A preparation method of lenvatinib mesylate

Abstract

The present invention provides a method for preparing lenvatinib mesylate. The preparation method provided by the present invention comprises: a) mixing methanesulfonic acid, acetic acid and water to obtain a mixed solution; b) mixing the mixed solution with lenvatinib, reacting to form a salt, and obtaining a reaction solution; c) mixing the reaction solution with a crystallization solvent for crystallization, solid-liquid separation, and then washing with a crystallization solvent, drying, and obtaining lenvatinib mesylate; the crystallization solvent is ethyl acetate and alcohol. The method provided by the present invention has mild reaction conditions, no agglomeration during the reaction process, increased yield and purity, and low impurity content such as intermediate B, ZZ6 and ZZ7.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a method for preparing lenvatinib mesylate. Background Art

[0002] Lenvatinib was approved for marketing by the U.S. FDA in February 2015. Its marketed salt is the mesylate salt, which is clinically used for liver cancer and thyroid cancer (local recurrence / metastasis, progressive radioactive iodine-refractory differentiated thyroid cancer).

[0003] The chemical name of lenvatinib is 4-[3-chloro-4-(N-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide, and its structural formula is as follows:

[0004]

[0005] The structural formula of lenvatinib mesylate is as follows:

[0006]

[0007] The preparation method of lenvatinib mesylate is reported as follows:

[0008] 200480036184.1 (publication number CN1890220A) discloses a method for preparing a mesylate (see Example 7 for details), wherein preparation method 3 is to react lenvatinib free base with acetic acid and methanesulfonic acid, then add 2-propanol and seed crystals to obtain crystals, then wash with 2-propanol and ethanol respectively, and dry to obtain. Preparation method 4 is to add lenvatinib to acetic acid, and then add methanesulfonic acid.

[0009] 202010735709.1 (publication number CN113999173A) discloses a method for preparing lenvatinib mesylate, and Example 5 thereof discloses the following scheme: 1) dissolving lenvatinib in acetone and acetic acid, and then dropping a tetrahydrofuran solution of methanesulfonic acid to obtain lenvatinib mesylate. The ratio of lenvatinib to acetic acid is 1 g: 1 mL, and the molar ratio of lenvatinib to methanesulfonic acid is 1: 1.

[0010] 201910190726.9 (publication number CN111689897A) discloses a method for preparing lenvatinib mesylate, which mainly comprises dissolving lenvatinib free base in a solvent, methanesulfonic acid or a methanesulfonic acid solution containing a solvent, filtering and drying to obtain lenvatinib mesylate. The solvent is methanol, ethanol, acetone, or ethyl acetate.

[0011] It can be known from the above patents that most of the prior art methods use lenvatinib free base dissolved in a solvent and methanesulfonic acid, and then react to obtain lenvatinib mesylate.

[0012] The commonly used synthetic route of lenvatinib mesylate is:

[0013]

[0014] The applicant has found that the following problems exist in the preparation process of lenvatinib mesylate:

[0015] 1) After adding lenvatinib to the reaction system (acetic acid and methanesulfonic acid) at room temperature, the reaction system will swell and agglomerate, and it is difficult to dissolve and clarify even after long-term stirring. If the production is scaled up, the stirring will easily get stuck, and it will also cause incomplete salt formation of some lenvatinib.

[0016] 2) Impurities ZZ4 and ZZ6 exist, among which the molecular formula of impurity ZZ4 is C 21 H 17 C1N 4 O 3 , the molecular weight is 408.84, and the impurity ZZ6 is generated by ZZ4, as follows:

[0017]

[0018] Production of ZZ4: During the preparation of lenvatinib mesylate, when preparing intermediate B, intermediate B reacts with excess phenyl chloroformate in the presence of DMF (dimethylformamide), resulting in the production of ZZ4. The reaction formula is as follows:

[0019]

[0020] Production of ZZ6: ZZ4 will continue to react with cyclopropylamine to obtain impurity ZZ6. The reaction formula is as follows:

[0021]

[0022] The structural characteristics of ZZ6 are extremely similar to those of lenvatinib, and its solubility properties are also similar, making it difficult to purify. Research has found that ZZ6 further increases after being enriched in the free base of lenvatinib, and recrystallization purification has no effect, but instead has an enrichment effect on the impurity.

