泊马度胺原料药杂质来源及其合成研究  

Source analysis and synthesis of pomalidomide impurities

作　　者：聂鲁[1] 周辛波[1] 魏朝[1] 蔡旭[1] 郝伯钧[1,2] 郑志兵[1] 李松[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850 [2]沈阳药科大学制药工程学院,辽宁沈阳110016

出　　处：《中国药物化学杂志》2015年第3期202-206,共5页Chinese Journal of Medicinal Chemistry

基　　金：国家"重大新药创制"科技重大专项基金资助(2012ZX09J1209-02C)

摘　　要：目的研究泊马度胺原料药的杂质来源与合成方法,为产品质量控制提供依据和杂质对照品。方法通过对泊马度胺原料药生产过程和存储过程的分析推测可能产生的杂质;以3-硝基邻苯二甲酸酐、3-氨基-2,6-哌啶二酮盐酸盐、2-氨基戊二酸等为原料合成有关杂质;根据对泊马度胺的杂质谱分析及合成的主要杂质对照品,建立了泊马度胺原料药杂质检测的高效液相色谱法。结果与结论合成了泊马度胺的7个相关杂质,其中一个为新结构杂质。7个杂质对照品的结构经1H-NMR、MS谱确证;建立了专属性好、灵敏度高的泊马度胺杂质分析的HPLC法,为泊马度胺原料药制备过程中的杂质控制提供帮助。Pomalidomide is the third generation of immunomodulatory drugs （ IMiDs）, aiming at treating re- lapsed and refractory multiple myeloma （RRMM）. In this paper, the possible source of impurities, which maybe come from the manufacturing and storing process of pomalidomide drug and its formula, was dis- cused. Among them, seven impurities that are most possibly involved in the pomalidomide product were syn- thesized. Treatment of 3-nitrophthalicanhydride with 2,5-diamino-5-oxopentanoic acid in the presence of N, N-dimethylformamide gave rise to impurity 1 in 73% yield. Treatment of 3-nitrophthalicanhydride with 3-aminopiperidine-2,6-dione hydrochloride in the presence of acetic acid and sodium acetate gave rise to im- purity 2 in 77% yield,which in turn was partially hydrogenated with Pd/C and hydrazine hydrate to provide impurity 7 in 68 % yield. The impurity 4 was synthesized by treating 3-nitrophthalicanhydride with 3-aminopi- peridine-2,6-dione hydrochloride in the presence of tetrahydrofuran and triethylamine at room temperature in 61.3% yield,which was hydrogenated with 10% Pd/C at 344. 8 kPa for 8 h to afford impurity 5 in 67% yield. 3-Nitrophthalicanhydride and 2-aminopentanedioic acid were heated to 185 ℃ to afford impurity 3 in 72% yield,which was hydrogenated with 10% Pd/C at 344. 8 kPa for 8 h to afford impurity 6 in 38% yield. The structures of all compounds were confirmed through 1H-NMR and MS. A HPLC method, which showed high specificity and sensibility of detecting the impurities of the pomalidomide, has been built.

关 键 词：泊马度胺 杂质 合成 高效液相色谱法 

分 类 号：R914[医药卫生—药物化学]