Study On Preparation Of New Anticoagulant Agent Rivaroxaban Intermediates 4-(4-aminophenyl)-3-morpholinone

Rivaroxaban is a new type of direct oral anticoagulant. Rivaroxaban is a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity and needless of continuous monitoring.With it's expanding of the clinical application, the demand of rivaroxaban will be large. Rivaroxaban's Systematic name is 5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomo rpHol -in-4-yl) phenyl] oxazolidin-5-yl] met -hyl} thiophene-2-carboxamide. There are two ways to prepare it, during both the process of them the key intermediate 4-(4-aminophen -yl)-3-morpHolinone is used. Some previous documents reported methods of how to synthesize 4-(4-aminophenyl)-3-morpholinone. But in these methods, the raw materials were difficult to get, expensive, need harsh craft, lower yield or hard to the environment. So these methods were not comfortable for industrial production. Therefore optimizing the way of the key intermediate 4-(4-aminophenyl)-3-morpholinone'producing process, reducting the price of the raw material will help to promote the application of the rivaroxaban.In our country there is no other report about the study the on preparation of rivaroxaban. We studied two preparaing processes. This thesis studied the Cyclization process of 3-morpHolinone, the result show that two-steps-Cyclization is the better choice, and in the first step the best experimental conditions are as follows: 2-anilinoethanol: Chloroacetyl chloride=1:1.5, the reaction temperature is 0℃, catalyst is triethylamine. During the second step the concentration of the sodium hydroxide solution is 0.625g/mL, and during the reaction we remove the solvent through distillation. The result implied that this new craft is feasible, it milded the reaction condition and reduced the contamination.In our country, there are no reports of synthesis of 4-(4-aminophenyl)-3-morpholino- ne that fit to industry until now and there are no factory produce or sell this intermediate. Through the study of the thesis, we find a new way for the industrialized production on the cyclization of 3-morpHolinone.So this research has practical significance and application prospects.