[0023] 3) When preparing lenvatinib mesylate, the reaction is carried out at 40°C, which will also degrade and generate impurity ZZ7 (an impurity within the registration standard for imported preparations); this will further make the subsequent crystal preparation difficult. At the same time, the addition of alcohol solvents requires long-term heating and stirring, which is easy to generate mesylate-based toxic impurities, increasing the risk of quality control.

[0024] The ZZ7 structure is as follows:

[0025]

[0026] Based on the above, it is crucial to solve problems such as incomplete reaction, difficulty in separating impurities, and impurities generated by high-temperature degradation. Summary of the invention

[0027] In view of this, the present invention provides a method for preparing lenvatinib mesylate. The preparation method provided by the present invention can solve the problems of incomplete reaction, difficulty in separating impurities, and impurities generated by high temperature degradation, and can effectively improve product yield and purity and reduce impurities.

[0028] The present invention provides a method for preparing lenvatinib mesylate, comprising the following steps:

[0029] a) mixing methanesulfonic acid, acetic acid and water to obtain a mixed solution;

[0030] b) mixing the mixed solution with lenvatinib to react into a salt to obtain a reaction solution;

[0031] c) mixing the reaction solution with a crystallization solvent for crystallization, solid-liquid separation, and then washing with the crystallization solvent and drying to obtain lenvatinib mesylate;

[0032] The crystallization solvents are ethyl acetate and alcohol.

[0033] Preferably, in step a), the ratio of methanesulfonic acid, acetic acid and water is 1 g: (25.0-26.5) mL: (0.35-8.40) mL; preferably 1: (25.0-26.5): (2-6.3); more preferably 1: (25.0-26.5): (4.2-6.3).

[0034] Preferably, the molar ratio of lenvatinib in step b) to methanesulfonic acid in step a) is 1:(1.00-1.10).

[0035] Preferably, the molar ratio of lenvatinib in step b) to methanesulfonic acid in step a) is 1:(1.00-1.06).

[0036] Preferably, in step c), the alcohol is at least one of ethanol, n-propanol and isopropanol.

[0037] Preferably, in step c), the volume ratio of ethyl acetate to alcohol in the crystallization solvent is (2.8-3.2):1.

[0038] Preferably, in step b), the reaction temperature is 20-30°C.

[0039] Preferably, in step b), the reaction time is 1 to 2 hours.

[0040] Preferably, in step c), the drying temperature is 35-55°C.

[0041] Preferably, in step c), the solid-liquid separation is carried out by filtration; and the washing is carried out by washing the filter cake obtained by filtration.

[0042] The preparation method provided by the present invention first mixes methanesulfonic acid, acetic acid and water to obtain a mixed solution, then adds lenvatinib to react to form a salt, and then adds a certain crystallization solvent (ethyl acetate and alcohol) to crystallize, separate the solid and liquid, and wash and dry with a crystallization solvent again to obtain lenvatinib mesylate. The present invention first prepares a mixed solution with methanesulfonic acid, acetic acid and water, and then adds lenvatinib, the system no longer agglomerates, the dissolution time is shortened, and after adding water and acetic acid as a primer, lenvatinib can be quickly dissolved, and the system will not have the phenomenon of suspended agglomeration, and the salt formation efficiency is higher; and changing the timing of adding methanesulfonic acid and adding water to the system, the room temperature can react to form a salt, and high temperature is not required, which is more economical and environmentally friendly; and the present invention adds water as a primer to prepare mesylate, which is easier to crystallize, and at the same time, sulfonate impurities are not easy to appear at room temperature. Therefore, the method provided by the present invention has mild reaction conditions, no agglomeration during the reaction process, increased yield and purity, and less impurity content such as intermediate B, ZZ6 and ZZ7.

[0043] The test results show that the preparation method of the present invention has mild reaction conditions, no agglomeration during the reaction process, a product yield of more than 95.3%, a purity of more than 99.88%, and impurities such as the content of intermediate B less than 0.01%, the content of ZZ6 less than 0.05%, and the content of ZZ7 less than 0.05%. DETAILED DESCRIPTION

[0044] The present invention provides a method for preparing lenvatinib mesylate, comprising the following steps:

[0045] a) mixing methanesulfonic acid, acetic acid and water to obtain a mixed solution;

[0046] b) mixing the mixed solution with lenvatinib to react into a salt to obtain a reaction solution;

[0047] c) mixing the reaction solution with a crystallization solvent for crystallization, solid-liquid separation, and then washing with the crystallization solvent and drying to obtain lenvatinib mesylate;

[0048] The crystallization solvents are ethyl acetate and alcohol.

