A method for synthesizing an ametinib intermediate

Abstract

The present invention relates to a method for synthesizing an ametinib intermediate, and belongs to the technical field of medicines. Indole is added to tetrahydrofuran, and after stirring and dissolving, a Grignard reagent is added under a nitrogen atmosphere and stirred; after adding 2,4-dichloropyrimidine, after reaction, the reaction is quenched with saturated ammonium chloride, an organic phase and an aqueous phase are separated, and the upper organic phase is taken for recrystallization and drying; the dried compound is added to tetrahydrofuran, and after stirring and dissolving, a resin-supported catalyst, bipyridine, sodium carbonate, and a cyclopropylating agent are added, and the reaction is stirred and mixed; after the reaction is completed, the reaction is cooled to room temperature, air is continuously introduced, filtered, the filtrate is concentrated and dried, and then dissolved with ethyl acetate, and then n-hexane is added for crystallization and filtration is performed, and acetonitrile is added for recrystallization to obtain an ametinib intermediate; the ametinib intermediate prepared by the present invention has a higher purity and yield.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for synthesizing an ametinib intermediate. Background Art

[0002] Lung cancer is a malignant tumor with extremely high morbidity and mortality in my country and even in the world, which seriously threatens human health. The launch of ametinib provides a new and effective treatment for adult patients with locally advanced or metastatic non-small cell lung cancer who have progressed after previous EGFR-TKI treatment and are T790M positive. It has also become one of the first-line treatment options for patients with locally advanced or metastatic non-small cell lung cancer who are EGFR mutation positive, enriching clinical treatment options.

[0003] The patent application with publication number CN116059209A discloses the use of ametinib mesylate in the preparation of drugs for treating radiation-induced lung injury, which belongs to the field of medical technology. An effective therapeutic drug is provided for radiation-induced lung injury. Animal in vivo experimental studies have shown that ametinib mesylate has a significant therapeutic effect on radiation-induced lung injury. Combined with ametinib mesylate treatment, it can effectively reduce lung injury inflammation and pulmonary fibrosis caused by radiation exposure. Therefore, ametinib mesylate can be used to prepare drugs for treating radiation-induced lung injury, which has good development prospects.

[0004] The patent with the authorization announcement number CN109761960B discloses a method for preparing an anti-drug resistance and anti-tumor EGFR inhibitor. Specifically, it relates to a method for preparing a 4-(1-cyclopropyl-1H-indol-3-yl)-N-phenylpyrimidine-2-amine derivative. The method overcomes the defects existing in the prior art, greatly reduces the cost, and the obtained product has good purity, high yield, strong process operability, and greatly improved process safety.

[0005] The patent with publication number MOJ007609C discloses EGFR inhibitors and their preparation and application. Specifically, it relates to a 4-substituted-2-(N-(5-substituted allylamido)phenyl)amino)pyrimidine derivative. This series of compounds has the activity of inhibiting L858REGFR mutants, T790MEGFR mutants and exon 19 deletion activation mutants, and can be used to treat diseases mediated solely or partially by EGFR mutant activity.

[0006] The above patents and prior art have the defects of high production cost, complicated operation, low product purity and yield, etc. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a method for synthesizing an ametinib intermediate, and the operation steps are as follows:

[0008] S1: Add 8-15 parts of indole to 100-150 parts of tetrahydrofuran, stir to dissolve, and then add 7-13 parts of Grignard reagent under a nitrogen atmosphere while controlling the temperature at -20-0°C, and stir for 30-60 minutes;

[0009] S2: After adding 1-5 parts of 2,4-dichloropyrimidine, react at 65-75°C for 7-10 hours. After the reaction is completed, quench the reaction with saturated ammonium chloride at 0-5°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry;

[0010] S3: Add the dried compound to 100-150 parts of tetrahydrofuran, stir to dissolve, then add 1-5 parts of resin-supported catalyst, 10-15 parts of bipyridine, 1-5 parts of sodium carbonate, and 1-5 parts of cyclopropylating agent, stir to mix, and react at 65-75° C. for 5-8 hours;

[0011] S4: After the reaction is completed, the temperature is lowered to room temperature, air is continuously introduced for 30-60 minutes, and the filtrate is filtered. The filtrate is concentrated and dried, and then dissolved in ethyl acetate. Then, n-hexane is added for crystallization, and then filtered. Acetonitrile is added for recrystallization to obtain an ametinib intermediate.

