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The refining method of lenvatinib mesylate

A technology of lenvatinib mesylate and a refining method, which is applied in the field of refining lenvatinib mesylate, can solve the problems of high impurity content, low refining yield, unsuitability for industrial production, etc., and achieve high purity, The effect of high refining yield

Active Publication Date: 2021-11-30
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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  • The refining method of lenvatinib mesylate
  • The refining method of lenvatinib mesylate
  • The refining method of lenvatinib mesylate

Examples

Experimental program
Comparison scheme
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 invention provides a method for refining lenvatinib mesylate, which comprises the following steps: cooling and crystallizing the solution formed by an organic solvent and lenvatinib mesylate crude product to obtain lenvatinib mesylate Ni can; the organic solvent is ethylene glycol di-C 1 -C 4 Alkyl ethers and C 1 -C 4 Mixed solvent of alkyl alcohol solvent, or ethylene glycol single C 1 -C 4 Alkyl ethers and acetic acid C 1 -C 4 A mixed solvent of alkyl ester solvents; the HPLC purity of the crude lenvatinib mesylate is 95.0% to 99.0%. The product obtained by the refining method of the invention has high purity, HPLC purity greater than 99.80%, single impurity less than 0.10%, high refining yield of 81%-87%, low production cost, and is suitable for industrialized 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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Patent Type & Authority Patents(China)
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