Study On The Synthetic Process Of Rivaro-Xaban And The Synthesis Of The Related Substances

Thrombotic disease seriously threaten human health and life in today's society.It can threaten various systems or organs of the body.It has a high prevalence,high morbidity and mortality characteristics.Rivaroxaban,which is a first oral direct factor Xa inhibitor,is the prevention of venous thrombosis drugs,with a high degree of selectivity and competition,high bioavailability,lasting efficacy.It's taken only once a day and is an effective drug to prevent venous thrombosis.At the present,rivaroxaban all in Chinese market was imported from abroad.there is no domestic goods API source.To break the foreign monopoly,it is important to study on the synthetic process of rivaroxaban.This paper designed and studied the synthesis of rivaroxaban and the synthesis of related substances.Rivaroxaban?1?was processed by 4-?4-aminophenyl?morpholin-3-one?4?and?S?-N-epoxypropyl phthalimide?22?as the starting material,followed by condensation,cyclization,deprotetion and amidation.The condensation reaction was optimized for the reaction solvent and the reaction temperature.Isopropyl alcohol/water?9:1?is used as the reaction solvent.The reaction temperature is 70 ?.The yield is 90%.The purity of the product is more than 97%.While it reduces the amount of compound 22 feeding,and than reduces the cost.The cyclization reaction was optimized for the reaction solvent and the reaction temperature.The reaction with iso-amyl acetate as solvent refluxed greatly shortened the reaction time?from the literature to more than 20 hours shortened to 1 hour?,replacing the toxic toluene or methylene chloride and other solvents.The yield is 97%,increased 9 percentage points more than 88%of the literature.The purity is more than 99.5%.It reduces the cost and working hours.The deprotection reaction optimizes the reaction temperature and the amount of methylamine feed.The reaction temperature was reduced from reflux?from literature?to 60?.The amount of methylamine was reduced from 13 times to 4 times,and the yield was basically the same as that of the literature.The energy consumption and raw material consumption were reduced.At the same time,LC-MS was used to analyze the four related substances in the rivaroxaban API.And the possible compound structure was deduced according to the reaction mechanism.According to the reaction mechanism,we synthesized the four related substances.The chemical structures of them were confirmed by MS,¹H NMR,and ¹³C NMR.After the optimization of the whole process,the total yield is 69.3%?61.6%reported in the literature?,and the purity of the product is up to 99.8%.The chemical structures of rivaroxaban was confirmed by MS,¹H NMR,and ¹³C NMR.