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(S)-4-氯-3-羟基丁腈与邻苯二甲酰亚胺钾盐反应后,经腈基水解得(S)-4-(1,3-二氧代异吲哚-2-基)-3-羟基丁酰胺,在二(三氟乙酸)碘苯作用下经Hofmann重排得(S)-2-[[2-氧代-1,3-噁唑烷-5-基]甲基]-1H-异吲哚-1,3(2H)-二酮,与4-(4-溴苯基)吗啉-3-酮发生Ullmann偶联得2-[[(S)-2-氧代-3-[4-(3-氧代-4-吗啉基)苯基]-1,3-噁唑烷-5-基]甲基]-1H-异吲哚-1,3(2H)-二酮,再经肼解、酰胺化得利伐沙班,总收率72.7%[以(S)-4-氯-3-羟基丁腈计]。
Reaction of (S) -4-chloro-3-hydroxybutyronitrile with potassium phthalimide gave the (S) -4- (1,3-dioxoisoindole-2 - yl) -3-hydroxybutanamide was Hofmann rearranged in the presence of iodobenzene bis (trifluoroacetate) to give (S) -2- [[2-oxo-1,3-oxazolidin- ] Methyl] -1H-isoindole-1,3 (2H) -dione was coupled to 4- (4-bromophenyl) morpholin-3-one to give 2 - [[(S) - Oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl] methyl] 3 (2H) -dione, and then hydrazinolysis, amidated to rivaroxaban, the total yield of 72.7% [in (S) -4-chloro-3-hydroxybutyronitrile].