Process for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative

Abstract

The present 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, which comprises the following steps: Compound VI is subjected to deprotection and salt formation reactions in a reaction solvent in the presence of hydrochloric acid to obtain Compound I; wherein, the method for preparing Compound VI comprises the following steps: Compound V undergoes a salt formation reaction in a hydrochloric acid solution to obtain Compound VI; after the reaction is complete, post-treatment is carried out, and the post-treatment includes: adding an anti-solvent and performing crystallization at a certain temperature. The present invention provides a method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative with high yield, high purity, low cost and simple operation. By optimizing multiple preparation steps, the present invention improves the yield and purity of the target compound, and the prepared finished product can meet the general standard requirements of bulk drugs.

Description

Technical Field

[0001] The present 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 an anti-renal fibrosis effect. This prior art discloses its preparation method, specifically: using p-fluoronitrobenzene and 1-Boc-piperazine as starting materials, dimethyl sulfoxide as the reaction solvent, and carrying out a nucleophilic substitution reaction under reflux for 5 h to obtain compound 3; then reducing the nitro group to an amino group with iron powder and ammonium chloride to obtain compound 4; compound 4 and 2,4-dichloro-5-fluoropyrimidine carry out a nucleophilic substitution reaction in methanol to obtain compound 5; compound 5 and 2-aminobenzimidazole, using Cs2CO3 as the base, Xantphos as the carrier, Pd2(dba)3 as the catalyst, and 1,4-dioxane as the solvent, carry out a Buchwald-hartwig coupling reaction to obtain compound 6a; compound 6a is de-Boc with trifluoroacetic acid at room temperature, basified, extracted, and concentrated to obtain the free base of compound I.

[0003] However, this synthesis method has the following defects:

[0004] 1. When synthesizing compound 5 by this synthesis method, although the obtained product has a high purity, the yield is very low. When reproducing its preparation method, the yield is only about 20%.

[0005] 2. When synthesizing compound 6a by this synthesis method, for the Buchwald-hartwig coupling reaction, it is necessary to use expensive ligands 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and catalyst tris(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 and high-pressure environment. The post-treatment after the reaction is complete also requires operations such as filtration, extraction, liquid separation, concentration, and column chromatography, which are relatively cumbersome and not suitable for large-scale industrial production, and the yield is only 47%.

[0006] 3. When synthesizing the free base of Compound I using this synthesis method, the post-treatment after the reaction is complete also requires multiple operations of extraction, liquid separation, and concentration. Moreover, the yield is only about 83%. Additionally, the prepared compound is a free base with poor solubility, which is not conducive to the purification of the active pharmaceutical ingredient, and its purity does not meet the general standard of the active pharmaceutical ingredient (the unknown single impurity shall not exceed 0.1%). Summary of the Invention

[0007] The object 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.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, comprising the following steps: using Compound II and Compound III as starting materials, obtaining Compound IV through a substitution reaction; obtaining Compound V from Compound IV through a substitution reaction; obtaining Compound VI from Compound V through a salt-forming reaction; obtaining Compound I from Compound VI through deprotection and salt-forming reactions; the reaction route is as follows: .

[0010] In one aspect, the method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative comprises the following steps: in a reaction solvent, at a reaction temperature, in the presence of hydrochloric acid, Compound VI undergoes deprotection and salt-forming reactions to obtain Compound I: .

[0011] In one of the preferred embodiments, the reaction solvent is acetonitrile and the reaction temperature is 20°C - 30°C.

[0012] In one of the preferred embodiments, the method for preparing Compound VI further comprises the following steps: in a hydrochloric acid solution, at a reaction temperature, Compound V undergoes a salt-forming reaction to obtain Compound VI; after the reaction is complete, post-treatment is carried out, and the post-treatment includes: adding an anti-solvent and performing crystallization at a certain temperature; wherein 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; 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; the temperature of crystallization is 0°C - 40°C; .

[0013] In a second aspect, the method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative is more specifically as follows:

[0014] S1. Compound II and compound III undergo a substitution reaction in a reaction solvent at a reaction temperature in the presence of an acid-binding agent to obtain compound IV. ;

[0015] 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. ;

[0016] S3. Compound V undergoes a salt-forming reaction in a hydrochloric acid solution at a reaction temperature. After the reaction is complete, post-treatment is carried out. The post-treatment includes: adding an anti-solvent and performing crystallization at a certain temperature to obtain compound VI. ;

[0017] S4. Compound VI undergoes deprotection and salt-forming reactions in a reaction solvent at a reaction temperature in the presence of hydrochloric acid to obtain a crude product of compound I. .

[0018] In one preferred embodiment, the reaction solvent in S1 includes at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, ethyl acetate, and acetonitrile.

[0019] In one preferred embodiment, the reaction solvent in S1 is methanol, which is beneficial to the progress of the reaction and post-treatment.

[0020] In one preferred embodiment, the reaction time in S1 is 2 - 4 h. Generally, the reaction is complete after 2 - 4 h.

[0021] In one preferred embodiment, in S1, the molar ratio of compound II to compound III is 1:1 - 1:3.

[0022] In one preferred embodiment, in S1, the molar ratio of compound II to compound III is 1:1.3 - 1.5, which is beneficial to the progress of the reaction and cost control.

[0023] In one 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.

[0024] In one preferred embodiment, in S1, the acid-binding agent is triethylamine, which is beneficial to the progress of the reaction and post-treatment.

[0025] In one preferred embodiment, in the step S1, the molar ratio of the acid-binding agent to Compound II is 1:1 - 1:3.

[0026] In one preferred embodiment, in the step S1, the molar ratio of the acid-binding agent to Compound II is 1:1.3 - 1.5, which is beneficial to the progress of the reaction and cost control.

