Study On The Technology For The Preparation Of Sunitinib Malate

Sunitinib L-malate (Sutent) is tyrosine kinase inhibitor, which has multiple targets effects and has shown abroad rang of anticancer activity. Since coming into the market, sunitinib L-malate is mainly used to treat metastatic or advanced renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST) and progressive neuroendocrine tumors. In recent years, new clinical research shows that sunitinib L-malate has achieved a good curative effect on metastatic breast cancer, hepatocellular carcinoma and non-small-cell lung cancer (NSCLC).Study of synthetic technological optimization about sunitinib L-malate is less at present. Based on the review of relevant literatures, we developed a synthetic route of sunitinib L-malate. Tert-butyl-3-oxobutanoate and ethyl3-oxobutanate were used as a raw materials,2-tert-Butyl-4-ethyl-3,5-dimethylpyrrole-2,4-dicarboxylate (SM-1) was obtained by Knorr Pyrrole Synthesis. Intermediate SM-1via decarboxylation in acidic condition and Vilsmeier Hack reaction,3-ethyl2,4-dimethyl-5-formylpyrrole-3-carboxylate (SM-3) was obtained. SM-3eater is hydrolyzed to carboxylic acid (SM-4) in alkali condition. Using5-fluoroisatin as material via Wolff-Kishner Reduction,5-fluoroindole-2-one (SM-6) was gained. By Knoevenagel condensation reaction of5-Formyl-2,4-dimethylpyrrole-3-carboxylic acid (SM-4) and5-fluoroindole-2-one (SM-6),5-[(Z)-(5-Fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxy-lie acid (SM-7) was got. By alkanoylation, aminolysis and salification reaction, the target compound sunitinib L-malate was finally obtained.The critical factors of every step in process, such as material input, solvent, reaction time, catalyst and so on were found and optimized. And the optimum reaction conditions were established. Compared with the reported literatures, the overall yield was increased to53.9%and the cost was reduced, providing a foundation for its industrialization.