CN104447749A - 一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法 - Google Patents

一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法 Download PDF

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CN104447749A
CN104447749A CN201410673286.XA CN201410673286A CN104447749A CN 104447749 A CN104447749 A CN 104447749A CN 201410673286 A CN201410673286 A CN 201410673286A CN 104447749 A CN104447749 A CN 104447749A
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郭海明
杜聪
谢明胜
王东超
牛红英
渠桂荣
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Henan Normal University
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Abstract

本发明公开了一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，反应方程式如下：

Description

一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法
技术领域
本发明属于化学与医药技术领域，具体涉及一种通过通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法。
背景技术
核苷类药物在抗病毒和抗肿瘤化疗药物中具有非常重要的地位，尤其是近十几年来这方面的药物发展速度很快。对天然核苷的结构改造是寻找新的，更加有效地抗病毒药物的重要手段，在目前已上市及处于临床试验阶段的抗病毒药物中，绝大多数都是核苷衍生物，非环核苷衍生物也因此成为最具抗病毒潜能的化合物。但是此类药物还是普遍存在着不良反应多、生物利用度低、易产生耐药性、代谢快等问题。因此对核苷类似物的各个部位进行改性以优化核苷类药物的生物活性具有重要意义。
发明内容
寻求到一种简便、绿色、高效的方法来合成非环核苷类似物，立足于解决此类化合物合成过程中原料昂贵，过程复杂的问题，对核苷类药物的合成及应用提供了参考价值，为新型抗病毒及抗肿瘤药物的研究提供了原料。
为了实现本发明的目的，本发明采用以下技术方案：一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，反应方程式如下：
其中：R1选自下列基团中的一种：F、Cl、Br、I、H、甲氧基、乙氧基、哌啶、吗啉、
二甲胺基、丙硫基、苯基、萘基；
R2选自下列基团中的一种：H、NH2、Cl、F；
R3选自下列基团中的一种：甲基、乙基、异丙基、叔丁基、苄基。
本发明的进一步改进包括：
所述反应方程中两个X相同。
所述反应方程中两个X不同，虚线表示的键为单键或者双键，并且虚线所在的环为芳环。
所述的方法具体为：(a)以二恶烷作溶剂，氮气保护下以加入Pd2(dba)3·CHCl3和配体L，然后依次加入两种反应物，30摄氏度反应18小时；
其中：配体L的结构式为：(b)以二恶烷作溶剂，氮气保护下以加入AlCl3，然后依次加入两种反应物，85摄氏度反应18小时；(c)以二恶烷作溶剂，氮气保护下以加入MgI2，然后依次加入两种反应物，85摄氏度反应18小时。
所述的非环核苷及其类似物选自下列38个具体化合物中的一个：
本发明通过使用特定的催化剂，则能以高产率和高化学选择性得到目标产物。该反应具有操作简单、反应条件温和、催化剂便宜易得等几个优点，为合成非环核苷类似物提供了一条简洁实用的合成方法。
具体实施方式
本发明为非环核苷及其类似物的合成提供了一种具有优秀化学选择性和高产率的方法，其特征在于反应方程式如下：
其中：R1选自下列基团中的一种：F、Cl、Br、I、H、甲氧基、乙氧基、哌啶、吗啉、二甲胺基、丙硫基、苯基、萘基；
R2选自下列基团中的一种：H、NH2、Cl、F；
R3选自下列基团中的一种：甲基、乙基、异丙基、叔丁基、苄基。
两个X可以相同，也可以不同，虚线表示的键为单键或者双键，并且虚线所在的环为芳环。
在本发明的一个优选实施方式中，所述的手性环核苷及其类似物选自38个具体化合物中的一个。
在本发明的一个优选实施方式中，所述的方法具体反应条件为：
(a)取一休朗克反应管，氮气保护下加入5mol％的Pd2(dba)3·CHCl3和10mol％的配体L，2-乙烯基环丙烷-1,1-二羧酸二乙酯(0.1mmol)、6-氯嘌呤(0.15mmol)，以重蒸的二恶烷作溶剂，30摄氏度反应18小时；通过薄层板检测(TLC)；经过柱层析得到目标产物，收率82％。
其中：配体L的结构式为：
(b)取一休朗克反应管，氮气保护下加入AlCl3(0.1mmol)，2-乙烯基环丙烷-1,1-二羧酸二乙酯(0.3mmol)、6-氯嘌呤(0.1mmol)，以重蒸的二恶烷作溶剂，85摄氏度反应18小时；通过薄层板检测(TLC)；经过柱层析得到目标产物，收率79％；
(c)取一休朗克反应管，氮气保护下加入10mol％MgI2，2-乙烯基环丙烷-1,1-二羧酸二乙酯(0.5mmol)、6-氯嘌呤(0.1mmol)，以重蒸的二恶烷作溶剂，85摄氏度反应18小时；通过薄层板检测(TLC)；经过柱层析得到目标产物，收率72％。
(E)-dimethyl 2-(4-(6-chloro-9H-purin-9-yl)but-2-en-1-yl)malonate(3a)
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.12(s,1H),5.87-5.75(m,2H),4.84(d,J＝5.2Hz,2H),3.72(s,6H),3.47(t,J＝7.2Hz,1H),2.69(t,J＝6.4Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.8,151.9,151.5,151.0,144.7,132.6,131.5,125.8,52.6,50.8,45.5,31.2ppm.HRMS:calcd for C14H15ClN4O4Na[M+Na]+361.0674,found361.0677.