[0027] In one preferred embodiment, in the step S1, depending on the solvent, the reaction temperature is 30°C - 120°C.

[0028] The reaction temperature is the reflux temperature, which is beneficial to the progress of the reaction and cost control.

[0029] In one preferred embodiment, the post-treatment of the step S1 is as follows: after the reaction is complete, crystallization, filtration, and drying are carried out to obtain Compound IV.

[0030] In one preferred embodiment, the crystallization is carried out by adding an anti-solvent after the product is cooled to 0°C - 40°C.

[0031] In one preferred embodiment, the anti-solvent is purified water.

[0032] In the embodiment, the post-treatment is carried out by the method of dropwise adding purified water for crystallization, which is beneficial to the improvement of the yield and cost control.

[0033] In one preferred embodiment, the protective atmosphere in the step S2 is a nitrogen atmosphere or an argon atmosphere.

[0034] In one preferred embodiment, the reaction solvent in the step S2 includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, and tert-butanol.

[0035] In one preferred embodiment, the reaction solvent in the step S2 is dimethyl sulfoxide, which is beneficial to the progress of the reaction and post-treatment.

[0036] In one preferred embodiment, in the step S2, the molar ratio of Compound IV to 2-aminobenzimidazole is 1:1 - 1:3.

[0037] In one preferred embodiment, in the step S2, the molar ratio of Compound IV to 2-aminobenzimidazole is 1:1.5, which is beneficial to the progress of the reaction and cost control.

[0038] In one preferred embodiment, the acid-binding agent in the step S2 includes at least one of potassium carbonate, sodium carbonate, cesium carbonate, and potassium phosphate.

[0039] In one preferred embodiment, the acid-binding agent in S2 is cesium carbonate, which is beneficial to the progress of the reaction and post-treatment.

[0040] In one preferred embodiment, the ligand in S2 includes at least one of 8-hydroxyquinoline, L-proline, and 2-[(1-oxidopyridin-2-yl)methylamino]-2-oxoacetic acid.

[0041] In one preferred embodiment, the ligand in S2 is 8-hydroxyquinoline, which is beneficial to the progress of the reaction.

[0042] In one preferred embodiment, the catalyst in S2 includes at least one of cuprous iodide, cuprous chloride, cuprous bromide, copper iodide, copper bromide, anhydrous copper chloride, cuprous oxide, copper oxide, and elemental copper.

[0043] In one preferred embodiment, the catalyst in S2 is cuprous iodide, which is beneficial to the progress of the reaction.

[0044] In one preferred embodiment, the reaction temperature is 100°C - 140°C, which is beneficial to the progress of the reaction and cost control.

[0045] In one preferred embodiment, the post-treatment of S2 is as follows: after the reaction is complete, crystallization, filtration, drying, and recrystallization are carried out to obtain compound V.

[0046] In one preferred embodiment, crystallization is carried out by adding an anti-solvent after the product is cooled to 0°C - 60°C.

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

[0048] In one preferred embodiment, the anti-solvent is a mixed solvent of ethanol and ammonia water, which is beneficial to improving the yield and purity.

[0049] In one preferred embodiment, the mass ratio of ethanol to ammonia water in the anti-solvent is 10:1 - 3:1, and the mixed solvent within this range is beneficial to improving the yield and purity.

[0050] In one preferred embodiment, in S2, recrystallization is carried out by adding an appropriate amount of hot solvent to the solid substance to be purified, heating until dissolved to form a nearly saturated solution; then dropping the anti-solvent, stirring and cooling to precipitate crystals from the supersaturated solution; after the crystals are completely precipitated, suction filtration is carried out to separate the crystals from the mother liquor; the crystals are washed with a small amount of cold solvent to remove the impurities attached to the surface, and then dried.

[0051] In one preferred embodiment, the hot solvent comprises at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0052] In one preferred embodiment, the hot solvent is N-methylpyrrolidone, which is beneficial to improving the yield and purity.

[0053] In one preferred embodiment, the anti-solvent comprises at least one of purified water, methanol, ethanol, isopropanol, and acetone.

[0054] In one preferred embodiment, the anti-solvent is ethanol, and the crystallization temperature is room temperature, which is beneficial to improving the yield and purity.

[0055] In one preferred embodiment, in S3, 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.

[0056] In one preferred embodiment, the solvent is a mixture of ethanol and purified water.

[0057] In one 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).

[0058] In one preferred embodiment, in S3, the anti-solvent comprises at least one of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran.

[0059] In one preferred embodiment, in S3, the anti-solvent is ethanol, which is beneficial to improving the yield and purity.

[0060] In one preferred embodiment, in S3, the temperature of the salt-forming reaction is 0°C - 40°C; the temperature of crystallization is 0°C - 40°C.

[0061] In one 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 beneficial to improving the yield and purity.

[0062] In one preferred embodiment, the hydrochloric acid in S4 is 37% concentrated hydrochloric acid.

[0063] In one preferred embodiment, in S4, the reaction solvent is acetonitrile, and the reaction temperature is 20°C - 30°C.

[0064] In one preferred embodiment, after the reaction of S4 is completed, it further includes refining the crude product of compound I obtained in S4, that is, S5, and S5 includes the following steps: adding purified water to the crude product, heating to dissolve, adding activated carbon for decolorization, filtering, and collecting the filtrate; adding a solution to the filtrate, heating again to completely dissolve, then cooling to 0°C - 30°C, filtering and drying to obtain compound I.

[0065] In one preferred embodiment, the weight of the purified water added in S5 is 3 - 5 times the mass of the crude product of compound I.

[0066] In one preferred embodiment, the heating in S5 means heating to 40°C - 80°C.

[0067] In one preferred embodiment, the solution in S5 includes at least one of methanol, ethanol, isopropanol, and acetone.

