Lenvatinib impurity and preparation method thereof

A technology for lenvatinib and impurities, which is applied in the field of lenvatinib impurities and its preparation, can solve the problems of difficult separation, low content of impurity compounds, and difficulty in quality control of lenvatinib intermediates and APIs, and achieves The effect of stable purity and yield, simple preparation method, and improved product quality

Pending Publication Date: 2021-02-26
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

[0005] The study found that there are often some impurity compounds of unknown structure in the lenvatinib

Method used

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  • Lenvatinib impurity and preparation method thereof
  • Lenvatinib impurity and preparation method thereof
  • Lenvatinib impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Preparation method of compound III

[0031] Add 12.71g of compound I, 23.66g of compound II, 500mL of DMSO, 6.0g of sodium hydroxide into a 1L reactor, raise the temperature to 100°C and react for 2h, disperse the reaction solution in the water phase and ethyl acetate phase, and separate the water layer , the organic phase was concentrated to dryness under reduced pressure to obtain 31 g of a purple solid with a purity of 96%.

[0032] (2) Preparation method of compound V

[0033] Add 28.4g of compound of formula III, 14.57g of compound IV, 800mL of DMSO, 6.0g of sodium hydroxide into a 1L reactor, heat up to 100°C for 2h, and purify the reaction solution by column chromatography to obtain 41.4g of a yellow solid with a purity of 100%. , HPLC test results see figure 1 . 1 H-NMR (DMSO-D6, 400MHz) δ ppm 8.61~8.62(d, 2H), 7.96(s, 1H), 7.82(s,1H), 7.47(s, 1H), 6.95~6.94(d, H) , 6.89(s, 1H), 6.87~6.76(m, 3H), 6.58~6.57(d, 1H), 6.46~6.44(d, 1H), 5.12(s, 2H),5.05(s, 2H...

Embodiment 2

[0037] (1) Preparation method of compound III

[0038] Add 12.71g of Compound I, 23.66g of Compound II, 500mL of DMF, and 12.6g of Potassium Hydroxide into a 1L reactor, raise the temperature to 120°C for 2 hours, disperse the reaction solution in the water phase and ethyl acetate phase, and separate the water layer , the organic phase was concentrated to dryness under reduced pressure to obtain 30.3 g of a purple solid with a purity of 95.8%.

[0039] (2) Preparation method of compound V

[0040] Add 28.4g of compound III, 14.57g of compound IV, 800mL of DMF, and 12.6g of potassium hydroxide into a 1L reactor, heat up to 80°C for 3h, and purify the reaction solution by column chromatography to obtain 40.8g of a yellow solid with a purity of 99.5%.

[0041] (3) Preparation method of compound VI

[0042] Add 10g of compound V, 100mL of DMF, 10.96g of isocyanatocyclopropane, and 10g of pyridine into a 500mL reactor, and react at a temperature of 20-30°C for 3h. Water was adde...

Embodiment 3

[0044] (1) Preparation method of compound III

[0045] Add 12.71g of compound I, 23.66g of compound II, 500mL of DMF, and 73.3g of cesium carbonate into a 1L reactor, heat up to 80°C for 2 hours, disperse the reaction solution in the water phase and ethyl acetate phase, and separate the water layer. The organic phase was concentrated to dryness under reduced pressure to obtain 30.2 g of a purple solid with a purity of 96.5%.

[0046] (2) Preparation method of compound V

[0047] Add 28.4g of compound III, 14.57g of compound IV, 800mL of DMF, and 73.3g of cesium carbonate into a 1L reactor, heat up to 120°C for 2 hours, and purify the reaction solution by column chromatography to obtain 40g of a yellow solid with a purity of 99.9%.

[0048] (3) Preparation method of compound VI

[0049]Add 10g of Compound V, 100mL of THF, 10.96g of isocyanatocyclopropane, and 10g of pyridine into a 500mL reactor, and react at a temperature of 20-30°C for 3h. Water was added dropwise to the r...

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Abstract

The present invention discloses a lenvatinib impurity and a preparation method thereof. The lenvatinib impurity has a structure represented by a formula VI, the impurity uses 2-fluoro-4-hydroxyanilineas a starting material, a lenvatinib impurity intermediate represented by a formula V is prepared through a two-step alkylation reaction, and then the lenvatinib impurity represented by the formula VI is prepared through a condensation reaction. The purity and yield of the prepared impurity are stable, the impurity can be used for quality control of lenvatinib intermediates, bulk drugs and related preparation products, and the quality VI of the bulk drugs and the related preparation products is improved by qualitative and quantitative determination of specific impurities.

Description

technical field [0001] The present invention relates to a lenvatinib impurity and a preparation method thereof, in particular to a lenvatinib impurity and a preparation method thereof which can accurately control the content of specific impurities and improve the quality of intermediates, raw materials and related preparations. Background technique [0002] Lenvatinib is an oral polytyrosine kinase inhibitor developed by Japan's Eisai Company. In August 2012, it was awarded Orphan Drug (ODD) for the treatment of thyroid cancer in Japan; in February 2013, it was granted Orphan Drug Designation by the US FDA for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced thyroid papillae In 2015, the US FDA and the European Medicines Agency EMA approved lenvatinib for the treatment of invasive, locally advanced or metastatic differentiated thyroid cancer; in 2016, the US FDA and the European Medicines Agency EMA approved lenvatinib Lenvatinib combi...

Claims

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Application Information

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IPC IPC(8): C07D215/48
CPCC07D215/48
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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