申请人:Zentiva, k.s.
公开号:EP2181999A1
公开(公告)日:2010-05-05
Method of manufacturing ruboxistaurin, comprising the steps of preparation of L-2-deoxyribose 1-cyano-3,4-dibenzoate, followed by deprotection to 1-cyano L-2-deoxyribose, oxidative cleaving to (S)-4-hydroxy-2-(2-hydroxy-ethoxy)-butyronitrile and transformation to the methanesulfonic acid (S)-3-cyano-3-(2-methanesulfonyloxyethoxy)-propyl ester, then coupling with 1-substituted-3,4-bis(3-indolyl)maleimide leading to 9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecine-18,20(19H)-dione, 6,7,10,11-tetrahydro-19-substituted-9(S)-cyano, followed by methylation of the amino group and deprotection forming 5,21:12,17-dimetheno-9H-dibenzo[e,k]furo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione, 6,7,10,11-tetrahydro-9-[(dimethylamino)methyl]-, (S)- (9CI), and the final step consisting of imido preparation to form ruboxistaurin.
生产鲁博西他林的方法,包括以下步骤:制备
L-2-去氧
核糖-1-
氰-3,4-二
苯甲酸酯,然后去保护成为1-
氰基
L-2-去氧
核糖,氧化断裂成(S)-
4-羟基-2-(2-羟基乙氧基)-
丁腈,并转化为
甲磺酸(S)-3-
氰基-3-(2-甲磺酰氧乙氧基)-丙基酯,然后与1-取代-3,4-双(3-
吲哚基)马来
酰亚胺偶联,得到9H,18H-5,21:12,17-二甲烯二苯并[e,k]
吡咯并[3,4-h][1,4,13]噁二氮杂
环十六烷-18,20(19H)-二酮,6,7,10,11-四氢-19-取代-9(S)-
氰基,然后甲基化
氨基团并去保护,形成5,21:12,17-二甲烯-9H-二苯并[e,k]
呋喃[3,4-h][1,4,13]噁二氮杂
环十六烷-18,20-二酮,6,7,10,11-四氢-9-[(
二甲氨基)甲基]-,(S)- (9CI),最后一步是制备亚砜以形成鲁博西他林。