Method for synthesizing lenvatinib

A technology of lenvatinib and synthetic route, which is applied in the field of lenvatinib synthesis and can solve the problems of low yield and complicated synthetic route of lenvatinib.

Inactive Publication Date: 2019-03-12
南京天越星生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, there are technical problems that the synthetic route of lenvatinib is complicated and the yield is not high

Method used

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  • Method for synthesizing lenvatinib
  • Method for synthesizing lenvatinib

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Embodiment 1

[0022] Embodiment 1: the synthesis of methyl 4-amino-2-methoxybenzoate (3)

[0023] Weigh 10g (65mmol) of p-aminosalicylic acid (2) into a 250mL three-neck flask, add 100mL of acetone, 10.45g (32.5mmol) of tetrabutylammonium bromide, stir until completely dissolved, then add 9.80g of potassium hydroxide (0.176mmol), control the reaction temperature at 20-30°C, stir until a large amount of precipitates are formed, add 15.40mL (16.3mmol) of dimethyl sulfate dropwise, control the temperature at 30-45°C, complete the dropwise addition within 20min, control the temperature , stirred for 2h. After the reaction was completed, the acetone was distilled off under reduced pressure, and 80 mL of ice water was added. A white solid precipitated out. Suction filtration, washing with water, and drying gave 10.51 g of white solid (3), yield 84%, mp 157-159°C.

Embodiment 2

[0024] Example 2: 5-[(3-methoxy-4-methoxycarbonylanilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-di Synthesis of Ketone (4)

[0025] Weigh 15g (104mmol) of McBurney's acid, add it into 50mL (300mmol) of triethyl orthoformate, and stir at 90°C for 3h. Then, 50 mL of isopropanol and 21.92 g (0.121 mmol) of methyl 4-amino-2-methoxybenzoate (3) were added, and the mixture was refluxed for 1 h. After the reaction was completed, a large amount of yellow precipitates were produced, cooled to room temperature, filtered, and the filter cake was fully washed with ether, and left to dry to obtain 29.76 g of light yellow solid (4), with a yield of 85%.

Embodiment 3

[0026] Example 3: Synthesis of 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester (5)

[0027] Weigh 45g (292mmol) of biphenyl and place it in a three-necked flask, add 150mL of diphenyl ether, heat the solvent to 180°C under nitrogen protection, and quickly add 18g (53.7mmol) of compound 4 under nitrogen atmosphere, a large amount of gas is released, Maintain the temperature at 170-185°C, react for 45 minutes, and stop heating. After cooling to room temperature, a large number of yellow solids precipitated, adding petroleum ether, filtering, and washing the filter cake with diethyl ether to obtain a crude product. The crude product was purified by slurrying with petroleum ether-ethyl acetate (volume ratio: 5:2), filtered by suction, and dried to obtain 10.11 g of yellow solid (5), with a yield of 80.7%.

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Abstract

The invention belongs to the field of chemical pharmacy, and specifically relates to a method for synthesizing lenvatinib. The method comprises the following steps: step 1, taking 4-aminosalicylic acid as a raw material, and preparing 4-chloro-7-methoxyquinoline-6-formamide through methylation, condensation with meldrum's acid, high-temperature cyclization, chlorination and ammoniation; step 2, taking 3-chloro-4-aminophenol as a raw material, and reacting with phenyl chloroformate and cyclopropylamine to obtain 1-(2-chloro-4-hydroxy phenyl)-3-cyclopropyl urea; and step 3, enabling the 4-chloro-7-methoxyquinoline-6-formamide prepared in step 1 to react with the 1-(2-chloro-4-hydroxy phenyl)-3-cyclopropyl urea prepared in step 2 under action of potassium tert-butoxide to obtain the lenvatinib. The invention provides a brand-new route for synthesising the lenvatinib. The used reagent is cheap and is easily available, is simple in operation, has a yield higher than that of other methods, and is easy for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a method for synthesizing lenvatinib. Background technique [0002] Lenvatinib (E7080, 1), the chemical name is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, which is manufactured by Japan Eisai The oral multi-receptor tyrosine kinase inhibitor developed by Eisai is a potential therapeutic drug for thyroid cancer, liver cancer, non-small cell lung cancer and other solid tumors. In February 2013, lenvatinib was granted orphan drug designation by the FDA for the treatment of follicular, medullary, undifferentiated and metastatic or locally advanced papillary thyroid carcinoma. On February 13, 2015, lenvatinib was approved by the FDA for the treatment of radioiodine-refractory differentiated thyroid cancer. In the prior art, there are technical problems that the synthetic route of lenvatinib is complicated and the yield is not ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 吴学平陈耀
Owner 南京天越星生物技术有限公司
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