The preparation method of lenvatinib mesylate M crystal form

A technology of lenvatinib and methanesulfonic acid, which is applied in the field of stable preparation of lenvatinib mesylate M crystal form, and can solve the problem of poor repeatability of the crystal form M process, unqualified content of genotoxic impurities, crystal transformation To achieve the effects of good physical and chemical stability, control of genotoxic impurity content, and stable product quality

Active Publication Date: 2022-03-11
南京方生和医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the process repeatability of the crystal form M prepared by the above-mentioned literature method is poor, and problems such as crystal transformation and unqualified genotoxic impurity content may occur during the amplification process.

Method used

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  • The preparation method of lenvatinib mesylate M crystal form
  • The preparation method of lenvatinib mesylate M crystal form
  • The preparation method of lenvatinib mesylate M crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Put 6.0kg of lenvatinib and 120.5kg of acetonitrile into a 500L enamel kettle equipped with a nitrogen protection device to cool down to -10-0°C, add 1.35kg of methanesulfonic acid dropwise, and keep stirring for 8 hours. At an ambient temperature of 0-5° C. and a humidity of less than 50% RH, the reaction solution was filtered to obtain a wet product of lenvatinib mesylate. Put the obtained wet product into a desiccator, at 25-30°C, pass high-purity nitrogen gas, control the vacuum degree at -0.085--0.080MPa, and dry the wet product until the residual acetonitrile is less than the limit of 410ppm stipulated in the Pharmacopoeia. After drying, control the temperature of the desiccator at 5-15°C, and pass in 15-25% RH humidified nitrogen until the product moisture is 3.0-6.0%, and 6.97kg of light yellow lenvatinib mesylate salt M crystal form is obtained. l H-NMR (400MHz, DMSO-d6) δppm8.91(d, J=6.0Hz, 1H), 8.73(s, 1H), 8.36(d, J=9.1Hz, 1H), 8.04(s, 1H), 7.93 (s,1H),7.85...

Embodiment 2

[0029] Put 6.0kg of lenvatinib and 150.8kg of acetonitrile into a 500L enamel kettle equipped with a nitrogen protection device to cool down to -5-5°C, add 1.42kg of methanesulfonic acid dropwise, and keep stirring for 8 hours. At an ambient temperature of 0-5° C. and a humidity of less than 50% RH, the reaction solution was filtered to obtain a wet product of lenvatinib mesylate. Put the obtained wet product into a desiccator, at 25-30°C, pass high-purity nitrogen gas, control the vacuum degree at -0.085--0.080MPa, and dry the wet product until the residual acetonitrile is less than the limit of 410ppm stipulated in the Pharmacopoeia. After drying, control the temperature of the desiccator at 5-15°C, and pass in 15-25% RH humidified nitrogen until the product moisture is 3.0-6.0%, and 6.9 kg of light yellow lenvatinib mesylate salt M crystal form is obtained.

Embodiment 3

[0043] Take an appropriate amount of the crystals prepared in Example 1 and Comparative Example 5 and place them under the humidity conditions of 40% RH, 50% RH, 60% RH and 70% RH respectively to investigate the hygroscopicity of the crystals. The results are shown in Table 2.

[0044] Table 2 The results of the investigation on the hygroscopicity of crystallization

[0045]

[0046] As can be seen from Table 2, compared with the crystals prepared without water replenishment operation:

[0047] (1) Under the same humidity conditions, the weight gain of the crystals after water replenishment is smaller, that is, the crystals after water replenishment are less affected by the ambient humidity than the crystals without water replenishment, therefore, it is more conducive to the production of raw material drug screening process operate;

[0048] (2) Under the condition of 40% RH humidity, the crushing and sieving process is carried out. It can be seen from the weight gain by h...

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Abstract

The invention discloses a preparation method of lenvatinib mesylate M crystal form. The preparation method comprises the following steps: (1) salt-forming reaction; (2) separating the wet product of the salt; (3) drying to obtain the salt (4) Dry products replenish water. The preparation method has good process reproducibility, high yield, high crystal form and chemical purity, the quality meets the quality control requirements, and can be stably scaled up to the kilogram level.

Description

technical field [0001] The invention relates to a preparation method of lenvatinib mesylate M crystal form, in particular to a preparation method capable of stably preparing lenvatinib mesylate M crystal form. Background technique [0002] Lenvatinib is an oral multireceptor categorical drug developed by Eisai for the treatment of patients with aggressive, locally advanced or metastatic differentiated thyroid cancer (HCC), and advanced metastatic, inoperable renal cancer. Aminolinase (RTK) inhibitor, which was approved by the FDA on February 13, 2015, and lenvatinib mesylate is used in the approved drug. The chemical name of the drug is 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide methanesulfonate, and its structural formula is as follows: [0003] [0004] In solid chemical drugs, there are usually large differences in the solubility and stability of products with different crystal forms. Therefore, obtaining a stable crystal form with go...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/48C07C303/32C07C303/44C07C309/04
CPCC07D215/48C07C303/32C07C303/44C07C309/04C07B2200/13
Inventor 周步高惠舰马俊彦
Owner 南京方生和医药科技有限公司
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