[0049] Regarding step a) :

[0050] a) Methanesulfonic acid, acetic acid and water are mixed to obtain a mixed solution.

[0051] In the present invention, the water is preferably deionized water. In the present invention, the usage ratio of the methanesulfonic acid, acetic acid and water is preferably 1g: (25.0-26.5) mL: (0.35-8.40) mL, and the above ratio 1g: (25.0-26.5) mL: (0.35-8.40) mL is also equivalent to 1kg: (25.0-26.5) L: (0.35-8.40) L, and the three amounts can be enlarged or reduced compared with each other, as long as they are in the above ratio. The above ratio can be specifically 1g:25.0mL:0.35mL, 1g:25.5mL:0.35mL, 1g:26.0mL:0.35mL, 1g:26.4mL:0.35mL, 1g:26.5mL:0.35mL, 1g:26.4mL:4.2mL, 1g:26.4mL:8.40mL, 1g:26.5mL:4.2mL, 1g:26.4mL:8.40mL, and the above ratio is further preferably 1g:(25.0-26.5)mL:(2-6.3)mL, further preferably 1g:(25.0-26.5)mL:(4.2-6.3)mL, and most preferably 1g:26.4mL:4.2mL.

[0052] The present invention has no particular limitation on the method of mixing methanesulfonic acid, acetic acid and water, and the materials can be mixed uniformly according to conventional mixing methods in the art, such as stirring and mixing. After mixing, a mixed solution is obtained.

[0053] Regarding step b) :

[0054] b) mixing the mixed solution with lenvatinib to react into a salt to obtain a reaction solution.

[0055] In the present invention, the source of lenvatinib is not particularly limited, and it can be a commercial product or prepared according to a conventional preparation method known to those skilled in the art. After the mixed solution is obtained in step a) of the present invention, lenvatinib can be added to the obtained mixed solution to mix the two and react to form a salt.

[0056] In the present invention, the molar ratio of lenvatinib in step b) to methanesulfonic acid in step a) is preferably 1:(1.00-1.10), specifically 1:1.00, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.10, more preferably 1:(1.00-1.06), most preferably 1:1.06.

[0057] In the present invention, the reaction can be carried out at room temperature, which can be 20-30°C, specifically 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C. The reaction time is preferably 1-2h, specifically 1h, 1.5h, 2h, until the system is dissolved. After the reaction, lenvatinib is salified to form lenvatinib mesylate, and a reaction solution containing the reaction product is obtained in the system.

[0058] In the present invention,

[0059] Regarding step c) :

[0060] c) mixing the reaction solution with a crystallization solvent for crystallization, separating the solid from the liquid, and then washing with the crystallization solvent and drying to obtain lenvatinib mesylate.

[0061] In the present invention, in some embodiments of the present invention, after obtaining the reaction solution in step b), solid-liquid separation is further performed, and the obtained separated liquid is used for subsequent steps. Wherein, the solid-liquid separation method is preferably filtration, and the obtained filtrate is used for the subsequent step, that is, the filtrate is mixed with a crystallization solvent for crystallization.

[0062] In the present invention, the crystallization solvent is a mixture of ethyl acetate and alcohol. Wherein, the alcohol is an alcohol solvent, preferably at least one of ethanol, n-propanol and isopropanol, and more preferably ethanol. In the present invention, in the crystallization solvent, the volume ratio of ethyl acetate to alcohol is preferably (2.8-3.2):1, specifically 2.8:1, 2.9:1, 3.0:1, 3.1:1, 3.2:1, and more preferably 3:1.

[0063] In the present invention, the ratio of the crystallization solvent to the amount of lenvatinib in step b) is preferably 1 g: (3.8-4.2) mL.

[0064] The temperature for crystallization of the reaction solution mixed with the crystallization solvent is not particularly limited, and can be carried out at room temperature, which can be 20 to 30°C, specifically 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C. The crystallization time is preferably 1 to 2h, specifically 1h, 1.5h, 2h. The crystallization solvent is used for crystallization treatment to obtain lenvatinib mesylate.

