is clear, slowly cool to about 5°C, crystallize for 2h, filter with suction, collect the filter cake and dry it to obtain 7.0g of off-white solid, with a yield of 70.00%, a purity of 99.83%, and no more than 0.1% single impurity. The HPLC spectrum is as follows: Fig.10 The appearance of the prepared compound I is as shown in Fig.11 shown.

[0084] Comparative Example 1 Preparation of compound IV (reference to the synthesis of the preparation method disclosed in prior art CN 116514779A) In a 100mL three-necked flask, add 414.65mg (1.00eq.) of compound II, 356.19mg (1.43eq.) of compound III, 10mL of methanol, and 10mL of purified water. Heat to 60°C for 18h, cool to room temperature, filter, collect the filter cake, and dry to obtain an off-white powder with a yield of 21.02% and a purity of 98.20%. The HPLC spectrum is as follows: Figure 3 shown.

[0085] contrast Figure 2 and Figure 3 It can be seen that the yield of compound IV in Example 1 was greatly improved while the purity was slightly reduced.

[0086] Comparative Example 2 Compared with Example 1, water is added during the reaction of step 1, and the other steps are the same as those of Example 1, and the operation is as follows: In a 100mL three-necked flask, add 30mL methanol, 30mL purified water, 3.0g (1.00eq.) compound II, 2.5g (1.40eq.) compound III, heat to 60°C, add 1.5g (1.40eq.) triethylamine, react for 4h, cool to room temperature after the reaction is complete, filter, collect the filter cake and dry to obtain 3.1g gray-brown powder with a yield of 70.27% and a purity of 87.47%.

[0087] It can be seen that adding water will greatly reduce the yield and purity of compound IV.

[0088] Comparative Example 3 Compared with Example 1, no acid binding agent is added during the reaction of step 1, and the other steps are the same as those of Example 1, and the operation is as follows: In a 100mL three-necked flask, add 30mL of methanol, 3.0g (1.00eq.) of compound II, and 2.5g (1.40eq.) of compound III, and heat to 60℃ for 4h. After the reaction is complete, add 30mL of purified water dropwise, cool to room temperature, filter, collect the filter cake and dry it to obtain 0.8g of off-white powder, with a yield of 18.13% and a purity of 99.14%.

[0089] It can be seen that not adding an acid-binding agent will greatly reduce the yield and purity of compound IV.

[0090] Comparative Example 4 Compared with Example 1, water is added during the reaction of step 1, and no acid binding agent is added. The other steps are the same as those of Example 1, and the operation is as follows: In a 100mL three-necked flask, add 30mL methanol, 30mL purified water, 3.0g (1.00eq.) compound II, and 2.5g (1.40eq.) compound III. Heat to 60℃ and react for 4h. After the reaction is complete, cool to room temperature and no solid precipitation is observed.

[0091] It can be seen that adding water and removing the acid-binding agent will result in the inability to precipitate compound IV.

[0092] Comparative Example 5 Preparation of tert-butyl 4-(4-((2-(2-amino-1H-benzo(imidazol-1-yl)-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound V) (Synthesis with reference to the preparation method disclosed in the prior art CN 116514779A) In a 100 mL single-mouth bottle, add 10 mL 1,4-dioxane, 0.50 g (1.00 eq.) compound IV, 0.25 g (1.50 eq.) 2-aminobenzimidazole, 0.68 g (1.70 eq.) cesium carbonate, 0.16 g (0.20 eq.) Xantphos, and 0.04 g (0.04 eq.) Pd2(dba)3. After N2 replacement, seal with a rubber stopper, heat to 120 ° C for 23 h, cool to room temperature, filter, add purified water and dichloromethane for extraction, separate the liquids, and concentrate the organic phase to dryness to obtain 0.20 g gray-black solid with a yield of 27.18% and a purity of 50.97%. The HPLC spectrum is as follows: Figure 6 shown.

[0093] It can be seen that even if the same equivalent of compound IV is added, the yield and purity of compound V obtained by the method of the prior art are much lower than those in Example 1 of the present invention.

