Synthesis method of tepotinib and key intermediate thereof

Abstract

The invention discloses a synthesis method of a key intermediate of Tepotinib, which comprises the following steps: step (1), carrying out Suzuki coupling reaction on 3-methylphenylboronic acid and 2-iodo-5-bromopyrimidine to obtain a coupling product; step (2), carrying out Ullmann coupling reaction on the obtained coupling product and N-Boc piperidine-4-methanol under a strong alkaline condition; and step (3), converting N-Boc in a coupling product obtained by the Ullmann coupling reaction into N-methyl, and then carrying out benzyl bromination reaction to generate the key tepotinib intermediate. The synthesis method has the advantages of short steps, simple operation, mild reaction conditions, less by-products, high product purity and high product yield, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to a method for synthesizing tepotinib and a key intermediate thereof. Background Art

[0002] Tepotinib is a highly selective oral MET inhibitor developed by Merck KGaA in Germany. It can potently and highly selectively inhibit oncogenic signals caused by MET gene changes, and has the potential to improve the treatment prognosis of patients with aggressive tumors carrying these specific MET changes. On March 25, 2020, the Ministry of Health, Labor and Welfare of Japan approved the marketing of Tepotinib Hydrochloride Tablets (trade name Tepmetko) of Merck Pharmaceuticals in Germany for the treatment of patients with unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping mutations. This is the first approval of the drug worldwide. In November 2020, Tepotinib was approved by the European EMA for the same indication. On February 3, 2021, the US FDA approved Tepotinib Hydrochloride Tablets (specification: 225 mg) as a once-daily oral MET inhibitor for the treatment of patients with metastatic NSCLC carrying METex14 skipping mutations. This is the second MET inhibitor approved by the FDA (the first is capmatinib), and it is also the world's first MET inhibitor that only needs to be taken orally once a day (450 mg / day). The approval is based on the results of the pivotal Phase I VISION study, which evaluated tepotinib as a monotherapy for patients with advanced NSCLC with METex14 skipping changes. Common side effects of tepotinib are increased ALT, peripheral edema, increased blood creatinine, fatigue, weakness, increased lipase, increased amylase, hypoalbuminemia, nausea, diarrhea, fatigue, vomiting, etc.

[0003] The molecular formula of tepotinib hydrochloride is C 29 H 28 N6O2·HC1·H20, molecular weight is 547.05, its chemical structure is as follows:

[0004]

[0005] In the patent EP2008005508 published by Merck, 3-(5-hydroxy-pyrimidin-2-yl)-benzoic acid methyl ester is used as the starting material, and the target product is obtained through etherification reaction, hydrolysis and deprotection, N-alkylation and other reactions. During the reaction, triphenylphosphine, diisobutylaluminum hydride and other highly dangerous and highly toxic reagents are used, and purification is carried out by column chromatography. The above operations are not conducive to the application of this process route in large-scale production.

[0006] In the patent EP2008003473 published by Merck, 3-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is used as the starting material, and the target product is obtained through N-alkylation reaction, catalytic borylation reaction, hydrolysis, etherification reaction, deprotection and N-methylation reaction. In the reaction process, not only a large number of expensive reagents are used, but also high-risk reagents such as triphenylphosphine are used, which is not conducive to the implementation of the route. In addition, the steps of this route are relatively long, resulting in a low overall yield.

[0007] In the 21-year patent CN114394957 of Jiuzhou Yumin Pharmaceutical, the direct SNAr reaction conditions between the aromatic ring and piperidine alcohol are harsh, and it is relatively difficult to directly crystallize the resulting product.

[0008] Therefore, the current synthesis methods of tepotinib and its key intermediates still need to be improved. Summary of the invention

[0009] In order to solve the above technical problems, the purpose of the present invention is to provide a method for synthesizing tepotinib and its key intermediates. The method has short steps, simple operation, mild reaction conditions, less by-products, high product purity, high product yield, and is suitable for scale-up production.