(E)-diethyl 2-(4-(6-chloro-9H-purin-9-yl)but-2-en-1-yl)malonate(3b)
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.12(s,1H),5.88-5.75(m,2H),4.84(d,J＝5.2Hz,2H),4.21-4.14(m,4H),3.42(t,J＝7.2Hz,1H),2.68(t,J＝6.4Hz,2H),1.24(t,J＝6.8Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.3,151.7,151.4,150.7,144.7,132.7,131.3,125.5,61.4,51.0,45.4,31.0,13.9ppm.HRMS:calcd forC16H19ClN4O4Na[M+Na]+389.0987,found 389.0987.
(E)-diisopropyl 2-(4-(6-chloro-9H-purin-9-yl)but-2-en-1-yl)malonate(3c)
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.12(s,1H),5.88-5.74(m,2H),5.07-4.98(m,2H),4.83(d,J＝5.6Hz,2H),3.34(t,J＝7.2Hz,1H),2.65(t,J＝6.4Hz,2H),1.21(t,J＝3.2Hz,12H)ppm.13C NMR(100MHz,CDCl3):δ168.0,152.0,151.6,151.0,144.8,133.1,131.6,125.4,69.2,51.5,45.6,31.1,21.6,21.5ppm.HRMS:calcdfor C18H23ClN4O4Na[M+Na]+417.1300,found 417.1301.
(E)-di-tert-butyl 2-(4-(6-chloro-9H-purin-9-yl)but-2-en-1-yl)malonate(3d)
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.13(s,1H),5.87-5.74(m,2H),4.84(d,J＝5.2Hz,2H),3.22(t,J＝7.2Hz,1H),2.59(t,J＝6.4Hz,2H),1.42(s,18H)ppm.13C NMR(100MHz,CDCl3):δ167.9,152.0,151.0,144.8,133.4,125.0,81.8,53.1,45.7,31.2,27.9ppm.HRMS:calcd for C20H27ClN4O4Na[M+Na]+445.1613,found 445.1606.
(E)-bis(2,2,2-trifluoroethyl)2-(4-(6-chloro-9H-purin-9-yl)but-2-en-1-yl)malonate(3e)
1H NMR(400MHz,CDCl3):δ8.75(s,1H),8.09(s,1H),5.88–5.72(m,2H),4.85(d,J＝5.6Hz,2H),4.53(q,J＝8.0Hz,4H),3.67(t,J＝7.2Hz,1H),2.76(t,J＝6.8Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ166.1,152.1,151.2,144.7,130.6,127.2,61.3,60.9,50.3,45.4,31.0ppm.HRMS:calcd for C16H13ClF6N4O4Na[M+Na]+497.0422,found 497.0412.
(E)-dimethyl 2-(4-(6-iodo-9H-purin-9-yl)but-2-en-1-yl)malonate(3f)
1H NMR(400MHz,CDCl3):δ8.63(s,1H),8.12(s,1H),5.80(q,J＝5.3Hz,2H),4.81(d,J＝4.6Hz,2H),3.72(s,6H),3.46(t,J＝7.2Hz,1H),2.68(t,J＝6.2Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.9,152.0,147.8,144.1,138.6,132.6,125.8,122.1,52.7,50.9,45.6,31.2ppm.HRMS:calcd for C14H15IN4O4Na[M+Na]+453.0030,found453.0032.
