A method for preparing lenvatinib

Abstract

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of Lenvatinib. The preparation method is as follows: 4-chloro-7-methoxy quinoline-6-amide is reacted with 3,4-dichlorophenol under the action of alkali, the obtained product is reacted with 1-cyclopropylimidazolidine-2,4,5-trione, and then Lenvatinib is obtained through alkaline 1-cyclopropylimidazolidine-2,4,5-trione ring opening. In the application, 1-cyclopropylimidazolidine-2,4,5-trione is used as a synthetic subunit of a functional group 'urea', the use of chloroformate phenyl, which is highly toxic, is avoided, the operation is simple, the yield is higher, and the application is more suitable for industrial mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing lenvatinib. Background Technology

[0002] Lenvatinib (also known as E7080), chemically named 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline carboxamide, is an oral multi-receptor tyrosine kinase inhibitor developed by Eisai Co., Ltd. of Japan. It was first marketed in the United States on February 13, 2015, under the brand name Lenvima, and is clinically used as a potential treatment for aggressive, locally advanced, or metastatic differentiated thyroid cancer, non-small cell lung cancer, and other solid tumors. In September 2018, it was approved for marketing in China and began to be used as first-line treatment for unresectable hepatocellular carcinoma (HCC), thus breaking the monopoly of sorafenib and adding another treatment option for unresectable HCC. Therefore, lenvatinib has a great market prospect. Its chemical structure is as follows:

[0003]

[0004] Patents EP1683785A1, EP1698623A1, EP1797881A1, US2007 / 4773, US7683172B2, WO2005044788, WO2006137474, CN100450998C, and CN101337930B use 3-chloro-4-aminophenol and phenyl chloroformate as starting materials. Under pyridine catalysis, acylation yields N-(2-chloro-4-hydroxyphenyl)carbamate, which is then reacted with cyclopropylamine to form a urea to give 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropionate. This urea is then reacted with 4-chloro-7-methoxyquinoline-6-carboxamide via an O-alkylation reaction to yield lenvatinib. The synthetic route is shown below:

[0005]

[0006] Chinese patent applications CN101029022B and CN106660964A describe a synthetic route that first reacts 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide, and then reacts it sequentially with phenyl chloroformate and cyclopropylamine to obtain lenvatinib. The synthetic route is shown below:

[0007]

[0008] References: J Med Chem, 2008, 51(6): 1649-1667, Synthesis of Lenvatinib, China Pharmaceutical Industry Journal, 2014, 45(6): 507-510, Improvement of Synthetic Process of Lenvatinib, Receptor Tyrosine Kinase Inhibitor, Chinese Journal of Medicinal Chemistry, 2016, 26(1): 29-32. Starting from o-chloronitrobenzene or its downstream intermediates, 4-amino-3-chlorophenol was obtained by reduction and substitution reaction, and then urea was formed with phenyl chloroformate and cyclopropylamine to obtain the key intermediate N-(2-chloro-4-hydroxyphenyl)carbamate. Furthermore, malonic acid undergoes cyclization with acetone under the catalysis of acetic anhydride and concentrated sulfuric acid to generate 2,2-dimethyl-1,3-dioxane-4,6-dione, which then reacts with methyl 2-methoxy-4-aminobenzoate under reflux with trimethyl orthoformate and isopropanol to generate methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-methylene)amino]-2-methoxybenzoate. This methyl benzoate then rearranges under heating with diphenyl ether to generate methyl 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate, which is further chlorinated with sulfoxide to give methyl 4-chloro-7-methoxyquinoline-6-carboxylate. This methyl 4-chloro-7-methoxyquinoline-6-carboxylate is then subjected to aminolysis to yield another key intermediate, 4-chloro-7-methoxyquinoline-6-carboxamide. Finally, the two key intermediates are reacted under the catalysis of cesium carbonate and activated copper powder to obtain the target compound. The synthetic route is shown below:

[0009]

