Preparation method of high-purity lenvatinib and salt thereof

A technology of lenvatinib and compounds, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as increased process costs, achieve the effects of reducing post-processing steps, controlling residues, and reducing the production of impurities 10 and 11

Active Publication Date: 2019-09-27
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to Example 2 of this patent, it can be seen that 25.7kg of crude lenvatinib needs to be refined with 359.6L of DMI, that is, 359.6L / 500ml×750 yuan = 539,400 yuan = 539,400 yuan, which greatly increases the process cost
And CN106660964A patent describes that DMF, DMSO, 2-propanol or isopropyl acetate can be used for crystallization, wherein the good solvent is DMF, DMSO, and the poor solvent is 2-propanol or isopropyl acetate, but other organic solvents except DMI As a good solvent is not shown in the examples, but the inventors of this patent found through experiments that although good solvents other than DMI can control the compound of formula 8 within limits, there are other new genotoxic impurities that can only be removed by DMI.

Method used

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  • Preparation method of high-purity lenvatinib and salt thereof
  • Preparation method of high-purity lenvatinib and salt thereof
  • Preparation method of high-purity lenvatinib and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-formamide

[0053]

[0054] Add 900ml of dimethyl sulfoxide and 90g of 3-chloro-4-aminophenol hydrochloride (Formula 1) into the reaction flask, add dropwise 120g of 48w / w% potassium hydroxide aqueous solution, after the dropwise addition is complete, stir at room temperature for 0.5h. Add 90 g of 4-chloro-7-methoxyquinoline-6-carboxamide (Formula 6). Heating reaction 14 ~ 15h. Add 1800ml of acetone aqueous solution (volume ratio 1:3) dropwise, stir for 1h after the completion of the dropwise addition, cool down to room temperature after stirring, crystallize for 2h, filter, wash with 1300ml of acetone aqueous solution (volume ratio 1:3), and dry. 4-(4-Amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (Formula 8) was obtained.

[0055] Table 1 Effect of different reaction temperatures on yield and purity

[0056]

[0057] It can be seen from the results in Table 1 that when the tem...

Embodiment 2

[0058] Embodiment 2: Preparation of {4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]-2-chloroanilino}formic acid phenyl ester

[0059]

[0060] Add 50 g of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (formula 8) obtained in Experiment 1-2 of Example 1 into the reaction flask and add N,N - 400ml of dimethylformamide, 30g of pyridine and 3g of purified water, reduce to the reaction temperature, add 50g of phenyl chloroformate (Formula 2) dropwise, and react for 2h after the dropwise completion. 1000ml of acetone was added dropwise, stirred and crystallized. Filter, wash with 200ml of acetone, and dry to obtain phenyl {4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]-2-chloroanilino}formate (Formula 9).

[0061] Under the condition that the above conditions remain unchanged, only the conditions shown below are changed to affect the compound of formula 9.

[0062] Table 2 Effect of different reaction temperatures

[0063]

[0064] In the prior art, the temperature is ...

Embodiment 3

[0065] Embodiment 3: the preparation of lenvatinib

[0066]

[0067] Add 80g of the compound of formula 9 obtained in Experiment 2-2 in Example 2 and 560ml of N,N-dimethylformamide into the reaction flask, add 34.5g of cyclopropylamine dropwise at 13°C, and keep the temperature for 2h. Add 1260ml of acetone aqueous solution (volume ratio 20:1) for crystallization, and stir for 2 hours after dropping. After filtering, washing with 160ml of acetone, and drying, 54g of delenvatinib was obtained, and the yield was 73%. Calculate the amount of lenvatinib content and impurities, and the results are shown in Table 3.

[0068] Table 3 Contents of different impurities in lenvatinib

[0069]

[0070] Note: "RT" is the retention time.

[0071] According to the threshold of toxicological concern stipulated in the "Guidelines on the Limits of Genotoxic Impurities" issued by the European Medicines Agency, the content of the compounds of formula 6 and formula 11 is 60ppm (0.006%) or...

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Abstract

The invention relates to a preparation method of lenvatinib and salt thereof. The adopted method for preparing the lenvatinib has the advantages that the process is simple, the cost is low, the purity is high, the single-purity content meets the regulations, and the industrial production is easier.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of high-purity lenvatinib and salts thereof. Background technique [0002] Lenvatinib mesylate, the molecular formula is C 21 h 19 ClN 4 o 4 ·CH 4 o 3 S, the chemical name is 4-[3-chloro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate, which is produced by the original manufacturer The oral anti-cancer drug developed by Japan's Eisai Company, the specifications include 4mg, 10mg (calculated as lenvatinib). In February 2015, lenvatinib mesylate was approved by the FDA for the treatment of differentiated thyroid cancer, and it was approved for the treatment of renal cell carcinoma in May 2016. Approved for first-line treatment of unresectable hepatocellular carcinoma. In May 2015, lenvatinib mesylate was approved by EMA for the treatment of differentiated thyroid cancer, and in August 2016 it was approv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 彭肖石郭明东刘峰张倩如张振海李鹏飞
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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