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Preparation method of high-purity lenvatinib mesylate crystal form C

A technology of lenvatinib and methanesulfonic acid, applied in the field of medicine and chemical industry, can solve the problems of unsuitability for industrial production, product purity not up to standard, and high impurity content, and achieve the effects of reducing impurity content, convenient operation and high purity

Pending Publication Date: 2020-09-22
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, in the reported preparation methods of Form C, there are still problems of high impurity content, product purity not up to standard, easy agglomeration, and unsuitable for industrial production

Method used

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  • Preparation method of high-purity lenvatinib mesylate crystal form C
  • Preparation method of high-purity lenvatinib mesylate crystal form C
  • Preparation method of high-purity lenvatinib mesylate crystal form C

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0047] Preparation Example 1: Preparation of Lenvatinib Free Base

[0048] (a) Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide:

[0049]

[0050] At 70°C, under nitrogen protection, 4.35g of 4-amino-3-chlorophenol hydrochloride, 5.38g of potassium hydroxide aqueous solution (48.5w / w%), 4.40g of 4-chloro-7-methoxy A mixture of methyl-quinoline-6-carboxamide and 40 ml of dimethyl sulfoxide was stirred for 20 h. Add acetone (22ml) / water (44ml) mixture at 55°C, cool down to 5-10°C, filter, wash the filter cake with acetone / water, and dry to obtain 5.87g of intermediate with a yield of 92.1%.

[0051] (b) Preparation of lenvatinib free base:

[0052]

[0053] At -20°C, under nitrogen protection, to 2.60g of 4-(4-amino-3-chlorophenoxy)-7-methoxy-quinoline-6-carboxamide, 1.32g of pyridine, 0.14g Add 2.66 g of phenyl chloroformate to a mixture of water and 20 ml of DMF, then keep stirring for 3 h. Then, 1.94 g of cyclopropylamine was further added ...

Embodiment 1

[0060] Example 1: Lenvatinib mesylate crystal form C

[0061] Add 1.0g of lenvatinib free base to 15ml of ethanol, control the temperature to 15-25°C, add 0.27g of methanesulfonic acid ethanol solution (5ml), keep stirring for 2h, filter with suction, and dry in vacuum at 60°C to obtain 1.17g Lenvatinib mesylate crystal form C, yield 95.5%, HLPC purity 99.9%; After determination, its X-ray powder diffraction pattern is as follows figure 1 As shown, its DSC-TGA spectrum is as image 3 shown.

Embodiment 2

[0062] Embodiment 2: lenvatinib mesylate crystal form C

[0063] Add 1.0 g of lenvatinib free base to 20 ml of ethanol, heat to dissolve, add 0.27 g of methanesulfonic acid at a temperature controlled to 15-25 °C, keep stirring for 3 hours, filter with suction, and dry under vacuum at 60 °C to obtain 1.14 g of methanesulfonic acid Lenvatinib crystal form C, yield 93.1%, HLPC purity 99.8%; After determination, its X-ray powder diffraction pattern and figure 1 Basically the same, its DSC-TGA spectrum and image 3 Basically the same.

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals and especially relates to a preparation method of a lenvatinib mesylate crystal form C. According to the method, the conditions of high temperature, acid serving as a solvent and the like are avoided, so that the content of impurities is greatly reduced, the purity is high, the yield is high, the purity is 99% or above and the yield is 95% or above. Therefore, the method is simple in process, convenient to operate, mild in condition, free of special reaction conditions, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of high-purity lenvatinib mesylate crystal form C. Background technique [0002] Lenvatinib mesylate shown in formula I, its chemical name is 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6 -Quinolinecarboxamide methanesulfonate. It is known that lenvatinib mesylate has a strong inhibitory effect on c-Kit kinase. Academically, it has better properties. [0003] [0004] Patent document WO2005063713 and its Chinese counterpart CN100569753C disclose a salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or its solvate Crystallization of compounds and methods for their preparation. Therein, lenvatinib mesylate crystal form A, crystal form B, crystal form C, crystal form F, crystal form I, dimethyl sulfoxide solvate and preparation methods thereof are disclosed....

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C309/04C07C303/32
CPCC07D215/48C07C309/04C07C303/32C07B2200/13
Inventor 张勇张占涛杨登站史正高范传文林栋
Owner QILU PHARMA
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