[0068] In one preferred embodiment, the preparation method of compound I more specifically includes the following steps:

[0069] S1. Mix compound II, compound III, a reaction solvent, and an acid-binding agent evenly, and carry out a reflux reaction; after the reaction is completed, crystallize, filter, and dry to obtain compound IV;

[0070] S2. Under a protective atmosphere, mix compound IV, 2-aminobenzimidazole, a reaction solvent, an acid-binding agent, a ligand, and a catalyst evenly, and react at 100 - 140°C. After the reaction is completed, crystallize, filter, dry, and recrystallize to obtain compound V;

[0071] S3. Add compound V to a hydrochloric acid solution for reaction, and then add an anti-solvent after the reaction is over to crystallize and form a salt to obtain compound VI;

[0072] S4. Add compound VI to acetonitrile, dropwise add hydrochloric acid for reaction, after the reaction is completed, filter and dry to obtain a crude product;

[0073] S5. Add purified water to the crude product, heat to dissolve, add activated carbon for decolorization, filter, and collect the filtrate; add a solution to the filtrate, heat again to completely dissolve, then cool to 0°C - 30°C, filter and dry to obtain compound I.

[0074] In one 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 that the crude product of compound I is refined to obtain the pure product of compound I.

[0075] The following further explains the present invention:

[0076] In the present invention, by removing water in the original reaction of the prior art in step S1, it is avoided that the salt formed by HCl and compound IV generated during the reaction dissolves in water, further reducing the generation of the impurity of compound IV hydrochloride and increasing the yield of compound IV; at the same time, removing water during the reaction can also prevent the hydrolysis of compound IV, further improving the yield of compound IV.

[0077] In the present invention, by adding an acid-binding agent in step S1, the formation of salt between HCl generated in the reaction and compound IV is inhibited, greatly increasing the yield of compound IV.

[0078] In the present invention, by replacing the original ligand, catalyst and solvent in step S2, on the one hand, the economic cost is reduced; on the other hand, the equipment is simplified, the post-treatment is simplified, and the yield and purity are improved. The post-treatment method in the prior art is filtration, extraction, liquid separation, concentration, column chromatography. Filtration is to remove the catalyst, the organic solvent is removed by concentration after liquid separation, and the purity after column chromatography purification is only 50%. In the present invention, after the product crystallizes out, it is washed with ammonia water solution and then recrystallized. In this crystallization step, the solvent and the impurities and ligands dissolved in the solvent are removed; the catalyst is removed in the step of washing with ammonia water; then recrystallization is carried out, and the purity exceeds 90%. By directly precipitating the product from the reaction solution, the present invention reduces the cumbersome operations; by purifying through recrystallization, column chromatography is avoided, making the process applicable to industrial production.

[0079] In the present invention, by performing salting-out treatment on compound V in step S3, most of the impurities are removed in the mother liquor, the purity is greatly improved, and the problem that the properties of compound I are poor due to low purity is avoided.

[0080] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0081] 1. The present invention has high selectivity for the reaction sites of the starting materials, which are cheap and easily available;

[0082] 2. The present invention can avoid the use of special equipment, is easy to operate, and the process is stable;

[0083] 3. The present invention has lower economic and time costs, and the yield and purity are greatly improved compared with the prior art;

[0084] 4. The finished product prepared by the present invention can meet the general standard requirements of bulk drugs;

[0085] 5. The free base of compound I is insoluble in water, and the finished product prepared by the present invention is easily soluble in water, which is more suitable as a bulk drug for preparations. Description of the Drawings

[0086] Figure 1HPLC chromatogram of Compound IV prepared in Example 1;

[0087] Figure 2 HNMR spectrum of Compound IV prepared in Example 1;

[0088] Figure 3 HPLC chromatogram of Compound IV prepared in Comparative Example 1;

[0089] Figure 4 HPLC chromatogram of Compound V prepared in Example 1;

[0090] Figure 5 HNMR spectrum of Compound V prepared in Example 1;

[0091] Figure 6 HPLC chromatogram of Compound V prepared in Comparative Example 5;

[0092] Figure 7 HPLC chromatogram of the hydrochloride salt of Compound V prepared in Example 1;

[0093] Figure 8 HPLC chromatogram of the crude Compound I prepared in Example 1;

[0094] Figure 9 HNMR spectrum of the crude Compound I prepared in Example 1;

[0095] Figure 10 HPLC chromatogram of the purified Compound I prepared in Example 1;

[0096] Figure 11 Appearance diagram of the purified Compound I prepared in Example 1;

[0097] Figure 12 HPLC chromatogram of the free base of Compound I prepared in Comparative Example 10;

[0098] Figure 13 Appearance diagram of Compound I prepared in Comparative Example 10. Detailed implementation manners

[0099] The present invention is not limited to the following specific implementation manners. Those of ordinary skill in the art can implement the present invention in other various specific implementation manners according to the content disclosed in the present invention, or any simple changes or modifications made by adopting the design structure and idea of the present invention fall within the protection scope of the present invention. It should be noted that, without conflict, the embodiments and features in the embodiments of the present invention can be combined with each other.

[0100] In the examples, the concentrated hydrochloric acid mentioned is concentrated hydrochloric acid with a mass concentration of 37%. "eq." is the abbreviation of "equivalent", which is used to represent the relative amount or proportional relationship of substances in chemical reactions. "RRT" is the abbreviation of "relative retention time", which is used to describe the ratio of the retention time of the target compound to that of the reference compound in chromatographic analysis (such as high-performance liquid chromatography, HPLC).