[0010] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0011] The present invention provides a method for synthesizing a key intermediate of Tepotinib, characterized in that it comprises the following steps:

[0012] Step (1), subjecting 3-methylphenylboronic acid shown in Formula 1 to Suzuki coupling reaction with 2-iodo-5-bromopyrimidine shown in Formula 2 to obtain a coupling product shown in Formula 3;

[0013] Step (2), subjecting the coupling product of Formula 3 to an Ullmann coupling reaction with N-Boc piperidine-4-methanol of Formula 4 under strong alkaline conditions to obtain a coupling product of Formula 5;

[0014] Step (3), the coupling product shown in Formula 5 is subjected to a reduction reaction, and N-Boc is converted into N-methyl to obtain a product shown in Formula 6;

[0015] Step (4), the product shown in Formula 6 is further subjected to benzyl bromination reaction to produce the key intermediate of Tepotinib shown in Formula A;

[0016] The synthetic route is as follows:

[0017]

[0018] Furthermore, the specific process of step (1) is as follows:

[0019] 3-Methylphenylboronic acid and 2-iodo-5-bromopyrimidine are dissolved in a solvent, an alkaline aqueous solution is added, a catalyst is added to replace nitrogen, and then the mixture is heated to a certain temperature. After continuous stirring for a period of time, the reaction is terminated, the mixture is cooled, water and an extraction solvent are added, and the liquid is separated. The organic layer is concentrated to near dryness to obtain a crude product; the crude product is heated to reflux in isopropanol, hot filtered to remove insoluble impurities, and the filtrate is cooled and crystallized to obtain 5-bromo-2-(3-methylphenyl)pyrimidine shown in Formula 3. The molar ratio of 3-methylphenylboronic acid to 2-iodo-5-bromopyrimidine is (1.05-1.5):1.

[0020] Furthermore, the reaction temperature of step (1) is 80-100° C., and the reaction time is 16-24 h. In step (1), the molar ratio of the base to 2-iodo-5-bromopyrimidine is (1-3):1, and the molar ratio of the catalyst to 2-iodo-5-bromopyrimidine is (0.01-0.05):1. The base is one or more of sodium carbonate, potassium carbonate, and sodium bicarbonate; the catalyst is one or more of tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, and [1,1'-bis(diphenylphosphino)ferrocene] nickel dichloride.

[0021] Furthermore, in step (1), the reaction solvent is one or more of toluene, ethanol, dioxane, and DMF; the volume mass ratio of the reaction solvent to 2-iodo-5-bromopyrimidine is (10-15) ml:1 g; the extraction solvent is one or more of toluene, ethyl acetate, 2-methyltetrahydrofuran, etc.; the volume molar ratio of the extraction solvent to 2-iodo-5-bromopyrimidine is (10-15) ml:1 g; in step (1), the volume molar ratio of isopropanol to 2-iodo-5-bromopyrimidine is (3-10):1.

[0022] Furthermore, the specific process of step (2) is as follows:

[0023] 5-Bromo-2-(3-methylphenyl)pyrimidine and N-Boc piperidine-4-methanol as shown in Formula 3 are placed in a solvent, a base and a catalyst are added, and proline is used to replace nitrogen, and the mixture is heated to 95-100° C. for reaction. After the reaction is completed, the mixture is cooled to room temperature, and water is added into the system for stirring. Solids are precipitated, and the solids are collected. Dichloromethane is used for dissolution, and after purification, tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate as shown in Formula 5 is obtained.

[0024] Furthermore, in step (2), the molar ratio of the coupling product 5-bromo-2-(3-methylphenyl)pyrimidine shown in formula 3 to N-Boc piperidine-4-methanol shown in formula 4 is 1:(1-1.5).

[0025] Furthermore, the reaction in step (2) is carried out in the presence of a base, a catalyst and proline, and the reaction temperature is 95-100° C.; the base is at least one of sodium tert-butoxide, potassium tert-butoxide, sodium hydride and potassium hydride; the catalyst is one of cuprous bromide and cuprous iodide or a mixture of the two; in step (2), the molar ratio of the base to the coupling product shown in formula 3 is (1-2):1, the molar ratio of the catalyst to 5-bromo-2-(3-methylphenyl)pyrimidine is (0.05-0.2):1; and the molar ratio of proline to the catalyst is 2:1.

