A kind of synthetic method of lenvatinib

A technology of lenvatinib and its synthetic method, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of difficult purchase, limited application, complicated synthesis, etc., and achieve the effects of simple operation, low requirements for production equipment and mild reaction conditions

Active Publication Date: 2021-12-21
IANGSU COLLEGE OF ENG & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The synthesis of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea, another key intermediate, mainly uses 4-hydroxy-2-chloroaniline as the starting material and reacts with phenyl chloroformate, Synthesize 1-(2-chloro-4-hydroxyl phenyl)-3-cyclopropyl urea with cyclopropylamine aminolysis reaction then, phenyl chloroformate is not easy to buy on the market, and synthesis is more complicated, and bigger limit its in Application in industrial production

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  • A kind of synthetic method of lenvatinib
  • A kind of synthetic method of lenvatinib
  • A kind of synthetic method of lenvatinib

Examples

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Effect test

Embodiment 1

[0044] A kind of synthetic method of lenvatinib, concrete steps are as follows:

[0045] Step 1, the synthesis of 4-cyano-3-methoxyaniline: Take 134g of 4-cyano-3-hydroxyaniline, dissolve it in 500mL N, N-dimethylformamide (DMF) and mix well, then take 300g of the mixture , add 32g of tetrabutylammonium bromide, 268g of potassium carbonate, the temperature of the reaction system is raised to 110°C, and 100g of dimethyl carbonate is added dropwise. After the dropwise addition, the reaction is continued for 8h. Remove the solvent by distillation under pressure, add 200g of water, extract with 500mL of ethyl acetate, dry the organic layer over anhydrous sodium sulfate, filter, recover the solvent from the filtrate, and recrystallize the residue with a mixture of petroleum ether and ethyl acetate. The volume ratio was 1:1300, and 139 g of light yellow solid was obtained.

[0046] Step 2, the synthesis of oxime: Take 74g of the first step product 4-cyano-3-methoxyaniline, dissolve...

Embodiment 2

[0054] Step 1, the synthesis of 4-cyano-3-methoxyaniline: Take 100g of 4-cyano-3-hydroxyaniline, dissolve it in 500mL DMF and mix evenly, take 300g of the mixture, add 25g of tetrabutylammonium bromide, carbonic acid Potassium 200g, the temperature of the reaction system was raised to 110°C, and 100g of dimethyl carbonate was added dropwise. After the dropwise addition, the reaction was continued for 7h. After the reaction, the operation was the same as in Example 1 to obtain 103g of a light yellow solid.

[0055] Step 2, the synthesis of oxime: take 50g of 4-cyano-3-methoxyaniline, dissolve in ethanol, heat to reflux, add 50g of propionic acid dropwise, after the dropwise addition, continue to react for 4h, after the end of the reaction, reduce Recover the solvent by pressure. The residue was continued to the next step without separation.

[0056] Step 3, the synthesis of 6-cyano-7-methoxy-4-quinolinone: add 100mL polyphosphoric acid to the residue of the previous step react...

Embodiment 3

[0063] Step 1, the synthesis of 4-cyano-3-methoxyaniline: Take 150g of 4-cyano-3-hydroxyaniline, dissolve it in 500mL DMF and mix evenly, take 300g of the mixture, add 34g of tetrabutylammonium bromide, carbonic acid Potassium 300g, the temperature of the reaction system was raised to 110°C, and 100g of dimethyl carbonate was added dropwise. After the dropwise addition, the reaction was continued for 9h. After the reaction, the operation was the same as in Example 1 to obtain 146g of a light yellow solid.

[0064] Step 2, the synthesis of oxime: take 100g of 4-cyano-3-methoxyaniline, dissolve in ethanol, heat to reflux, add 50g of propionic acid dropwise, after the dropwise addition, continue the reaction for 6h, after the reaction, reduce Recover the solvent by pressure. The residue was continued to the next step without separation.

[0065] Step 3, the synthesis of 6-cyano-7-methoxy-4-quinolinone: add 100mL polyphosphoric acid to the residue of the previous step reaction, r...

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Abstract

The invention provides a synthesis method of lenvatinib. Firstly, the present invention uses 4-cyano-3-hydroxyaniline as the starting material, methylated by dimethyl carbonate, oximated by propionic acid at room temperature, and forms 6-cyano-7 by ring closure under PPA conditions. -Methoxy-4-quinolinone, which forms 6-cyano-7-methoxy-4-chlorolinone under the action of thionyl chloride, and synthesizes one of lenvatinib by hydrolysis of cyano group under acidic conditions Intermediate 6-formamido-7-methoxy-4-chloroquinoline. Then 4-hydroxy-2-chloroaniline and cyanogen bromide are formed at low temperature into 4-hydroxy-2-chlorocyanamide, and 4-hydroxy-2-chlorocyanamide is reacted with bromopropane to synthesize lenvati Another key intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea of ​​Ni. Finally, the two intermediates 6-formamido-7-methoxy-4-chloroquinoline and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea were carried out in alkaline environment Kylation reaction to prepare lenvatinib. The scheme has the advantages of mild reaction conditions, no highly toxic reagents, and environmental protection.

Description

technical field [0001] The invention relates to a synthesis method of lenvatinib, which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Lenvatinib (E7080) is an oral multi-receptor tyrosine kinase inhibitor developed by Japan's Eisai Co., Ltd. (Eisai). It 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. [0003] The synthesis of lenvatinib mainly involves the synthesis of two key intermediates, one is the synthesis of 6-formamido-7-methoxy-4-chloroquinoline, and the other is 1-(2-chloro-4-hydroxyl Synthesis of phenyl)-3-cyclopropylurea. A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/48
Inventor 冯成亮严宾
Owner IANGSU COLLEGE OF ENG & TECH
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