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Preparation method of lenvatinib and its salts

A technology of lenvatinib and compounds, which is applied in the field of drug synthesis, can solve the problems of lenvatinib finished product residue, low lenvatinib yield, and difficult monitoring of intermediates, so as to avoid potential safety hazards, reduce production costs, React Safe Effects

Active Publication Date: 2019-05-31
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The intermediate produced by the reaction of cyclopropylamine and carbonyldiimidazole in this process is not easy to monitor, and the yield of lenvatinib obtained by condensing compound a with the condensate of cyclopropylamine and carbonyldiimidazole is low, and the purity is 98.7%. There is room for improvement; moreover, the synthesis process may also introduce a new impurity imidazole, which is not easy to remove, and there is a risk of residue in the finished product of lenvatinib

Method used

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  • Preparation method of lenvatinib and its salts
  • Preparation method of lenvatinib and its salts
  • Preparation method of lenvatinib and its salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of formula 2 compound

[0052]Potassium hydroxide (41.50 g, 3.5 eq) was added into a three-neck reaction flask containing 500 ml of dimethyl sulfoxide containing 10% water. At room temperature, SM2 (57.00 g, 1.5 eq) was added in one portion. After the addition, stir at room temperature for about 3 minutes. Add 50.00 g of the compound of formula 1 at one time, raise the temperature to 110°C, keep it warm for 2 hours, add acetone:water=1:10 (1.5L) while it is hot, cool down to room temperature for crystallization, collect the filter cake by filtration, and dry it under vacuum at 45°C overnight . 68g of the reddish-brown solid compound of Formula 2 was collected, the purity of the reaction solution was 97.81%, the purity of the crude product was 98.51%, and the yield was 94.44%.

Embodiment 2

[0054] The preparation of formula 3 compound

[0055] 28.7g of the compound of formula 2 was added to a reaction flask containing 215ml of N-methylpyrrolidone, and pyridine (14.5g, 2.2eq) was added at the same time, the temperature was lowered to 1°C and 1eq of water was added at the same time, and phenyl chloroformate ( 28.9 g, 2.2 eq). After about 50 minutes of dripping, keep at 2°C for 2 hours, take a drop of the reaction solution and dilute it with 1ml of methanol for HPLC detection. HPLC showed that the purity of the reaction liquid was 96.205%, and the remaining reaction liquid was used to prepare the compound of formula 4.

Embodiment 3

[0057] The preparation of formula 4 compound

[0058] At room temperature, add 21.45 g of cyclopropylamine dropwise to the reaction solution of the compound of formula 3 prepared above, drop it in about 20 minutes, raise it to room temperature, keep stirring and react for 2 hours. The liquid purity is 96.58%. Add 1.29L of acetone-water mixed solution (acetone:water=1:5), crystallize overnight at room temperature, collect the filter cake by filtration, and vacuum-dry the filter cake at 50°C to obtain 30 g, the purity of which is 99.6% by HPLC.

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Abstract

The invention discloses a preparation method of lenvatinib and its salts, wherein N-methylpyrrolidone is used as a reaction solvent in the step of condensation with phenyl chloroformate. The preparation method has the advantages that the danger is successfully avoided that N,N-dimethylformamide and phenyl chloroformate react to produce massive gas during large-scale production; the preparation method is stable, the reaction time is short so that better safety is ensured, posttreatment is facilitated, and quality control is facilitated for the production of active pharmaceutical ingredients.

Description

technical field [0001] The present invention relates to but not limited to the field of drug synthesis, especially relates to the preparation method of lenvatinib and its salt. Background technique [0002] Lenvatinib mesylate (Lenvatinib) is a multi-targeted tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEFG) receptors VEGFR1, VEGFR2 and VEGFR3. The chemical name of lenvatinib mesylate is 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinoline carboxamide mesylate, The structural formula is: [0003] [0004] The prior art discloses the preparation method of lenvatinib, such as CN1878751A, CN106660964A and CN105985289A. At present, its preparation method mainly contains A, B, C three routes. [0005] Route A: use 4-amino-3-chlorophenol as the starting material, condense with phenyl chloroformate, then transesterify with cyclopropylamine to obtain the intermediate of lenvatinib, and then react with 4-chloro-7-methox...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
Inventor 袁鑫祥徐浩宇范兴宝刘海峰周崴海郝秀斌黄淑萍李浩冬
Owner YANGTZE RIVER PHARM GRP CO LTD
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