Preparation method of rizobrutinib and intermediate thereof

Abstract

The invention discloses a preparation method of rizabrutinib and an intermediate thereof, the reaction route is shown in the specification, and the preparation steps are as follows: 2-fluoro-4-phenoxy benzoic acid (I) is subjected to acylating chlorination reaction and is condensed with malononitrile to obtain an intermediate shown in a formula III, then the hydroxyl of the intermediate is converted into a leaving group LG to obtain an intermediate shown in a formula IV, and the intermediate shown in the formula IV is subjected to post-treatment to obtain the rizabrutinib. The preparation method comprises the following steps: carrying out a pyrazole cyclization reaction with a compound shown in a formula V to obtain an intermediate shown in a formula VI, carrying out a pyrimidine cyclization reaction, removing an amino protecting group to obtain an intermediate shown in a formula VIII, and finally carrying out a condensation reaction with an intermediate shown in a formula X to obtain rizobrutinib. In addition, the intermediate shown in the formula X can be obtained by a Knoevenagel condensation reaction of a compound shown in a formula IX and a compound shown in a formula XI. The preparation method provided by the invention adopts a convergent synthesis route, and is high in reaction yield, simple in process, economical, environment-friendly and suitable for industrial production.

Description

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 2024111702656, filed with the China National Intellectual Property Administration on August 23, 2024, entitled "Method for Preparation of Rizarutinib and Intermediates Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to methods for preparing rizarutinib and its intermediates, and belongs to the field of pharmaceutical synthesis technology. Background Technology

[0004] Rilzabrutinib is an oral, reversible covalent Bruton's tyrosine kinase (BTK) inhibitor. In April 2024, Sanofi announced that its oral reversible BTK inhibitor, rilzabrutinib, met the primary endpoint of the LUNA 3 Phase 3 clinical trial, demonstrating significant improvement in symptoms in patients with immune thrombocytopenic purpura (ITP).

[0005]

[0006] The preparation of rizarutinib has been previously reported. US Patent US9266895B2 discloses a synthetic method for rizarutinib and its analogues, using 1H-pyrazolo[3,4-d]pyrimidine-4-amine as a starting material. 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine is prepared via N-iodosuccinimide, followed by a Mitsunobu reaction, Suzuki coupling reaction, deprotection, acylation, and Knoevenagel condensation reaction to obtain the target compound (reaction route shown below). The key steps, the Mitsunobu reaction and acylation, have low yields, at 30% and 25%, respectively. The reaction route is linear, with an overall yield of only 2% across the six steps. Furthermore, the triphenylphosphine oxide produced during the reaction causes problems with post-processing purification and environmental pollution. In summary, the existing process suffers from low yields, difficult purification, and environmental pollution, hindering the industrialization of the product.

[0007] Summary of the Invention

[0008] The purpose of this invention is to address the deficiencies in the prior art by providing a method for preparing rizarutinib that is easy to obtain from raw materials, has a simple process, is environmentally friendly and economical, and is suitable for industrialization, as well as a method for preparing intermediates (compounds represented by formulas III, IV, VI, or X) and their preparation methods.

[0009] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0010] On the one hand, the present invention provides a method for preparing rizalutinib, the reaction route of which is as follows:

[0011]

[0012] The preparation method includes:

[0013] Step A: The compound shown in Formula I is reacted with an acyl chloride reagent to prepare the compound shown in Formula II;

[0014] Step B: The compound shown in Formula II undergoes a condensation reaction with malononitrile to prepare the compound shown in Formula III;

[0015] Step C: The compounds shown in Formulas I and II react with a halogenating agent, an alkylating agent, or a sulfonating agent to give the compound shown in Formula IV;

[0016] Step D: The compound shown in Formula IV reacts with the compound shown in Formula V to obtain the compound shown in Formula VI;

[0017] Step E: The compound shown in Formula VI reacts with a cyclizing agent to give the compound shown in Formula VII;

[0018] Step F: The compound shown in Formula VII is deamino protecting to obtain the compound shown in Formula VIII;

[0019] Step G: The compound shown in Formula IX and the compound shown in Formula XI undergo a Knoevenagel condensation reaction to obtain the compound shown in Formula X;

[0020] Step H: The compound represented by Formula VIII and the compound represented by Formula X undergo a condensation reaction to obtain rizalutinib;

[0021] The detailed explanations of all the above steps are as follows for each step in the text.

[0022] In another aspect, the present invention provides a method for preparing rizalutinib, the reaction formula of which is as follows:

[0023]

[0024] Wherein, R2 is a hydroxyl group or a C1-C group. 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy or tert-butoxy;

[0025] The preparation method includes:

[0026] Step H: The compound shown in Formula VIII and the compound shown in Formula X undergo a condensation reaction to obtain rizarutinib.

[0027] When R2 is a hydroxyl group, the reaction is carried out in an organic solvent in the presence of a condensing agent and a base.

[0028] The condensing agent is selected from one or more of oxaloyl chloride, thionyl chloride, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, N,N-dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; and / or

[0029] The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine;

[0030] The solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, dichloroethane, chlorobenzene, toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide;

[0031] Preferably, the molar ratio of the compound represented by Formula VIII to the compound represented by Formula X is 1:(1 to 3), for example 1:1; the molar ratio of the compound represented by Formula VIII to the condensing agent and the base is 1:(1 to 3):(1 to 6), for example 1:1.5 to 3:3;

[0032] Preferably, the reaction temperature is -10 to 50°C, and the reaction time is 1 to 24 hours.

[0033] When R2 is C1-C 10 When alkoxy is involved, the reaction is carried out in a solvent with or without the addition of an organometallic base;

[0034] The organometallic base is selected from one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, tert-butylmagnesium chloride, and tert-butylmagnesium bromide, preferably one or more of sodium methoxide, sodium ethoxide, and tert-butylmagnesium chloride.

