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Preparation method of lovatinib salt amorphous substance

A technology of lenvatinib and amorphous substances, which is applied in the field of preparation of amorphous substances, can solve the problems of increasing the risk of genotoxic impurity mesylate, high requirements for preparation conditions, and not being environmentally friendly, achieving significant dissolution advantages, The effect of high purity and avoiding the increase of genotoxic impurities

Pending Publication Date: 2021-12-24
南京科默生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method avoids high temperature and reduces the generation of degradation impurities; but because the method uses alcohols, it increases the risk of genotoxic impurity mesylate
In addition, the amorphous lenvatinib compound is prepared by the method disclosed in this patent. Although the freezing point of the mixed solvent of alcohols and water is higher than that of alcohols, it still requires a very low temperature (-45~-10°C ), and the freeze-drying time is long, the preparation conditions are high, the energy consumption is large, and it is not environmentally friendly

Method used

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  • Preparation method of lovatinib salt amorphous substance
  • Preparation method of lovatinib salt amorphous substance
  • Preparation method of lovatinib salt amorphous substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1 Reaction condition investigation

[0028] Add lenvatinib mesylate crystal C (5g) into a three-necked flask, add a solvent, and the parameters are selected from the following:

[0029] (1) Solvent screening

[0030] Table 1 Solvent Screening

[0031]

[0032] Conclusion: Choosing purified water as the solvent can completely dissolve lenvatinib mesylate form C at 20-30°C without using organic solvents, which is environmentally friendly and cost-saving.

[0033] (2) Screening of purified water volume

[0034] Table 2 Screening of Purified Water Consumption

[0035]

[0036] Conclusion: For every 1g of lenvatinib mesylate, 100-200mL of purified water can be selected as the solvent, and 550mL of purified water is preferred for 5g of lenvatinib mesylate.

[0037] (3) Selection of cooling temperature for the dissolved solution

[0038] Stir at 20~30°C for 2~3 hours until it dissolves, and then start to cool down. The cooling temperature is selected as f...

Embodiment 2

[0048] Add lenvatinib mesylate crystal C (5g) into a three-necked flask, add 550ml of purified water, and stir at 20~30°C for 2~3 hours until it dissolves, and then cools down to -5~0°C. When the solvent in the system is all solidified into a solid, place the above solid in a freeze dryer, set the temperature of the freeze dryer at -5~0°C, turn on the vacuum pump, and freeze dry for 9~12 hours until it becomes powdery. After the freeze-drying is completed, take out the solid powder and place it in a vacuum drying oven, set the temperature of the drying oven at 50~55°C, and control the vacuum degree to less than -0.09MPa and vacuum dry for 10~12 hours to obtain 4.8g of lenvalate methanesulfonate Amorphous substance of tinib. The relative purity is 99.796%, and the water content is 0.32%. Its powder X-ray diffraction pattern is as figure 2 The infrared absorption spectrum is shown as image 3 As shown, the HPLC spectrum is as Figure 4 shown.

Embodiment 3

[0050] Add lenvatinib mesylate crystal C (5g) into a three-necked flask, add 550ml of purified water, and stir at 20~30°C for 2~3 hours until it dissolves, and then cools down to -10~5°C. When the solvent in the system is all solidified into a solid, place the above solid in a freeze dryer, set the temperature of the freeze dryer at -5~0°C, turn on the vacuum pump, and freeze dry for 9~12 hours until it becomes powdery. After the freeze-drying is completed, take out the solid powder and place it in a vacuum drying oven, set the temperature of the drying oven at 50~55°C, and control the vacuum degree to less than -0.09MPa and vacuum dry for 10~12 hours to obtain 4.7g of lenvalate methanesulfonate Amorphous substance of tinib. The relative purity is 99.797%, and the water content is 0.35%. Its powder X-ray diffraction pattern is as Figure 5 As shown, the HPLC spectrum is as Figure 6 shown.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly discloses a preparation method of a lovatinib mesylate amorphous substance, pure water is adopted as a solvent, the lovatinib mesylate C crystal form is dissolved in purified water, and the lovatinib mesylate amorphous substance is prepared through the procedures of stirring, cooling, freeze-drying and drying. The method is free of organic solvents, green and environment-friendly, cost-saving, low in energy consumption and simple to operate, the high-purity mesylate lenvatinib salt can be prepared by freeze-drying and vacuum drying within 24 hours, meanwhile, the risk that genotoxic impurities are increased in the existing patent is avoided, no impurity is generated in the preparation process, the prepared mesylate lenvatinib is high in purity and low in water content, the solubility is increased, and the medicinal standard is met; and the pharmaceutical composition prepared from the amorphous substance has a remarkable dissolution advantage.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a method for preparing an amorphous lenvatinib salt, in particular to 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy The preparation method of the amorphous substance of base-6-quinoline formamide methanesulfonate. Background technique [0002] Lenvatinib Mesilate, chemical name: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate Acetate, is an oral and effective multi-kinase inhibitor developed by Japan's Eisai Company, which mainly acts on multiple targets such as c-Kit, Ret and VEGFR-2, and is used to treat glioma, thyroid tumor, kidney tumor Solid tumors such as cancer, liver cancer and ovarian cancer. In February 2013, it was approved as an orphan drug by the US FDA, and it is clinically used for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced papillary thyroid car...

Claims

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Application Information

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IPC IPC(8): C07D215/48A61K31/47A61P35/00
CPCC07D215/48A61P35/00
Inventor 苏梅李振张孝清
Owner 南京科默生物医药有限公司
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