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Method for preparing sunitinib

A technology of sunitinib and dimethyl, which is applied in the field of preparation of sunitinib, can solve the problems of long production cycle, high production cost and low total yield, achieve long reaction time, reduce synthesis cost, and synthesize The effect of improving the total yield

Inactive Publication Date: 2014-08-20
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0016] The purpose of the present invention is to provide a preparation method of sunitinib to solve the problems of long production cycle, low total yield, high production cost and cumbersome operation

Method used

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  • Method for preparing sunitinib
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  • Method for preparing sunitinib

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preparation example Construction

[0044] The improvement steps in the preparation method of sunitinib of the present invention are as follows: 1) Pre-increasing the temperature of 3,5-dimethyl-1H-pyrrole-2,4-bis by controlling the temperature when adding sodium nitrite and zinc powder The productive rate of diethyl carboxylate; 2) to find out synthetic 3,5-dimethyl-1H-pyrrole-4-ethoxycarbonyl-2-carboxylate by the investigation of factors such as feed ratio, alkali concentration, reaction temperature; 3) propose a new synthetic method for 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester); 4) improve N-(2-diethylaminoethyl)-2 , 4-dimethyl-5-formyl-1H-pyrrole-3-carboxamide post-treatment method to more simply remove the by-product dicyclohexyl urea (DCU), and improve the yield of compound 8; 5) Shorten the synthesis steps of 5-fluoro-1,3-indolin-2-one; 6) improve the optimal reaction conditions for the synthesis of sunitinib and increase its yield through the selection of solvents and catalysts.

[0045] (1...

Embodiment 1

[0053] Add 47.2mmol of ethyl acetoacetate and 12mL of glacial acetic acid into a 100mL three-necked bottle equipped with a thermometer and a magnet, and add dropwise nitrous acid with a concentration of 23.6mmol of sodium nitrite and a concentration of 9.8mol / L under stirring in an ice bath. Sodium aqueous solution, and the temperature is controlled at 0°C during the dropwise addition process. After the addition, react in an ice bath for 2.5 hours, then raise the temperature to 30°C and add 47.2mmol of zinc powder in batches. After the addition, remove the ice bath and replace it with constant temperature heating Magnetic stirrer, heated to reflux for 1h, the reaction system was a yellow liquid at this time. The reaction solution was poured into 80 mL of ice water while it was hot, and a light yellow solid precipitated out, which was filtered with suction, and the filter cake was washed with ice water. Dry to obtain 5.33g of 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate diethyl es...

Embodiment 2

[0056]Add 236.0mmol of ethyl acetoacetate and 60mL of glacial acetic acid into a 25mL three-neck bottle equipped with a thermometer and a magnet, and add dropwise under stirring in an ice bath. L of sodium nitrite aqueous solution, and the temperature was controlled at 5°C during the dropping process. After the addition was completed, it was reacted under ice bath conditions for 2.5h, then the temperature was raised to 25°C and 236.0mmol zinc powder was added in batches at this temperature, and the After completion of the reflux reaction for 1.0h, the reaction system was a yellow liquid. Pour the reaction solution into 400mL of ice water while it was hot, and a large amount of yellow solid precipitated out, then stood still for 2-3h, filtered with suction, washed the filter cake with ice water and dried, and weighed to obtain 26.7g of yellow crystal 3,5-dimethyl-1H -Diethyl pyrrole-2,4-dicarboxylate, the crude yield is 94.4%. m.p.133-134°C (lit.135-136°C; Schnettler RA, Dage ...

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Abstract

The invention relates to a method for preparing sunitinib. The method comprises the steps of dissolving 5-fluoro-1,3-indoline-2-ketone and N-(2-diethylin ethyl)-2,4-dimethyl-5-formyl group-1H-pyrrole-3-formamide into methylbenzene, then carrying out backflow reaction for 2.5-3.5 hours with piperidine as a catalyst, cooling to room temperature, carrying out suction filtering, and washing and drying filter cakes obtained by suction filtration through petroleum ether, so as to obtain the sunitinib, wherein the N-(2-diethylin ethyl)-2,4-dimethyl-5-formyl group-1H-pyrrole-3-formamide is prepared through hot melting and decarboxylation of 3,5-dimethyl-1H-pyrrole-4-carbethoxy-2-carboxylic acid, Vilsmeier-Haack formylation, hydrolysis reaction and amidation. According to the method, an intermediate of the sunitinib is prepared and synthesized through a solvent-free method, so that the overall yield of the sunitinib is greatly increased; in addition, the technology for elementary reaction is optimized; furthermore, the raw materials are easy to obtain, and by optimizing all reaction steps in the synthetic process, the elementary reaction yield of each step is increased, the total yield of the sunitinib is increased, and thus the synthetic cost of the sunitinib is lowered.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry synthesis, in particular to a preparation method of sunitinib. Background technique [0002] Sunitinib is an oral, multi-targeted receptor tyrosine kinase (Receptor tyrosine kinases, RTKs) inhibitor developed by Sugen and Pfizer, and is a currently known target One of the most targeted anti-tumor drugs, including vascular endothelial growth factor receptor (VEGFR) 1, 2, 3, platelet growth factor receptor (PDG-FR) α, β, KIT, FLT3 and RET, including Many receptor RTKs have strong inhibitory activity. These RTKs are transmembrane proteins and belong to the class III and V cleavage kinase domain family members. Clinically, it is often used to treat malignant gastrointestinal stromal tumors or metastatic renal cell carcinomas that are ineffective or intolerable to standard treatment. It can inhibit the phosphorylation of a variety of receptor tyrosine kinases in the body, and fight again...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D207/34
CPCC07D207/34C07D403/06
Inventor 孟歌石娟师建华刘春艳郑美林张志国韦晓密王慧慧覃莉雯贺晓双赵桂兰
Owner XI AN JIAOTONG UNIV
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