[0035] The solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene;

[0036] Preferably, the molar ratio of the compound represented by formula VIII to the compound represented by formula X is 1:(1 to 3), for example 1:1; the molar ratio of the compound represented by formula VIII to the organometallic base is 1:(1 to 3), for example 1:1.2;

[0037] Preferably, the reaction temperature is -10 to 140°C, and the reaction time is 1 to 24 hours.

[0038] This invention also provides a method for preparing the intermediate compound shown in Formula VIII, the reaction formula of which is as follows:

[0039]

[0040] Wherein, R1 is an H or amino protecting group;

[0041] The preparation method includes:

[0042] Step E: The compound shown in Formula VI reacts with a cyclizing agent to give the compound shown in Formula VII;

[0043] Step F: The compound shown in Formula VII is deamino protecting to obtain the compound shown in Formula VIII;

[0044] When R1 is H, the preparation method does not include step F.

[0045] The acyl amino protecting group is selected from one of formyl, acetyl, tertvalyl, trichloroacetyl, trifluoroacetyl, benzoyl, phthalyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl; the alkoxycarbonyl amino protecting group is selected from one of tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, and ethoxycarbonyl; the alkyl amino protecting group is selected from one of triphenylmethyl, benzyl, and p-methoxybenzyl; preferably, the amino protecting group is tert-butoxycarbonyl or benzyloxycarbonyl; and / or

[0046] In some implementations, in step E:

[0047] The cyclizing agent is one or more selected from formamide, formamidine, formamidine hydrochloride, and formamidine acetate;

[0048] The reaction is carried out in a solvent at 20–200°C, with or without the addition of alkali.

[0049] Preferably, the base is one or more selected from triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine;

[0050] Preferably, the molar ratio of the compound shown in Formula VI to the cyclizing agent is 1:(1-20), for example 1:3;

[0051] Preferably, the reaction temperature is 20–200°C; the reaction time is 1–24 h, for example 12 h;

[0052] Preferably, the solvent is selected from one or more of formamide, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, propanol, isopropanol, n-butanol, isobutanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether, and is preferably formamide, ethanol, or ethylene glycol.

[0053] In step F, different removal methods can be used depending on the different amino protecting groups in the compound shown in formula VII: 1) Alkoxycarbonyl amino protecting groups: for example, tert-butoxycarbonyl can be removed by hydrolysis under acidic conditions, benzyloxycarbonyl can be removed by catalytic hydrogenolysis, and methoxycarbonyl can be removed under alkaline conditions; 2) Acyl amino protecting groups: for example, trifluoroacetyl can be removed in a K2CO3 or Na2CO3 / MeOH / H2O system, and phthaloyl can be removed by treatment with hydrazine hydrate; 3) Alkyl amino protecting groups: for example, p-methoxybenzyl can be removed by oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone or cerium ammonium nitrate.

[0054] This invention also provides a method for preparing the intermediate compound shown in Formula VI, the reaction formula of which is as follows:

[0055]

[0056] Wherein, LG is a leaving group, selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl;

[0057] R1 is an H or amino protecting group, and the definition of the amino protecting group is as described above;

[0058] The preparation method includes:

[0059] Step D: The compound shown in Formula IV reacts with the compound shown in Formula V to obtain the compound shown in Formula VI.

[0060] In some implementations, in step D:

[0061] The reaction is carried out in a solvent at 0–100°C, with or without the addition of alkali.

[0062] Preferably, the alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and organometallic alkalis; wherein the non-metallic organic alkali is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; the inorganic alkali is selected from one or a combination of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, preferably one or a combination of sodium carbonate and potassium carbonate; the organometallic alkali is selected from one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, and potassium tert-butoxide, preferably one or a combination of sodium methoxide and sodium ethoxide.

[0063] Preferably, the molar ratio of the compound shown in Formula IV to the compound shown in Formula V is 1:(0.8-2), more preferably 1:(1-1.5); the molar ratio of the compound shown in Formula IV to the base is 1:(0.8-3), more preferably 1:(1-1.5).

[0064] Preferably, the reaction temperature is 10–80°C, and the reaction time is 1–12 hours, for example, 6 hours;

[0065] Preferably, the solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, chlorobenzene, toluene, and xylene, and more preferably one or a combination of methanol, ethanol, tetrahydrofuran, and 1,4-dioxane.

[0066] This invention also provides a method for preparing the intermediate compound shown in Formula IV, the reaction formula of which is as follows:

[0067]

[0068] Wherein, LG is a leaving group, which can be selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl;

[0069] The preparation method includes:

[0070] Step A: The compound shown in Formula I is reacted with an acyl chloride reagent to prepare the compound shown in Formula II;

[0071] Step B: The compound shown in Formula II undergoes a condensation reaction with malononitrile to prepare the compound shown in Formula III;

[0072] Step C: The compounds shown in Formulas I and II react with a halogenating agent, an alkylating agent, or a sulfonating agent to give the compound shown in Formula IV.

[0073] In some implementations, in step A:

[0074] The acyl chloride reagent is selected from one or more of thionyl chloride, oxalyl chloride, triphosgene, phosphorus oxychloride, and phosphorus pentachloride;

[0075] The reaction is carried out in a solvent at -30 to 50°C.

[0076] Preferably, the molar ratio of the compound shown in Formula I to the acyl chloride reagent is 1:(0.8-10), more preferably 1:(1-2.5), for example 1:1.2;

[0077] Preferably, the reaction temperature is -10 to 50°C, and the reaction time is 1 to 12 hours.

[0078] Preferably, the solvent is one or more selected from dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene.

[0079] In some implementations, in step B:

[0080] The reaction is carried out in a solvent in the presence of a base at 0–100°C.

