微波辐射下水中6-氯嘌呤(核苷)及8-溴嘌呤核苷的脱卤反应*

郭海明， 饶伟浩， 牛红英， 王东超， 渠桂荣

(1. 河南师范大学 化学与环境科学学院，河南 新乡 453007; 2. 河南科技学院 化学与化工学院，河南 新乡 453003)

对天然嘌呤及嘌呤核苷的修饰与改造是近年来研究的热点，主要在于修饰与改造后的嘌呤与嘌呤核苷具有很好的药物活性以及作为重要的药物中间体。天然存在的嘌呤核苷Nebularine (水粉蕈素，9-β-D-核糖基嘌呤)是合成抗生素助间型霉素的原料，而且Nebularine一直作为肿瘤抑制剂和酶抑制剂[1～4]。传统生产Nebularine的方法是对6-氯嘌呤核苷进行氢解。阿糖腺苷(vidarabine, 9-β-D-阿拉伯呋喃核糖基腺嘌呤)，能有效抑制多种病毒DNA的复制,具有广谱的抗菌、抗病毒活性[5～7]。阿糖鸟苷是抗白血病药物[8]，在体内能够转化为三磷酸阿糖鸟苷从而与三磷酸脱氧核苷竞争嵌入到DNA链中来选择性的终止或抑制病毒DNA的复制[9～11]。目前，国内外合成阿糖腺苷与阿糖鸟苷的方法主要有化学合成法[12]和生物合成法[13]，普遍存在着反应条件苛刻，原料成本高等不足之处[14,15]。

Scheme 1

本文以乙醇为溶剂，6-氯嘌呤(1a～1e), 6-氯嘌呤核苷(1g和1f), 8-溴阿糖腺苷(1h)或8-溴阿糖鸟苷(1i)在微波辐射下与亲核试剂水合肼快速反应制得6-肼嘌呤(2a～2e), 6-肼嘌呤核苷(2g和2f)或8-肼嘌呤核苷(2h和2i); 2在氢氧化钠水溶液中反应30 min合成了6-脱氯嘌呤(3a～3e), 6-脱氯嘌呤核苷(3g和3f)或8-脱溴嘌呤核苷(3h和3i, Scheme 1),总收率46%～83%,其结构经1H NMR和13C NMR表征。

1 实验部分

1．1 仪器与试剂

MAS-Ⅰ型微波反应仪；XRC-1型显微熔点仪(温度计未校正)；BrukerAV-400型核磁共振仪。

1a～1g，新乡拓新生化科技有限公司；1h和1i按文献[16]方法自制；水合肼，天津科密欧化学试剂有限公司；去离子水；其余所用试剂均为化学纯。GF254高效薄层层析硅胶板,青岛海洋化工有限公司。

1．2 合成

(1)2的合成(以2a为例)

在圆底烧瓶中依次加入无水乙醇50 mL和1a770 mg(5 mmol)，轻轻摇匀后置微波反应仪中，磁力搅拌下于400 W回流反应15 min。冷却至室温析晶，抽滤，滤饼用冷水(15 mL)洗涤后于室温自然晾干得淡黄色粉末2a。

用类似的方法合成淡黄色粉末2b～2i。

(2) 3的合成(以3a为例)

在圆底烧瓶中加入2a149 mg(1 mmol),水20 mL和NaOH 0.24 g(6 mmol),于室温搅拌使其充分溶解后置微波反应仪中,磁力搅拌下于300 W回流反应30 min。冷却至室温，减压蒸除水分，残余物经硅胶柱层析[洗脱剂:V(CH2Cl2) ∶V(MeOH) = 50 ∶1]纯化得无色晶体3a。

用类似的方法合成无色晶体3b～3i。

2和3的实验结果见表1， 3的1H NMR和13C NMR数据见表2。

表 1 2和3的实验结果Table 1 Experimental results of 2 and 3

表 2 3的NMR数据Table 2 NMR data of 3

2 结果与讨论

我们认为1与水合肼的反应是芳香亲核取代反应(SN2Ar)。据此鉴于有文献[17～19]报道微波能促进SN2Ar反应，所以就尝试使用微波来促进本反应。合成3时，尝试了多种碱，发现使用NaOH的结果最好，而且以水做溶剂对环境友好，符合绿色化学的要求。

该方法反应时间短，产率较高，对环境友好，为此类化合物的合成开辟了一条新的途径。

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