路東亮，邢艷玲，高曉培

(贛南師范學(xué)院 化學(xué)化工學(xué)院，江西 贛州　341000)

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一個(gè)新的嘧啶酮-肉桂酸雜合體的設(shè)計(jì)與合成* 1

路東亮，邢艷玲，高曉培

(贛南師范學(xué)院 化學(xué)化工學(xué)院，江西 贛州341000)

摘要：由(1E, 4Z)-5-羥基-1-(3, 4, 5-三甲氧基苯)-1, 4-己二烯-3-酮 、3, 4, 5-三甲氧基苯甲醛、尿素三組分“一鍋法”將3, 4-二氫嘧啶酮類化合物和肉桂酸骨架相結(jié)合，得到一個(gè)具有雙重藥效團(tuán)的雜合分子骨架，并采用正交試驗(yàn)優(yōu)化反應(yīng)條件.通過單晶衍射、核磁共振以及紅外光譜對產(chǎn)物進(jìn)行結(jié)構(gòu)表征，該方法操作簡便、經(jīng)濟(jì)，是在環(huán)境友好、無毒、無污染的條件下完成的，符合綠色化學(xué)的要求.

關(guān)鍵詞：Biginelli反應(yīng)；一鍋法；雜合體；新型的二氫嘧啶酮

近年來臨床應(yīng)用研究發(fā)現(xiàn)3,4-二氫嘧啶-2-酮衍生物(DHPMs)作為氮雜環(huán)化合物具有廣泛的生理和藥理活性.其在抗病毒、抗微生物、殺菌、消炎等藥物領(lǐng)域有廣泛的應(yīng)用[1-2]；還可用作鈣拮抗劑，降壓劑，α1a-拮抗物，止痛劑，抗人類免疫缺陷病毒和癌預(yù)防劑等[3-9]，在醫(yī)藥領(lǐng)域中發(fā)揮著重要的作用.而且，一些從海洋來源分離得到的生物堿其核心結(jié)構(gòu)也包含二氫嘧啶酮的結(jié)構(gòu)，并表現(xiàn)一些有趣的生物性[10-11].因而DHPMs是有機(jī)雜環(huán)化合物研究的熱點(diǎn)之一.Biginelli反應(yīng)[12]是合成該類化合物常用、簡便的方法.

隨著對Biginelli反應(yīng)研究的深入，人們對Biginelli產(chǎn)物結(jié)構(gòu)的修飾和改造，以及結(jié)構(gòu)和性能之間關(guān)系的研究越來越廣泛.研究發(fā)現(xiàn)，通過對嘧啶酮進(jìn)一步的結(jié)構(gòu)修飾，即多官能化的二氫嘧啶酮衍生物具有更好的生物和藥理活性，例如：吡啶并嘧啶類化合物具有高效抑制多種癌細(xì)胞的生物活性[13-17]；N-甲酰胺，甲酯取代的二氫嘧啶酮可以用作口服的降壓，鈣拮抗和α1α拮抗藥物[18-20].為了進(jìn)一步提高嘧啶酮衍生物的生理和藥理活性，我們以3,4-二氫嘧啶酮為先導(dǎo)化合物將肉桂酸骨架導(dǎo)入到嘧啶環(huán)的5位，在分子中引入活性基團(tuán)，希望得到具有更優(yōu)的生物和藥理活性的雜合體藥物分子.

本文報(bào)道了一個(gè)新型的3,4-二氫嘧啶酮化合物(如圖1化合物2)即將3,4-二氫嘧啶酮和天然抗氧化劑肉桂酸結(jié)合，得到了一個(gè)具有雙重藥效團(tuán)的雜合分子[21-23].在以往DHPMs的合成中一般只在C(5)位引入飽和酰基或酯基，如甲酰胺[24]，芳甲酰基[25]，二茂鐵基的 DHPMs 化合物[26]，乙?；鵞27]，乙氧?；鵞28]等都是飽和的酰基和酯基.本文合成的雜合體藥物分子打破了以往只在嘧啶酮骨架5位引入飽和酯基和?；南壤窃卩奏ね?位引入一個(gè)苯環(huán)取代的α, β-不飽和羰基化合物，從而在嘧啶酮結(jié)構(gòu)單元中引入了一個(gè)Michael加成受體.有研究證明Michael 加成受體單元在藥物癌預(yù)防和治療中有很重要的作用[29].細(xì)胞的氧化還原狀態(tài)往往可通過含有Michael 加成受體單元的分子改變[30].因此，這種化合物有很大的發(fā)展前景.