[0010] Chinese patent application CN109456267A and the literature "Synthesis of Lenvatinib", Chinese Journal of Medicinal Chemistry, 2015, 25(4):285-288, use 4-aminosalicylic acid as a raw material. Methyl 4-amino-2-methoxybenzoate is obtained by methylation with dimethyl sulfate, followed by condensation with 2,2-dimethyl-1,3-dioxane-4,6-dione. This is then followed by high-temperature cyclization, chlorination, and amination to obtain 4-chloro-7-methoxyquinoline-6-carboxamide. Finally, the two intermediates are reacted under alkaline conditions of potassium carbonate and potassium tert-butoxide to obtain the target product. However, the yield of the intermediates after condensation in this route is low, they are unstable and easily decompose, and the synthetic route is relatively long, resulting in a low overall yield. The synthetic route is shown below:

[0011]

[0012] US Patent 7253286B2 uses 3-chloro-4-cyanoaniline as a starting material, which is methylated and then condensed with Madrum acid. The cyclization is then carried out in a biphenyl-biphenyl ether mixed solvent upon heating, followed by hydrolysis, chlorination, and amination to give 4-chloro-7-methoxyquinoline-6-carboxamide. 3-chloro-4-aminophenol and phenyl chloroformate are used as starting materials, and acylation is performed to give N-(2-chloro-4-hydroxyphenyl)carbamate, which is then reacted with cyclopropylamine to form a urea to give 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropionate. Finally, the two intermediates are reacted with potassium tert-butoxide catalyzed to give the target compound. The synthetic route is shown below:

[0013]

[0014] Chinese patent application CN108658859A uses m-chlorophenol as a raw material. After reacting with a nitrating agent under heat, 3-chloro-4-nitrophenol is obtained through simple purification. Then, it reacts with 4-chloro-7-methoxyquinoline-6-carboxamide under heat in an organic solvent to generate 4-(3-chloro-4-nitrophenoxy)-7-methoxy-6-quinolinecarboxamide. The nitro group is then reduced, and subsequently reacted with phenyl chloroformate and cyclopropylamine to generate lenvatinib. The synthetic route is shown below:

[0015]

[0016] However, all of the above routes use phenyl chloroformate, which is highly toxic. Phenyl chloroformate is not only highly toxic, but also difficult to obtain on the market and its preparation is relatively complicated. Moreover, this route will produce phenol, which is highly toxic, in the subsequent reaction.

[0017] Chinese patent application CN104876864A uses 4-amino-3-chlorophenol as a starting material. The amino group is protected by Boc to obtain tert-butyl (2-chloro-4-hydroxy-phenyl)carbamate. Then, it reacts with 4-chloro-7-methoxyquinoline-6-carboxamide under cesium carbonate catalysis to obtain 4-(6-carbamoyl-7-methoxyquinoline-4-oxy)-2-chlorophenylcarbamate tert-butyl. After Boc removal in hydrochloric acid-methanol solution, it reacts with cyclopropylamine and CDI to obtain the target product. This process involves pre-protecting the amino group of 4-amino-3-chlorophenol by Boc (tert-butyloxycarbonyl) before participating in the remaining reactions. Amino group protection can reduce the occurrence of side reactions. However, the resulting protection and deprotection increase the number of reaction steps and purification operations, reducing the overall yield and affecting industrial efficiency. The synthetic route is shown below:

[0018]

[0019] Chinese patent application CN109734661A uses 4-cyano-3-hydroxyaniline as a starting material, which is methylated with dimethyl carbonate, oximeized with propionic acid at room temperature, and cyclized under PPA conditions to form 6-cyano-7-methoxy-4-quinolinone. This is followed by 6-cyano-7-methoxy-4-chlorolinone under thionyl chloride reaction. The cyano group is then hydrolyzed under acidic conditions to synthesize 6-formamido-7-methoxy-4-chloroquinoline, one of the intermediates of lenvatinib. Subsequently, 4-hydroxy-2-chloroaniline is reacted with cyanogen bromide at low temperature to form 4-hydroxy-2-chlorocyanamide. The 4-hydroxy-2-chlorocyanamide is then reacted with bromopropane via a Ritter reaction to synthesize 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, another key intermediate of lenvatinib. Finally, lenvatinib was obtained by alkylation of the two intermediates, 6-formamido-7-methoxy-4-chloroquinoline and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea, under alkaline conditions. However, the starting material 4-cyano-3-hydroxyaniline is difficult to obtain, and the overall reaction route is long with a low yield, making it difficult to scale up for industrial production. The synthetic route is shown below:

