选择性还原硝基合成来那度胺有关物质

Synthesis of related substances of lenalidomide by selective reduction of nitro group

为了满足药品研究、生产、质量标准制订对有关物质化合物的需求,以来那度胺前体化合物3-(4-硝基-1-氧代-1,3-二氢异吲哚-2-基)哌啶-2,6-二酮(1)为原料,选择性还原苯环硝基,合成了来那度胺N-羟基杂质:3-(4-羟氨基-1-氧代-1,3-二氢异吲哚-2-基)哌啶-2,6-二酮(2),同时经碱催化开环、还原硝基合成了来那度胺开环杂质:5-氨基-4-(4-硝基-1-氧代-1,3-二氢异吲哚啉-2-基)-5-氧代戊酸甲酯(3)和5-氨基-4-(4-氨基-1-氧代-1,3-二氢异吲哚啉-2-基)-5-氧代戊酸甲酯(4)。来那度胺有关物质化合物HPLC纯度均大于99%,化学结构经NMR和HRMS确证。

In order to meet the demand for related substances in drug research,production and the formulation of quality standard,the precursor lenalidomide compound 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(1)was used as raw material to synthe-size lenalidomide N-OH impurity,3-(4-hydroxyamino-1-oxoisoindolin-2-yl)piperidine-2,6-dione(2),by selectively reduction of ar-omatic nitro group.Lenalidomide ring-opening impurities,methyl-5-amino-4-(4-nitro-1-oxoisoindolin-2-yl)-5-oxopentanoate(3)and methyl 5-amino-4-(4-amino-1-oxoisoindolin-2-yl)-5-oxopentanoate(4),were also synthesized by alkali-catalyzed ring-opening and nitro group reduction.The purity of three impurities identified by HPLC was up to 99%,and their structures were confirmed by NMR and HRMS.