[0026] Furthermore, in step (2), the reaction solvent is one or more of toluene, dioxane, DMF, etc.; the volume mass ratio of the reaction solvent to 5-bromo-2-(3-methylphenyl)pyrimidine is (5-8) ml: 1 g.

[0027] Further, step (3) converts N-Boc in the coupling product shown in Formula 5 into N-methyl through a reduction reaction, which is carried out in the presence of a reducing agent; the specific process is: dissolving tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-carboxylate shown in Formula 5 in a solvent, adding a reducing agent to reduce the Boc group to a methyl group, and after the reaction is completed, quenching the system with alkaline water, solvent extraction, and concentrating the organic phase to dryness or solvent replacement to obtain 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine shown in Formula 6. The reducing agent is at least one of sodium borohydride, lithium aluminum tetrahydride, and diisobutylaluminum hydride; the molar ratio of the coupling product shown in Formula 5 to the reducing agent is 1:(1-5). Among them, the alkaline water is one or more aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, ammonia, etc.; the extraction solvent is one or more of dichloromethane, tetrahydrofuran, ethyl acetate, 2-methyltetrahydrofuran, etc.; the volume mass ratio of the extraction solvent to tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate is (5-8) ml:1g; the replacement solvent can be one or more of n-heptane, methyl tert-butyl ether, cyclopentyl methyl ether, etc.

[0028] As another preferred technical solution, step (3) can also convert N-Boc in the coupling product shown in Formula 5 into N-methyl through a methylation reaction. The specific process is: dissolving tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate in a solvent, adding acid to remove Boc and then alkalizing, extracting with an organic solvent, and methylating the N of the piperidine ring with a methylating agent under alkaline conditions to obtain the product shown in Formula 6.

[0029] Furthermore, the specific process of step (4) is: placing 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine shown in formula 6 in a solvent, adding a brominating agent and a free radical initiator, filtering to remove insoluble by-products after bromination is completed, concentrating the filtrate to dryness, and recrystallizing to obtain 2-[3-(bromomethyl)phenyl]-5-{[(1-methylpiperidin-4-yl)methyl]oxy}pyrimidine.

[0030] The molar ratio of the product shown in Formula 6 to the brominating agent used in the benzyl bromination reaction is 1:(0.5-1.05); the molar ratio of the product shown in Formula 6 to the free radical initiator is 1:(0.05-0.1).

[0031] In step (4), the brominating agent is one or more of bromine, bromosuccinimide, dibromohydantoin, etc.; the free radical initiator can be benzoyl peroxide or azobisisobutyronitrile. The reaction solvent is carbon tetrachloride or acetonitrile; the mass volume ratio of 5-{[(1-methylhexahydropyridin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine to the reaction solvent is 1g:(15-20)ml; the recrystallization solvent is one or more of n-heptane, methyl tert-butyl ether, cyclopentyl methyl ether, etc.

[0032] The present invention also provides a method for synthesizing tepotinib, specifically: 3-methylphenylboronic acid and 2-iodo-5-bromopyrimidine are subjected to Suzuki coupling reaction, the obtained coupling product is subjected to Ullmann coupling reaction with N-Boc piperidine-4-methanol under strong alkaline conditions, the coupling product obtained by the Ullmann coupling reaction is subjected to reduction reaction or methylation reaction, N-Boc is converted into N-methyl, and then a key intermediate of tepotinib is generated by benzyl bromination reaction, and the key intermediate of tepotinib is docked with a pyridazine compound to generate tepotinib. Wherein, the pyridazine compound is preferably 6-(3-cyanophenyl)-3-pyridazinone. The specific process for preparing tepotinib from the key intermediate of tepotinib and 6-(3-cyanophenyl)-3-pyridazinone is as follows: 2-[3-(bromomethyl)phenyl]-5-{[(1-methylhexahydropyridin-4-yl)methyl]oxy}pyrimidine and 6-(3-cyanophenyl)-3-pyridazinone are mixed in a non-protonic solvent and heated to react under alkaline conditions. After the reaction is completed, the system is cooled, water is added into the system and stirred, solids precipitate, the solids are collected, dissolved with dichloromethane, decolorized, recrystallized and purified to obtain the target product tepotinib.