[0081] Specifically, malononitrile and alkali are added to the solvent in the range of 0 to 100°C, and the reaction is stirred for 0.1 to 2 hours. The solution of the compound shown in Formula II in the solvent is added dropwise, and the reaction is stirred for 1 to 12 hours.

[0082] Preferably, the alkali is selected from one or a combination of inorganic alkalis and non-metallic organic alkalis; wherein the inorganic alkali is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; the non-metallic organic alkali is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; the alkali is preferably one or more of sodium hydride, sodium hydroxide, and potassium hydroxide.

[0083] Preferably, the molar ratio of the compound shown in Formula 1I to malononitrile is 1:(1-3), more preferably 1:(1-1.5); the molar ratio of the compound shown in Formula 1I to the base is 1:(1-5), more preferably 1:(1-1.5).

[0084] Preferably, the solvent is one or more selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene.

[0085] In some implementations, in step C:

[0086] (1) When LG is chlorine, bromine or iodine, the compound shown in formula I and II reacts with the halogenated reagent in a solvent at 0 to 100 °C with or without alkali to obtain the compound shown in formula IV.

[0087] Preferably, the halogenated reagent is selected from one or more of thionyl chloride, oxalyl chloride, triphosgene, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, lithium chloride, phosphorus tribromide, phosphorus oxychloride, and lithium bromide;

[0088] Preferably, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine;

[0089] Preferably, the reaction time is 1 to 24 hours;

[0090] Preferably, the solvent is selected from one or more of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene;

[0091] The molar ratio of the compound shown in Formula I and II to the halogenated reagent is 1:(0.5-3); the molar ratio of the compound shown in Formula I and II to the base is 1:(0.5-3).

[0092] (2) When LG is a C1-C6 alkoxy group, the compound shown in formula I and II reacts with the alkylating agent in the presence of a base in a solvent at 0-100°C to obtain the compound shown in formula IV.

[0093] Preferably, the alkali is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, and N,N-diisopropylethylamine, and more preferably from one or more of sodium hydride, sodium hydroxide, potassium hydroxide, and potassium carbonate.

[0094] Preferably, the alkylating agent is selected from dimethyl sulfate, diethyl sulfate, iodomethane, and iodoethane;

[0095] Preferably, the molar ratio of the compound represented by Formula III to the alkylating agent is 1:(0.5-3), more preferably 1:1.05; the molar ratio of the compound represented by Formula III to the base is 1:(0.5-3), more preferably 1:1.1.

[0096] Preferably, the reaction time is 1 to 10 hours;

[0097] The solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene.

[0098] (3) When LG is methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl, the compound shown in Formula I and II reacts with the sulfonating agent in the presence of a base in a solvent at 0 to 100 °C to obtain the compound shown in Formula IV.

[0099] Preferably, the sulfonating agent is selected from methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, and p-toluenesulfonic anhydride;

[0100] Preferably, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine;

[0101] Preferably, the molar ratio of the compound represented by Formula III to the sulfonating agent is 1:(1-3), more preferably 1:1.1; the molar ratio of the compound represented by Formula III to the base is 1:(1-3), more preferably 1:1.5;

[0102] The reaction time is 1–10 hours;

[0103] The solvent is selected from one or more of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene.

[0104] This invention also provides a method for preparing the intermediate compound shown in formula X, the reaction formula of which is as follows:

[0105]

[0106] Wherein, R2 is a hydroxyl group or a C1-C group. 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy or tert-butoxy;

[0107] The preparation method includes:

[0108] Step G: The compound shown in Formula IX and the compound shown in Formula XI undergo a Knoevenagel condensation reaction to obtain the compound shown in Formula X;

[0109] In some implementations, in step G of the reaction:

[0110] The reaction is carried out in a solvent at 0–100°C under the action of an alkaline reagent.

[0111] Preferably, the alkaline reagent is selected from one or more of sodium hydroxide, sodium carbonate, diethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, piperidine acetate, ammonium acetate, and tetrahydropyrrole, and more preferably one or more of piperidine, piperidine acetate, and tetrahydropyrrole;

[0112] Preferably, the reaction molar ratio of the compound of formula IX to the compound of formula XI is 1:0.8 to 10, more preferably 1:1 to 2.5; the reaction molar ratio of the compound of formula IX to the alkaline reagent is 1:(0.01 to 5), more preferably 1:0.05 to 3.

[0113] Preferably, the reaction temperature is 0–100°C; the reaction time is 1–24 h.

[0114] Preferably, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene, and more preferably from one or more of methanol, ethanol, tetrahydrofuran, and dichloromethane.

[0115] In the preparation method of the present invention, Formulas I to XI represent the prototype compounds corresponding to the structural formulas shown, and may also include salts and solvates of the prototype compounds. The salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, sodium carboxylate, potassium carboxylate, and lithium carboxylate. The solvates include hydrates, alcohols (e.g., methanol, ethanol, isopropanol), dichloromethane compounds, tertiary methyl ether compounds, or toluene compounds.

[0116] In another aspect, the present invention provides intermediate compounds, or salts or solvates thereof, as shown in Formula III, IV, VI or X, and salts of intermediate compounds shown in Formula VIII:

[0117]

[0118] Wherein, R1 is an H or amino protecting group;

[0119] R2 is a hydroxyl group, C1-C 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy, or tert-butoxy.

[0120] LG is a leaving group, which can be selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl.

[0121] The amino protecting group includes acyl amino protecting groups, alkoxycarbonyl amino protecting groups, and alkyl amino protecting groups; the acyl amino protecting group is selected from one of formyl, acetyl, p-valeryl, trichloroacetyl, trifluoroacetyl, benzoyl, phthalyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl; the alkoxycarbonyl amino protecting group is selected from one of tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, and ethoxycarbonyl; the alkyl amino protecting group is selected from one of triphenylmethyl, benzyl, and p-methoxybenzyl; preferably, the amino protecting group is tert-butoxycarbonyl or benzyloxycarbonyl.