[0065] In the present invention, after the above crystallization treatment, solid-liquid separation is performed to separate the liquid and the crystals. In the present invention, the solid-liquid separation is preferably performed by filtration.

[0066] In the present invention, after the above-mentioned solid-liquid separation, the obtained solid crystals are washed with a crystallization solvent, specifically, the filter cake obtained by the previous solid-liquid separation (such as filtration) is washed. The types of components and the proportional relationship between the components in the crystallization solvent are consistent with those described above, that is, the crystallization solvent is a mixture of ethyl acetate and alcohol. Among them, the alcohol is an alcohol solvent, preferably at least one of ethanol, n-propanol and isopropanol, and more preferably ethanol. In the crystallization solvent, the volume ratio of ethyl acetate to alcohol is preferably (2.8-3.2):1, specifically 2.8:1, 2.9:1, 3.0:1, 3.1:1, 3.2:1, and more preferably 3:1. The volume ratio of the crystallization solvent used for washing to the crystallization solvent used in the crystallization step is preferably 1:3. In the present invention, the washing method is preferably filtration washing, that is, washing the filter cake obtained by the previous solid-liquid separation. Washing with a crystallization solvent is to wash acetic acid and other substances on the surface of lenvatinib mesylate. In some embodiments of the present invention, after washing with a crystallization solvent, ethanol is used for pulping, filtering and washing; specifically, the filter cake obtained after washing with a crystallization solvent is pulped and filtered with ethanol, and then the filter cake is washed with ethanol; the above operation can be repeated.

[0067] In the present invention, after the above washing, drying is performed. The drying method can be air drying. In the present invention, the drying temperature is preferably 35 to 55° C., specifically 35° C., 40° C., 45° C., 50° C., 55° C. After drying, lenvatinib mesylate is obtained.

[0068] The synthesis method provided by the present invention has the following beneficial effects:

[0069] 1. Based on the problems of incomplete reaction and difficulty in removing impurities in the synthesis process of lenvatinib in the prior art, the applicant has made many attempts:

[0070] Using preparation methods 3 and 4 of CN1890220A, whether adding lenvatinib to a mixed solution of acetic acid and methanesulfonic acid, or adding lenvatinib to acetic acid and then adding methanesulfonic acid, the system expands rapidly and the stirring is blocked. After trying multiple solutions, the agglomeration problem still cannot be solved. This solution is difficult to solve.

[0071] When solving the problem of impurity ZZ6, by adding an appropriate amount of water to the reaction system, ZZ6 can be partially hydrolyzed into amide under acidic conditions of salt formation to generate lenvatinib, thereby achieving the purpose of reducing the content of ZZ6. The hydrolysis of ZZ6 is shown in the following formula:

[0072]

[0073] Adding water can solve the problem of impurity ZZ6. Then we tried to add water to the reaction system and found that when lenvatinib was added to a mixed solution of acetic acid and water and then methanesulfonic acid was added, the dispersion effect of the system was improved, but agglomeration still occurred and required long-term stirring to dissolve.

[0074] After a large number of experiments, the applicant finally found that by first preparing a mixed solution of methanesulfonic acid, acetic acid and water and then adding lenvatinib, the system no longer agglomerates and the dissolution time is shortened.

[0075] At the same time, it was unexpectedly discovered that by changing the timing of adding methanesulfonic acid and adding water, the salt can be reacted at room temperature without the need for high temperature.

[0076] 2. In the process of preparing salt, the present invention overcomes the shortcomings of the prior art by adjusting the addition time of methanesulfonic acid, adding water, and using acetic acid and water as solvents:

[0077] (1) The use of substrate water promotes the removal of the process dehydration impurity ZZ6 and improves the quality. In the process of preparing the mesylate, 0.5 to 2 volumes of water are added to the weight ratio of lenvatinib to partially hydrolyze ZZ6, so that the removal rate of ZZ6 reaches more than 50%.

[0078] (2) Better process conditions: Lenvatinib free base has poor solubility in acetic acid and easily forms solvates with acetic acid. During the dissolution process, the system swells, further leading to agglomeration. However, after adding water or other acids as a base in the present invention, Lenvatinib can be quickly dissolved, and the system will not suspend and agglomerate, and the salt formation efficiency is higher.