[0094] Comparative Example 6 Compared with Example 1, the catalyst and ligand disclosed in the prior art CN 116514779A are used in the reaction process of step 2, and the other steps are the same as those of Example 1, and the operation is as follows: In a 100 mL three-necked flask, add 20 mL of dimethyl sulfoxide, 5.0 g (1.00 eq.) of compound IV, 2.5 g (1.50 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, 1.4 g (0.12 eq.) of Pd2(dba)3, and 1.1 g (0.15 eq.) of Xantphos. Replace with nitrogen three times and continue nitrogen protection. Heat to 120 °C, keep stirring until the reaction is complete, and cool to 50 ℃, add 20mL of anhydrous ethanol + 5mL of ammonia water, after the addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL of 25% ammonia water to slurry three times, filter, add 20mL of N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL of ethanol dropwise at about 80℃, after the addition is complete, cool to 25℃, stir and crystallize for 12h, filter, collect the filter cake and dry to obtain 2.1g of gray solid, with a yield of 33.95% and a purity of 85.42%.

[0095] It can be seen that even if the same equivalent of compound IV is added, the yield and degree of compound V obtained by using the catalyst and ligand of the prior art are much lower than those in Example 1 of the present invention.

[0096] Comparative Example 7 Compared with Example 1, the solvent was changed during the reaction of step 2, and the other operations were the same as in Example 1, and the operation was as follows: In a 100mL three-necked flask, add 20mL 1,4-dioxane, 5.0g (1.00eq.) compound IV, 2.5g (1.50eq.) 2-aminobenzimidazole, 6.8g (1.70eq.) cesium carbonate, 0.2g (0.15eq.) 8-hydroxyquinoline, 0.2g (0.12eq.) cuprous iodide, replace with N2 three times and continue nitrogen protection, heat to 120℃, keep stirring until the reaction is complete, cool to 50℃, add 20mL anhydrous Ethanol + 5mL ammonia water, after addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL 25% ammonia water to slurry three times, filter, add 20mL N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL ethanol dropwise at about 80℃, after the addition is complete, cool to 25℃, stir and crystallize for 12h, filter, collect the filter cake and dry to obtain 2.9g gray solid, with a yield of 46.88% and a purity of 90.16%.

[0097] It can be seen that even if the same equivalent of compound IV is added, the yield and degree of compound V obtained by using an inappropriate solvent are much lower than those in Example 1 of the present invention.

[0098] Comparative Example 8 Compared with Example 1, the catalyst is replaced during the reaction of step 2, and the other operations are the same as Example 1, and the operation is as follows: In a 100 mL three-necked flask, 20 mL of 1,4-dimethyl sulfoxide, 5.0 g (1.00 eq.) of compound IV, 2.5 g (1.50 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, 0.2 g (0.15 eq.) of 8-hydroxyquinoline, and 1.4 g (0.12 eq.) of Pd2(dba)3 were added, and N2 was replaced three times with continuous nitrogen protection, and the temperature was raised to 120° C., and the subsequent treatment was the same as in step 2 of Example 1. The obtained product was monitored by HPLC, and the main peak of HPLC was not the target product.

[0099] Comparative Example 9 Compared with Example 1, the ligand is replaced during the reaction of step 2, and the other operations are the same as Example 1, and the operation is as follows: In a 100 mL three-necked flask, 20 mL of 1,4-dimethyl sulfoxide, 5.0 g (1.00 eq.) of compound IV, 2.5 g (1.50 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, 1.1 g (0.12 eq.) of Xantphos, and 0.2 g (0.12 eq.) of cuprous iodide were added, and N2 was replaced three times with continuous nitrogen protection, and the temperature was raised to 120° C., and the subsequent treatment was the same as in step 2 of Example 1. The obtained product was monitored by HPLC, and the main peak of HPLC was not the target product.