[0033] The beneficial effects of the present invention are:

[0034] The present invention provides a novel synthesis method of tepotinib and a key intermediate thereof. The synthesis method has short steps, simple operation, mild reaction conditions, no use of highly dangerous and highly toxic reagents, fewer by-products, high product purity, high product yield, and is suitable for scaled-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the NMR spectrum of the key intermediate of Tepotinib prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0036] The technical solutions in the present invention will be described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The present invention provides a method for synthesizing a key intermediate of Tepotinib, comprising the following steps:

[0038] Step (1), subjecting 3-methylphenylboronic acid shown in Formula 1 to Suzuki coupling reaction with 2-iodo-5-bromopyrimidine shown in Formula 2 to obtain a coupling product shown in Formula 3;

[0039] Step (2), subjecting the coupling product of Formula 3 to an Ullmann coupling reaction with N-Boc piperidine-4-methanol of Formula 4 under strong alkaline conditions to obtain a coupling product of Formula 5;

[0040] Step (3), converting the N-Boc in the coupling product shown in Formula 5 into N-methyl to obtain the product shown in Formula 6;

[0041] Step (4), the product shown in Formula 6 is further subjected to benzyl bromination reaction to produce the key intermediate of Tepotinib shown in Formula A;

[0042] The synthetic route is as follows:

[0043]

[0044] In step (1), the molar ratio of 3-methylphenylboronic acid to 2-iodo-5-bromopyrimidine is (1.05-1.5): 1. The reaction in step (1) is carried out in the presence of a base and a catalyst, the reaction temperature is 80-100° C., and the reaction time is 16-24 hours; in step (1), the molar ratio of the base to 2-iodo-5-bromopyrimidine is (1-3): 1, and the molar ratio of the catalyst to 2-iodo-5-bromopyrimidine is (0.01-0.05): 1.

[0045] In step (2), the molar ratio of the coupling product shown in formula 3 to the N-Boc piperidine-4-methanol shown in formula 4 is 1:(1-1.5). The reaction in step (2) is carried out in the presence of a base, a catalyst and proline, and the reaction temperature is 95-100°C; in step (2), the molar ratio of the base to the coupling product shown in formula 3 is (1-2):1, the molar ratio of the catalyst to the coupling product shown in formula 3 is (0.05-0.2):1; the molar ratio of proline to the catalyst is 2:1.

[0046] In step (3), step (3) can convert N-Boc in the coupling product shown in formula 5 into N-methyl through a reduction reaction, which is carried out in the presence of a reducing agent; the reducing agent is at least one of sodium borohydride, lithium aluminum tetrahydride, and diisobutylaluminum hydride; the molar ratio of the coupling product shown in formula 5 to the reducing agent is 1:(1-5).

[0047] In addition, step (3) can also convert the N-Boc in the coupling product shown in Formula 5 into N-methyl through a methylation reaction.

[0048] In step (4), the molar ratio of the product shown in formula 6 to the brominating agent used in the benzylic bromination reaction is 1:(0.5-1.05). The reaction in step (4) is carried out in the presence of a free radical initiator; the molar ratio of the product shown in formula 6 to the free radical initiator is 1:(0.05-0.1).