[0101] Example 1

[0102] According to the total synthesis route, Compound I was synthesized. The total synthesis route is as follows: 。

[0103] Step 1 Preparation of tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound IV)

[0104] In a 100 mL three-necked flask, 30 mL of methanol, 3.0 g (1.00 eq.) of 1-Boc-4-(4-aminophenyl)piperazine (Compound II), 2.5 g (1.40 eq.) of 2,4-dichloro-5-fluoropyrimidine (Compound III) were added. The temperature was raised to 60 °C, 1.5 g (1.40 eq.) of triethylamine was added, and the reaction was carried out for 4 h. After the reaction was complete, 30 mL of purified water was added dropwise, and the temperature was lowered to room temperature. The mixture was filtered by suction, and the filter cake was collected and dried to obtain 4.3 g of a gray powder with a yield of 96.73% and a purity of 96.74%.

[0105] MS measured value: [M-H]- was 406.14.

[0106] The HPLC chromatogram is as Figure 1 shown, and the HNMR chromatogram is as Figure 2 shown. Figure 1 The corresponding data in

[0107] Step 2 Preparation of tert-butyl 4-(4-((2-(2-amino-1H-benzoimidazol-1-yl)-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (Compound V)

[0108] In a 100 mL three-necked flask, add 20 mL of dimethyl sulfoxide, 5.0 g (1.00 eq.) of tert-butyl 4-(4-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (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, 0.2 g (0.12 eq.) of copper(I) iodide. Replace the air with N₂ three times and continuously protect. Heat to 120 °C, keep stirring until the reaction is complete, cool to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for slurrying three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat to make the solution clear, add 50 mL of ethanol dropwise at about 80 °C. After the addition is complete, cool to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry it to obtain 4.1 g of a gray solid, with a yield of 65.48% and a purity of 95.57%.

[0109] The MS measured value of [M-H]- is 503.23.

[0110] The HPLC chromatogram is as shown in Figure 4 shown, and the HNMR chromatogram is as shown in Figure 5 shown. Figure 4 The corresponding data in it are shown in the following table:

[0111] Step 3 Preparation of tert-butyl 4-(4-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-5-fluoropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate hydrochloride (Compound V hydrochloride)

[0112] In a 100 mL three-necked flask, add 10.0 g of purified water, 5.0 g of absolute ethanol, 5.0 g of concentrated hydrochloric acid, stir, cool to about 5 °C, add 5.0 g of Compound V. After adding, heat to 25 °C, add 40.0 g of absolute ethanol dropwise. After the addition is complete, keep the temperature for crystallization for 3 h. Filter by suction, collect the filter cake and dry it to obtain 5.2 g of an off-white solid, with a yield of 97.83% and a purity of 99.23%. The HPLC chromatogram (the impurity at RT = 10.151 is Compound I, and the purity is calculated by combining) is as shown in Figure 7 shown.

[0113] 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)

[0114] In a 250 mL three-necked flask, 1.1 g (1.00 eq.) of compound V hydrochloride and 17.5 g of acetonitrile were added. After stirring and cooling to about 10 °C, 1.0 g of concentrated hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to room temperature for reaction. The raw materials were controlled to react completely. Then, filtration was carried out, and the filter cake was collected and dried to obtain 0.8 g of a white solid with a purity of 99.42% and a yield of 99.43%.

[0115] The MS measured value of [M-H]- was 403.18.

[0116] The HPLC chromatogram is as Figure 8 shown, and the HNMR chromatogram is as Figure 9 shown. Figure 8 The corresponding data in it are shown in the following table:

[0117] 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)

[0118] In a 100 mL three-necked flask, 10.0 g of the crude product of Compound I and 30.0 g of purified water were added. After stirring and dissolving, activated carbon was added for decolorization. Then, filtration was carried out, and the filtrate was collected. 200.0 g of absolute ethanol was added, and the temperature was raised to 60 °C until the solution became clear. Then, it was slowly cooled to about 5 °C, and crystallization was carried out for 2 h. Filtration was carried out, and the filter cake was collected and dried to obtain 7.0 g of a white solid with a yield of 70.00%, a purity of 99.83%, and no single impurity greater than 0.1%. The HPLC chromatogram is as Figure 10 shown. The appearance of the prepared Compound I is as Figure 11 shown.

[0119] Comparative Example 1

[0120] Preparation of Compound IV (synthesized by referring to the preparation method disclosed in the prior art CN 116514779A)

[0121] In a 100 mL three-necked flask, 414.65 mg (1.00 eq.) of Compound II, 356.19 mg (1.43 eq.) of Compound III, 10 mL of methanol, and 10 mL of purified water were added. The temperature was raised to 60 °C for reaction for 18 h, then cooled to room temperature, and filtration was carried out. The filter cake was collected and dried to obtain an off-white powder with a yield of 21.02% and a purity of 98.20%. The HPLC chromatogram is as Figure 3 shown.

[0122] Comparison Figure 2 and Figure 3 It can be seen that, with a slightly reduced purity, the yield of Compound IV in Example 1 was greatly improved.

[0123] Comparative Example 2

[0124] 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:

[0125] 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%.

[0126] It can be seen that adding water will greatly reduce the yield and purity of compound IV.

[0127] Comparative Example 3

[0128] 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:

[0129] 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%.

[0130] It can be seen that not adding an acid-binding agent will greatly reduce the yield and purity of compound IV.

[0131] Comparative Example 4

[0132] Compared with Example 1, water is added during the reaction of step 1, but no acid binding agent is added. The other steps are the same as those of Example 1, and the operation is as follows:

[0133] 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.

[0134] It can be seen that adding water and removing the acid-binding agent will result in the inability to precipitate compound IV.