[0100] Comparative Example 10 Preparation of 1-[5-fluoro-4-[[4-(piperazin-1-yl)phenyl]amino]pyrimidin-2-yl]-1H-benzo[d]imidazole-2-amine bis(compound I free base, refer to the preparation method of 7a in CN 116514779A), specifically as follows: In a 100mL three-necked flask, add 20mL of dichloromethane, 3.30g of compound V, and 3.5mL of trifluoroacetic acid, stir at room temperature, add sodium hydroxide to adjust the pH to alkaline, separate the liquids, wash the organic phase with water three times, and concentrate to dryness to obtain 2.2g of gray-black solid, with a yield of 83.17% and a purity of 85.63%. The HPLC spectrum is as follows: Fig.12 shown.

[0101] The impurity structure when RRT=9.079 is as follows: .

[0102] Preparation of Compound I: 2.0 g of the gray-black solid obtained in Comparative Example 10 was added to 32.0 g of acetonitrile, stirred, cooled to about 10°C, and 2.0 g of hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to room temperature for reaction. After the raw materials reacted completely, they were filtered by suction, and the filter cake was collected and dried to obtain 1.8 g of dark gray solid with a yield of 76.17%. The properties are as follows Fig.13 .

[0103] Example 2 Based on Example 1, the preparation steps of compound IV were adjusted as follows: In a 50mL three-necked flask, add 1.0g (1.00eq.) of compound II, 0.84g (1.40eq.) of compound III, and 10mL of anhydrous ethanol, stir, heat to 80°C, add 0.5g (1.40eq.) of triethylamine, keep warm and stir for 4h until the reaction is complete, add 10mL of purified water dropwise, cool to room temperature, filter, collect the filter cake and dry to obtain 1.34g of gray solid, with a yield of 91.12% and a purity of 94.99%.

[0104] The other steps are the same as in Example 1.

[0105] Example 3 Based on Example 1, the preparation steps of compound IV were adjusted as follows: In a 500mL three-necked flask, add 10.0g (1.00eq.) of compound II, 6.8g (1.00eq.) of compound III, and 100mL of methanol, stir, heat to 60°C, add 7g (1.40eq.) of potassium carbonate, keep warm and stir for 5h until the reaction is complete, add 100mL of purified water dropwise, cool to room temperature, filter, collect the filter cake and dry to obtain 12.8g of gray solid, with a yield of 87.05% and a purity of 95.13%.

[0106] The other steps are the same as in Example 1.

[0107] Example 4 Based on Example 1, the preparation steps of compound IV were adjusted as follows: In a 500mL three-necked flask, add 10.0g (1.00eq.) of compound II, 8.4g (1.40eq.) of compound III, and 100mL of methanol, stir, heat to 60°C, add 5.1g (1.40eq.) of N,N-diisopropylethylamine, and stir for 4h until the reaction is complete. Add 100mL of purified water dropwise, cool to room temperature, filter, collect the filter cake and dry it to obtain 14.1g of gray solid with a yield of 95.89% and a purity of 96.01%.

[0108] The other steps are the same as in Example 1.

[0109] Example 5 Based on Example 1, the preparation steps of compound IV were adjusted as follows: In a 500mL three-necked flask, add 10.0g (1.00eq.) of compound II, 8.4g (1.40eq.) of compound III, and 100mL of acetone, stir, heat to 30°C, add 10.2g (2.80eq.) of triethylamine, and stir for 5h until the reaction is complete. Add 100mL of purified water dropwise, cool to room temperature, filter, collect the filter cake and dry it to obtain 13.1g of gray solid with a yield of 89.09% and a purity of 96.43%.

[0110] The other steps are the same as in Example 1.

[0111] Example 6 Based on Example 1, the preparation steps of compound IV were adjusted as follows: In a 500mL three-necked flask, add 10.0g (1.00eq.) of compound II, 16.8g (2.80eq.) of compound III, and 100mL of methanol, stir, heat to 60°C, add 3.7g (1.0eq.) of triethylamine, and stir for 4h until the reaction is complete. Add 100mL of purified water dropwise, cool to 0°C, filter, collect the filter cake and dry it to obtain 14.3g of gray solid with a yield of 97.25% and a purity of 95.02%.

[0112] The other steps are the same as in Example 1.