[0012] The resin-supported catalyst is prepared by carrying o-phenanthroline, 2-amino-1,3,5-triazine and copper acetate to form a stable complex after a substitution reaction between chloromethylated polystyrene resin and ethylenediamine.

[0013] The Grignard reagent is one of a methyl Grignard reagent, an ethyl Grignard reagent and an isopropyl Grignard reagent.

[0014] The cyclopropylation reagent is one of cyclopropane bromide, cyclopropylboronic acid and cyclopropylboronic ester.

[0015] The air introduction rate is 5-10 L / min.

[0016] The specific preparation method of the resin-supported catalyst is:

[0017] T1 swelling and initial substitution reaction:

[0018] Weigh 100-200 parts of chloromethylated polystyrene resin (CAS: 55844-94-5) (200-400 mesh, 1-5% DVB), add it into a three-necked flask containing 1000-1200 parts of dimethylformamide, and stir it at a stirring speed of 200-300 r / min for 2-3 hours under a nitrogen atmosphere to fully swell the chloromethylated polystyrene resin; then weigh 5-20 parts of ethylenediamine, dilute it with an appropriate amount of DMF, and slowly drip it into the swollen resin system through a constant pressure dropping funnel at a speed of 1-2 drops / second; control the reaction temperature at 50-70°C, and stir the reaction at a speed of 300-400 r / min for 3-5 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, and part of the chloromethyl groups are replaced by ethylenediamine;

[0019] T2 copper salt loading reaction:

[0020] After the reaction of step T1 is completed, 1-3 parts of o-phenanthroline, 0.03-0.3 parts of 2-amino-1,3,5-triazine, and 2-5 parts of copper acetate are added to the reaction system in sequence, the temperature is raised to 60-80° C., and the reaction is stirred at a speed of 300-400 r / min for 12-24 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper on the resin;

[0021] T3 post-processing:

[0022] After the reaction is completed, the reaction system is cooled to room temperature, and then the resin is filtered out with a sand core funnel, and the resin is washed with appropriate amounts of DMF, methanol, and deionized water in turn, each washing time is 10-15 minutes to fully remove unreacted reagents and impurities; the washed resin is placed in a vacuum drying oven and dried at 50-60°C to constant weight to obtain a resin-loaded catalyst.

[0023] Reaction mechanism:

[0024] 1. Nucleophilic substitution reaction of ethylenediamine and chloromethylated polystyrene resin:

[0025] The chloromethyl group on the chloromethylated polystyrene resin has a certain electrophilicity, and the amino group in the ethylenediamine molecule has nucleophilicity. Under appropriate temperature and solvent conditions, the amino group of ethylenediamine attacks the carbon atom of the chloromethyl group, a nucleophilic substitution reaction occurs, and the chlorine atom leaves in the form of chloride ions, thereby connecting ethylenediamine to the resin.

[0026] 2. Formation of complex:

[0027] The o-phenanthroline molecule contains two nitrogen atoms, which has a strong coordination ability; the nitrogen atom in the 2-amino-1,3,5-triazine molecule can also participate in the coordination. Copper ions (such as Cu²⁺) have empty d orbitals and can accept the lone pair of electrons provided by the nitrogen atoms in the o-phenanthroline and 2-amino-1,3,5-triazine molecules to form a stable complex.

[0028] 3. Coordination reaction between complex and resin:

[0029] The amino group of ethylenediamine connected to the resin still has a certain coordination ability, and it can further undergo coordination reaction with the complex formed by copper ions to fix the complex on the resin, thereby realizing the loading of copper salt on the resin.

[0030] Compared with the prior art, the method for synthesizing an ametinib intermediate of the present invention has the following significant effects:

[0031] 1. Increase the reaction rate: Resin-loaded catalysts can reduce the activation energy of the reaction and speed up the reaction rate. The catalyst can provide a new reaction pathway, making it easier for the reactant molecules to react, thereby achieving a higher conversion rate in a shorter time. For example, in the absence of a catalyst, the cyclopropanation reaction may take longer and at a higher temperature to proceed, but after using a catalyst, the reaction can be completed within 5-8 hours at a relatively low temperature of 65-75°C.

