利伐沙班的合成工艺改进

Improved Synthetic Process of Rivaroxaban

(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]。

（S）-4-Chloro-3-hydroxybutanenitrile reacted with phthalimide potassium followed by hydrolysis of nitrile-group to give （S）-4-（1,3-dioxoisoindolin-2-yl）-3-hydroxybutanamide, which was subjected to Hofmann rearrangement in the presence of [bis （trifluoroacetoxy）iodo]benzene to afford （S）-2-[ （2-oxo-l,3-oxazolidin-5- yl） methyl]- 1H-isoindolin-1,3 （2H）-dione, the latter reacted with 4-（4-bromophenyl）morpholin-3-one via Ullmann reaction to give 2- [ [ （S） -2-oxo-3- [4- （3-oxo-4-morpholinyl） phenyl] - 1,3-oxazolidin-5-1y] methyl] -1H-isoindolin- 1,3 （2H） -dione, then it was subjected to hydrazinolysis and amidation to prepare rivaroxaban with an overall yield of 72.7 % [based on （S） -4-chloro-3-hvdroxvbutanenitrile].