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Preparation method of lenvatinib mesylate crystal form X

A technology of lenvatinib and methanesulfonic acid, which is applied in the field of pharmaceutical crystal forms, can solve the problems of undisclosed, base toxic impurities and alcoholysis impurities exceeding the standard, undisclosed crystal form X, etc., to achieve improved yield, simple operation, The effect of reducing energy consumption

Pending Publication Date: 2021-01-05
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

After a series of preliminary screening tests, the applicant found that crystal form X can only be prepared in a solvent system of methanol and pure water, while methanol and methanesulfonic acid are easy to generate mesylate (basic poisonous impurity), methanol and methanesulfonic acid Lenvatinib free base is easy to generate alcoholysis impurities under heating conditions, which can easily lead to excessive base toxic impurities and alcoholysis impurities in the product
[0007] The prior art does not disclose the crystal form X, nor does it disclose the preparation method of the crystal form X without using alcohol solvents. Therefore, there is still a need in the art for a crystal form X with simple preparation process and better product quality. method of preparation, and this application meets the need for

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  • Preparation method of lenvatinib mesylate crystal form X
  • Preparation method of lenvatinib mesylate crystal form X
  • Preparation method of lenvatinib mesylate crystal form X

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Experimental program
Comparison scheme
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specific Embodiment approach

[0042] Specific implementation method: screening test

[0043] In order to avoid the impact of alcoholysis impurities and mesylate impurities on product quality and to avoid the use of alcoholic solvents, the inventors of the present application carried out the solvent types and combinations used in step (1) in the process of obtaining the technical solution. A large number of screens were conducted, and data statistics were carried out on the crystal form of the final product and related substances. The results are shown in Table 1 below.

[0044] Table 1 Experimental results for the preparation of Form X in different solvent systems

[0045] solvent system crystal form alcoholysis impurities Mesylate impurity Methanol Form A 0.17％ 97ppm ethanol Form A 0.15％ 89ppm Isopropanol Form A 0.13％ 91ppm acetone Form A 0 23ppm ethyl acetate Form A 0 21ppm Acetonitrile Form A 0 17ppm methanol and water Form...

Embodiment 1

[0048] Embodiment 1: Preparation of lenvatinib mesylate crystal form X

[0049] Disperse 10.0g of lenvatinib in 20ml of purified water and 30ml of acetonitrile, stir and beat at 30°C to form a suspension; then add the mixed solution of 2.7g of methanesulfonic acid, 10ml of acetic acid and 20ml of acetonitrile into the suspension; After the dropwise addition was complete and the suspension was dissolved, 3% seed crystal X was added, and then 20ml of acetonitrile was added dropwise to the suspension. After the dropwise addition, the mixture was stirred at 25°C for 12h, filtered and dried to obtain 8.93g of solid powder. Yield 89.3%. The HPLC purity is 99.78%, alcoholysis impurities are not detected, and base toxic impurities are not increased. Its powder diffraction data are as figure 2 shown.

[0050] That 1 The H-NMR data are as follows:

[0051] 1 H NMR (400MHz, d 6 -DMSO) δ9.00(d, J=6.5Hz, 1H), 8.72(s, 1H), 8.36(d, J=9.1Hz, 1H), 8.09(s, 1H), 7.95(d, J=24.3 Hz,2H),7....

Embodiment 2

[0056] Embodiment 2: Preparation of lenvatinib mesylate crystal form X

[0057] Disperse 10.0g of lenvatinib in 30ml of purified water and 30ml of acetonitrile, and stir at 30°C to form a suspension; then add the mixed solution of 2.7g of methanesulfonic acid, 10ml of acetic acid and 30ml of acetonitrile dropwise into the suspension; After the dropwise addition was completed and the suspension was dissolved, 3% seed crystal X was added, then 50ml of acetonitrile was added dropwise to the suspension, after the dropwise addition was completed, stirring was continued at 25°C for 12h, and the solid powder was obtained by suction filtration and drying to obtain 8.53g of solid powder. 85.3%. The HPLC purity is 99.77%, alcoholysis impurities are not detected, and base toxic impurities are not increased. Its powder diffraction data are basically consistent with the data of Example 1.

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Abstract

A preparation method of a lenvatinib mesylate crystal form X comprises the following steps that lenvatinib is stirred in acetonitrile and purified water and pulped, wherein the mass volume ratio of lenvatinib to acetonitrile to purified water is 1 g: (2-6 ml): (2-6 ml), and the stirring and pulping temperature is 20-30 DEG C; then, a mixed solution of acetic acid, acetonitrile and methanesulfonicacid is dropwise added, wherein the mass volume ratio of lenvatinib to acetic acid to acetonitrile is 1 g: (1-3 ml): (2-6 ml), and the mass ratio of lenvatinib to methanesulfonic acid is 1 g: (0.22-0.45 g); and after the system is clarified, 0-5% by mass of a seed crystal in a crystal form X is added, acetonitrile is dropwise added into the solution, the mass volume ratio of acetonitrile to lenvatinib is (1-6 ml: 1 g), the temperature is kept at 15-30 DEG C, the heat preservation stirring time is 12-24 h, and suction filtration and drying are conducted to obtain solid powder. The method is simple in preparation process, better in product quality and suitable for industrial production.

Description

technical field [0001] The application relates to the field of pharmaceutical crystal forms, in particular to a crystal form X of lenvatinib mesylate and a preparation method thereof. Background technique [0002] Lenvatinib, chemical name: 4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy]-7-methoxy-6-quinolinecarboxamide, its structural formula is as follows (I) shown in the formula. [0003] [0004] Lenvatinib is a thyroid cancer drug developed by Japan's Eisai Co., Ltd. Lenvatinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode to its receptors. Can selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptor. On February 13, 2015, it was approved by the FDA for the treatment of patients with advanced differentiated thyroid cancer with local recurrence or metastasis refractory to radioactive iodine, and was subsequently approved for marketing in the European Union and Japan. [0005] Lenvati...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C303/32C07C303/44C07C309/04
CPCC07D215/48C07C309/04C07C303/32C07C303/44C07B2200/13
Inventor 谷慧科先小超庞学海王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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