[0032] 2. Selective catalysis: Resin-supported catalysts may have a certain degree of selectivity, which can selectively promote the target reaction and reduce the occurrence of side reactions. This helps to improve the yield and purity of the target product and reduce the difficulty of subsequent separation and purification. DETAILED DESCRIPTION

[0033] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the following is a detailed description in combination with embodiments and comparative examples:

[0034] Example 1: A method for synthesizing an ametinib intermediate, the operation steps are as follows:

[0035] S1: Add 8 g of indole to 100 g of tetrahydrofuran, stir to dissolve, then add 7 g of Grignard reagent under nitrogen atmosphere and control the temperature at -20°C, and stir for 30 minutes;

[0036] S2: After adding 1g of 2,4-dichloropyrimidine, react at 65°C for 7h. After the reaction is completed, quench the reaction with saturated ammonium chloride at 0°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry;

[0037] S3: Add the dried compound to 100 g of tetrahydrofuran, stir to dissolve, then add 1 g of resin-supported catalyst, 10 g of bipyridine, 1 g of sodium carbonate, and 1 g of cyclopropylation agent, stir to mix, and react at 65° C. for 5 h;

[0038] S4: After the reaction is completed, the temperature is lowered to room temperature, and air is continuously introduced for 30 minutes. The reaction mixture is filtered (at this time, the resin-loaded catalyst can be recovered by filtration). The filtrate is concentrated and dried, and then dissolved in ethyl acetate. N-hexane is added for crystallization, and then filtered. Acetonitrile is added for recrystallization to obtain an ametinib intermediate.

[0039] The grignard reagent is a methyl grignard reagent.

[0040] The cyclopropylation reagent is bromocyclopropane.

[0041] The air introduction rate is 5 L / min.

[0042] The preparation method of the resin-supported catalyst:

[0043] T1 swelling and initial substitution reaction:

[0044] 100 g of chloromethylated polystyrene resin (CAS: 55844-94-5) (200 mesh, 1% DVB) was weighed and added to a three-necked flask containing 1000 g of dimethylformamide. Under a nitrogen atmosphere, the mixture was stirred at a stirring speed of 200 r / min for 2 hours to fully swell the chloromethylated polystyrene resin. Then, 5 g of ethylenediamine was weighed, diluted with an appropriate amount of DMF, and slowly added to the swollen resin system at a speed of 1 drop / second through a constant pressure dropping funnel. The reaction temperature was controlled at 50° C., and the reaction was stirred at a speed of 300 r / min for 3 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, and part of the chloromethyl groups were replaced by ethylenediamine.

[0045] T2 copper salt loading reaction:

[0046] After the reaction of step T1 is completed, 1 g of o-phenanthroline, 0.03 g of 2-amino-1,3,5-triazine, and 2 g of copper acetate are added to the reaction system in sequence, the temperature is raised to 60° C., and the reaction is stirred at a speed of 300 r / min for 12 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper onto the resin;

[0047] T3 post-processing:

[0048] After the reaction is completed, the reaction system is cooled to room temperature, and then the resin is filtered out with a sand core funnel, and the resin is washed with appropriate amounts of DMF, methanol, and deionized water in turn, with each washing time being 10 minutes to fully remove unreacted reagents and impurities; the washed resin is placed in a vacuum drying oven and dried at 50°C to constant weight to obtain a resin-loaded catalyst.

[0049] Example 2: A method for synthesizing an ametinib intermediate, the operation steps are as follows:

[0050] S1: Add 10 g of indole to 110 g of tetrahydrofuran, stir to dissolve, and then add 9 g of Grignard reagent under a nitrogen atmosphere while controlling the temperature at -15°C, and stir for 40 minutes;

[0051] S2: After adding 2g 2,4-dichloropyrimidine, react at 68°C for 8h. After the reaction is completed, quench the reaction with saturated ammonium chloride at 2°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry;

[0052] S3: Add the dried compound to 110 g of tetrahydrofuran, stir to dissolve, then add 2 g of resin-supported catalyst, 12 g of bipyridine, 2 g of sodium carbonate, and 2 g of cyclopropylation agent, stir to mix, and react at 68° C. for 6 h;

[0053] S4: After the reaction is completed, the temperature is lowered to room temperature, and air is continuously introduced for 40 minutes. The reaction is filtered (at this time, the resin-loaded catalyst can be recovered by filtration). The filtrate is concentrated and dried, and then dissolved in ethyl acetate. Then, n-hexane is added for crystallization, and then filtered. Acetonitrile is added for recrystallization to obtain the ametinib intermediate.

