Study On The Synthetic Method Of The Intermediate Of Capecitabine

Capecitabine have targeted and mild systemic toxicity reaction, is currently the only curative effect of oral preparations more than intravenous administration of fluorine generation of pyrimidine carbamate antitumor drugs. Have been used in clinical treatment of patients with colorectal cancer, gastric cancer, breast cancer and good results have been achieved. Capecitabine(trade name "Xeloda") was first listed in the United States in April 1998. 5′-deoxy-2′,3′-double-O-acetyl-5-fluorine cytidine is the key intermediates of synthesis capecitabine. As capecitabine is widely used in clinical, the market of its raw materials grows quickly. So strengthen research of the 5′-deoxy-2′,3′-double-O-acet-yl-5-fluorine cytidine is great significant.In this paper, based on analysis of existing synthetic route and several experiments, we developed a new synthetic process which is suitable for industrial production. The improved synthetic route takes D-ribose as raw material via he protection of hydroxy, toluene sulfonyl seaborne, reduction, hydrolysis, acetylation and Silyl reaction to synthesis 5′-deoxy-2′,3′-double-O-acetyl-5-fluorine cytidine. This paper mainly completed the following work:(1) Hydroxylation protective reaction. The first time successfully using the method of "one pot" directly protect 2,3,4 hydroxy, intermediate without separation, refining, drying and other steps. New process with trimethyl orthoformate insteading of methanol and acetone as reaction reagent, at the same time as the reaction of SAP, make response to the positive direction, greatly improve the conversion rate. Determine the strong hydrochloric acid as catalyst, raw material residual rate is only 2.3%. Hydroxy protective reaction was determined by the orthogonal experiment, the optimal process parameters: the molar ratio of concentrated hydrochloric acid and D-ribose 0.74:1.0, trimethyl orthoformate and D-ribose mole ratio of 5.5:1 and the reaction temperature of 30-35℃ which have maked the trimethyl orthoformate and the molar ratio of D-ribose 6.5:1 to 5.5:1, save the cost of production. After optimization, the reaction yield up to 89.5%, yield of the original process is increased by 4.3%.(2) Toluene sulfonyl seaborne. New process with dichloromethane as reaction reagent, triethylamine as acid binding agent replacing pyridine with adding a small amount of DMAP at the same time, simplify the post-processing procedure. By orthogonal experiments, determined the better of a sulfonated benzene acylation reaction process conditions as p-toluene sulfonyl chloride with D-ribose mole ratio of 1.0:1.0, at 3℃ adding p-toluene sulfonyl chloride, the molar ratio of D-ribose and trimethylamine of 1:1.4, the highest in the first two steps of total yield reached 74%, compared with the original process improving by about 5%.(3) Reduction. Dioxane replacing DMSO system solved the problem of the trouble post-processing.(4) Hydrolysis. Taking off the protection in the sulfuric acid, a pot method removal the ketal and methyl protecting base. By investigating two key factors(the sulfuric acid concentration and reaction temperature) of the releasing sugar ring protection base have determined the optimum process conditions for hydrolysis reaction that sulfuric acid concentration is 0.04 mol/L, reaction temperature 90℃, product yield of 98% and purity of 99.1%.(5) Acetylation. The new technology of heating dissolve dry hydrolysis products with isopropyl alcohol, boiled with water at low temperature and high vacuum condition for three times in a row which solved the water of hydrolyzate into effect on the acylation reaction. In view of the adding time of acetic anhydride is optimized and time control in 1 hour, acceleration is about 3~5 seconds/drops. The triethylamine-DMAP mixed catalyst feed molar ratio of 1.6:0.03:1 is the best. Through the optimization of acylation reaction process conditions make the final product yield of 84.9%, compared with the original process improved by about 6%.(6) Silyl. In order to improve the market competitiveness of products, the product recrystallizated by isopropyl alcohol, through the optimization of Silyl reaction process conditions make the final product purity up to 99.6% which have improved by about 1.6% contrast to the original process.The new technology are fully competitive in the market.