恩曲他滨的合成工艺研究  

Study on synthetic process of emtricitabine

作　　者：赫畅[1,2] 刘国峰 马英 王钝[1] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016 [2]东北制药集团股份有限公司,辽宁沈阳110004

出　　处：《中国药物化学杂志》2017年第2期117-121,共5页Chinese Journal of Medicinal Chemistry

摘　　要：目的合成核苷逆转录酶抑制剂恩曲他滨(emtricitabine,FTC)。方法以水合乙醛酸为起始原料,与L-薄荷醇酯化后,经脱水、与2,5-二羟基-1,4-二硫噻烷反应得到两个异构体,再经构型转化得反式异构体(2R,5R)-5-羟基-1,3-氧硫杂环戊烷-2-羧酸-L-薄荷酯,该中间体经氯代、与硅烷化5-氟胞嘧啶偶联制得5(2R,5S)-(5-氟胞嘧啶-1)-1,3-氧硫杂环戊烷2-羧酸-L-薄荷酯,再经硼氢化钾还原得恩曲他宾粗品,最后经成盐、游离制得目标物恩曲他滨。结果与结论新设计的合成路线总收率为29.8%(以水合乙醛酸计),较文献报道的路线有所提高。纯度为99.88%(HPLC法),旋光为-116°。目标化合物的结构经~1H-NMR、^(13)C-NMR、EI-MS确证。新合成路线降低了成本,各步反应试剂价廉易得且手性原料薄荷醇可重复套用,反应步骤简捷(仅需四步即可得到恩曲他滨粗品),产品纯度高,该条路线具有较强的规模化生产能力及可操作性。Emtricitabine （FTC）is a new nucleoside reverse transcriptase inhibitor, which has the antiviral activity against HIV-1, HIV-2 and HBV. In this thesis, the path ogenesis of HIV and drugs which can cure HIV were described concisely. Emtricitabine were introduced based on reported synthetic processes in rele- vant literatures. Emtricitabine was synthesized with glyoxylic acid and L-menthol as starting materials via es- terification, dehydration, cyclization, configuration transformation and chlorination reaction followed by hydrocarbylation reaction with silyl-protected 5-fluorocytosine. The crude product thus obtained was purified by salt forming reaction with salicylic acid and then neutralized to give the final product. The overall yield was 29.8 %. The above synthetic process is worthy of further study due to its more convenient operation and higher yield than that reported in literatures. The structures of target compound emtricitabine and some inter- mediates were confirmed by ^1H-NMR, ^13 C-NMR and MS. So this synthetic route has much higher scale production capacity and maneuverability.

关 键 词：HIV 核苷类逆转录酶抑制剂 恩曲他滨 合成 

分 类 号：R914.5[医药卫生—药物化学]