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Method for refining Lenvatinib mesylate

A technology of lenvatinib mesylate and a refining method, which is applied in the refining field of lenvatinib mesylate, can solve the problems of low refining yield, high impurity content and high production cost, and achieves high refining yield and high production cost. The effect of high product purity

Active Publication Date: 2020-02-21
上海新礼泰药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is in order to overcome the refining process of lenvatinib mesylate in the prior art, the impurity content is high (0.2%~0.5%), needs to be refined repeatedly to reach raw material drug requirement, refining yield Low (50%~70%), high production cost, not suitable for defects such as industrialized production and provide a kind of refining method of lenvatinib mesylate

Method used

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  • Method for refining Lenvatinib mesylate
  • Method for refining Lenvatinib mesylate
  • Method for refining Lenvatinib mesylate

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of lenvatinib mesylate I crude product (referring to the method of CN200480036184.1)

[0034]

[0035]Under the protection of nitrogen, add 37.9g ​​(0.264mol) of 4-amino-3-chlorophenol to 160mL of N,N-dimethylformamide, cool to 0-5°C, add 36.6g (0.475mol) of pyridine, dropwise 42.9 g (0.274 mol) of phenyl chloroformate was raised to room temperature and stirred for 1 hour. Add water and ethyl acetate, stir, stand still, and separate liquids; separate the organic phase, and extract the aqueous phase with ethyl acetate once more. Organic phase merges, and with mass concentration successively be 7% sodium bicarbonate aqueous solution (the described mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution), mass concentration is 15% sodium chloride aqueous solution (the stated mass concentration The mass concentration mentioned refers to the quality...

Embodiment 2

[0036] Embodiment 2: the preparation of lenvatinib mesylate I crude product (referring to the method of CN200480036184.1)

[0037] Under the protection of nitrogen, add 2.37Kg (16.5mol) of 4-amino-3-chlorophenol to 10L of N,N-dimethylformamide, cool to 0-5°C, add 2.29Kg (29.7mol) of pyridine, dropwise Phenyl chloroformate 2.68 Kg (17.1 mol), raised to room temperature and stirred for 1 hour. Add water and ethyl acetate, stir, stand still, and separate liquids; separate the organic phase, and extract the aqueous phase with ethyl acetate once more. Organic phase merges, and with mass concentration successively be 7% sodium bicarbonate aqueous solution (the described mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution), mass concentration is 15% sodium chloride aqueous solution (the stated mass concentration The mass concentration mentioned refers to the quality of sodium chloride a...

Embodiment 3

[0038] Embodiment 3: the preparation of lenvatinib mesylate I crude product (referring to the method of CN200480036184.1)

[0039] Under the protection of nitrogen, add 11.7g (0.081mol) of 4-amino-3-chlorophenol to 50mL of N,N-dimethylformamide, cool to 0-5°C, add 11.4g (0.148mol) of pyridine, dropwise 13.4 g (0.085 mol) of phenyl chloroformate was raised to room temperature and stirred for 1 hour. Add water and ethyl acetate, stir, stand still, and separate liquids; separate the organic phase, and extract the aqueous phase with ethyl acetate once more. Organic phase merges, and with mass concentration successively be 7% sodium bicarbonate aqueous solution (the described mass concentration refers to the percentage that the quality of sodium bicarbonate accounts for the total mass of sodium bicarbonate aqueous solution), mass concentration is 15% sodium chloride aqueous solution (the stated mass concentration The mass concentration mentioned refers to the quality of sodium chl...

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Abstract

The invention discloses a method for refining Lenvatinib mesylate. The method for refining the Lenvatinib mesylate, provided by the invention, comprises the following step: subjecting a solution formed by an organic solvent and crude Lenvatinib mesylate to cooling and crystallization, thereby obtaining the Lenvatinib mesylate, wherein the organic solvent is a mixed solvent of ethylene glycol di-C1-C4 alkyl ether and C1-C4 alkyl alcoholic solvent or a mixed solvent of ethylene glycol mono-C1-C4 alkyl ether and acetic acid C1-C4 alkyl ester solvent; and the crude Lenvatinib mesylate has an HPLCpurity of 95.0% to 99.0%. The product prepared by the method disclosed by the invention is high in purity, the HPLC purity is higher than 99.80%, the content of a single impurity is lower than 0.10%,the yield of refining is high and reaches 81% to 87%, the production cost is low, and thus, the method is applicable to industrial production.

Description

technical field [0001] The invention relates to a refining method of lenvatinib mesylate. Background technique [0002] Lenvatinib mesylate (I), developed by Eisai, was approved by the U.S. Food and Drug Administration (FDA) on February 13, 2015, and then approved by Japan on March 26, 2015. Approved by the Pharmaceuticals and Medical Devices Agency (PMDA), and then approved by the European Medicines Agency (EMA) on May 28, 2015, it is marketed by Eisai under the trade name [0003] Lenvatinib mesylate is an oral multi-receptor tyrosine kinase inhibitor with a unique binding mode that selectively inhibits vascular endothelial growth factor receptor kinase activity, in addition to inhibiting other promoters involved in tumor proliferation. Tyrosine kinases associated with angiogenic and oncogenic signaling pathways. The drug is suitable for the treatment of recurrent or progressive and radioactive iodine-refractory differentiated thyroid cancer. [0004] Oral capsules,...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C309/04C07C303/44
CPCC07D215/48
Inventor 陈健邹宝勤应述欢
Owner 上海新礼泰药业有限公司
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