[0113] Example 7 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 10 mL sealed tube, add 0.5 g (1.00 eq.) of compound IV, 0.25 g (1.50 eq.) of 2-aminobenzimidazole, 0.68 g (1.70 eq.) of cesium carbonate, and 2 mL N,N-dimethylacetamide, 0.03g (0.12eq.) cuprous iodide, 0.03g (0.15eq.) 8-hydroxyquinoline, N2 replacement three times and continuous nitrogen protection, stirring, heating to 120℃, keeping warm and stirring until the reaction is complete, cooling to 50℃, adding 5mL of anhydrous ethanol + 1mL of ammonia water, after the addition, cooling to room temperature for crystallization, filtering the reaction solution, collecting the wet product, adding 5mL of 25% ammonia water for pulping three times, filtering, adding 5mL of N-methylpyrrolidone to the obtained wet product, heating until the solution is clear, adding 10mL of ethanol at about 80℃, adding until solid precipitates, cooling to 25℃, stirring and crystallizing for 12h, filtering, collecting the filter cake and drying to obtain 0.4g of gray solid, with a yield of 66.28% and a purity of 95.31%.

[0114] The other steps are the same as in Example 1.

[0115] Example 8 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 1.6 g (1.00 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, 20 mL of dimethyl sulfoxide, 0.2 g (0.12 eq.) of anhydrous cupric chloride, 0.27 g (0.15 eq.) of 8-hydroxyquinoline, replace with N2 three times and protect, stir, heat to 120 ° C, keep stirring until the reaction is complete, cool to 30 ° C, add 20mL of anhydrous ethanol + 5mL of ammonia water, after addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL of 25% ammonia water to slurry three times, filter, add 20mL of N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL of ethanol at about 80℃, add until solid precipitates, cool to 25℃, stir and crystallize for 12h, filter, collect the filter cake and dry it to obtain 3.7g of gray solid, with a yield of 59.82% and a purity of 93.69%.

[0116] The other steps are the same as in Example 1.

[0117] Example 9 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 1.6 g (1.00 eq.) of 2-aminobenzimidazole, 2.9 g (1.70 eq.) of potassium carbonate, 20 mL of dimethyl sulfoxide, 0.28 g (0.12 eq.) of cuprous iodide, 0.27 g (0.15 eq.) of 8-hydroxyquinoline, replace with N2 three times and protect, stir, heat to 120 ° C, keep stirring until the reaction is complete, cool to 50 ° C, add 20mL of anhydrous ethanol + 5mL of ammonia water, after addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL of 25% ammonia water to slurry three times, filter, add 20mL of N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL of ethanol at about 80℃, add until solid precipitates, cool to 25℃, stir and crystallize for 12h, filter, collect the filter cake and dry it to obtain 3.9g of gray solid, with a yield of 63.05% and a purity of 94.18%.

[0118] The other steps are the same as in Example 1.

[0119] Example 10 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 1.6 g (1.00 eq.) of 2-aminobenzimidazole, 2.2 g (1.70 eq.) of sodium carbonate, 20 mL of dimethyl sulfoxide, 0.20 g (0.12 eq.) of anhydrous cupric chloride, 0.27 g (0.15 eq.) of 8-hydroxyquinoline, replace with N2 three times and protect, stir, heat to 120 ° C, keep stirring until the reaction is complete, cool to 50 ° C, add Add 20mL of anhydrous ethanol + 5mL of ammonia water, and after the addition is completed, cool to room temperature for crystallization. Filter the reaction solution, collect the wet product, add 20mL of 25% ammonia water to slurry three times, filter, add 20mL of N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL of ethanol dropwise at about 80°C, and add until solid precipitates, cool to 25°C, stir and crystallize for 12h, filter, collect the filter cake and dry it to obtain 3.5g of gray solid, with a yield of 56.58% and a purity of 92.07%.

[0120] The other steps are the same as in Example 1.

