Study On Synthesis Of Anticancer Drug Sunitinib

Sutent(sunitinib malate) was a new kind of anti-cancer drug produced by Pfizer Inc which went on sale in January 2006. Sutent is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sutent is indicated for the treatment of gastrointestinal stromal tumour(GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. However, there is only one US patent describing about the synthesis of Sutent at present, Studying on the synthesis of Sutent plays a important role.This paper reported a total synthetic route of Sutent. The key imtermediate 2, 4-dimethyl-3,5-diethoxycarbonyl-lH-pyrrole was synthesized from ethyl acetoacetate via Knorr reaction, yield 60% (46% yield in literature). Literature methods in which hydrolysis reaction used quinoline as decarboxylation solvent was improved, whose boiling point is 50℃higher than the decarboxylation reaction temperature. Choosed triethyl phosphate to replace quinoline for high temperature decarboxylation, reprocessing was convenient, and purification products became easy, and copper powder is not need. Further improved methods were investigated for the synthesis of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide, in the steps of acylation, hydrolysis, condensation with DCC as condensing agent.Beginning with fluoroaniline, chloral hydrate, hydroxylamine hydrochloride, the reaction steps included acylation, oxime, cyclization in the presence of concentrated sulfuric acid, 5-fluoro-isatin was obtained. 5-fluoro-1,3-dihydro-indole-2-one was obtained by referred similar compounds synthesized by Wolff-Kishner reduction in alkali. Compared with the literature, reaction time significantly reduced with the yield of 85% (73% yields in literature) and better purified. In the presence of cheap weak base triethylamine, the target compound was obtained.This paper investigated the influence of the raw materials used, the reaction time, temperature, the use of the catalyst on the reaction, Optimized the best experimental conditions. Determinated the physical properties such as the melting point on the intermediate and end products, reported the melting points of six compounds for the first time. The structure of the final step of the product and the intermediates was preliminary identified through ~1H NMR spectra.Total synthetic route was available of the raw materials, with higher yields and more moderate conditions. The intermediates were solid, easy to purify and treat. Thus, the route was suitable for industrial production.