[0020]

[0021] In summary, given the many shortcomings of current methods for preparing lenvatinib in terms of process safety, cumbersome operation, low yield, and high production cost, finding a reaction route suitable for the industrial production of lenvatinib with mild reaction conditions, simple operation, high product yield and purity, and low production cost remains a problem that needs to be solved. Summary of the Invention

[0022] To address the problems of long routes, cumbersome operations, low yield, low purity, high technical requirements, and high production costs in existing lenvatinib preparation techniques, this invention provides a novel method for synthesizing lenvatinib. Lenvatinib prepared by this method exhibits high purity and yield, making it suitable for industrial production.

[0023] The specific technical solution of the present invention is as follows: A method for preparing lenvatinib, characterized in that intermediate compound I-1 is prepared from compounds SM-1 and SM-2 as starting materials, and compound I-1 and SM-3 react to obtain target compound I; the reaction route is as follows:

[0024]

[0025] Preferably, the above steps will be described in detail in the following sections:

[0026] Preparation of compound I-1

[0027] The preparation of compound I-1 includes the following steps: at room temperature, compound SM-1, compound SM-2, and a base are added to organic solvent A, and the temperature is controlled at T. A After the reaction is complete, compound I-1 is obtained. The reaction route is as follows:

[0028]

[0029] Preferably, the alkali is selected from one or a combination of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium methoxide, with potassium hydroxide being particularly preferred.

[0030] Preferably, the organic solvent A is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone, with dimethyl sulfoxide being particularly preferred.

[0031] Preferably, the molar ratio of compound SM-1, compound SM-2, and alkali is 1:1.1 to 1.8:2.5 to 5.0, and particularly preferably 1:1.3:3.0.

[0032] Preferably, the temperature control T A The temperature range is 60–100℃, with 70–75℃ being preferred.

[0033] In a preferred embodiment, a post-processing operation is required after the reaction is completed. Specifically, the reaction solution is cooled to room temperature, purified water is added, the mixture is cooled, stirred to induce crystallization, and then filtered. The resulting filter cake is dried under reduced pressure to obtain compound I-1.

[0034] Preparation of Compound I

[0035] The preparation of compound I includes the following steps: compound I-1, compound SM-3, and an acid-binding agent are added to organic solvent B, and the mixture is subjected to ultrasonic treatment at a controlled temperature T. B1 After the reaction is complete, add alkaline water to adjust the pH and control the temperature at T. B2 The target compound I was obtained via the following reaction route:

[0036]

[0037] Preferably, the organic solvent B is selected from one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone, with dimethyl sulfoxide being particularly preferred.

[0038] Preferably, the acid-binding agent is selected from one of N,N-diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and sodium carbonate, with N,N-diisopropylethylamine being particularly preferred.

[0039] Preferably, the molar ratio of compound I-1, compound SM-3, and acid-binding agent is 1:1.0-1.5:1.1-1.8, and particularly preferably 1:1.05:1.2.

[0040] Preferably, the alkaline solution is selected from one or a combination of sodium hydroxide solution, potassium hydroxide solution, and barium hydroxide solution, with sodium hydroxide solution being particularly preferred.

[0041] Preferably, the pH of the solution system after adding alkaline water is 11-14, and more preferably pH is 12.

[0042] Preferably, the temperature control T B1 The temperature range is 15–50℃, with 30–35℃ being particularly preferred; T B2 The temperature range is 50–100℃, with 75–80℃ being particularly preferred.

[0043] In a preferred embodiment, a post-processing operation is required after the reaction, specifically: acetone / purified water is added to the reaction solution, the mixture is cooled, stirred to induce crystallization, and then filtered. The resulting filter cake is dried under reduced pressure to obtain target compound I. Preferably, the volume ratio of acetone to purified water is 1:2 to 4 ml / ml, particularly preferably 1:3 ml / ml.

[0044] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0045] (1) The present invention uses compound SM-3 as the synthon for constructing the functional group "urea", which can effectively avoid the use of phenyl chloroformate, which has high toxicity.