[0121] Embodiment 11 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 1.6 g (1.00 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, 20 mL of dimethyl sulfoxide, 0.28 g (0.12 eq.) of cuprous iodide, 0.21 g (0.15 eq.) of L-proline, N2 replacement three times and protection, stir, heat to 120 ° C, keep stirring until the reaction is complete, cool to 50 ° C, add 20mL of anhydrous ethanol + 5mL of ammonia water, after addition, cool to room temperature for crystallization, filter the reaction solution, collect the wet product, add 20mL of 25% ammonia water to slurry three times, filter, add 20mL of N-methylpyrrolidone to the wet product, heat until the solution is clear, add 50mL of ethanol at about 80℃, add until solid precipitates, cool to 25℃, stir and crystallize for 12h, filter, collect the filter cake and dry it to obtain 3.3g of gray solid, with a yield of 53.35% and a purity of 93.18%.

[0122] The other steps are the same as in Example 1.

[0123] Example 12 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 2.5 g (1.50 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, and 20 mL N,N-dimethylacetamide, 0.28g (0.12eq.) cuprous iodide, 0.27g (0.15eq.) 8-hydroxyquinoline, N2 replacement three times and protection, stirring, heating to 140°C, stirring at this temperature until the reaction is complete, cooling to 50°C, adding 20mL of anhydrous ethanol + 5mL of ammonia water, after the addition, cooling to room temperature for crystallization, filtering the reaction solution, collecting the wet product, adding 20mL of 25% ammonia water for slurrying three times, filtering, adding 20mL of N-methylpyrrolidone to the obtained wet product, heating to dissolve, adding 50mL of isopropanol at about 80°C, adding until solid precipitates, cooling to 25°C, stirring for crystallization for 12h, filtering, collecting the filter cake and drying to obtain 4.2g of gray solid, with a yield of 67.90% and a purity of 93.69%.

[0124] The other steps are the same as in Example 1.

[0125] Example 13 Based on Example 1, the preparation steps of Compound V were adjusted as follows: In a 100 mL three-necked flask, add 5.0 g (1.00 eq.) of compound IV, 2.5 g (1.50 eq.) of 2-aminobenzimidazole, 6.8 g (1.70 eq.) of cesium carbonate, and 20 mL N,N-dimethylacetamide, 0.28g (0.12eq.) cuprous iodide, 0.27g (0.15eq.) 8-hydroxyquinoline, N2 replacement three times and protection, stirring, heating to 120°C, keeping warm and stirring until the reaction is complete, cooling to 50°C, adding 20mL isopropanol + 5mL ammonia water, after the addition, cooling to room temperature for crystallization, filtering the reaction solution, collecting the wet product, adding 20mL 25% ammonia water to slurry three times, filtering, adding 20mL N,N-dimethylacetamide to the obtained wet product, heating to dissolve, adding 50mL ethanol at about 80°C, adding until solid precipitates, cooling to 25°C, stirring and crystallizing for 12h, filtering, collecting the filter cake and drying to obtain 4.0g gray solid, yield 64.66%, purity 96.33%.

[0126] The other steps are the same as in Example 1.

[0127] Embodiment 14 Based on Example 1, the preparation steps of Compound V hydrochloride were adjusted as follows: In a 25mL three-necked flask, add 1.0g purified water, 0.5g isopropanol, and 0.5g concentrated hydrochloric acid, stir, cool to about 5°C, add 0.5g compound V, raise the temperature to 25°C, add 4.0g isopropanol dropwise, and after the addition is complete, keep warm for crystallization for 3h, filter with suction, collect the filter cake and dry it to obtain 0.52g of off-white solid with a yield of 96.99% and a purity of 99.08%.

[0128] The other steps are the same as in Example 1.

[0129] Embodiment 15 Based on Example 1, the preparation steps of Compound V hydrochloride were adjusted as follows: In a 100mL three-necked flask, add 20.0g purified water, 5.0g acetone, and 5.0g concentrated hydrochloric acid, stir, cool to about 5°C, add 5.0g compound V, raise the temperature to 25°C, add 40.0g acetone dropwise, and after the addition is complete, keep warm for crystallization for 3h, filter with suction, collect the filter cake and dry it to obtain 4.8g off-white solid with a yield of 89.53% and a purity of 99.36%.

[0130] The other steps are the same as in Example 1.