[0122] Preferably, the salts of the compounds shown in Formula VI, Formula VIII or Formula X include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate. Preferably, the salts of the compounds shown in Formula X also include sodium carboxylate, potassium carboxylate, and lithium carboxylate.

[0123] Preferably, the solvates of the compounds represented by Formula III, Formula IV, Formula VI or Formula X include hydrates, alcohols (e.g., methanol, ethanol, isopropanol), dichloromethane compounds, tertiary methyl ether compounds or toluene compounds.

[0124] The beneficial effects achieved by the technical solution of this invention are as follows:

[0125] The preparation method of this invention adopts a convergent synthesis route, with high reaction yield (the yield of de novo synthesis can reach 55% to 65%), simple process, economic and environmentally friendly, and suitable for industrial production. Detailed Implementation

[0126] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0127] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0128] Intermediate I was synthesized according to the method reported in patents WO2022063101A1 and JP2022173143A. Specifically, it was synthesized from 2,4-difluorobenzaldehyde as the starting material, which underwent a nucleophilic substitution reaction with phenol to obtain 4-phenoxy-2-fluorobenzaldehyde, and then the aldehyde group was oxidized to a carboxylic acid.

[0129] Intermediate V-1 was synthesized according to the methods reported in patents WO2014139970A1 and WO2020234379. Specifically, it was prepared by using 1-N-CBZ-3-piperidinone as a raw material, reacting it with tert-butyloxycarbonylhydrazine to generate an imine, then reducing the imine with sodium cyanoborohydride, removing the tert-butyloxycarbonyl protecting group with hydrochloric acid, and finally obtaining it by chiral resolution.

[0130] Intermediate IX was prepared according to the literature "J.Med.Chem.2022,65,5300-5316". Specifically, it was prepared by reacting isobutyraldehyde as the starting material with bromine to obtain a brominated product, which was then obtained by nucleophilic substitution reaction with 1-(3-oxecyclobutyl)piperazine.

[0131] Example 1: Preparation of Compound III

[0132]

[0133] Intermediate I (10 g, 43 mmol) was added to dichloromethane (50 mL), followed by N,N-dimethylformamide (1 mL). Under ice bath conditions, thionyl chloride (6.14 g, 52 mmol, 1.2 eq.) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated to obtain intermediate II (a yellow oily substance), which was then directly added to the next reaction step.

[0134] Malononitrile (3.42 g, 52 mmol, 1.2 eq.) was added to anhydrous tetrahydrofuran (50 mL). Under ice bath conditions, 60% NaH (2.08 g, 52 mmol, 1.2 eq.) was added in portions. After the addition was complete, the mixture was kept warm and stirred for 10 minutes. Then, a solution of intermediate II (10.8 g, 43 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The pH of the reaction solution was adjusted to 2 using 1 M dilute hydrochloric acid. The solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain intermediate III 11.1 g. The overall yield of the two steps was 92%. 1 H NMR(400MHz, DMSO-d6)δ7.47–7.40(m,2H),7.31(t,J=8.2Hz,1H),7.24–7.18(m,1H), 7.13–7.07(m,2H),6.78(dd,J=11.0,2.3Hz,1H),6.74(dd,J=8.3,2.4Hz,1H).ESI[MH] - =279.0.

[0135] Example 2: Preparation of compound IV-1

[0136]

[0137] Intermediate III (3.0 g, 10.7 mmol) was added to tetrahydrofuran (30 mL), followed by dimethyl sulfate (1.42 g, 11.24 mmol, 1.05 eq.) and K₂CO₃ (1.62 g, 11.77 mmol, 1.1 eq.). After the addition was complete, the mixture was refluxed for 3 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were concentrated under reduced pressure to give IV-1 3.0 g, with a yield of 95%. 1 H NMR(400MHz,DMSO-d6)δ7.73(t,J=8.4Hz,1H),7.57–7.45(m,2H),7.38–7.29(m,1H),7.28–7 .19(m,2H),7.13(dd,J=11.6,2.3Hz,1H),7.00(dd,J=8.6,2.3Hz,1H),3.92(s,3H).ESI[M+H] + =295.1.

[0138] Example 3: Preparation of compound IV-2

[0139]

[0140] Intermediate III (3.0 g, 10.7 mmol) was added to dichloromethane (30 mL), followed by triethylamine (1.62 g, 16.05 mmol, 1.5 eq.). Then, p-toluenesulfonyl chloride (2.24 g, 11.77 mmol, 1.1 eq.) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were concentrated under reduced pressure to give 4.3 g of IV-2, in 92% yield. 1 H NMR(500MHz,DMSO-d6)δ7.85–7.78(m,2H),7.48–7.35(m,5H),7.14(tt,J=7.5,2.0Hz,1H),7.0 7–7.01(m,2H),6.92(dd,J=7.4,2.0Hz,1H),6.81(dd,J=8.8,2.0Hz,1H),2.42(s,3H).ESI[M+H] + =435.1.

[0141] Example 4: Preparation of compound VI-1

[0142]

[0143] Intermediates IV-1 (2.0 g, 6.80 mmol, 1.0 eq.), V-1 (2.19 g, 6.8 mmol, 1.0 eq.), and potassium carbonate (938 mg, 6.8 mmol, 1.0 eq.) were added sequentially to ethanol (50 mL). After the addition was complete, the mixture was refluxed for 6 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated, dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give VI-1, a yellow oily substance, 3.1 g, yield 90%. 1 H NMR(400MHz, DMSO-d6)δ7.55(t,J=8.5Hz,1H),7.50–7.41(m,2H),7.40–7.27(m,5H),7.23(td,J =7.3,1.1Hz,1H),7.17–7.09(m,2H),6.96(dd,J=11.6,2.4Hz,1H),6.88(dd,J=8.6,2.5Hz,1H),6 .76(s,2H),5.07(d,J=3.3Hz,2H),4.28(s,1H),4.03(q,J=7.1Hz,1H),3.93(d,J=12.7Hz,1H),2. 93(t,J=12.3Hz,1H),1.98(d,J=5.0Hz,2H),1.93–1.79(m,2H),1.50(d,J=12.4Hz,1H).ESI[M+H] + =512.1.