[0049] The present invention also provides a method for synthesizing tepotinib, specifically: 3-methylphenylboronic acid and 2-iodo-5-bromopyrimidine are subjected to Suzuki coupling reaction, the obtained coupling product and N-Boc piperidine-4-methanol are subjected to Ullmann coupling reaction under strong alkaline conditions, the coupling product obtained by the Ullmann coupling reaction is subjected to reduction reaction or methylation reaction, N-Boc is converted into N-methyl, and then a benzyl bromination reaction is performed to generate a key intermediate of tepotinib, and the key intermediate of tepotinib is docked with a pyridazine compound to generate tepotinib. The pyridazine compound is preferably 6-(3-cyanophenyl)-3-pyridazinone.

[0050] The synthesis method of the present invention is further described below by means of specific examples.

[0051] Example 1

[0052] 3-Methylphenylboronic acid (25.0 g, 183.9 mmol, 1.3 eq.) and 2-iodo-5-bromopyrimidine (40.3 g, 141.4 mmol, 1.0 eq.) were dissolved in a mixed solvent of toluene (162.5 ml) and ethanol (325 ml), and a solution prepared by Na2CO3 (39.0 g, 367.8 mmol, 2.6 eq.) and water (100.8 g) was added, and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (2.70 g, 3.7 mmol, 0.02eq.) was replaced with nitrogen and then heated to 80-90°C. After continuous stirring for 16 hours, the liquid phase was controlled and the remaining 2-iodo-5-bromopyrimidine was less than 2%, and the reaction was judged to be over. The mixture was cooled and water (202ml) and ethyl acetate (403ml) were added, and the liquids were separated. The organic layer was concentrated to near dryness to obtain a crude product. The crude product was heated to reflux with isopropanol (202ml), and insoluble impurities were removed by hot filtration. The filtrate was cooled and crystallized to obtain 28.5g of pure 5-bromo-2-(3-methylphenyl)pyrimidine, with a liquid phase purity of 97.4% and a yield of 81%.

[0053] 5-Bromo-2-(3-methylphenyl)pyrimidine (44.0 g, 176.6 mmol, 1.0 eq.) and N-Bocpiperidine-4-methanol (45.6 g, 211.9 mmol, 1.2 eq.) were placed in DMF (264 mL), potassium tert-butoxide (29.8 g, 264.9 mmol), cuprous iodide (3.4 g, 17.7 mmol, 0.1 eq) and proline (4.1 g, 35.6 mmol) were added to replace the nitrogen, and the mixture was heated to 95-100 ° C for reaction. After the reaction was completed, the mixture was cooled to room temperature, water (530 ml) was added into the system and stirred, and a solid precipitated, which was collected. The mixture was dissolved in dichloromethane (530 ml), concentrated to dryness, and purified by beating with tert-methyl ether (106 ml) as solvent to obtain 62.7 g of tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate with a purity of 99% and a yield of 93%.

[0054] 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidin-1-carboxylic acid tert-butyl ester (16.8g, 43.8mmol, 1.0eq.) was dissolved in THF (185ml), and LiAlH4 (2.0g, 53.0mmol, 1.2eq.) was added and stirred at room temperature for 12-16h. After the reaction was completed, alkaline water (100mL) was added to quench the system, and the filtrate was separated by passing through a diatomaceous earth (25g) pad, and extracted with ethyl acetate (100ml). The organic phase was washed with acid (2M hydrochloric acid, 100ml). The acid water layer obtained was the salt solution of the product. The acid water layer was alkalized to pH 9-10 using alkali (1M NaOH aqueous solution), extracted with ethyl acetate, and the ethyl acetate stripping solution was concentrated to dryness to obtain 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine 10.7g, with a yield of 82%.

[0055] 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine (10 g, 33.7 mmol, 1.0 eq.) was placed in acetonitrile (200 mL), and a brominating agent, bromosuccinimide (6.2 g, 34.7 mmol, 1.03 eq.) and a free radical initiator (AIBN, 0.3 g, 1.7 mmol, 0.05 eq.) were added. The mixture was heated at 80°C for 3 h. After the bromination was completed, the insoluble by-products were filtered out, and the filtrate was concentrated to dryness. The mixture was recrystallized to obtain 11.7 g of 2-[3-(bromomethyl)phenyl]-5-{[(1-methylpiperidin-4-yl)methyl]oxy}pyrimidine in a yield of 92%.