[0054] The Grignard reagent is an ethyl Grignard reagent.

[0055] The cyclopropylation reagent is cyclopropylboronic acid.

[0056] The air introduction rate is 6L / min.

[0057] The preparation method of the resin-supported catalyst:

[0058] T1 swelling and initial substitution reaction:

[0059] 140 g of chloromethylated polystyrene resin (CAS: 55844-94-5) (300 mesh, 2% DVB) was weighed and added to a three-necked flask containing 1050 g of dimethylformamide. Under a nitrogen atmosphere, the mixture was stirred at a stirring speed of 250 r / min for 2.5 hours to fully swell the chloromethylated polystyrene resin. Then, 10 g of ethylenediamine was weighed and diluted with an appropriate amount of DMF, and then slowly added to the swollen resin system at a speed of 1 drop / second through a constant pressure dropping funnel. The reaction temperature was controlled at 55° C., and the reaction was stirred at a speed of 350 r / min for 4 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, and part of the chloromethyl groups were replaced by ethylenediamine.

[0060] T2 copper salt loading reaction:

[0061] After the reaction of step T1 is completed, 2 g of o-phenanthroline, 0.1 g of 2-amino-1,3,5-triazine, and 2-5 g of copper acetate are added to the reaction system in sequence, the temperature is raised to 65° C., and the reaction is stirred at a speed of 350 r / min for 16 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper onto the resin;

[0062] T3 post-processing:

[0063] After the reaction, the reaction system was cooled to room temperature, and then the resin was filtered out with a sand core funnel, and the resin was washed with appropriate amounts of DMF, methanol, and deionized water in turn, with each washing time being 12 minutes to fully remove unreacted reagents and impurities; the washed resin was placed in a vacuum drying oven and dried at 55°C to constant weight to obtain a resin-loaded catalyst.

[0064] Example 3: A method for synthesizing an ametinib intermediate, the operation steps are as follows:

[0065] S1: Add 13 g of indole to 140 g of tetrahydrofuran, stir to dissolve, then add 11 g of Grignard reagent under a nitrogen atmosphere while controlling the temperature at -5°C, and stir for 50 minutes;

[0066] S2: After adding 4g of 2,4-dichloropyrimidine, react at 73°C for 9h. After the reaction is completed, quench the reaction with saturated ammonium chloride at 4°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry;

[0067] S3: Add the dried compound to 140 g of tetrahydrofuran, stir to dissolve, then add 4 g of resin-supported catalyst, 14 g of bipyridine, 4 g of sodium carbonate, and 4 g of cyclopropylation agent, stir to mix, and react at 73° C. for 7 h;

[0068] S4: After the reaction is completed, the temperature is lowered to room temperature, and air is continuously introduced for 50 minutes. The product is filtered (at this time, the resin-loaded catalyst can be recovered by filtration). The filtrate is concentrated and dried, and then dissolved in ethyl acetate. Then, n-hexane is added for crystallization, and then filtered. Acetonitrile is added for recrystallization to obtain the ametinib intermediate.

[0069] The Grignard reagent is an ethyl Grignard reagent.

[0070] The cyclopropylation reagent is cyclopropylboronic acid.

[0071] The air introduction rate is 8 L / min.

[0072] The preparation method of the resin-supported catalyst:

[0073] T1 swelling and initial substitution reaction:

[0074] 180 g of chloromethylated polystyrene resin (CAS: 55844-94-5) (300 mesh, 4% DVB) was weighed and added to a three-necked flask containing 1150 g of dimethylformamide. Under a nitrogen atmosphere, the mixture was stirred at a stirring speed of 250 r / min for 2.5 hours to fully swell the chloromethylated polystyrene resin. Then, 15 g of ethylenediamine was weighed, diluted with an appropriate amount of DMF, and slowly added to the swollen resin system at a speed of 2 drops / second through a constant pressure dropping funnel. The reaction temperature was controlled at 65° C., and the reaction was stirred at a speed of 350 r / min for 4 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, and part of the chloromethyl groups were replaced by ethylenediamine.