[0131] Example 16 Based on Example 1, the preparation steps of Compound V hydrochloride were adjusted as follows: In a 100mL three-necked flask, add 10.0g purified water, 5.0g anhydrous ethanol, and 5.0g concentrated hydrochloric acid, stir, cool to about 5°C, add 5.0g compound V, raise the temperature to 40°C, add 40.0g anhydrous ethanol dropwise, and after the addition is complete, keep warm for crystallization for 3h, filter with suction, collect the filter cake and dry it to obtain 4.5g off-white solid with a yield of 83.93% and a purity of 99.22%.

[0132] The other steps are the same as in Example 1.

[0133] Embodiment 17 Based on Example 1, the preparation steps of Compound I were adjusted as follows: In a 250mL three-necked flask, add 1.1g (1.00eq.) of compound V hydrochloride and 17.5g of acetonitrile, stir, cool to about 10°C, add 1.0g of concentrated hydrochloric acid dropwise, and after the addition is complete, warm to room temperature for reaction. The reaction of the raw material in the control is complete, filter with suction, collect the filter cake and dry it to obtain 0.9g of off-white solid with a yield of 94.44% and a purity of 99.26%.

[0134] The other steps are the same as in Example 1.

[0135] Embodiment 18 Based on Example 1, the preparation steps of Compound I were adjusted as follows: In a 5L three-necked flask, add 164.0g (1.00eq.) of compound V hydrochloride and 2626.0g of acetonitrile, stir, cool to about 10°C, add 164.0g of concentrated hydrochloric acid dropwise, and after the addition is complete, warm to room temperature to react. The raw material in the middle control reacts completely, filter with suction, collect the filter cake and dry it to obtain 138.0g of off-white solid with a yield of 95.36% and a purity of 99.36%.

[0136] The other steps are the same as in Example 1.

[0137] Embodiment 19 Based on Example 1, the purification steps of Compound I were adjusted as follows: In a 100mL three-necked flask, add 10.0g of crude compound I and 30.0g of purified water, stir to dissolve, add activated carbon for decolorization, filter with suction, collect the filtrate, add 200.0g of isopropanol, raise the temperature to 60°C until the solution is clear, slowly cool to about 15°C, crystallize for 2h, filter with suction, collect the filter cake and dry it to obtain 6.3g of off-white solid with a yield of 63.00%, a purity of 99.89%, and no more than 0.1% of single impurities.

[0138] The other steps are the same as in Example 1.

[0139] Embodiment 20 Based on Example 1, the purification steps of Compound I were adjusted as follows: In a 100mL three-necked flask, add 10.0g of crude compound I and 50.0g of purified water, stir to dissolve, add activated carbon for decolorization, filter with suction, collect the filtrate, add 200.0g of acetone, raise the temperature to 70°C until the solution is clear, slowly cool to about 5°C, crystallize for 2h, filter with suction, collect the filter cake and dry it to obtain 6.9g of off-white solid with a yield of 69.00%, a purity of 99.81%, and no more than 0.1% of single impurities.

[0140] The other steps are the same as in Example 1.

[0141] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the embodiments here. Any obvious changes or modifications derived from the technical solution of the present invention are still within the scope of protection of the present invention.

