A Study On The Process Synthesis Of The Anticoagulant Drug:Apixaban

This paper briefly described the status of the incidence of thrombosis and the development overview of antithrombotic drugs, introduced of the new anticoagulants-oral direct factor Xa inhibitor and the mechanism of action. With the substantial increase in the number of deaths which suffered from thrombotic disease each year in the global, pathogenesis and anti-thrombosis drug research had become one of the global issue. At present, the development of the antithrombotic drugs, anti-platelet drugs and the new anticoagulant drug which is based on the target coagulation factor Xa, Ⅱ a, Ⅸa specific inhibition. Apixaban as an effective oral direct factor Xa inhibitor with many advantages:with a high safety factor, a little interactions among very few drug, the dose response could be predicted, could be dosed in oral and parenteral and effect quickly. So it has been widely used and recognized by the patients and medical treatments. In order to achieve the industrial production of the drug better, we designed a novel and efficient synthetic routes for Apixaban by studying the synthesis methods and processes.Many synthetic routes had been reported in the domestic and abroad, the starting materials and intermediates were organic iodide, that the price was more expensive, the reaction operation were tedious, raw materials and intermediate were not easy to get, and the total yield was low. Many deficiencies in the routes which were reported, so designed a high-yield, low-cost process route to achieve the total synthesis of apixaban was an urgent problem. In view of the patent route for apixaban, in order to give lactam which using inexpensive nitroaniline and5-chlorovaleryl chloride as starting material through amide and cyclization, and then used phosphorus pentachloride chloriding a-reactive hydrogen, followed by condensation-elimination reaction with an excess of morpholine, and then used sodium sulfide reducing the nitro group, followed by amidation-cyclization with5-chloro-pentanoyl chloride, followed by reaction with the intermediate (Z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazono) acetate by cyclization elimination, finally, ammonia solution produced the target product. The total yield was35%, which was applied in drawing more synthetic route, but the ring of sodium hydrogen mixture used in the reaction schemes more intense, for security reasons the industry is not conducive to mass production industry. And intermediate (Z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazono) acetate is not stable for a long time at room temperature or at elevated temperatures, and constituted a significant limitation for large-scale industrial production. Herein, we develop a novel route to apixaban with two new synthetic strategy, which is described below:using nitroaniline and5-chlorovaleryl chloride as starting material through amide and cyclization, and then used phosphorus pentachloride chloriding a-reactive hydrogen, followed by condensation-elimination reaction with an excess of morpholine, and then used sodium sulfide reducing the nitro group, followed by amidation-cyclization with5-chloro-pentanoyl chloride, And then reacted with oxalyl chloride monoethyl ester to give the key intermediate ethyl2-(5-morpholino-6-oxo-1-(4-(2-oxopiperidin-1-yl)phenyl)-1,2,3,6-tetrahydropyridin-4-y1)2-oxo acetate. The first strategy, ethyl2-(5-morpholino-6-oxo-1-(4-(2-oxopiperidin-l-yl) phenyl)-1,2,3,6-tetrahydropyridin-4-yl)2-oxoacetate with hydrazine hydrate by cyclization and then coupling with methoxy boronic acid, and finally ammonia solution to get the final product apixaban. The second strategy, ethyl2-(5-morpholino-6-oxo-1-(4-(2-oxopiperidin-1-y1) phenyl)-1,2,3,6-tetrahydropyridin-4-yl)2-oxoacetate removed the morpholino, after that, the reaction with (4-methoxyphenyl) hydrazine hydrochloride, and finally get the final product apixaban after ammonia solution.The first strategy with a low overall yield of33%, and the second strategy with a high overall yield of43%. Through comparing two kinds of synthetic strategy of production rate and optimizing process condition, then established a cheap raw materials, simple operation, simple post-processing, higher total yield, very suitable synthetic route for industrialized production.