[0135] Comparative Example 5

[0136] 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)

[0137] In a 100 mL single-necked flask, add 10 mL of 1,4-dioxane, 0.50 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, 0.16 g (0.20 eq.) of Xantphos, 0.04 g (0.04 eq.) of Pd2(dba)3. After purging with N2, seal it with a rubber stopper, heat it to 120 °C and react for 23 h. Cool it to room temperature, filter, add purified water and dichloromethane for extraction, separate the layers, concentrate the organic phase to dryness to obtain 0.20 g of a grayish-black solid, with a yield of 27.18% and a purity of 50.97%. The HPLC chromatogram is as Figure 6 shown.

[0138] It can be seen that even when adding the same equivalent of Compound IV, the yield and purity of Compound V obtained by the method of the prior art are much lower than those of Example 1 of the present invention.

[0139] Comparative Example 6

[0140] Compared with Example 1, during the reaction process of Step 2, the catalyst and ligand disclosed in the prior art CN 116514779A are used, and the others are the same as in Example 1. The operation is as follows:

[0141] 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, 1.1 g (0.15 eq.) of Xantphos. Purge with N2 three times and continuously protect with nitrogen. Heat it to 120 °C, keep it warm and stir until the reaction is complete. Cool it to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool it to room temperature for crystallization. Filter the reaction solution, collect the wet product, add 20 mL of 25% ammonia water for slurrying three times. After filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat it until the solution is clear, dropwise add 50 mL of ethanol at about 80 °C. After dropping, cool it to 25 °C and stir for crystallization for 12 h. Filter, collect the filter cake and dry it to obtain 2.1 g of a gray solid, with a yield of 33.95% and a purity of 85.42%.

[0142] It can be seen that even when adding the same equivalent of Compound IV, the yield and degree of Compound V obtained by using the catalyst and ligand of the prior art are much lower than those of Example 1 of the present invention.

[0143] Comparative Example 7

[0144] Compared with Example 1, the solvent is changed during the reaction process of Step 2, and the others are the same as in Example 1. The operation is as follows:

[0145] In a 100 mL three-necked flask, add 20 mL of 1,4-dioxane, 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, 0.2 g (0.12 eq.) of cuprous iodide. Replace the gas with N₂ three times and continuously protect with nitrogen. Heat up to 120 °C, keep stirring until the reaction is complete, cool down to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for slurrying three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up until the solution becomes clear, dropwise add 50 mL of ethanol at about 80 °C. After the addition is complete, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 2.9 g of gray solid, with a yield of 46.88% and a purity of 90.16%.

[0146] It can be seen that even when adding the same equivalent of Compound IV, the yield and degree of Compound V obtained using an inappropriate solvent are much lower than those of Example 1 of the present invention.

[0147] Comparative Example 8

[0148] Compared with Example 1, the catalyst was replaced during the reaction process of Step 2, and the others were the same as in Example 1. The operation is as follows:

[0149] In a 100 mL three-necked flask, add 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, 1.4 g (0.12 eq.) of Pd₂(dba)₃. Replace the gas with N₂ three times and continuously protect with nitrogen. Heat up to 120 °C, and the subsequent treatment is the same as that of Step 2 in Example 1. The obtained product was monitored by HPLC, and the HPLC main peak showed that it was not the target product.

[0150] Comparative Example 9

[0151] Compared with Example 1, the ligand was replaced during the reaction process of Step 2, and the others were the same as in Example 1. The operation is as follows:

[0152] In a 100 mL three-necked flask, add 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 copper(I) iodide. Replace the air with N₂ three times and maintain N₂ protection. Heat the mixture to 120 °C, and the subsequent treatment is the same as in Step 2 of Example 1. The obtained product was monitored by HPLC, and the main peak in the HPLC showed that it was not the target product.

[0153] Comparative Example 10

[0154] Prepare 1-[5-fluoro-4-[[4-(piperazin-1-yl)phenyl]amino]pyrimidin-2-yl]-1H-benzo[d]imidazol-2-amine bis (free base of Compound I, refer to the preparation method of 7a in CN 116514779A) as follows:

[0155] In a 100 mL three-necked flask, add 20 mL of dichloromethane, 3.30 g of Compound V, and 3.5 mL of trifluoroacetic acid. Stir at room temperature, add sodium hydroxide to adjust the pH to alkaline, separate the layers, wash the organic phase three times with water, and concentrate to dryness to obtain 2.2 g of a grayish-black solid with a yield of 83.17% and a purity of 85.63%. The HPLC chromatogram is as Figure 12 shown.

[0156] The impurity structure at RRT = 9.079 is as follows: .

[0157] Prepare Compound I:

[0158] Add 2.0 g of the grayish-black solid obtained in Comparative Example 10 to 32.0 g of acetonitrile, stir, cool down to about 10 °C, add 2.0 g of hydrochloric acid dropwise. After the addition is complete, warm up to room temperature and react. After the raw materials have completely reacted, filter by suction, collect the filter cake and dry it to obtain 1.8 g of a dark gray solid with a yield of 76.17%. The properties are as Figure 13 .

[0159] Example 2

[0160] On the basis of Example 1, adjust the preparation steps of Compound IV as follows:

[0161] In a 50 mL three-necked flask, add 1.0 g (1.00 eq.) of Compound II, 0.84 g (1.40 eq.) of Compound III, 10 mL of absolute ethanol, stir, heat up to 80 °C, add 0.5 g (1.40 eq.) of triethylamine, keep stirring at this temperature for 4 h until the reaction is complete, add 10 mL of purified water dropwise. After the addition is complete, cool down to room temperature, filter by suction, collect the filter cake and dry it to obtain 1.34 g of a gray solid with a yield of 91.12% and a purity of 94.99%.

[0162] The other steps are the same as those in Example 1.

