Study On The Synthetic Process Of Two Nucleoside Anticancer Drugs

Malignant cancer is one of the diseases of serious threat to mankind’s health and life. According to Global Cancer Report 2014 released by World Health Organization (WHO), the world faces a large outbreak of cancer, especially for China with the highest morbidity. As the nucleoside drug is a very important anti-tumor and anti-viral drug, this paper studied and optimized the synthetic process of capecitabine and gemcitabine on the basis of domestic and foreign literature and patents.As for capecitabine, after analyzing and study, we chose a synthetic route with D-ribose as starting material and conducted in the sequence of methyl glucoside and ketalization protection, esterification, reduction, acid technology, Silyl reaction, amidation, and hydrolysis. Among them, we carefully studied the third step by different routes. There are two methods for reduction, directly utilizing sodium borohydride, or firstly iodinating and then Pd/C infusing hydrogen. By comparing the two methods, the direct reduction was chosen to settle liquid flooding during enlarging sodium borohydride. As for amidation, the single amidation product is generated by adjusting reaction temperature and dropping rate, and then this product was purified by recrystallization with isopropanol and petroleum ether for the first time. Finally, high-purity capecitabine product (99.85%) can be obtained by one-off purification. At the same time the total production rate (8.9%) was greatly improved by optimizing the operation sequence.As for gemcitabine, a new route was designed to synthesize gemcitabine, and the first four steps of this route were verified and optimized. Particularly in bromization, the target compound has α and β configurations which are respectively meliceris and solid. Therefore, the final scheme is to recrystallize raw reaction product, spin dry the remaining product and then conduct the next steps so as to avoid column chromatography. Although this route finally fails, it is hopeful that this route will contribute to synthesize tabine anticancer drugs and avoid drug patent protection from abroad.