[0056] The NMR spectrum of the key intermediate of Tepotinib prepared in Example 1 is as follows: Figure 1 As shown, the data is as follows:

[0057] 1 H NMR (400MHz, CDCl3): δ8.25(dt,1H,J1=8.0Hz,J2=2.4Hz),7.9(S,1H),7.77(S,2H),7.54(t,1H,J1=8.0Hz),7.44(dt,1H,J1 =8.0Hz, J2=2.4Hz), 4.88(s,2H),3.90(d,2H,J=10.6Hz),2.50(m,2H),2.40(m,2H),2.17(S,3H),1.86(m,3H),1.40(m,2H).

[0058] Example 2

[0059] 3-Methylphenylboronic acid (25.0 g, 183.9 mmol, 1.3 eq.) and 2-iodo-5-bromopyrimidine (40.3 g, 141.4 mmol, 1.0 eq.) were dissolved in a mixed solvent of toluene (162.5 ml) and ethanol (325.0 ml), and a solution of Na2CO3 (39.0 g, 367.8 mmol, 2.6 eq.) and water (100.8 g) was added, and tetrakistriphenylphosphine palladium (9.5 g, 7.36 mmol, 0.04 eq.) was added. ) after nitrogen replacement, heated to 80-90°C, stirred continuously for 16 hours, the liquid phase was controlled, and the remaining 2-iodo-5-bromopyrimidine was less than 2%, judging that the reaction was over, cooled, added with water (201.5ml) and ethyl acetate (403.0ml), separated, and the organic layer was concentrated to near dryness to obtain a crude product; the crude product was heated to reflux with isopropanol (201.5ml), hot filtered to remove insoluble impurities, and the filtrate was cooled and crystallized to obtain 25.7g of pure 5-bromo-2-(3-methylphenyl)pyrimidine, with a liquid phase purity of 98.2% and a yield of 73%.

[0060] 5-Bromo-2-(3-methylphenyl)pyrimidine (24.3 g, 97.5 mmol, 1.0 eq.) and N-Boc piperidine-4-methanol (25.2 g, 117.1 mmol, 1.2 eq.) were placed in dioxane (145 mL), potassium tert-butoxide (17.5 g, 156.1 mmol, 1.6 eq.) and cuprous iodide (1.9 g, 9.8 mmol, 0.1 eq.) and proline (2.2 g, 19.5 mmol.) were added to replace the nitrogen, and the mixture was heated to 95-100°C for reaction. After the reaction was completed, the mixture was cooled to room temperature, water (290 ml) was added into the system and stirred, and solid precipitated and collected. The product was purified by beating with tert-methyl ether (90 ml) as solvent to obtain 33.7 g of tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate with a purity of 98.7% and a yield of 90%.

[0061] Dissolve tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate (22.3 g, 58.2 mmol, 1.0 eq.) in THF (200 ml), cool to 5°C, add DiBAl-H (2.0 M, 116.3 ml, 232.6 mmol, 4 eq.) dropwise over about half an hour, and heat to room temperature naturally and stir for 12-16 hours. After the reaction was completed, the system was quenched with water (100 mL), passed through a diatomaceous earth (25 g) pad, the filtrate was separated, extracted with ethyl acetate (100 ml), and the organic phase was washed with acid (2 M hydrochloric acid, 140 ml). The acidic aqueous layer obtained was a salt solution of the product. The acidic aqueous layer was alkalized to pH 9-10 with alkali (1 M NaOH aqueous solution), extracted with ethyl acetate, and the ethyl acetate stripping solution was concentrated to dryness to obtain 12.8 g of 5-{[(1-methylhexahydropyridin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine with a yield of 74%.

