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Refining method of deuterated lenvatinib

A technology of lenvatinib and refining method, which is applied in the direction of organic chemical method, chemical instrument and method, heterocyclic compound isotope introduction, etc., can solve the problems of high impurity I content and low purity, and achieve high product purity, simple heterocyclic compound The effect of controllable content and simple operation

Inactive Publication Date: 2018-10-23
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The invention provides a method for refining deuterated lenvatinib, the purpose of which is to solve the problems of low product purity and excessive content of main impurity I

Method used

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  • Refining method of deuterated lenvatinib
  • Refining method of deuterated lenvatinib
  • Refining method of deuterated lenvatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 2.5g of deuterated lenvatinib crude product with a content of 98.6% in a 500ml three-necked flask, then add 33g of methanol, 38g of water, 5g of sodium hydroxide, and 1.25g of activated carbon in sequence, start stirring, and heat to a slight reflux state. 64 ~ 68 ℃, continue to reflux and stir for 2 hours, filter while it is hot, keep the system temperature not lower than 40 ℃ when filtering, stir and cool the filtrate to crystallize to 2 ℃, keep stirring for 6 hours, then filter and wash with 50% methanol aqueous solution Filter cake, the filter cake is vacuum-dried, the vacuum drying oven temperature is set to 50 ℃, and the drying time is 15h, obtains the crystallization 2.15g of light yellow deuterated lenvatinib, content 99.58%, impurity I content 0.03%, other single Impurities are less than 0.1%.

Embodiment 2

[0025] Add 2.5g of deuterated lenvatinib crude product with a content of 98.6% in a 500ml three-necked flask, then add 40g of methanol, 40g of water, 5.5g of sodium hydroxide, and 1.3g of activated carbon in sequence, start stirring, and heat to a slight reflux state. The temperature is 64-68°C, continue to reflux and stir for 4 hours, filter while it is hot, keep the system temperature not lower than 45°C when filtering, stir and cool the filtrate to crystallize to 5°C, keep stirring for 10 hours, then filter, and use 50% methanol aqueous solution Wash the filter cake, vacuum-dry the filter cake, set the temperature of the vacuum drying oven to 50° C., and dry for 15 hours to obtain 2.03 g of light yellow deuterated lenvatinib crystals, with a content of 99.69%, impurity I content of 0.02%, and other Simple and impurity are less than 0.1%.

Embodiment 3

[0027] In a 500ml three-necked flask, add 2.5g of deuterated lenvatinib crude product with a content of 98.6%, then add 45g of methanol, 43g of water, 6.2g of sodium hydroxide, and 1.8g of activated carbon in sequence, start stirring, and heat to a slight reflux state. The temperature is 64-68°C, continue to reflux and stir for 3 hours, filter while it is hot, keep the system temperature not lower than 45°C when filtering, stir the filtrate to cool and crystallize to 5°C, keep stirring for 11 hours, then filter, and use 60% methanol aqueous solution Wash the filter cake, vacuum-dry the filter cake, set the temperature of the vacuum drying oven to 50° C., and dry for 16 hours to obtain 1.86 g of light yellow deuterated lenvatinib crystals, with a content of 99.82%, impurity I content of 0.05%, and other Simple and impurity are less than 0.1%.

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Abstract

The invention discloses a refining method of deuterated lenvatinib. The refining method of the deuterated lenvatinib comprises the operation steps of adding a crude product of the deuterated lenvatinib into a mixed solvent of methyl alcohol, water, sodium hydroxide and activated carbon, heating to a micro backflow state at 64 to 68 DEG C, continuously backflowing and stirring for 2 to 6 hours, immediately filtering, stirring a filter liquor, cooling and crystallizing to 2 to 6 DEG C, keeping warm for 6 to 8 hours, filtering, vacuum drying, and obtaining a pure product of the deuterated lenvatinib which has the purity being larger than 99.5 percent, the individual impurity content being smaller than 0.1 percent, and the total impurity content being smaller than 0.5 percent, and meets the requirement of the content of a general drug.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for refining deuterated lenvatinib. Background technique [0002] Chinese patent CN 2018105615621 reports a deuterated lenvatinib [0003] [0004] method of preparation, such as figure 1 as shown, [0005] [0006] figure 1 [0007] The impurity compound I shown in the following formula that the 3rd step reaction mainly exists, [0008] [0009] Its structure was confirmed by H NMR and mass spectrometry: 1 H-NMR (400MHz, DMSO-d 6 )δppm11.03 (brs, 1H), 7.49 (d, J = 3.95Hz, 1H), 6.79 (s, 1H), 6.64 (d, J = 3.95Hz, 1H), 4.98 (br s, 1H); ESI / MS: m / z=436 (M+H)+. According to the post-processing method reported in the patent, the purity of the obtained product is 98.2%, and the content of impurity I is 0.20% to 0.45%. It does not meet the requirement of less than 0.1% single impurity content in general drug quality standards. Moreover, due to the high imp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07B59/00
CPCC07D215/48C07B59/002C07B2200/05
Inventor 陈芳军王岳奇
Owner 湖南华腾制药有限公司