[0079] (3) More economical and environmentally friendly: Heating acetic acid at high temperature increases the emission of corrosive gases such as acetic acid, increases the pressure of the air conditioning system and the tail gas emission treatment system in the fine drying bag, and lenvatinib is OEB4 level, and high-temperature preparation increases the biosafety risk. The addition of water in the present invention reduces the amount of acetic acid used, and at the same time avoids salt formation under high temperature conditions, which can be achieved at room temperature, which is more economical and environmentally friendly.

[0080] (4) It is easier to convert to C crystal form and the quality is easier to control: In the present invention, water is added as a base to prepare the methanesulfonate, which is easier to convert to crystal form. At the same time, sulfonate impurities are not likely to appear at room temperature.

[0081] 3. The solution provided by the present invention has mild reaction conditions, no agglomeration during the reaction process, increased yield and purity, and impurity content analysis shows that the content of intermediates B, ZZ6 and ZZ7 is low.

[0082] 4. According to conventional understanding, using diluted acetic acid as a solvent will inevitably have a negative impact on reaction conditions, yield, purity, etc. However, the applicant has found that by adopting the scheme of the present invention, reaction conditions such as temperature are not only not increased, but reduced, and the yield and purity are also improved to varying degrees.

[0083] The test results show that the preparation method of the present invention has mild reaction conditions, no agglomeration during the reaction process, a product yield of more than 95.3%, a purity of more than 99.88%, and impurities such as the content of intermediate B less than 0.01%, the content of ZZ6 less than 0.05%, and the content of ZZ7 less than 0.05%.

[0084] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0085] Note: The amounts of acetic acid, ethyl acetate and ethanol in some embodiments are relatively large, and the units used for weighing are kg, which are obtained by converting volume and density. Among them, the relative density of acetic acid is 1.05 (g / ml), the relative density of ethyl acetate is 0.9 (g / ml), and the relative density of ethanol is 0.789 (g / ml).

[0086] Screening Example 1: Preparation of Lenvatinib Mesylate

[0087] S1, methanesulfonic acid (0.345 kg, 3.59 mol), and 1.514 kg acetic acid (1.44 L) were mixed to prepare a mixed solution;

[0088] S2. Disperse lenvatinib (1.442 kg, 3.38 mol) in 7.571 kg of acetic acid (7.21 L), add to the mixed solution obtained in step S1 within 1 hour, and react at 25° C. for 3 hours until the system is dissolved.

[0089] S3, add 35.041kg ethyl acetate (38.93L) and 10.240kg ethanol (12.98L) mixed solution (the volume ratio of ethyl acetate to ethanol is 3:1) to the reaction system, crystallize for 2h, filter, and wash the filter cake with 11.680kg ethyl acetate (12.98L) and 3.413kg ethanol (4.33L) mixed solution (the volume ratio of ethyl acetate to ethanol is 3:1). Dry with air at 50℃ to obtain 1.560kg lenvatinib mesylate, with a yield of 88.3% and a purity of 99.84%.

[0090] Screening Example 2: Preparation of Lenvatinib Mesylate

[0091] S1, methanesulfonic acid (0.48 g, 4.994 mmol), 2 mL of acetic acid and 169 μL of water were mixed to prepare a mixed solution;

[0092] S2. Add lenvatinib (2 g, 4.685 mmol) to the mixed solution obtained in step S1, and react at 25° C. for 2 h until the system is dissolved.

[0093] S3. Add 54 mL of a mixed solution of ethyl acetate and 18 mL of ethanol to the reaction system, crystallize for 1 hour, filter, and wash the filter cake with a mixed solution of 18 mL of ethyl acetate and 6 mL of ethanol. Dry at 50°C with air blast to obtain 2.31 g of lenvatinib mesylate. The yield is 94.3% and the purity is 99.83%.

[0094] Screening Example 3: Preparation of Lenvatinib Mesylate

[0095] S1, methanesulfonic acid (0.48 g, 4.994 mmol), 2 mL of acetic acid and 4 mL of water were mixed to prepare a mixed solution;

[0096] S2. Add lenvatinib (2 g, 4.685 mmol) to the mixed solution obtained in step S1, and react at 25° C. for 2 h until the system is dissolved.