本文在適宜溫度下以ZnCl2為催化劑，無溶劑條件下進(jìn)行反應(yīng)，并采用正交實(shí)驗(yàn)優(yōu)化反應(yīng)條件.通過單晶衍射、核磁共振以及紅外光譜確證了產(chǎn)物結(jié)構(gòu).

1實(shí)驗(yàn)部分

1.1儀器與試劑

紅外光譜儀(360FT)美國Nicolet公司；X射線衍射儀(SMART APEX)德國布魯克AXS公司；金葉牌旋轉(zhuǎn)蒸發(fā)儀(RE-3000)上海亞榮生化儀器廠；核磁共振儀(AM-400)德國布魯克AXS公司；金葉牌真空泵(SHZ-Ⅲ)上海亞榮生化儀器廠；熔點(diǎn)測定儀(WRS-3)上海精科.

3,4,5-三甲氧基苯甲醛，乙酰丙酮，正丁胺，硼酸三正丁酯，三氧化二硼，尿素均購買于阿拉丁公司，其余試劑均為市售分析純試劑.

圖1　“一鍋法”合成嘧啶酮-肉桂酸雜合體的路線圖

圖2　化合物2的晶體結(jié)構(gòu)圖

1.2合成方法

標(biāo)題化合物的合成路線見圖1.

標(biāo)題化合物的合成步驟： 乙酰丙酮1.62 mL(15.84 mmol)，B2O31.00 g(14.36 mmol)和乙酸乙酯5 mL在80 ℃下回流30 min，然后加入溶于乙酸乙酯(5mL)的3,4,5-三甲氧基苯甲醛(7.2 mmol)和硼酸三正丁酯0.8 mL(2.96 mmol)，同溫度下反應(yīng)30 min后，將正丁胺0.28 mL(2.86 mmol)逐滴加入，滴畢，反應(yīng)體系在100 ℃下反應(yīng)1 h，TLC跟蹤反應(yīng).將反應(yīng)溫度降到50 ℃，加入HCl(15 mL, 1.5 N)繼續(xù)攪拌30 min.反應(yīng)結(jié)束后，冷卻至室溫，乙酸乙酯萃取，飽和食鹽水洗滌，Na2SO4干燥，柱層析分離(乙酸乙酯∶石油醚=3∶1)，用乙醇和水重結(jié)晶得到黃色針狀固體合物1，產(chǎn)率75%.

將化合物1 0.066 g(0.24 mmol)，3,4,5-三甲氧基苯甲醛0.039 g(0.2 mmol)，和尿素0.018 g(0.3 mmol)加于20 mL圓底燒瓶中，90 ℃下反應(yīng)3 h，TLC跟蹤反應(yīng).反應(yīng)結(jié)束后，冷卻至室溫，用甲醇溶解，過濾除去不溶物，濾液減壓旋蒸至少量液體，柱層析分離(CH2Cl2∶CH2OH = 20∶1)，用乙醇和水重結(jié)晶得黃色錐狀固體化合物2，產(chǎn)率71.9%，即為嘧啶酮-肉桂酸雜合體.

1.3結(jié)構(gòu)表征

1.3.1化合物2的核磁共振譜與紅外光譜數(shù)據(jù)

Mp 99.7-100.2 ℃； Rf=0.56(CH2Cl2∶CH2OH=20∶1)；1H NMR (400 MHz,CDCl3)δ 8.20 (s,1H), 7.81-7.49(m,2H), 7.38(d,J=15.5 Hz,1H), 6.72(d,J=15.6 Hz,1H), 6.60(d,3H), 5.92(s,1H), 5.54(s,1H), 3.83(dd,J=22.0,5.0 Hz,17H), 2.31(s,4H);13C NMR(100 MHz,DMSO)δ 188.38, 153.50, 153.29, 152.50, 147.36, 141.23, 140.66, 139.64, 130.98, 126.17, 109.88, 106.23, 104.31, 60.54, 60.40, 56.42, 56.23, 54.84, 19.13; IR(KBr)ν:3 345.3, 3 242.6, (-NH-); 2 934.6(-CH3), 1 693.1(C=O); 1 633.6, 971.0(反式C=C); 1 633.6, 1 585.8, 1 503.9, 1 459.6, (Ar-C-C); 1 414.7, 1 328.9, 1 281.9, (C-N); 1 237.6, 1 184.6, 1 125.8, (C-O-C).