[0163] Example 3

[0164] On the basis of Example 1, the preparation steps of Compound IV are adjusted as follows:

[0165] In a 500 mL three-necked flask, add 10.0 g (1.00 eq.) of Compound II, 6.8 g (1.00 eq.) of Compound III, 100 mL of methanol, stir, heat up to 60 °C, add 7 g (1.40 eq.) of potassium carbonate, keep stirring at this temperature for 5 h until the reaction is complete, add dropwise 100 mL of purified water. After the addition is completed, cool down to room temperature, filter by suction, collect the filter cake and dry it to obtain 12.8 g of a gray solid, with a yield of 87.05% and a purity of 95.13%.

[0166] The other steps are the same as those in Example 1.

[0167] Example 4

[0168] On the basis of Example 1, the preparation steps of Compound IV are adjusted as follows:

[0169] In a 500 mL three-necked flask, add 10.0 g (1.00 eq.) of Compound II, 8.4 g (1.40 eq.) of Compound III, 100 mL of methanol, stir, heat up to 60 °C, add 5.1 g (1.40 eq.) of N,N-diisopropylethylamine. After the addition is completed, keep stirring at this temperature for 4 h until the reaction is complete, add dropwise 100 mL of purified water. After the addition is completed, cool down to room temperature, filter by suction, collect the filter cake and dry it to obtain 14.1 g of a gray solid, with a yield of 95.89% and a purity of 96.01%.

[0170] The other steps are the same as those in Example 1.

[0171] Example 5

[0172] On the basis of Example 1, the preparation steps of Compound IV are adjusted as follows:

[0173] In a 500 mL three-necked flask, add 10.0 g (1.00 eq.) of Compound II, 8.4 g (1.40 eq.) of Compound III, 100 mL of acetone, stir, heat up to 30 °C, add 10.2 g (2.80 eq.) of triethylamine. After the addition is completed, keep stirring at this temperature for 5 h until the reaction is complete, add dropwise 100 mL of purified water. After the addition is completed, cool down to room temperature, filter by suction, collect the filter cake and dry it to obtain 13.1 g of a gray solid, with a yield of 89.09% and a purity of 96.43%.

[0174] The other steps are the same as those in Example 1.

[0175] Example 6

[0176] On the basis of Example 1, the preparation steps of Compound IV were adjusted as follows:

[0177] In a 500 mL three-necked flask, 10.0 g (1.00 eq.) of Compound II, 16.8 g (2.80 eq.) of Compound III, and 100 mL of methanol were added. After stirring, the temperature was raised to 60 °C, and 3.7 g (1.0 eq.) of triethylamine was added. After completion, the mixture was stirred at a constant temperature for 4 h until the reaction was complete. Then, 100 mL of purified water was added dropwise. After the addition was complete, the temperature was lowered to 0 °C, and the mixture was filtered by suction. The filter cake was collected and dried to obtain 14.3 g of a gray solid with a yield of 97.25% and a purity of 95.02%.

[0178] Other steps were the same as those in Example 1.

[0179] Example 7

[0180] On the basis of Example 1, the preparation steps of Compound V were adjusted as follows:

[0181] In a 10 mL sealed tube, 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, 2 mL of N,N-dimethylacetamide, 0.03 g (0.12 eq.) of copper(I) iodide, and 0.03 g (0.15 eq.) of 8-hydroxyquinoline were added. The tube was purged with N2 three times and continuously protected with nitrogen. After stirring, the temperature was raised to 120 °C, and the mixture was stirred at a constant temperature until the reaction was complete. Then, the temperature was lowered to 50 °C, and 5 mL of absolute ethanol + 1 mL of ammonia water were added. After the addition was complete, the temperature was lowered to room temperature for crystallization. The reaction solution was filtered by suction, and the wet product was collected. The wet product was slurried three times with 5 mL of 25% ammonia water. After filtration, 5 mL of N-methylpyrrolidone was added to the obtained wet product. The temperature was raised until the solution became clear, and 10 mL of ethanol was added dropwise at about 80 °C until a solid precipitated. The temperature was lowered to 25 °C and stirred for crystallization for 12 h. The mixture was filtered by suction, and the filter cake was collected and dried to obtain 0.4 g of a gray solid with a yield of 66.28% and a purity of 95.31%.

[0182] Other steps were the same as those in Example 1.

[0183] Example 8

[0184] On the basis of Example 1, the preparation steps of Compound V were adjusted as follows:

[0185] 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 copper chloride, 0.27 g (0.15 eq.) of 8-hydroxyquinoline. Replace the air with N₂ three times and protect. Stir, heat up to 120 °C, keep stirring at this temperature until the reaction is complete, cool down to 30 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for pulping three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up until the solution becomes clear, dropwise add 50 mL of ethanol at about 80 °C, dropwise add until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 3.7 g of gray solid, with a yield of 59.82% and a purity of 93.69%.

[0186] Other steps are the same as in Example 1.

[0187] Example 9

[0188] On the basis of Example 1, adjust the preparation steps of Compound V as follows:

[0189] 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 copper iodide, 0.27 g (0.15 eq.) of 8-hydroxyquinoline. Replace the air with N₂ three times and protect. Stir, heat up to 120 °C, keep stirring at this temperature until the reaction is complete, cool down to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for pulping three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up until the solution becomes clear, dropwise add 50 mL of ethanol at about 80 °C, dropwise add until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 3.9 g of gray solid, with a yield of 63.05% and a purity of 94.18%.

[0190] Other steps are the same as in Example 1.

[0191] Example 10

[0192] On the basis of Example 1, adjust the preparation steps of Compound V as follows:

[0193] 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 copper chloride, 0.27 g (0.15 eq.) of 8-hydroxyquinoline. Replace with N₂ three times and protect. Stir, heat up to 120 °C, keep stirring at this temperature until the reaction is complete, cool down to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for pulping three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up until the solution becomes clear, dropwise add 50 mL of ethanol at about 80 °C until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 3.5 g of gray solid, with a yield of 56.58% and a purity of 92.07%.

