抗病毒药物甲磺酸阿比朵尔的合成

针对盐酸阿比朵尔在水中几乎不溶、制剂溶出较慢、口服生物利用度低等问题,对甲磺酸阿比朵尔的合成工艺进行了优化.以乙酰乙酸乙酯为起始原料,经过胺化、傅克反应反应、溴化、缩合、曼尼希反应,得到阿比朵尔碱基,再与甲磺酸成盐反应生成甲磺酸阿比朵尔.通过优化胺化反应,革除了一类溶剂二氯乙烷和四氯化碳的使用.对合成中的关键步骤,溴化反应进行了改进,简化了吲哚环上活泼羟基的保护和脱保护反应,收率比文献值提高10％.     

The delivery of arbidol by salt engineering: synthesis,physicochemical properties and pharmacokinetics

Abstract

The aim of the present study was to evaluate the feasibility of using the methanesulfonic salt of arbidol in order to improve its aqueous solubility and thus oral bioavailability. Arbidol mesylate (AM) was synthesized and then characterized using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM), and its apparent solubility and octanol–water partition coefficient were also studied. The results of NMR, IR, PXRD, SEM and DSC tests confirmed the salt formation. The apparent solubility of AM in water was 32-fold higher than that of the commercial product. A superior pH-dependent profile and an improved dissolution rate of AM were obtained in a variety of solutions with different pH values. In addition, AM exhibited a relatively higher peak plasma concentration (1460 versus 1297?ng/mL) and an increased AUC_0–t (2475 versus 1277?ng/mL?×?h) when comparing with the commercial product, indicating the improved bioavailability of the drug. This study suggests that AM may be able to improve the therapeutic efficacy of arbidol, which rendering it to be a promising candidate for further development.     

6-溴-2-溴甲基-5-羟基-1-甲基吲哚-3-羧酸乙酯的合成工艺研究

采用5-乙酰氧基-1,2-二甲基吲哚-3-羧酸乙酯和溴素为原料,于四氯化碳中,在过氧化苯甲酰催化下,合成6-溴-2-溴甲基-5-羟基-1-甲基吲哚-3-羧酸乙酯,HPLC进行跟踪检测。采用正交设计研究确定了最佳合成工艺参数为:物料比1为n(5-乙酰氧基-1,2-二甲基吲哚-3-羧酸乙酯)∶n(四氯化碳)=1∶18.3,物料比2为n(5-乙酰氧基-1,2-二甲基吲哚-3-羧酸乙酯)∶n(溴素)=1∶2.84,反应时间5 h,反应温度45℃。在最佳条件下收率为84.6%,纯度为98%以上,达到了优化的目的。     

6-硝基-4-二甲氨基甲基-5-羟基-1-甲基-2-苯硫甲基-1H-吲哚-3-羧酸乙酯的合成

以对苯醌和3-(甲基氨基)-2-丁烯酸乙酯为起始原料,经Nenitzescu反应、乙酰化、硝化、溴代、缩合、Mannich反应得到一个新化合物6-硝基-4-二甲氨基甲基-5-羟基-1-甲基-2-苯硫甲基-1H-吲哚-3-羧酸乙酯,总产率19.3％.反应中间产物和目标产物结构采用1 HNMR和质谱确认.     

6-硝基-4-二甲氨基甲基-5-羟基-1-甲基-2-苯硫甲基一1H-吲哚-3-羧酸乙酯的合成

以对苯醌和3-（甲基氨基）-2-丁烯酸乙酯为起始原料,经Nenitzescu反应、乙酰化、硝化、溴代、缩合、Man—nich反应得到一个新化舍物6-硝基-4-二甲氨基甲基-5-羟基-1-甲基-2-苯硫甲基-1H-吲哚-3-羧酸乙酯,总产率19．3％。反应中间产物和目标产物结构采用。HNMR和质谱确认。