[0144] Example 5: Preparation of compound VII-1

[0145]

[0146] Intermediate VI-1 (2.0 g, 3.91 mmol, 1.0 eq.) and formamidin acetate (1.22 g, 11.73 mmol, 3.0 eq.) were added sequentially to ethanol (50 mL). After the addition was complete, the mixture was heated to reflux and stirred for 12 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and purified water (50 mL) was slowly added dropwise, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the filter cake was dried to obtain VII-1, yielding 2.0 g of off-white solid, with a yield of 95%. 1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),7.53(t,J=8.5Hz,1H),7.50–7.43(m,2H),7.43–7.26(m,7H),7.23(dd,J=8.1,6 .8Hz,1H),7.21–7.14(m,2H),7.02(dd,J=11.2,2.4Hz,1H),6.94(dd,J=8.4,2.4Hz,1H),5.08(s,2H),4.84–4.68(m,1 H),4.23–4.08(m,1H),4.02–3.85(m,1H),3.59–3.41(m,1H),3.04(ddd,J=14.0,11.5,3.1Hz,1H),2.19(td,J=11.9, 10.9,3.4Hz,1H),2.12(dt,J=13.3,3.7Hz,1H),1.95(d,J=38.4Hz,1H),1.60(dtt,J=17.1,9.4,4.6Hz,1H).ESI[M+H] + =539.3.

[0147] Example 6: Preparation of compound VIII

[0148]

[0149] Intermediate VII-1 (1.5 g, 2.79 mmol) was added to methanol (5 mL), followed by 10% dry palladium on carbon (15 mg). After the addition was complete, the mixture was purged with hydrogen three times, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated to give compound VIII, 1.1 g of white solid, with a yield of 97%. 1 H NMR(400MHz, DMSO-d6)δ8.22(s,1H),7.53(t,J=8.5Hz,1H),7.50–7.42(m,2H),7.26–7.21( m,1H),7.21–7.16(m,2H),7.01(dd,J=11.2,2.4Hz,1H),6.94(dd,J=8.4,2.5Hz,1H),4.68( tt,J=10.7,4.3Hz,1H),3.14–3.02(m,1H),3.00–2.85(m,2H),2.64(d,J=21.2Hz,1H),2.46 (dd,J=12.3,2.9Hz,1H),2.18–2.00(m,2H),1.80–1.70(m,1H),1.64–1.50(m,1H).ESI[M+H] + =405.1.

[0150] Example 7: Preparation of compound X-1

[0151]

[0152] Intermediate IX (1.0 g, 4.71 mmol) was added to dichloromethane (10 mL), followed by ethyl cyanoacetate (533 mg, 4.71 mmol, 1.0 eq.) and piperidine (20 mg, 0.24 mmol, 0.05 eq.). After the addition was complete, the mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated and separated by column chromatography to give compound X-1 1.3 g, with a yield of 90%. 1 H NMR(400MHz,Chloroform-d)δ7.57(s,1H),4.57(dt,J=18.5,6.4Hz,4H),4.25(q,J=7.1Hz, 2H),3.46(p,J=6.4Hz,1H),2.58(t,J=4.8Hz,4H),2.37(s,4H),1.46–1.20(m,9H).ESI[M+H] + =308.1.

[0153] Example 8: Preparation of rizalutinib by reaction of intermediate VIII and X-1

[0154]

[0155] Intermediate VIII (2.0 g, 4.94 mmol) and X-1 (1.52 g, 4.94 mmol, 1.0 eq.) were added to anhydrous tetrahydrofuran. Under ice bath conditions, a 1 M solution of tert-butylmagnesium chloride in tetrahydrofuran (6.0 mL, 6.0 mmol, 1.2 eq.) was slowly added dropwise. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 8 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with ethyl acetate, and the layers were separated. The organic layer was dried, concentrated, and separated by column chromatography to obtain 3.0 g of the target compound rizarutinib, with a yield of 91%. 1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.54(t,J=8.7Hz,1H),7.49–7.44(m,2H),7.24(td,J=7.4,1.3Hz ,1H),7.21–7.15(m,2H),7.01–6.95(m,2H),6.74(s,1H),6.65(s,2H),4.86(tt,J=9.2,4.3Hz,1H),4. 49(td,J=6.5,3.4Hz,2H),4.44–4.35(m,2H),4.13(s,1H),3.89(s,1H),3.65(s,1H),3.36(s,1H),3.3 0(s,1H),3.05(s,2H),2.30–2.18(m,6H),2.06–1.97(m,1H),1.75–1.66(m,1H),1.22(s,6H).ESI[M+H] + =666.25.

[0156] Example 9: Preparation of compound X-2

[0157]

[0158] Intermediate IX (1.0 g, 4.71 mmol) was added to dichloromethane (10 mL), followed by tert-butyl cyanoacetate (664 mg, 4.71 mmol, 1.0 eq.) and piperidine (20 mg, 0.24 mmol, 0.05 eq.). After the addition was complete, the mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated and separated by column chromatography to give compound X-2 1.5 g, with a yield of 95%. 1 H NMR(500MHz,DMSO-d6)δ7.35(s,1H),4.70(dt,J=18.5,6.4Hz,4H),3.28(p,J=7.1Hz,1H),2.39(s,8H),1.31(d,J=5.3Hz,15H).ESI[M+H] + =336.1.