[0062] 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine (10 g, 33.7 mmol, 1.0 eq.) was placed in acetonitrile (200 mL), and a brominating agent, bromosuccinimide (6.2 g, 34.7 mmol, 1.03 eq.) and a free radical initiator (BPO, 0.5 g, 1.7 mmol, 0.05 eq.) were added. The mixture was heated at 80°C for 3 h. After the bromination was completed, the insoluble by-products were filtered out, and the filtrate was concentrated to dryness. The mixture was recrystallized to give 10.9 g of 2-[3-(bromomethyl)phenyl]-5-{[(1-methylpiperidin-4-yl)methyl]oxy}pyrimidine in a yield of 86%.

[0063] Example 3

[0064] 3-Methylphenylboronic acid (15.0 g, 110.3 mmol, 1.3 eq.) and 2-iodo-5-bromopyrimidine (24.8 g, 84.9 mmol, 1.0 eq.) were dissolved in a mixed solvent of toluene (97.5 ml) and ethanol (195.0 ml), and a solution prepared by Na2CO3 (24.0 g, 220.6 mmol, 2.6 eq.) and water (60.0 g) was added, and tris(dibenzylideneacetone)dipalladium (4.0 g, 4.4 mmol, 0.04 eq.) was added. .) After nitrogen is replaced, the mixture is heated to 80-90°C and stirred for 16 hours. The liquid phase is controlled and the remaining 2-iodo-5-bromopyrimidine is less than 2%. The reaction is judged to be over. The mixture is cooled and water (125 ml) and ethyl acetate (250.0 ml) are added. The liquids are separated and the organic layer is concentrated to near dryness to obtain a crude product. The crude product is refluxed with isopropanol (125 ml) and hot filtered to remove insoluble impurities. The filtrate is cooled and crystallized to obtain 10.7 g of pure 5-bromo-2-(3-methylphenyl)pyrimidine with a liquid phase purity of 96.8% and a yield of 69%.

[0065] 5-Bromo-2-(3-methylphenyl)pyrimidine (15.9 g, 63.8 mmol, 1.0 eq.) and N-Bocpiperidine-4-methanol (16.5 g, 76.6 mmol, 1.2 eq.) were placed in DMF (95 mL), potassium tert-butoxide (11.5 g, 102.1 mmol, 1.6 eq.) and cuprous iodide (1.21 g, 6.4 mmol, 0.1 eq.) and proline (1.5 g, 12.8 mmol, 0.2 eq.) were added to replace the nitrogen, and the mixture was heated to 95-100 ° C for reaction. After the reaction was completed, the mixture was cooled to room temperature, water (190 ml) was added into the system and stirred, and a solid precipitated, which was collected by suction filtration. Solid tert-methyl ether (60 ml) was used as a solvent for slurrying and purification to obtain 21.7 g of tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate with a purity of 97.9% and a yield of 89%.

[0066] Dissolve tert-butyl 4-({[2-(3-methylphenyl)pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate (22.3 g, 58.2 mmol, 1.0 eq.) in THF (200 ml), cool to 5°C, add DiBAl-H (2.0 M, 116.3 ml, 232.6 mmol, 4 eq.) dropwise over about half an hour, and heat to room temperature naturally and stir for 12-16 hours. After the reaction was completed, the system was quenched with water (100 mL), passed through a diatomaceous earth (25 g) pad, the filtrate was separated, extracted with ethyl acetate (100 ml), and the organic phase was washed with acid (2 M hydrochloric acid, 140 ml). The acid aqueous layer obtained was a salt solution of the product. The acid aqueous layer was alkalized to pH 9-10 with a base (1 M NaOH aqueous solution), extracted with ethyl acetate, and the ethyl acetate stripping solution was concentrated to dryness to obtain 13.3 g of 5-{[(1-methylhexahydropyridin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine with a yield of 77%.

