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Lenvatinib synthesis method

A technology of lenvatinib and a synthesis method, which is applied in the field of medicinal chemical synthesis, can solve the problems of limited application, complicated synthesis, difficult to purchase, etc., and achieves the effects of low production equipment requirements, mild reaction conditions, and simple operation.

Active Publication Date: 2019-05-10
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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Experimental program
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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 lenvatinib synthesis method. The method includes: taking 4-cyano-3-hydroxyaniline as a starting material, subjecting to dimethyl carbonate methylation and oximation through reaction with malonaldehydic acid at the room temperature, performing cyclization under the PPA condition to form 6-cyano-7-methoxy-4-quinolinone, forming 6-cyano-7-methoxy-4-chlorolinone under the action of thionyl chloride, performing cyano hydrolyzing synthesis of 6-formamido-7-methoxy-4-chloroquine which is an intermediate of lenvatinib under an acidic condition, subjecting 4-hydroxy-2-chloroaniline and cyanogen bromide to low-temperature reaction to form 4-hydroxy-2-chlorocyanogen amine, and subjecting 4-hydroxy-2-chlorocyanogen amine and bromopropane to ritter reaction to synthesize 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea which is another key intermediate of lenvatinib; finally, subjecting the two intermediates including 6-formamido-7-methoxy-4-chloroquine and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl urea to alkylation reaction in an alkaline environment to obtain lenvatinib. By the scheme, mild reaction conditions, avoidance of highly toxic reagents, environmentally friendliness and the like are realized.

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