[0159] Example 10: Preparation of compound X-3

[0160]

[0161] Intermediate X-1 (1.0 g, 3.25 mmol) was added to tetrahydrofuran (10 mL), followed by dropwise addition of 2M LiOH aqueous solution (2.5 mL, 5.0 mmol, 1.5 eq.). After the addition was complete, the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The organic solvent was removed by distillation under reduced pressure. The pH of the aqueous solution was adjusted to 2-3 using 1M hydrochloric acid. A white solid precipitated from the solution. The solid was filtered and dried to obtain X-3 0.8 g, with a yield of 88%. 1 H NMR(400MHz,D2O)δ7.47(s,1H),4.85–4.80(m,2H),4.67(dd,J=7.0,6.0Hz,2H),3.69–3.55(m,1H),2.75(s,4H),2.52(s,4H),1.46(s,6H).ESI[M+H] + =280.2.

[0162] Example 11: Preparation of compound X-3

[0163]

[0164] Intermediate IX (5.0 g, 23.6 mmol), cyanoacetic acid (3.0 g, 35.3 mmol, 1.5 eq.), and tetrahydropyrrole (5.0 g, 70.8 mmol, 3.0 eq.) were added sequentially to anhydrous ethanol. After the addition was complete, the mixture was heated to 50 °C and stirred overnight. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the concentrate was added to methyl tert-butyl ether (50 mL), stirred, and filtered to obtain a white solid. The solid was added to anhydrous ethanol (30 mL), and the pH was adjusted to 3–4 using 2M hydrochloric acid-ethanol solution under ice bath conditions. A large amount of solid precipitated, which was filtered and dried to obtain 4.1 g of white solid X-3, with a yield of 63%. 1 H NMR(400MHz,D2O)δ7.47(s,1H),4.85–4.80(m,2H),4.67(dd,J=7.0,6.0Hz,2H),3.69–3.55(m,1H),2.75(s,4H),2.52(s,4H),1.46(s,6H).ESI[M+H] + =280.2.

[0165] Example 12: Preparation of rizalutinib from intermediate VIII and X-3

[0166]

[0167] Intermediates VIII (1.45 g, 3.58 mmol, 1.0 eq.) and X-3 (1.0 g, 3.58 mmol, 1.0 eq.) were added to dichloromethane (2 mL), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.03 g, 5.37 mmol, 1.5 eq.), 1-hydroxybenzotriazole (HOBT) (0.73 g, 5.37 mmol, 1.5 eq.), and triethylamine (1.08 g, 10.74 mmol, 3.0 eq.). After the addition was complete, the mixture was stirred in an ice bath for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with dichloromethane, and the organic layer was dried, concentrated, and separated by column chromatography to obtain 2.0 g of the target compound rizarutinib, in 84% yield. 1 HNMR(600MHz,DMSO-d6)δ8.24(s,1H),7.54(t,J=8.7Hz,1H),7.49–7.44(m,2H),7.24(td,J=7.4,1. 3Hz,1H),7.21–7.15(m,2H),7.01–6.95(m,2H),6.74(s,1H),6.65(s,2H),4.86(tt,J=9.2,4.3Hz,1H ),4.49(td,J=6.5,3.4Hz,2H),4.44–4.35(m,2H),4.13(s,1H),3.89(s,1H),3.65(s,1H),3.36(s,1 H),3.30(s,1H),3.05(s,2H),2.30–2.18(m,6H),2.06–1.97(m,1H),1.75–1.66(m,1H),1.22(s,6H).

[0168] Example 13: Preparation of compound X-4

[0169]

[0170] X-2 (1.0 g, 2.98 mmol) was added to 4M hydrogen chloride / 1,4-dioxane solution (5 mL). After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until it was complete. The reaction solution was concentrated to obtain crude X-4, which was then directly added to the next reaction step.

[0171] Example 14: Preparation of rizalutinib by reaction of intermediate VIII and X-4

[0172]

[0173] Intermediates VIII (1.2 g, 2.98 mmol, 1.0 eq.) and X-4 (940 mg, 2.98 mmol, 1.0 eq.) were added to dichloromethane (20 mL), followed by the addition of EDCI (857 mg, 4.47 mmol, 1.5 eq.), HOBT (604 mg, 4.47 mmol, 1.5 eq.), and triethylamine (903 mg, 8.94 mmol, 3.0 eq.). After the addition was complete, the mixture was stirred in an ice bath for 2 hours. The reaction was monitored by TLC until complete. The reaction solution was poured into water, extracted with dichloromethane, and the organic layer was dried, concentrated, and separated by column chromatography to obtain 1.8 g of the target compound rizarutinib. The overall yield of the two steps was 91%. 1 H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.54(t,J=8.7Hz,1H),7.49–7.44(m,2H),7.24(td,J=7.4,1.3 Hz,1H),7.21–7.15(m,2H),7.01–6.95(m,2H),6.74(s,1H),6.65(s,2H),4.86(tt,J=9.2,4.3Hz,1H ),4.49(td,J=6.5,3.4Hz,2H),4.44–4.35(m,2H),4.13(s,1H),3.89(s,1H),3.65(s,1H),3.36(s,1 H),3.30(s,1H),3.05(s,2H),2.30–2.18(m,6H),2.06–1.97(m,1H),1.75–1.66(m,1H),1.22(s,6H).

[0174] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing rizalutinib, the reaction formula of which is as follows: in, R2 is a hydroxyl group or C1-C. 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy or tert-butoxy; The preparation method includes: Step H: The compound shown in Formula VIII and the compound shown in Formula X undergo a condensation reaction to obtain rizarutinib.