[0194] Other steps are the same as in Example 1.

[0195] Example 11

[0196] On the basis of Example 1, adjust the preparation steps of Compound V as follows:

[0197] 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. Replace with N₂ three times and protect. Stir, heat up to 120 °C, keep stirring at this temperature until the reaction is complete, cool down to 50 °C, add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for pulping three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up until the solution becomes clear, dropwise add 50 mL of ethanol at about 80 °C until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 3.3 g of gray solid, with a yield of 53.35% and a purity of 93.18%.

[0198] Other steps are the same as in Example 1.

[0199] Example 12

[0200] On the basis of Example 1, adjust the preparation steps of Compound V as follows:

[0201] 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, 20 mL of N,N-dimethylacetamide, 0.28 g (0.12 eq.) of copper(I) iodide, 0.27 g (0.15 eq.) of 8-hydroxyquinoline. Replace the air with N₂ three times and protect. Stir, heat up to 140 °C, keep stirring at this temperature until the reaction is complete, then cool down to 50 °C. Add 20 mL of absolute ethanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for slurrying three times. After suction filtration, add 20 mL of N-methylpyrrolidone to the obtained wet product, heat up to dissolve it completely, dropwise add 50 mL of isopropanol at about 80 °C until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 4.2 g of gray solid, with a yield of 67.90% and a purity of 93.69%.

[0202] Other steps are the same as in Example 1.

[0203] Example 13

[0204] On the basis of Example 1, adjust the preparation steps of Compound V as follows:

[0205] 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, 20 mL of N,N-dimethylacetamide, 0.28 g (0.12 eq.) of copper(I) iodide, 0.27 g (0.15 eq.) of 8-hydroxyquinoline. Replace the air with N₂ three times and protect. Stir, heat up to 120 °C, keep stirring at this temperature until the reaction is complete, then cool down to 50 °C. Add 20 mL of isopropanol + 5 mL of ammonia water. After adding, cool down to room temperature for crystallization. Filter the reaction solution by suction, collect the wet product, add 20 mL of 25% ammonia water for slurrying three times. After suction filtration, add 20 mL of N,N-dimethylacetamide to the obtained wet product, heat up to dissolve it completely, dropwise add 50 mL of ethanol at about 80 °C until solid precipitates, cool down to 25 °C and stir for crystallization for 12 h. Filter by suction, collect the filter cake and dry to obtain 4.0 g of gray solid, with a yield of 64.66% and a purity of 96.33%.

[0206] Other steps are the same as in Example 1.

[0207] Example 14

[0208] On the basis of Example 1, adjust the preparation steps of Compound V hydrochloride as follows:

[0209] In a 25 mL three-necked flask, add 1.0 g of purified water, 0.5 g of isopropanol, and 0.5 g of concentrated hydrochloric acid. Stir and cool down to about 5 °C. Add 0.5 g of Compound V. After addition, warm up to 25 °C, dropwise add 4.0 g of isopropanol. After dropwise addition, keep the temperature for crystallization for 3 h, perform suction filtration, collect the filter cake and dry it to obtain 0.52 g of off-white solid, with a yield of 96.99% and a purity of 99.08%.

[0210] Other steps are the same as in Example 1.

[0211] Example 15

[0212] Based on Example 1, adjust the preparation steps of Compound V hydrochloride as follows:

[0213] In a 100 mL three-necked flask, add 20.0 g of purified water, 5.0 g of acetone, and 5.0 g of concentrated hydrochloric acid. Stir and cool down to about 5 °C. Add 5.0 g of Compound V. After addition, warm up to 25 °C, dropwise add 40.0 g of acetone. After dropwise addition, keep the temperature for crystallization for 3 h, perform suction filtration, collect the filter cake and dry it to obtain 4.8 g of off-white solid, with a yield of 89.53% and a purity of 99.36%.

[0214] Other steps are the same as in Example 1.

[0215] Example 16

[0216] Based on Example 1, adjust the preparation steps of Compound V hydrochloride as follows:

[0217] In a 100 mL three-necked flask, add 10.0 g of purified water, 5.0 g of absolute ethanol, and 5.0 g of concentrated hydrochloric acid. Stir and cool down to about 5 °C. Add 5.0 g of Compound V. After addition, warm up to 40 °C, dropwise add 40.0 g of absolute ethanol. After dropwise addition, keep the temperature for crystallization for 3 h, perform suction filtration, collect the filter cake and dry it to obtain 4.5 g of off-white solid, with a yield of 83.93% and a purity of 99.22%.

[0218] Other steps are the same as in Example 1.

[0219] Example 17

[0220] Based on Example 1, adjust the preparation steps of Compound I as follows:

[0221] In a 250 mL three-necked flask, add 1.1 g (1.00 eq.) of Compound V hydrochloride and 17.5 g of acetonitrile. Stir and cool down to about 10 °C. Dropwise add 1.0 g of concentrated hydrochloric acid. After dropwise addition, warm up to room temperature for reaction. Monitor the reaction by TLC to ensure complete reaction of the raw materials. Perform suction filtration, collect the filter cake and dry it to obtain 0.9 g of off-white solid, with a yield of 94.44% and a purity of 99.26%.

[0222] Other steps are the same as in Example 1.

[0223] Example 18

[0224] On the basis of Example 1, the preparation steps of Compound I were adjusted as follows:

[0225] In a 5 L three-necked flask, 164.0 g (1.00 eq.) of Compound V hydrochloride and 2626.0 g of acetonitrile were added. After stirring and cooling to about 10 °C, 164.0 g of concentrated hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to room temperature for reaction. The raw materials were monitored by in-process control until the reaction was complete. Then, filtration was carried out under suction, and the filter cake was collected and dried to obtain 138.0 g of a white solid. The yield was 95.36% and the purity was 99.36%.