[0046] (2) The target product can be prepared by reacting compound SM-3 with compound I-1, adjusting the alkali and continuing the reaction, which can effectively reduce unit operations and working time.

[0047] (3) The target product obtained by this process has high purity and yield, and is suitable for industrial-scale production.

[0048] In summary, this invention provides a novel method for preparing lenvatinib, which effectively avoids the use of hazardous chemical reagents, and the synthesis operation is simpler, with high yield and purity, making it suitable for industrial production. Detailed Implementation

[0049] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0050] The structure of the lenvatinib intermediate compound I-1 obtained in this invention is confirmed as follows:

[0051]

[0052] ESI-HRMS(m / z):363.0301, 365.0272[M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 8.90 (d, J=7.6Hz, 1H), 8.64 (s, 1H), 7.90 (s, 2H), 7.71 (s, 1H), 7.63 (d, J= 7.6Hz, 1H), 7.50 (d, J = 7.5Hz, 1H), 7.24 (dd, J = 7.5, 1.3Hz, 1H), 7.10 (d, J = 1.3Hz, 1H), 3.96 (s, 3H); 13 CNMR(151MHz,DMSO-d6)δ:168.42,161.53,160.26,155.42,152.20,148.14,132.43 ,130.45,124.37,126.78,121.29,118.46,116.49,115.02,111.45,108.93,54.64.

[0053] The structure of lenvatinib compound I obtained in this invention is confirmed as follows:

[0054]

[0055] ESI-HRMS(m / z):427.1170, 429.1154[M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 8.65 (d, J = 5.2 Hz, 1H), 8.57 (s, 1H), 8.28 (d, J = 9.1 Hz,1H),7.90(s,1H),7.64(s,1H),7.58(s,1H),7.52(s,1H),7.48(d,J=2.8H z,1H),7.24(dd,J=9.1,2.8Hz,1H),7.20(d,J=2.8Hz,1H),6.53(d,J=5.2Hz ,1H),4.04(s,3H),2.54~2.62(m,1H),0.64~0.68(m,2H),0.41~0.45(m,2H); 13C NMR (151MHz, DMSO-d6) δ: 165.40,161.96,159.48,155.38,153.29,152.21,148.37,134.94,1 25.19,124.42,122.46,121.81,121.56,120.07,114.23,107.08,102.23,56.79,22.96,6.92.

[0056] This invention uses HPLC to determine the purity of lenvatinib, and the chromatographic conditions are as follows:

[0057] Column: YMC-Pack Pro C 18 Column (4.6 mm × 150 mm, 3 μm) or equivalent chromatographic column;

[0058] Mobile phases: Mobile phase A: Water-acetonitrile-perchloric acid (70%) (990:10:1) (V:V:V); Mobile phase B: Water-acetonitrile-perchloric acid (70%) (100:900:1) (V:V:V)

[0059] Column temperature: 25℃;

[0060] Detection wavelength: 252nm;

[0061] Flow rate: 1.0 ml / min;

[0062] Injection volume: 10 μl;

[0063] Lenvatinib has a retention time of approximately 23.0 minutes.

[0064] The elution gradient is shown in Table 1:

[0065] Table 1 Elution gradient table

[0066]

[0067] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0068] Synthesis of compound I-1

[0069] Example 1

[0070] At room temperature, a solution of compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (42.38 g, 0.26 mol), and potassium hydroxide (33.66 g, 0.60 mol) in water (40 ml) was added to dimethyl sulfoxide (600 ml). The reaction was carried out at 70–75 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 97.5% and an HPLC purity of 99.92%.

[0071] Example 2

[0072] Compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (35.86 g, 0.22 mol), and potassium tert-butoxide (67.33 g, 0.60 mol) were added to dimethyl sulfoxide (600 ml) at room temperature. The reaction was carried out at 85–90 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 93.7% and an HPLC purity of 99.62%.

[0073] Example 3

[0074] Compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (32.60 g, 0.20 mol), and sodium methoxide (32.41 g, 0.60 mol) were added to dimethyl sulfoxide (600 ml) at room temperature. The reaction was carried out at 90–95 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 87.3% and an HPLC purity of 98.82%.