2. The method for preparing rizarutinib according to claim 1, characterized in that, When R2 is a hydroxyl group, the reaction is carried out in an organic solvent in the presence of a condensing agent and a base. Preferably, the condensing agent is selected from one or more of oxaloyl chloride, thionyl chloride, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, N,N-dicyclohexylcarbodiimide, N,N-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; and / or The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; and / or The solvent is one or more selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide; and / or The molar ratio of the compound represented by formula VIII to the compound represented by formula X is 1:(1-3); the molar ratio of the compound represented by formula VIII to the condensing agent and the base is 1:(1-3):(1-6); and / or The reaction temperature is -10 to 50℃, and the reaction time is 1 to 24 hours. When R2 is C1-C 10 When alkoxy is involved, the reaction is carried out in a solvent with or without the addition of an organometallic base; Preferably, the organometallic base is one or more selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, tert-butylmagnesium chloride, and tert-butylmagnesium bromide; and / or The solvent is one or more selected from methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene; and / or The molar ratio of the compound represented by formula VIII to the compound represented by formula X is 1:(1–3); the molar ratio of the compound represented by formula VIII to the organometallic base is 1:(1–3); and / or The reaction temperature is -10 to 140℃, and the reaction time is 1 to 24 hours.

3. The method for preparing rizarutinib according to claim 1, characterized in that, The preparation method of the intermediate compound shown in Formula VIII, with the following reaction formula, is as follows: Wherein, R1 is an H or amino protecting group; The preparation method includes: Step E: The compound shown in Formula VI reacts with a cyclizing agent to give the compound shown in Formula VII; Step F: The compound shown in Formula VII is deamino protecting to obtain the compound shown in Formula VIII; When R1 is H, the preparation method does not include step F.

4. The method for preparing rizarutinib according to claim 3, characterized in that, The amino protecting groups include acyl amino protecting groups, alkoxycarbonyl amino protecting groups, and alkyl amino protecting groups; Further, the acyl amino protecting group is selected from one of formyl, acetyl, pivaloyl, trichloroacetyl, trifluoroacetyl, benzoyl, phthaloyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl; the alkoxycarbonyl amino protecting group is selected from one of tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, and ethoxycarbonyl; the alkyl amino protecting group is selected from one of triphenylmethyl, benzyl, and p-methoxybenzyl; preferably, the amino protecting group is tert-butoxycarbonyl or benzyloxycarbonyl; and / or In step E: The cyclizing agent is one or more selected from formamide, formamidine, formamidine hydrochloride, and formamidine acetate; and / or The reaction is carried out in a solvent at 20–200°C, with or without the addition of alkali. The base is one or more selected from triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; and / or The reaction molar ratio of the compound shown in Formula VI with the cyclizing agent is 1:(1–20); and / or The reaction temperature is 20–200°C; the reaction time is 1–24 h; and / or The solvent is selected from one or more of formamide, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, propanol, isopropanol, n-butanol, isobutanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

5. The method for preparing rizarutinib according to claim 3, characterized in that, The preparation method of the intermediate compound shown in Formula VI, and its reaction formula are as follows: Wherein, LG is a leaving group, selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl; R1 is an H or an amino protecting group, and the amino protecting group is defined as described in claim 4; The preparation method includes: Step D: The compound shown in Formula IV reacts with the compound shown in Formula V to obtain the compound shown in Formula VI; Preferably, in step D: The reaction is carried out in a solvent at 0–100°C, with or without the addition of alkali. The base is selected from one or a combination of non-metallic organic bases, inorganic bases, and organometallic bases; wherein the aforementioned non-metallic organic base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; the inorganic base is selected from one or a combination of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide; the organometallic base is selected from one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, and potassium tert-butoxide; and / or The molar ratio of the compound shown in Formula IV to the compound shown in Formula V is 1:(0.8–2), preferably 1:(1–1.5); the molar ratio of the compound shown in Formula IV to the base is 1:(0.8–3), preferably 1:(1–1.5); and / or The reaction temperature is 10–80°C, and the reaction time is 1–12 h; and / or The solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, chlorobenzene, toluene, and xylene.

6. The method for preparing rizarutinib according to claim 5, characterized in that, The preparation method of the intermediate compound shown in Formula IV, and its reaction formula are as follows: Wherein, LG is a leaving group, selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl; The preparation method includes: Step A: The compound shown in Formula I is reacted with an acyl chloride reagent to prepare the compound shown in Formula II; Step B: The compound shown in Formula II undergoes a condensation reaction with malononitrile to prepare the compound shown in Formula III; Step C: The compounds shown in Formulas I and II react with a halogenating agent, an alkylating agent, or a sulfonating agent to give the compound shown in Formula IV.

