Synthesis And Process Research Of Rivaroxaban

The chemical name of rivaroxaban is 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morph olinyl)phenyl]-5-oxazolidinyl}methyl)-2-thiophenecarboxamide.Using for the preve-ntion of venous thromboembolism after hip or knee replacement surgery,it is excellent in vivo activity and bioavailability.Recently,the sales of antithrombotic drugs have been gradually increasing as the number of patient groups raising.Rivaroxaban will become a new heavyweight drug in the new cardiovascular sector with great market prospects.This paper is consisted with three parts:1.The synthesis of compound 44-(4-aminophenyl)-3-morpholinone;2.The synthesis of compound 5(S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione;3.The synthesis of rivaroxaban.Using 2-(phenylamino)ethanol and chloroacetyl chloride as start materials,4-phenyl-3-morpholinone was synthesized by cyclization under the condition of sodium hydroxide as acid binding agent,and then by nitration to give 4-(4-nitrophenyl)-3-morpholinone,which was finally reduced to compound 44-(4-aminophenyl)-3-morpholinone with ammonium sulfide.Total yield was 82.1%.Dissolved in isopropanol solvent,the potassium salt of phthalimide reacted with(S)-epichlorohydrin to give compound 5(S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione.The yield is 88.9%.The compound 4 and compound 5 were subjected to electrophilic substitution to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione.The final product rivaroxaban was synthesized by a series of chemical reactions including nitrification and reduction.The product was verified by melting point,IR,~1H-NMR,MS,single crystal analysis and other means.The yield of the target compound was 64.7%.Changing the molar ratio,solvent and reagent,the process optimization route was mainly based on the optimum reaction temperature and time that have been determined.By exploring the conditions,a satisfactory yield was obtained.Compared with the traditional process,this synthetic route has the advantages of low cost,environmental protection,energy saving,mild reaction condition,simple post-processing,high yield and good industrial prospect.