[0075] T2 copper salt loading reaction:

[0076] After the reaction of step T1 is completed, 2 g of o-phenanthroline, 0.2 g of 2-amino-1,3,5-triazine, and 2-5 g of copper acetate are added to the reaction system in sequence, the temperature is raised to 75° C., and the reaction is stirred at a speed of 350 r / min for 20 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper onto the resin;

[0077] T3 post-processing:

[0078] After the reaction, the reaction system was cooled to room temperature, and then the resin was filtered out with a sand core funnel, and the resin was washed with appropriate amounts of DMF, methanol, and deionized water in turn, with each washing time being 14 minutes to fully remove unreacted reagents and impurities; the washed resin was placed in a vacuum drying oven and dried at 55°C to constant weight to obtain a resin-loaded catalyst.

[0079] Example 4: A method for synthesizing an ametinib intermediate, the operation steps are as follows:

[0080] S1: Add 15 g of indole to 150 g of tetrahydrofuran, stir to dissolve, then add 13 g of Grignard reagent under nitrogen atmosphere with the temperature controlled at 0°C, and stir for 60 minutes;

[0081] S2: After adding 5g of 2,4-dichloropyrimidine, react at 75°C for 10h. After the reaction is completed, quench the reaction with saturated ammonium chloride at 5°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry;

[0082] S3: Add the dried compound to 150 g of tetrahydrofuran, stir to dissolve, then add 5 g of resin-supported catalyst, 15 g of bipyridine, 5 g of sodium carbonate, and 5 g of cyclopropylation agent, stir to mix, and react at 75° C. for 8 h;

[0083] S4: After the reaction is completed, the temperature is cooled to room temperature and air is continuously introduced for 60 minutes. The reaction mixture is filtered (at this time, the resin-loaded catalyst can be recovered by filtration). The filtrate is concentrated and dried, and then dissolved in ethyl acetate. N-hexane is added for crystallization and then filtered. Acetonitrile is added for recrystallization to obtain an ametinib intermediate.

[0084] The Grignard reagent is an isopropyl Grignard reagent.

[0085] The cyclopropylation reagent is cyclopropyl borate.

[0086] The air introduction rate is 10 L / min.

[0087] The preparation method of the resin-supported catalyst:

[0088] T1 swelling and initial substitution reaction:

[0089] 200 g of chloromethylated polystyrene resin (CAS: 55844-94-5) (400 mesh, 5% DVB) was weighed and added to a three-necked flask containing 1200 g of dimethylformamide. Under a nitrogen atmosphere, the mixture was stirred at a stirring speed of 300 r / min for 3 hours to fully swell the chloromethylated polystyrene resin. Then, 20 g of ethylenediamine was weighed and diluted with an appropriate amount of DMF, and then slowly added to the swollen resin system at a speed of 2 drops / second through a constant pressure dropping funnel. The reaction temperature was controlled at 70° C. and the mixture was stirred at a speed of 400 r / min for 5 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, and part of the chloromethyl groups were replaced by ethylenediamine.

[0090] T2 copper salt loading reaction:

[0091] After the reaction of step T1 is completed, 3 g of o-phenanthroline, 0.3 g of 2-amino-1,3,5-triazine, and 5 g of copper acetate are added to the reaction system in sequence, the temperature is raised to 80° C., and the reaction is stirred at a speed of 400 r / min for 24 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper onto the resin;

[0092] T3 post-processing:

[0093] After the reaction, the reaction system was cooled to room temperature, and then the resin was filtered out with a sand core funnel, and the resin was washed with appropriate amounts of DMF, methanol, and deionized water in turn, with each washing time being 15 minutes to fully remove unreacted reagents and impurities; the washed resin was placed in a vacuum drying oven and dried at 60°C to constant weight to obtain a resin-loaded catalyst.

[0094] Comparative Example 1: The chloromethylated polystyrene resin is not modified, and the other properties are the same as those of Example 1.

[0095] Comparative Example 2: No o-phenanthroline was added, and the other steps were the same as in Example 1.

[0096] Comparative Example 3: No 2-amino-1,3,5-triazine was added, and the other steps were the same as those in Example 1.