[0097] S3. Add 54 mL of a mixed solution of ethyl acetate and 18 mL of ethanol to the reaction system, crystallize for 1 hour, filter, and wash the filter cake with a mixed solution of 18 mL of ethyl acetate and 6 mL of ethanol. Dry at 50°C with air blast to obtain 2.27 g of lenvatinib mesylate. The yield is 92.6% and the purity is 99.87%.

[0098] Example 1: Preparation of Lenvatinib Mesylate

[0099] a) methanesulfonic acid (13.1 g, 0.136 mol), 330 mL of acetic acid and 55 mL of water were mixed to prepare a mixed solution;

[0100] b) adding lenvatinib (55 g, 0.129 mol) to the mixed solution obtained in step 1), and reacting at 25° C. for more than 1 h until the system is dissolved;

[0101] c) Add 1485 mL of a mixed solution of ethyl acetate and 495 mL of ethanol (the weight ratio of ethyl acetate to ethanol is 1:0.33) to the reaction system, crystallize for 2 hours, and filter; wash the filter cake with a mixed solution of 495 mL of ethyl acetate and 165 mL of ethanol (the volume ratio of ethyl acetate to ethanol is 3:1). Dry at 40°C with air blast to obtain 64.96 g of lenvatinib mesylate. The yield is 96.4% and the purity is 99.93%.

[0102] Example 2: Preparation of Lenvatinib Mesylate

[0103] a) methanesulfonic acid (0.293 kg, 3.05 mol), 7.742 kg acetic acid (7.37 L) and 1.226 kg water (1.226 L) were mixed to prepare a mixed solution;

[0104] b) adding lenvatinib (1.226 kg, 2.87 mol) to the mixed solution obtained in step 1), and reacting at 25° C. for 1 h until the system is dissolved;

[0105] c) A mixed solution of 29.792 kg ethyl acetate (33.10 L) and 8.705 kg ethanol (11.03 L) (the volume ratio of ethyl acetate to ethanol is 3:1) was added to the reaction system, crystallized for 2 h, filtered, and the filter cake was washed with a mixed solution of 9.931 kg ethyl acetate (11.03 L) and 2.906 kg ethanol (3.68 L) (the volume ratio of ethyl acetate to ethanol is 3:1). The filter cake was slurried with 7.736 kg ethanol for 1 h, filtered, and the filter cake was washed with 1.937 kg ethanol. The filter cake was slurried with 7.736 kg ethanol for 1 h, filtered, and the filter cake was washed with 1.937 kg ethanol. 1.446 kg lenvatinib mesylate was obtained by air drying at 40 ° C. The yield was 96.3%, and the purity was 99.94%.

[0106] Example 3: Preparation of Lenvatinib Mesylate

[0107] a) methanesulfonic acid (0.48 g, 4.994 mmol), 2 mL of acetic acid and 1 mL of water were mixed to prepare a mixed solution;

[0108] b) adding lenvatinib (2 g, 4.685 mmol) to the mixed solution obtained in step 1), and reacting at 25° C. for 2 h until the system is clear;

[0109] c) adding a mixed solution of 54 mL of ethyl acetate and 18 mL of ethanol, crystallizing for 1 hour, filtering; washing the filter cake with a mixed solution of 18 mL of ethyl acetate and 6 mL of ethanol. Drying by air blast at 50° C. to obtain lenvatinib mesylate with a yield of 95.9% and a purity of 99.88%.

[0110] Example 4: Preparation of Lenvatinib Mesylate

[0111] a) methanesulfonic acid (0.48 g, 4.994 mmol), 2 mL of acetic acid and 3 mL of water were mixed to prepare a mixed solution;

[0112] b) adding lenvatinib (2 g, 4.685 mmol) to the mixed solution obtained in step 1), and reacting at 25° C. for 2 h until the system is clear;

[0113] c) Add a mixed solution of 54 mL of ethyl acetate and 18 mL of ethanol to the reaction system, crystallize for 1 hour, filter; wash the filter cake with a mixed solution of 18 mL of ethyl acetate and 6 mL of ethanol. Dry at 50° C. to obtain 2.34 g of lenvatinib mesylate, with a yield of 95.5% and a purity of 99.90%.

