郭海明， 饒偉浩， 牛紅英， 王東超， 渠桂榮

(1. 河南師范大學(xué) 化學(xué)與環(huán)境科學(xué)學(xué)院，河南 新鄉(xiāng) 453007; 2. 河南科技學(xué)院 化學(xué)與化工學(xué)院，河南 新鄉(xiāng) 453003)

對天然嘌呤及嘌呤核苷的修飾與改造是近年來研究的熱點，主要在于修飾與改造后的嘌呤與嘌呤核苷具有很好的藥物活性以及作為重要的藥物中間體。天然存在的嘌呤核苷Nebularine (水粉蕈素，9-β-D-核糖基嘌呤)是合成抗生素助間型霉素的原料，而且Nebularine一直作為腫瘤抑制劑和酶抑制劑[1～4]。傳統(tǒng)生產(chǎn)Nebularine的方法是對6-氯嘌呤核苷進行氫解。阿糖腺苷(vidarabine, 9-β-D-阿拉伯呋喃核糖基腺嘌呤)，能有效抑制多種病毒DNA的復(fù)制,具有廣譜的抗菌、抗病毒活性[5～7]。阿糖鳥苷是抗白血病藥物[8]，在體內(nèi)能夠轉(zhuǎn)化為三磷酸阿糖鳥苷從而與三磷酸脫氧核苷競爭嵌入到DNA鏈中來選擇性的終止或抑制病毒DNA的復(fù)制[9～11]。目前，國內(nèi)外合成阿糖腺苷與阿糖鳥苷的方法主要有化學(xué)合成法[12]和生物合成法[13]，普遍存在著反應(yīng)條件苛刻，原料成本高等不足之處[14,15]。

Scheme 1

本文以乙醇為溶劑，6-氯嘌呤(1a～1e), 6-氯嘌呤核苷(1g和1f), 8-溴阿糖腺苷(1h)或8-溴阿糖鳥苷(1i)在微波輻射下與親核試劑水合肼快速反應(yīng)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在氫氧化鈉水溶液中反應(yīng)30 min合成了6-脫氯嘌呤(3a～3e), 6-脫氯嘌呤核苷(3g和3f)或8-脫溴嘌呤核苷(3h和3i, Scheme 1),總收率46%～83%,其結(jié)構(gòu)經(jīng)1H NMR和13C NMR表征。

1 實驗部分

1．1 儀器與試劑

MAS-Ⅰ型微波反應(yīng)儀；XRC-1型顯微熔點儀(溫度計未校正)；BrukerAV-400型核磁共振儀。

1a～1g，新鄉(xiāng)拓新生化科技有限公司；1h和1i按文獻[16]方法自制；水合肼，天津科密歐化學(xué)試劑有限公司；去離子水；其余所用試劑均為化學(xué)純。GF254高效薄層層析硅膠板,青島海洋化工有限公司。

1．2 合成

(1)2的合成(以2a為例)

在圓底燒瓶中依次加入無水乙醇50 mL和1a770 mg(5 mmol)，輕輕搖勻后置微波反應(yīng)儀中，磁力攪拌下于400 W回流反應(yīng)15 min。冷卻至室溫析晶，抽濾，濾餅用冷水(15 mL)洗滌后于室溫自然晾干得淡黃色粉末2a。

用類似的方法合成淡黃色粉末2b～2i。

(2) 3的合成(以3a為例)

在圓底燒瓶中加入2a149 mg(1 mmol),水20 mL和NaOH 0.24 g(6 mmol),于室溫攪拌使其充分溶解后置微波反應(yīng)儀中,磁力攪拌下于300 W回流反應(yīng)30 min。冷卻至室溫，減壓蒸除水分，殘余物經(jīng)硅膠柱層析[洗脫劑:V(CH2Cl2) ∶V(MeOH) = 50 ∶1]純化得無色晶體3a。

用類似的方法合成無色晶體3b～3i。

2和3的實驗結(jié)果見表1， 3的1H NMR和13C NMR數(shù)據(jù)見表2。

表 1 2和3的實驗結(jié)果Table 1 Experimental results of 2 and 3

表 2 3的NMR數(shù)據(jù)Table 2 NMR data of 3

2 結(jié)果與討論

我們認為1與水合肼的反應(yīng)是芳香親核取代反應(yīng)(SN2Ar)。據(jù)此鑒于有文獻[17～19]報道微波能促進SN2Ar反應(yīng)，所以就嘗試使用微波來促進本反應(yīng)。合成3時，嘗試了多種堿，發(fā)現(xiàn)使用NaOH的結(jié)果最好，而且以水做溶劑對環(huán)境友好，符合綠色化學(xué)的要求。

該方法反應(yīng)時間短，產(chǎn)率較高，對環(huán)境友好，為此類化合物的合成開辟了一條新的途徑。

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