(E)-diethyl 2-(4-(6-(propylthio)-9H-purin-9-yl)but-2-en-1-yl)malonate(3g)
1H NMR(400MHz,CDCl3):δ8.69(s,1H),7.91(s,1H),5.81-5.71(m,2H),4.77(d,J＝4.4Hz,2H),4.22-4.10(m,4H),3.41-3.34(m,3H),2.66(t,J＝6.4Hz,2H),1.86-1.77(m,2H),1.22(t,J＝7.2Hz,6H),1.07(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ168.5,161.6,151.9,148.1,142.0,131.9,131.3,126.3,61.6,51.3,45.0,31.2,30.6,22.9,14.0,13.4ppm.HRMS:calcd for C19H26N4O4SNa[M+Na]+429.1567,found 429.1569.
(E)-diethyl2-(4-(2-chloro-6-(pyrrolidin-1-yl)-9H-purin-9-yl)but-2-en-1-yl)malonate(3h)
1H NMR(400MHz,CDCl3):δ7.63(s,1H),5.77–5.69(m,2H),4.68(s,2H),4.17–4.16(m,6H),3.74(s,2H),3.39(t,J＝7.2Hz,1H),2.64(t,J＝6.4Hz,2H),2.06-1.97(m,4H),1.23(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,154.2,153.3,151.1,138.6,131.4,126.7,119.0,61.5,51.4,48.9,47.7,44.8,31.2,26.1,24.1,14.0ppm.HRMS:calcd for C20H26ClN5O4Na[M+Na]+458.1566,found 458.1563.
(E)-diethyl2-(4-(2-chloro-6-(piperidin-1-yl)-9H-purin-9-yl)but-2-en-1-yl)malonate(3i)
1H NMR(400MHz,CDCl3):δ7.63(s,1H),5.78-5.66(m,2H),4.66(d,J＝4.8Hz,2H),4.23-4.141(m,4H),3.39(t,J＝7.2Hz,1H),2.65(t,J＝6.4Hz,2H),1.70(s,6H),1.23(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,154.0,153.9,151.8,137.8,131.4,126.6,118.5,61.5,51.3,44.8,31.2,26.1,24.6,14.0ppm.HRMS:calcdfor C21H28ClN5O4Na[M+Na]+472.1722,found 472.1728.
(E)-diethyl 2-(4-(2-chloro-6-morpholino-9H-purin-9-yl)but-2-en-1-yl)malonate(3j)
1H NMR(400MHz,CDCl3):δ7.66(s,1H),5.73(dd,J＝7.6,5.0Hz,2H),4.68(d,J＝4.3Hz,2H),4.22-4.15(m,8H),3.82(t,J＝4.8Hz,4H),3.40(t,J＝7.2Hz,1H),2.70–2.60(m,2H),1.24(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,154.0,153.9,152.0,138.4,131.7,126.5,118.7,66.9,61.6,51.4,44.9,31.2,14.1ppm.HRMS:calcd for C20H26ClN5O5Na[M+Na]+474.1515,found 474.1518.
(E)-dimethyl 2-(4-(6-phenyl-9H-purin-9-yl)but-2-en-1-yl)malonate(3k)
1H NMR(400MHz,CDCl3):δ9.02(s,1H),8.77(d,J＝7.6Hz,2H),8.10(s,1H),7.60–7.51(m,3H),5.87–5.75(m,2H),4.86(d,J＝4.4Hz,2H),3.71(s,6H),3.47(t,J＝7.2Hz,1H),2.69(t,J＝6.4Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.9,154.9,152.4,152.2,143.9,135.6,131.8,131.0,131.0,129.7,128.6,126.5,52.7,51.0,45.0,31.3ppm.HRMS:calcd for C20H20N4O4Na[M+Na]+403.1377,found 403.1371.
(E)-diethyl 2-(4-(6-(phenanthren-9-yl)-9H-purin-9-yl)but-2-en-1-yl)malonate(3l)
1H NMR(400MHz,CDCl3):δ9.17(s,1H),8.77(dd,J＝19.6,8.4Hz,2H),8.27(s,1H),8.22(d,J＝8.0Hz,1H),8.11(s,1H),7.98(d,J＝7.6Hz,1H),7.75-7.55(m,4H),5.92-5.83(m,2H),4.92(d,J＝3.2Hz,2H),4.23-4.14(m,4H),3.45(t,J＝7.2Hz,1H),2.71(t,J＝5.6Hz,2H),1.24(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.5,158.0,152.3,151.9,144.4,132.9,132.3,131.3,131.3,131.1,130.9,129.6,129.6,128.5,127.7,126.8,126.8,126.7,126.5,126.2,122.9,122.6,61.6,51.3,45.2,31.2,14.1ppm.HRMS:calcd for C30H28N4O4Na[M+Na]+531.2003,found531.2002.