7. The method for preparing rizarutinib according to claim 6, characterized in that, In step A: The acyl chloride reagent is selected from one or more of thionyl chloride, oxalyl chloride, triphosgene, phosphorus oxychloride, and phosphorus pentachloride; and / or The reaction is carried out in a solvent at -30 to 50°C; and / or The reaction molar ratio of the compound shown in Formula I with the acyl chloride reagent is 1:(0.8–10), preferably 1:(1–2.5); and / or The reaction temperature is -10 to 50°C, and the reaction time is 1 to 12 hours; and / or The solvent is selected from one or more of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene; and / or In step B: The reaction is carried out in a solvent in the presence of a base at 0–100°C. Preferably, step B comprises: adding malononitrile and a base to a solvent at a temperature of 0–100°C, stirring the reaction for 0.1–2 hours, adding dropwise a solution of the compound of formula II in the solvent, and continuing to stir the reaction for 1–12 hours; and / or The base is selected from one or a combination of inorganic bases and non-metallic organic bases; wherein the inorganic base is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; the non-metallic organic base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; and / or The molar ratio of the compound shown in Formula III to malononitrile is 1:(1-3), preferably 1:(1-1.5); the molar ratio of the compound shown in Formula III to the base is 1:(1-5), preferably 1:(1-1.5); and / or The solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene; and / or In step C: (1) When LG is chlorine, bromine or iodine, the compound shown in formula I and II reacts with the halogenated reagent in a solvent at 0 to 100 °C with or without alkali to obtain the compound shown in formula IV. Preferably, the halogenated reagent is one or more selected from thionyl chloride, oxalyl chloride, triphosgene, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, lithium chloride, phosphorus tribromide, phosphorus oxybromide, and lithium bromide; and / or The base is one or more selected from triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; and / or The reaction time is 1–24 h; and / or The solvent is one or more selected from dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene; and / or The molar ratio of the compound shown in Formula I and II to the halogenated reagent is 1:(0.5-3); the molar ratio of the compound shown in Formula I and II to the base is 1:(0.5-3). (2) When LG is a C1-C6 alkoxy group, the compound shown in formula I and II reacts with the alkylating agent in the presence of a base in a solvent at 0-100°C to obtain the compound shown in formula IV. Preferably, the alkali is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, and N,N-diisopropylethylamine, and more preferably from one or more of sodium hydride, sodium hydroxide, potassium hydroxide, and potassium carbonate; and / or The alkylating agent is selected from dimethyl sulfate, diethyl sulfate, iodomethane, and iodoethane; and / or The molar ratio of the compound represented by Formula I or II to the alkylating agent is 1:(0.5–3); the molar ratio of the compound represented by Formula I or II to the base is 1:(0.5–3); and / or The reaction time is 1–10 h; and / or The solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene; (3) When LG is methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl, the compound shown in Formula I and II reacts with the sulfonating agent in the presence of a base in a solvent at 0 to 100 °C to obtain the compound shown in Formula IV. Preferably, the sulfonating agent is one or more selected from methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, and p-toluenesulfonic anhydride; and / or The base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine; and / or The molar ratio of the compound shown in Formula I or II to the sulfonating agent is 1:(1-3); the molar ratio of the compound shown in Formula I or II to the base is 1:(1-3); and / or The reaction time is 1–10 hours; The solvent is selected from one or more of dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, chlorobenzene, toluene, and xylene.

8. The method for preparing rizarutinib according to claim 1, characterized in that, The preparation method of the intermediate compound shown in formula X, and its reaction formula are as follows: Wherein, R2 is a hydroxyl group or a C1-C group. 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy or tert-butoxy; The preparation method includes: Step G: The compound shown in Formula IX and the compound shown in Formula XI undergo a Knoevenagel condensation reaction to obtain the compound shown in Formula X; Preferably, in step G of the reaction: The reaction is carried out at 0–100°C in the presence of an alkaline reagent in a solvent; and / or The alkaline reagent is one or more selected from sodium hydroxide, sodium carbonate, diethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, piperidine acetate, ammonium acetate, and tetrahydropyrrole; and / or The reaction molar ratio of the compound of formula IX to the compound of formula XI is 1:0.8 to 10, preferably 1:1 to 2.5; the reaction molar ratio of the compound of formula IX to the alkaline reagent is 1:(0.01 to 5), preferably 1:0.05 to 3; and / or The reaction temperature is 0–100°C; the reaction time is 1–24 h; and / or The solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, trichloromethane, dichloroethane, chlorobenzene, toluene, and xylene.

9. The method for preparing rizalutinib according to any one of claims 1 to 8, wherein the reaction route is as follows: The preparation method includes: Step A: The compound shown in Formula I is reacted with an acyl chloride reagent to prepare the compound shown in Formula II; Step B: The compound shown in Formula II undergoes a condensation reaction with malononitrile to prepare the compound shown in Formula III; Step C: The compounds shown in Formulas I and II react with a halogenating agent, an alkylating agent, or a sulfonating agent to give the compound shown in Formula IV; Step D: The compound shown in Formula IV reacts with the compound shown in Formula V to obtain the compound shown in Formula VI; Step E: The compound shown in Formula VI reacts with a cyclizing agent to give the compound shown in Formula VII; Step F: The compound shown in Formula VII is deamino protecting to obtain the compound shown in Formula VIII; Step G: The compound shown in Formula IX and the compound shown in Formula XI undergo a Knoevenagel condensation reaction to obtain the compound shown in Formula X; Step H: The compound represented by Formula VIII and the compound represented by Formula X undergo a condensation reaction to obtain rizalutinib; LG, R1, R2, and steps A to H are as described in claims 1 to 8.

10. Intermediate compounds represented by Formula III, Formula IV, Formula VI or Formula X, or their salts or solvates, and salts of intermediate compounds represented by Formula VIII: in, R1 is an H or amino protecting group; R2 is a hydroxyl group, C1-C 10 Alkyl group; preferably, R2 is hydroxyl, methoxy, ethoxy, or tert-butoxy. LG is a leaving group, which can be selected from one of chlorine, bromine, iodine, C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy), methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl. Preferably, the amino protecting group includes acyl amino protecting groups, alkoxycarbonyl amino protecting groups, and alkyl amino protecting groups; the acyl amino protecting group is selected from one of formyl, acetyl, p-valeryl, trichloroacetyl, trifluoroacetyl, benzoyl, phthalyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl; the alkoxycarbonyl amino protecting group is selected from one of tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, and ethoxycarbonyl; and the alkyl amino protecting group is selected from one of triphenylmethyl, benzyl, and p-methoxybenzyl. Preferably, the salts of the compounds shown in Formula VI, Formula VIII or Formula X include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; preferably, the salts of the compounds shown in Formula X also include sodium carboxylate, potassium carboxylate, or lithium carboxylate. Preferably, the solvates of the compounds represented by Formula III, Formula IV, Formula VI or Formula X include hydrates, alcohols (e.g., methanol, ethanol, isopropanol), dichloromethane compounds, tertiary methyl ether compounds or toluene compounds.

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