表1　化合物2的主要晶體結(jié)構(gòu)數(shù)據(jù)

1.3.2化合物2的單晶結(jié)構(gòu)測定

選擇1顆尺寸大小為0.38×0.12×0.08 mm的化合物2，進(jìn)行X-射線單晶結(jié)構(gòu)測定，晶體結(jié)構(gòu)見圖2，結(jié)構(gòu)衍射數(shù)據(jù)見表1.

2結(jié)果與討論

2.1合成路線第Ⅱ步反應(yīng)的正交試驗(yàn)設(shè)計(jì)與結(jié)果

根據(jù)正交試驗(yàn)表2，考察反應(yīng)時(shí)間(A) ，反應(yīng)溫度(B)，溶劑(C)，和催化劑(D)四因素對化合物2產(chǎn)率的影響。實(shí)驗(yàn)結(jié)果見表2所示。由表2可知，各因素的影響次序?yàn)锳>B>C=D ，優(yōu)化方案為 A2B2C3D3，即反應(yīng)時(shí)間4 h，反應(yīng)溫度90 ℃，無溶劑條件，催化劑為ZnCl2時(shí)化合物2的產(chǎn)率較高.

2.2化合物2合成過程討論

表2　化合物2合成的正交試驗(yàn)表

3結(jié)論

本文通過Biginelli-like反應(yīng)合成了一種新型嘧啶酮-肉桂酸雜合體藥物分子，并研究了反應(yīng)催化劑，溶劑，時(shí)間和溫度對合成雜合體藥物分子產(chǎn)率的影響。通過正交試驗(yàn)得出：在ZnCl2為催化劑，無溶劑，反應(yīng)溫度為90 ℃，反應(yīng)時(shí)間4 h的條件下，雜合體藥物分子的產(chǎn)率最高；本文運(yùn)用藥物雜合理論(藥物雜合是將作用機(jī)制不同的兩類或多類藥物分子或活性官能團(tuán)有效拼合或連接的設(shè)計(jì)方法，能合成具有多靶點(diǎn)的藥物)，在嘧啶酮分子骨架的C5位引入天然抗氧化劑3,4,5-三甲氧基肉桂酸，它不僅實(shí)現(xiàn)了兩個(gè)活性組分的結(jié)合，并且在嘧啶酮骨架上引入了Michael 加成受體，有望使二氫嘧啶酮的生理和藥理活性顯著提高，最重要的是為嘧啶酮衍生物的設(shè)計(jì)合成提供新的思路，有助于進(jìn)一步研究其生理和藥理活性

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* 收稿日期：2016-01-13

DOI：10.13698/j.cnki.cn36-1037/c.2016.03.013

基金項(xiàng)目：國家自然科學(xué)基金(21461002)；江西省自然科學(xué)基金(20151BAB213005)；研究生創(chuàng)新專項(xiàng)資金項(xiàng)目(YCX14B005)

作者簡介：路東亮(1985-)，男，河南林州人，贛南師范學(xué)院化學(xué)化工學(xué)院講師、博士，研究方向：光功能藥物分子的設(shè)計(jì)合成與活性評價(jià).

中圖分類號：TQ463

文獻(xiàn)標(biāo)志碼：A

文章編號：1004-8332(2016)03-0051-04

Design and Synthesis of a Novel Hybrid Containing Pyrimidone and Cinnamic Acid

LU Dongliang, XING Yanling, GAO Xiaopei

(ShoolofChemistryandChemicalEngineering,GannanNormalUniversitry,Ganzhou341000,China)

Abstract:3, 4-Dihydropyrimidin-2(1H)-one of cinnamic acid, which has dual-pharmacophore due to the backbone combined by 3,4-dihydropyrimidone and hydroxycinnamic acid compound was synthesized in good yield by a one-pot multi-component cyclocondensation using (1E, 4Z)-5-hydroxy-1-(3, 4, 5-trimethoxyphenyl)hexa-1,4-dien-3-one, 3, 4, 5-trimethoxybenzaldehyde and urea. Orthogonal test was used to explore the optimum reaction conditions. The structure of the compound was identified by XRD,1H-NMR,13C-NMR and IR. This method have the advantages of simple work-up procedure, economy and under environmentally friendly conditions, which are acceptable in the context of green synthesis.

Key words:biginelli reaction; one-pot; hybrids; new dihydropyrimidinone

網(wǎng)絡(luò)出版地址：http://www.cnki.net/kcms/detail/36.1037.C.20160510.1210.024.html