[0067] 5-{[(1-methylpiperidin-4-yl)methyl]oxy}-2-(3-methylphenyl)pyrimidine (12.7 g, 42.7 mmol, 1.0 eq.) was placed in acetonitrile (254 mL), and brominating agent bromosuccinimide (7.8 g, 44.0 mmol, 1.03 eq.) and a free radical initiator (AIBN, 0.4 g, 2.1 mmol, 0.05 eq.) were added. The mixture was heated to 80°C for 3 h. After the bromination was completed, the insoluble by-products were filtered out, the filtrate was concentrated to dryness, and recrystallized to obtain 14.1 g of 2-[3-(bromomethyl)phenyl]-5-{[(1-methylpiperidin-4-yl)methyl]oxy}pyrimidine in a yield of 88%.

[0068] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0069] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a key intermediate of Tepotinib, characterized in that: The following steps are involved: Step (1), subjecting 3-methylphenylboronic acid shown in Formula 1 to Suzuki coupling reaction with 2-iodo-5-bromopyrimidine shown in Formula 2 to obtain a coupling product shown in Formula 3; Step (2), subjecting the coupling product of Formula 3 to an Ullmann coupling reaction with N-Boc piperidine-4-methanol of Formula 4 under strong alkaline conditions to obtain a coupling product of Formula 5; Step (3), converting the N-Boc in the coupling product shown in Formula 5 into N-methyl to obtain the product shown in Formula 6; Step (4), the product shown in Formula 6 is further subjected to benzyl bromination reaction to produce the key intermediate of Tepotinib shown in Formula A; The synthetic route is as follows:

2. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: The molar ratio of 3-methylphenylboronic acid to 2-iodo-5-bromopyrimidine is (1.05-1.5):

1.

3. A method for synthesizing a key intermediate of Tepotinib according to claim 1 or 2, characterized in that: The reaction in step (1) is carried out in the presence of a base and a catalyst, the reaction temperature is 80-100° C., and the reaction time is 16-24 hours. In the step (1), the molar ratio of the base to 2-iodo-5-bromopyrimidine is (1-3):1, and the molar ratio of the catalyst to 2-iodo-5-bromopyrimidine is (0.01-0.05):

1.

4. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: The molar ratio of the coupling product shown in Formula 3 to the N-Boc piperidine-4-methanol shown in Formula 4 is 1:(1-1.5).

5. A method for synthesizing a key intermediate of Tepotinib according to claim 1 or 4, characterized in that: The reaction in step (2) is carried out in the presence of a base, a catalyst and proline, and the reaction temperature is 95-100° C. In the step (2), the molar ratio of the base to the coupling product shown in formula 3 is (1-2):1, the molar ratio of the catalyst to the coupling product shown in formula 3 is (0.05-0.2):1; and the molar ratio of proline to the catalyst is 2:

1.

6. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: Step (3) converts N-Boc in the coupling product shown in Formula 5 into N-methyl through a reduction reaction, which is carried out in the presence of a reducing agent; the reducing agent is at least one of sodium borohydride, lithium aluminum tetrahydride, and diisobutylaluminum hydride; the molar ratio of the coupling product shown in Formula 5 to the reducing agent is 1:(1-5).

7. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: Step (3) converts the N-Boc in the coupling product shown in Formula 5 into N-methyl through a methylation reaction.

8. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: In step (4), the molar ratio of the product represented by formula 6 to the brominating agent used in the benzylic bromination reaction is 1:(0.5-1.05).

9. The method for synthesizing a key intermediate of Tepotinib according to claim 1, characterized in that: The reaction in step (4) is carried out in the presence of a free radical initiator; the molar ratio of the product shown in formula 6 to the free radical initiator is 1:(0.05-0.1).

10. A method for synthesizing Tepotinib, characterized in that: 3-Methylphenylboronic acid and 2-iodo-5-bromopyrimidine are subjected to a Suzuki coupling reaction, and the obtained coupling product is subjected to an Ullmann coupling reaction with N-Boc piperidine-4-methanol under strong alkaline conditions. The coupling product obtained by the Ullmann coupling reaction is subjected to a reduction reaction or a methylation reaction, and N-Boc is converted into N-methyl, and then a benzyl bromination reaction is performed to generate a key intermediate of tepotinib, and the key intermediate of tepotinib is docked with a pyridazine compound to generate tepotinib.

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