[0114] Comparative Example 1

[0115] S1. Disperse lenvatinib (2 g, 4.685 mmol) in 12 mL of acetic acid, add methanesulfonic acid (0.48 g, 4.994 mol), and react at 25°C for 2 h until the system is dissolved;

[0116] S2. Add 54 mL of a mixed solution of ethyl acetate and 18 mL of ethanol to the reaction system, crystallize for 1 hour, filter, and wash the filter cake with a mixed solution of 18 mL of ethyl acetate and 6 mL of ethanol. Dry at 50°C with air blast to obtain 2.17 g of lenvatinib mesylate. The yield is 88.6% and the purity is 99.82%.

[0117] Experimental Example 1: Experimental observation and product yield and purity

[0118] 1. Samples: Screening Examples 1-3, Examples 1-4, Comparative Example 1.

[0119] 2. Detection method:

[0120] 2.1. Observe the reaction phenomena during the experiment;

[0121] 2.2 Calculation of yield:

[0122] The output of lenvatinib mesylate / the input amount of lenvatinib×0.816×100%.

[0123] 2.3. Purity detection:

[0124] The determination was carried out in accordance with high performance liquid chromatography (General Rules 0512 of the Chinese Pharmacopoeia 2020 Edition).

[0125] Preparation of test sample: Weigh about 10 mg of sample, place in a 50 ml volumetric flask, add appropriate amount of DMSO (about 3 ml) to dissolve, add mobile phase B to the scale, shake well, and set aside.

[0126] Chromatographic conditions:

[0127] Mobile phase: Octadecylsilane bonded silica gel is used as filler (YMCpack C18, 75×4.6mm, 3μm or chromatographic column with equivalent performance); water-acetonitrile-perchloric acid (990:10:0.5) is used as mobile phase A, water-acetonitrile-perchloric acid (100:900:0.5) is used as mobile phase B, the flow rate is 1.2min per minute; the detection wavelength is 252nm; the column temperature is 45℃; the gradient elution is performed according to Table 1. Accurately measure 5μL of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the purity by the area normalization method.

[0128] Table 1: Gradient elution table

[0129] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 90 10 25 85 15 50 65 35 55 40 60 55.1 90 10 60 90 10

[0130] 3. Test results: See Table 2 for the test results of the above tests.

[0131] Table 2: Summary of experimental observations and product yield and purity

[0132] Reaction phenomenon Yield purity Screening Example 1 Local agglomeration does not affect stirring. Gradually disperse with dropwise addition 88.3％ 99.84％ Screening Example 2 No agglomeration 94.3％ 99.83％ Screening Example 3 No agglomeration 92.6％ 99.87％ Example 1 No caking occurs and it dissolves quickly. 96.4％ 99.93％ Example 2 Dispersed evenly, no agglomeration, fast dissolving speed 96.3％ 99.94％ Example 3 No caking, dissolves quickly 95.9％ 99.88％ Example 4 No caking, dissolves quickly 95.5％ 99.90％ Comparative Example 1 Local agglomeration 88.6％ 99.82％

[0133] It can be seen from the test results in Table 2 that both Screening Example 1 and Comparative Example 1 showed agglomeration, and the yields of Screening Examples 2-3 were low. However, Examples 1-4 showed no agglomeration, the reactions were relatively smooth, and the product yield and purity were both high.

[0134] 4. Analysis results and reasons:

[0135] 1) Mix methanesulfonic acid and acetic acid first, then add lenvatinib, or add lenvatinib to acetic acid and methanesulfonic acid. Local agglomeration occurs during the reaction and stirring is required (see Screening Example 1 and Comparative Example 1);

[0136] 2) Too little or too much water is added to methanesulfonic acid and acetic acid, and the yield is reduced (see Screening Example 2, where the amount of water is 0.35 times the weight of methanesulfonic acid, and Screening Example 3, where the amount of water is 8.3 times the weight of methanesulfonic acid);

[0137] 3) Mix methanesulfonic acid, acetic acid and water first, and then add lenvatinib. This will prevent agglomeration and increase the yield and purity (see Examples 1-4).

[0138] Experimental Example 2: Detection of Impurities

[0139] 1. Samples: Screening Examples 1-3, Examples 1-4, Comparative Example 1

[0140] 2. Detection method:

[0141] Specific detection methods for intermediate B, impurity ZZ6, and impurity ZZ7, wherein the structural formulas of intermediate B, impurities ZZ6, and ZZ7 are as described in the background technology. Among them, intermediate B may be brought by the raw materials, or it may be an impurity produced by intermediate degradation.