Claims

1. A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, characterized in that: The following steps are involved: Compound VI is subjected to a deprotection reaction and a salt formation reaction in a reaction solvent in the presence of hydrochloric acid to obtain compound I; ； The preparation method of compound VI comprises the following steps: compound V undergoes a salt-forming reaction in a hydrochloric acid solution to obtain compound VI; after the reaction is complete, post-treatment is performed, and the post-treatment comprises: adding an anti-solvent and performing crystallization at a certain temperature; wherein the hydrochloric acid solution comprises hydrochloric acid and a solvent, and the solvent comprises at least one of methanol, ethanol, isopropanol, acetone, and purified water; the anti-solvent comprises at least one of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; the temperature of the salt-forming reaction is 0°C-40°C; the temperature of the crystallization is 0°C-40°C; 。 2. A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, characterized in that: The following steps are involved: S1, compound II and compound III undergo substitution reaction in a reaction solvent at reaction temperature in the presence of an acid-binding agent to obtain compound IV. ； S2. Under a protective atmosphere, compound IV and 2-aminobenzimidazole undergo a substitution reaction in a reaction solvent at a reaction temperature in the presence of an acid-binding agent, a ligand, and a catalyst to obtain compound V. ； S3, compound V undergoes salt formation reaction in hydrochloric acid solution at reaction temperature, and after the reaction is complete, post-treatment is performed, wherein the post-treatment comprises: adding an anti-solvent and performing crystallization at a certain temperature to obtain compound VI, ； S4, compound VI is subjected to a deprotection reaction and a salt-forming reaction in a reaction solvent at a reaction temperature in the presence of hydrochloric acid to obtain a crude product of compound I, 。 3. The preparation method according to claim 2, characterized in that: The reaction solvent in S1 includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, ethyl acetate, and acetonitrile; the acid binding agent includes at least one of triethylamine, N,N-diisopropylethylamine, ammonia water, pyridine, tert-butylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and potassium phosphate; and the reaction temperature is 30°C-120°C.

4. The preparation method according to claim 2, characterized in that: In S1, the molar ratio of compound II to compound III is 1:1-1:3; the molar ratio of the acid binding agent to compound II is 1:1-1:

3.

5. The preparation method according to claim 2, characterized in that: The reaction solvent in S2 includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, and tert-butanol; the acid binding agent in S2 includes at least one of potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate; the ligand in S2 is at least one of 8-hydroxyquinoline, L-proline, and 2-[(1-oxidized-2-pyridyl)methylamino]-2-oxoacetic acid; the catalyst in S2 includes at least one of cuprous iodide, cuprous chloride, cuprous bromide, cupric iodide, cupric bromide, anhydrous cupric chloride, cuprous oxide, cupric oxide, and elemental copper; and the reaction temperature is 100°C-140°C.

6. The preparation method according to claim 2, characterized in that: In S2, the molar ratio of compound IV to 2-aminobenzimidazole is 1:1-1:

3.

7. The preparation method according to claim 2, characterized in that: In S3, the hydrochloric acid solution includes hydrochloric acid and a solvent, the solvent includes at least one of methanol, ethanol, isopropanol, acetone, and purified water; the anti-solvent includes at least one of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; the temperature of the salt-forming reaction is 0°C-40°C; and the temperature of the crystallization is 0°C-40°C.

8. The preparation method according to claim 2, characterized in that: In the step S4, the reaction solvent is acetonitrile and the reaction temperature is 20°C-30°C.

9. The preparation method according to claim 2, characterized in that: The method also includes refining the crude product of compound I obtained in S4: adding purified water to the crude product, heating it until dissolved, adding activated carbon for decolorization, filtering, and collecting the filtrate; adding the solution to the filtrate, heating it again until completely dissolved, then cooling it to 0°C-30°C, filtering, and drying to obtain compound I.

10. The preparation method according to any one of claims 2 to 9, characterized in that: The following steps are involved: S1, mixing compound II, compound III, a reaction solvent and an acid binding agent uniformly, and subjecting the mixture to reflux reaction; after the reaction is complete, crystallizing, filtering and drying to obtain compound IV; S2. Under a protective atmosphere, compound IV, 2-aminobenzimidazole, a reaction solvent, an acid-binding agent, a ligand and a catalyst are uniformly mixed, and reacted at 100° C.-140° C. After the reaction is complete, crystallization, filtration, drying and recrystallization are performed to obtain compound V; S3, adding compound V to a hydrochloric acid solution for reaction, and then adding an anti-solvent to crystallize into a salt after the reaction is completed to obtain compound VI; S4, adding compound VI to acetonitrile, adding hydrochloric acid dropwise for reaction, filtering and drying after the reaction is complete to obtain a crude product of compound I; S5. Add purified water to the crude product of Compound I, heat it until dissolved, then add activated carbon for decolorization, filter, and collect the filtrate; add the solution to the filtrate, heat it again until completely dissolved, then cool it to 0°C-30°C, filter, and dry to obtain Compound I.

Images