[0097] The purity test was carried out by high performance liquid chromatography, and the test results are shown in Table 1.

[0098] Table 1: Test results of various embodiments and comparative examples

[0099]

[0100] Through the data analysis of the above examples and comparative examples, the ametinib intermediate prepared by the present invention has higher purity and yield.

[0101] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing an ametinib intermediate, characterized in that: The operation steps are: S1: Add 8-15 parts of indole to 100-150 parts of tetrahydrofuran, stir to dissolve, and then add 7-13 parts of Grignard reagent under a nitrogen atmosphere while controlling the temperature at -20-0°C, and stir for 30-60 minutes; S2: After adding 1-5 parts of 2,4-dichloropyrimidine, react at 65-75°C for 7-10 hours. After the reaction is completed, quench the reaction with saturated ammonium chloride at 0-5°C, separate the organic phase and the aqueous phase, take the upper organic phase for recrystallization, and dry; S3: Add the dried compound to 100-150 parts of tetrahydrofuran, stir to dissolve, then add 1-5 parts of resin-supported catalyst, 10-15 parts of bipyridine, 1-5 parts of sodium carbonate, and 1-5 parts of cyclopropylating agent, stir to mix, and react at 65-75° C. for 5-8 hours; S4: After the reaction is completed, the temperature is lowered to room temperature, air is continuously introduced for 30-60 minutes, and the filtrate is filtered. The filtrate is concentrated and dried, and then dissolved in ethyl acetate. Then, n-hexane is added for crystallization, and then filtered. Acetonitrile is added for recrystallization to obtain an ametinib intermediate. The resin-supported catalyst is prepared by a substitution reaction between chloromethylated polystyrene resin and ethylenediamine, followed by loading o-phenanthroline, 2-amino-1,3,5-triazine and copper acetate to form a stable complex. The specific preparation method of the resin-supported catalyst is: T1 swelling and initial substitution reaction: Weigh 100-200 parts of chloromethylated polystyrene resin, add them into a three-necked flask containing 1000-1200 parts of dimethylformamide, stir at a stirring speed of 200-300 r / min for 2-3 hours under a nitrogen atmosphere to fully swell the chloromethylated polystyrene resin; then weigh 5-20 parts of ethylenediamine, dilute it with an appropriate amount of DMF, and slowly drip it into the swollen resin system through a constant pressure dropping funnel at a speed of 1-2 drops / second; control the reaction temperature at 50-70°C, and stir the reaction at a speed of 300-400 r / min for 3-5 hours to promote a nucleophilic substitution reaction between ethylenediamine and the chloromethyl groups on the chloromethylated polystyrene resin, so that part of the chloromethyl groups are replaced by ethylenediamine; T2 copper salt loading reaction: After the reaction of step T1 is completed, 1-3 parts of o-phenanthroline, 0.03-0.3 parts of 2-amino-1,3,5-triazine, and 2-5 parts of copper acetate are added to the reaction system in sequence, the temperature is raised to 60-80° C., and the reaction is stirred at a speed of 300-400 r / min for 12-24 hours; during this process, o-phenanthroline, 2-amino-1,3,5-triazine and copper ions form a stable complex, and the complex further undergoes a coordination reaction with the resin to which ethylenediamine has been connected, thereby loading copper on the resin; T3 post-processing: After the reaction is completed, the reaction system is cooled to room temperature, and then the resin is filtered out with a sand core funnel, and the resin is washed with appropriate amounts of DMF, methanol, and deionized water in turn, each washing time is 10-15 minutes to fully remove unreacted reagents and impurities; the washed resin is placed in a vacuum drying oven and dried at 50-60°C to constant weight to obtain a resin-loaded catalyst.

2. The method for synthesizing an ametinib intermediate according to claim 1, characterized in that: The Grignard reagent is one of a methyl Grignard reagent, an ethyl Grignard reagent and an isopropyl Grignard reagent.

3. The method for synthesizing an ametinib intermediate according to claim 1, characterized in that: The cyclopropylation reagent is one of cyclopropane bromide, cyclopropylboronic acid and cyclopropylboronic ester.

4. The method for synthesizing an ametinib intermediate according to claim 1, characterized in that: The air introduction rate is 5-10 L / min.

Images