[0075] Example 4

[0076] Compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (58.68 g, 0.36 mol), and N-methylmorpholine (60.69 g, 0.60 mol) were added to dimethyl sulfoxide (600 ml) at room temperature. The reaction was carried out at 65–70 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 94.1% and an HPLC purity of 99.56%.

[0077] Example 5

[0078] Compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (64.79 g, 0.40 mol), and N,N-diisopropylethylamine (77.55 g, 0.60 mol) were added to acetonitrile (600 ml) at room temperature. The reaction was carried out at 60–65 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 88.7% and an HPLC purity of 98.53%.

[0079] Example 6

[0080] At room temperature, a solution of compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (42.38 g, 0.26 mol), and sodium hydroxide (20.00 g, 0.50 mol) in water (30 ml) was added to N-methylpyrrolidone (600 ml). The reaction was carried out at 60–65 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 93.8% and an HPLC purity of 99.71%.

[0081] Example 7

[0082] At room temperature, a solution of compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (42.38 g, 0.26 mol), and potassium hydroxide (25.81 g, 0.46 mol) in water (30 ml) was added to dimethyl sulfoxide (600 ml). The reaction was carried out at 55–60 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 85.3% and an HPLC purity of 98.75%.

[0083] Example 8

[0084] At room temperature, a solution of compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (42.38 g, 0.26 mol), and potassium carbonate (138.20 g, 1.00 mol) in water (120 ml) was added to N,N-dimethylacetamide (600 ml). The reaction was carried out at 95–100 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 94.8% and an HPLC purity of 99.60%.

[0085] Example 9

[0086] Compound SM-1 (47.33 g, 0.2 mol), compound SM-2 (42.38 g, 0.26 mol), and triethylamine (105.24 g, 1.04 mol) were added to N,N-dimethylformamide (600 ml) at room temperature. The reaction was carried out at 100–105 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature, purified water (5000 ml) was added, and the mixture was further cooled by 5–10 °C with stirring to induce crystallization. The mixture was then filtered, and the resulting filter cake was dried under reduced pressure to obtain compound I-1 with a yield of 88.7% and an HPLC purity of 98.51%.

[0087] Synthesis of Compound I

[0088] Example 10

[0089] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (16.18 g, 0.1 mol), and N,N-diisopropylethylamine (15.51 g, 0.12 mol) were added to dimethyl sulfoxide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete (compound I-1 was completely reacted), 30% sodium hydroxide solution was added and the pH was adjusted to 12. The mixture was then sonicated and reacted at a controlled temperature of 75–80 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled by 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 98.6% and an HPLC purity of 99.95%.

[0090] Example 11

[0091] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (15.41 g, 0.1 mol), and N,N-diisopropylethylamine (15.51 g, 0.12 mol) were added to dimethyl sulfoxide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 15–20 °C. After the reaction was confirmed to be complete, 30% barium hydroxide solution was added and the pH was adjusted to 11. The mixture was then sonicated and reacted at a controlled temperature of 50–55 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled to 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 93.6% and an HPLC purity of 99.72%.

[0092] Example 12

[0093] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (23.11 g, 0.15 mol), and N,N-diisopropylethylamine (15.51 g, 0.12 mol) were added to dimethyl sulfoxide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 45–50 °C. After the reaction was confirmed to be complete, 30% sodium hydroxide solution was added and the pH was adjusted to 13. The mixture was then sonicated and reacted at a controlled temperature of 95–100 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:4) was added. The mixture was cooled to 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 94.3% and an HPLC purity of 99.55%.

[0094] Example 13

[0095] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (26.19 g, 0.17 mol), and N,N-diisopropylethylamine (15.51 g, 0.12 mol) were added to dimethyl sulfoxide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 50–55 °C. After the reaction was confirmed to be complete, 30% sodium hydroxide solution was added and the pH was adjusted to 14. The mixture was then sonicated and reacted at a controlled temperature of 100–105 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:2) was added. The mixture was cooled to 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 87.9% and an HPLC purity of 98.56%.