[0142] Determined by high performance liquid chromatography (General Rules 0512 of the Chinese Pharmacopoeia 2020 Edition).

[0143] Chromatographic conditions and gradient elution procedure were the same as in Experiment 1 above.

[0144] Accurately measure 5 μL of the test solution, inject it into the liquid chromatograph, record the chromatogram, and calculate the impurity content by the area normalization method.

[0145] 3. Test results: See Table 3.

[0146] Table 3: Impurity content test results

[0147]

[0148] Before the experiment, the detection method of the present invention was used to detect the content of ZZ6 in the reaction raw material lenvatinib free base (ie, lenvatinib), and the results showed that ZZ6 was generally between 0.10% and 0.15%.

[0149] It can be seen from the test results in Table 3 that in the products of Examples 1-2, intermediate B was not detected, the content of ZZ6 was less than 0.05%, and the content of ZZ7 was less than 0.05%; in Examples 3-4, the amount of water was too much, and ZZ6 did not continue to decrease, while the amount of water was too little, and ZZ6 increased; in other screening examples and Comparative Example 1, intermediate B and ZZ6 were both high.

[0150] 4. Analysis results:

[0151] 1) Without adding water, the contents of intermediates B, ZZ6 and ZZ7 were high (see Screening Example 1 and Comparative Example 1);

[0152] 2) Even if water is added, the impurity content varies depending on the amount added. When the amount of water is 0.35 times or 8.3 times that of methanesulfonic acid, the content of intermediate A is 0.02%, and the content of impurity ZZ6 is also high (see screening example 2-3);

[0153] 3) By adopting the method of the present invention, adjusting the addition time of methanesulfonic acid and adding an appropriate amount of water, the content of intermediate B is below 0.01%, ZZ6 is below 0.05%, and the content of ZZ7 is below 0.05%, which meets the impurity control requirements.

[0154] In summary, the solution provided by the present invention has mild reaction conditions, no agglomeration during the reaction process, a yield of more than 95.3%, a purity of more than 99.88%, and a small amount of impurities such as analytical intermediates B, ZZ6 and ZZ7.

[0155] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A method for preparing lenvatinib mesylate, It is characterized in that The following steps are involved: a) mixing methanesulfonic acid, acetic acid and water to obtain a mixed solution; The usage ratio of methanesulfonic acid, acetic acid and water is 1g: (25.0-26.5)mL: (0.35-8.40)mL; b) mixing the mixed solution with lenvatinib to react into a salt to obtain a reaction solution; c) mixing the reaction solution with a crystallization solvent for crystallization, solid-liquid separation, and then washing with the crystallization solvent and drying to obtain lenvatinib mesylate; The crystallization solvents are ethyl acetate and alcohol; wherein the volume ratio of ethyl acetate to alcohol is (2.8-3.2):1; and the alcohol is ethanol.

2. The preparation method according to claim 1, It is characterized in that In step a), the usage ratio of methanesulfonic acid, acetic acid and water is 1 g: (25.0-26.5) mL: (2-6.3) mL.

3. The preparation method according to claim 1, It is characterized in that In step a), the usage ratio of methanesulfonic acid, acetic acid and water is 1 g: (25.0-26.5) mL: (4.2-6.3) mL.

4. The preparation method according to claim 1, It is characterized in that The molar ratio of lenvatinib in step b) to methanesulfonic acid in step a) is 1:(1.00-1.10).

5. The preparation method according to claim 1 or 4, It is characterized in that The molar ratio of lenvatinib in step b) to methanesulfonic acid in step a) is 1:(1.00-1.06).

6. The preparation method according to claim 1, It is characterized in that In step b), the reaction temperature is 20-30°C.

7. The preparation method according to claim 1 or 6, It is characterized in that In step b), the reaction time is 1 to 2 hours.

8. The preparation method according to claim 1, It is characterized in that In step c), the drying temperature is 35-55°C.

9. The preparation method according to claim 1, It is characterized in that In step c), the solid-liquid separation method is filtration; The washing is to wash the filter cake obtained by filtration.

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