[0226] Other steps were the same as those in Example 1.

[0227] Example 19

[0228] On the basis of Example 1, the purification steps of Compound I were adjusted as follows:

[0229] In a 100 mL three-necked flask, 10.0 g of the crude product of Compound I and 30.0 g of purified water were added. After stirring and dissolving, activated carbon was added for decolorization. Filtration was carried out under suction, and the filtrate was collected. Then, 200.0 g of isopropanol was added, and the temperature was raised to 60 °C until it was dissolved clearly. Then, the temperature was slowly lowered to about 15 °C, and crystallization was carried out for 2 h. Filtration was carried out under suction, and the filter cake was collected and dried to obtain 6.3 g of a white solid. The yield was 63.00% and the purity was 99.89%, and there was no single impurity greater than 0.1%.

[0230] Other steps were the same as those in Example 1.

[0231] Example 20

[0232] On the basis of Example 1, the purification steps of Compound I were adjusted as follows:

[0233] In a 100 mL three-necked flask, 10.0 g of the crude product of Compound I and 50.0 g of purified water were added. After stirring and dissolving, activated carbon was added for decolorization. Filtration was carried out under suction, and the filtrate was collected. Then, 200.0 g of acetone was added, and the temperature was raised to 70 °C until it was dissolved clearly. Then, the temperature was slowly lowered to about 5 °C, and crystallization was carried out for 2 h. Filtration was carried out under suction, and the filter cake was collected and dried to obtain 6.9 g of a white solid. The yield was 69.00% and the purity was 99.81%, and there was no single impurity greater than 0.1%.

[0234] Other steps were the same as those in Example 1.

[0235] It should be noted that the above examples are merely illustrations for clearly explaining the present invention and are not limitations on the implementation modes of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made on the basis of the above description. It is impossible to list all the implementation modes here. Any obvious changes or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, characterized in that, It includes the following steps: Compound VI is in a reaction solvent and, in the presence of hydrochloric acid, undergoes deprotection and salt formation reactions to obtain compound I; the reaction solvent is acetonitrile, and the reaction temperature is 20°C - 30°C; ； The preparation method of compound VI includes the following steps: Compound V undergoes a salt formation reaction in a hydrochloric acid solution to obtain compound VI; after the reaction is complete, post-treatment is carried out, and the post-treatment includes: adding an anti-solvent and performing crystallization at a certain temperature; wherein the hydrochloric acid solution includes hydrochloric acid and a solvent, and the solvent is a mixture of ethanol and purified water; the anti-solvent is ethanol; the temperature of the salt formation reaction is 0°C - 40°C; the temperature of crystallization is 0°C - 40°C; 。 2. A method for preparing a salt of a 2,4-disubstituted-5-fluoropyrimidine derivative, characterized in that, It includes the following steps: S1. Compound II and compound III are in a reaction solvent, at a reaction temperature, and in the presence of an acid-binding agent, undergo a substitution reaction to obtain compound IV. The reaction solvent in S1 is methanol; the acid-binding agent is triethylamine; the reaction temperature is 30°C - 120°C; ； S2. Under a protective atmosphere, compound IV and 2-aminobenzimidazole are in a reaction solvent, at a reaction temperature, and in the presence of an acid-binding agent, a ligand, and a catalyst, undergo a substitution reaction to obtain compound V. The reaction solvent in S2 is dimethyl sulfoxide; the acid-binding agent in S2 is cesium carbonate; the ligand in S2 is 8-hydroxyquinoline; the catalyst in S2 is copper iodide; the reaction temperature is 100°C - 140°C; ； S3. Compound V is in a hydrochloric acid solution, at a reaction temperature, undergoes a salt formation reaction. After the reaction is complete, post-treatment is adopted, and the post-treatment includes: adding an anti-solvent and performing crystallization at a certain temperature to obtain compound VI. Wherein the hydrochloric acid solution includes hydrochloric acid and a solvent, and the solvent is a mixture of ethanol and purified water; the anti-solvent is ethanol; the temperature of the salt formation reaction is 0°C - 40°C; the temperature of crystallization is 0°C - 40°C; ； S4. Compound VI is in a reaction solvent, at a reaction temperature, and in the presence of hydrochloric acid, undergoes deprotection and salt formation reactions to obtain a crude product of compound I. In S4, the reaction solvent is acetonitrile, and the reaction temperature is 20°C - 30°C; 。 3. The method according to claim 2, wherein 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.

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

3.

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

6. The method according to any one of claims 2-5, characterized in that, It includes the following steps: S1. Mix compound II, compound III, the reaction solvent, and the acid-binding agent evenly and reflux react; after the reaction is complete, crystallize, filter, and dry to obtain compound IV; S2. Under a protective atmosphere, mix compound IV, 2-aminobenzimidazole, a reaction solvent, an acid-binding agent, a ligand, and a catalyst uniformly, and react at 100°C - 140°C. After the reaction is complete, crystallize, filter, dry, and recrystallize to obtain compound V; S3. Add compound V to a hydrochloric acid solution for reaction. After the reaction is completed, add an anti-solvent to crystallize and form a salt to obtain compound VI; S4. Add compound VI to acetonitrile, dropwise add hydrochloric acid for reaction. After the reaction is complete, filter and dry to obtain the crude product of compound I; S5. Add purified water to the crude product of compound I, heat to dissolve, add activated carbon for decolorization, filter, and collect the filtrate; add a solution to the filtrate, heat again to completely dissolve, then cool to 0°C - 30°C, filter, and dry to obtain compound I.

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