[0096] Example 14

[0097] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (16.18 g, 0.105 mol), and sodium carbonate (11.66 g, 0.11 mol) were added to N-methylpyrrolidone (300 ml). The mixture was sonicated and reacted at a controlled temperature of 40–45 °C. After the reaction was confirmed to be complete, 30% sodium hydroxide solution was added and the pH was adjusted to 12. The mixture was then sonicated and reacted at a controlled temperature of 75–80 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled to 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 94.0% and an HPLC purity of 99.68%.

[0098] Example 15

[0099] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (16.18 g, 0.105 mol), and potassium carbonate (13.82 g, 0.1 mol) were added to dimethyl sulfoxide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 10–15 °C. After the reaction was confirmed to be complete, 30% potassium hydroxide solution was added and the pH was adjusted to 12. The mixture was then sonicated and reacted at a controlled temperature of 45–50 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled to 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 88.9% and an HPLC purity of 98.92%.

[0100] Example 16

[0101] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (16.18 g, 0.105 mol), and pyridine (14.24 g, 0.18 mol) were added to N,N-dimethylacetamide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 30–35 °C. After the reaction was confirmed to be complete, 30% sodium hydroxide solution was added and the pH was adjusted to 12. The mixture was then sonicated and reacted at a controlled temperature of 75–80 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled by 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 94.8% and an HPLC purity of 99.58%.

[0102] Example 17

[0103] Compound I-1 (36.32 g, 0.1 mol), compound SM-3 (16.18 g, 0.105 mol), and triethylamine (20.24 g, 0.20 mol) were added to N,N-dimethylformamide (300 ml). The mixture was sonicated and reacted at a controlled temperature of 25–30 °C. After the reaction was confirmed to be complete, 30% sodium hydroxide solution was added and the pH was adjusted to 12. The mixture was then sonicated and reacted at a controlled temperature of 75–80 °C. After the reaction was confirmed to be complete, acetone / purified water (900 ml, V:V = 1:3) was added. The mixture was cooled by 5–10 °C, stirred to induce crystallization, and then filtered. The resulting filter cake was dried under reduced pressure to obtain the target compound I, with a yield of 89.3% and an HPLC purity of 98.62%.

Claims

1. A method for preparing lenvatinib, characterized in that, The preparation method includes the following steps: 1) At room temperature, add compound SM-1, compound SM-2, and the base to organic solvent A, and control the temperature T. A After the reaction is complete, compound I-1 is obtained; 2) Add compound I-1, compound SM-3, and the acid-binding agent to organic solvent B, and sonicate at a controlled temperature T. B1 After the reaction is complete, add alkaline water to adjust the pH and control the temperature at T. B2 Target compound I was obtained; Among them, the temperature control T mentioned in step 2) B1 The temperature range is 15℃ to 50℃, T B2 The temperature range is 50℃ to 100℃. The synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 1) is selected from N , N -Diisopropylethylamine, Triethylamine, N One or a combination of methylmorpholine, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium methoxide.

3. The preparation method according to claim 1, characterized in that, The organic solvent A mentioned in step 1) is selected from... N , N -Dimethylformamide, N , N - Dimethylacetamide, dimethyl sulfoxide, acetonitrile or N One or a combination of methylpyrrolidones.

4. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM-1, compound SM-2, and alkali in step 1) is 1:1.1~1.8:2.5~5.

0.

5. The preparation method according to claim 1, characterized in that, Step 1) Temperature control T A The temperature ranges from 60 to 100℃.

6. The preparation method according to claim 1, characterized in that, The organic solvent B mentioned in step 2) is selected from... N , N -Dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide or N One or a combination of methylpyrrolidones.

7. The preparation method according to claim 1, characterized in that, Step 2) The acid-binding agent is selected from N , N - One of diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and sodium carbonate.

8. The preparation method according to claim 1, characterized in that, In step 2), the molar ratio of compound I-1, compound SM-3, and acid-binding agent is 1:1.0~1.5:1.1~1.

8.

9. The preparation method according to claim 1, characterized in that, The alkaline solution mentioned in step 2) is selected from one of sodium hydroxide solution, potassium hydroxide solution, and barium hydroxide solution.

10. The preparation method according to claim 1, characterized in that, Step 2) involves adding alkaline water to adjust the pH to 11-14.

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