(E)-diethyl2-(4-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)but-2-en-1-yl)malonate(3m)
1H NMR(400MHz,CDCl3):δ7.53(s,1H),5.84-5.73(m,2H),4.87(d,J＝4.0Hz,2H),4.21-4.13(m,4H),3.58(s,3H),3.42-3.38(m,4H),2.66(t,J＝6.4Hz,2H),1.24(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,155.2,151.7,148.8,140.5,132.2,126.8,106.8,61.6,51.3,48.3,31.2,29.8,28.0,14.1ppm.HRMS:calcd forC18H24N4O6Na[M+Na+]415.1588,found 415.1587.
(E)-dimethyl 2-(4-(2-chloro-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)malonate(3n)
1H NMR(400MHz,CDCl3):δ7.71–7.69(m,1H),7.30–7.26(m,3H),5.71–5.56(m,2H),4.76(d,J＝5.2Hz,2H),3.66(s,6H),3.41(t,J＝7.2Hz,1H),2.64(t,J＝7.2Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.9,141.7,140.3,134.8,130.2,126.1,123.2,122.7,119.5,109.6,52.5,51.1,45.8,31.2ppm.HRMS:calcd forC16H17ClN2O4Na[M+Na]+359.0769,found 359.0763.
(E)-diethyl 2-(4-(4-nitro-1H-imidazol-1-yl)but-2-en-1-yl)malonate(3o)
1H NMR(400MHz,CDCl3):δ8.00(s,1H),7.58(s,1H),5.79-5.68(m,2H),4.91(d,J＝4.4Hz,2H),4.22-4.14(m,4H),3.39(t,J＝6.4Hz,1H),2.65(t,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.5,140.7,133.5,132.7,125.9,61.6,51.2,49.4,31.1,14.0ppm.HRMS:calcd for C14H19N3O6Na[M+Na]+348.1166,found 348.1174.
dimethyl 2-(2-(6-chloro-9H-purin-9-yl)but-3-en-1-yl)malonate(5a)
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.12(s,1H),6.23-6.14(m,1H),5.38(d,J＝10.4Hz,1H),5.32-5.28(m,2H),3.73(s,3H),3.63(s,3H),3.24(t,J＝7.2Hz,1H),2.75(t,J＝7.6Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.5,168.5,151.9,151.5,151.2,143.8,134.0,131.7,119.8,56.5,52.9,52.9,48.3,32.8ppm.HRMS:calcd for C14H16ClN4O4Na[M+Na]+361.0674,found 361.0664.
diethyl 2-(2-(6-chloro-9H-purin-9-yl)but-3-en-1-yl)malonate(5b)
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.12(s,1H),6.23-6.22(m,1H),5.38(d,J＝10.4Hz,1H),5.32-5.28(m,2H),4.23–4.03(m,4H),3.20(t,J＝7.4Hz,1H),2.73(t,J＝8.0Hz,2H),1.26-1.17(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.1,168.1,151.8,151.5,151.0,143.8,134.1,131.6,119.6,61.9,61.8,56.5,48.6,32.6,13.9,13.8ppm.HRMS:calcd for C16H19ClN4O4Na[M+Na]+389.0987,found 389.0978.
diisopropyl 2-(2-(6-chloro-9H-purin-9-yl)but-3-en-1-yl)malonate(5c)
1H NMR(400MHz,CDCl3):δ8.73(s,1H),8.13(s,1H),6.23-6.14(m,1H),5.37(dd,J＝10.4,0.7Hz,1H),5.31–5.27(m,2H),5.10-5.00(m,1H),4.98-4.89(m,1H),3.11(t,J＝7.2Hz,1H),2.70(t,J＝7.2Hz,2H),1.24–1.14(m,12H)ppm.13CNMR(100MHz,CDCl3):δ167.8,167.7,151.9,151.5,151.2,143.8,134.2,131.7,119.7,69.7,69.6,56.6,49.0,32.6,21.6,21.5,21.5,21.4ppm.HRMS:calcd for C18H23ClN4O4Na[M+Na]+417.1300,found 417.1292.
di-tert-butyl 2-(2-(6-chloro-9H-purin-9-yl)but-3-en-1-yl)malonate(5d)
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.13(s,1H),6.23–6.14(m,1H),5.36(d,J＝10.0Hz,1H),5.30–5.26(m,2H),2.99(t,J＝7.2Hz,1H),2.62(t,J＝7.6Hz,2H),1.45(s,9H),1.39(s,9H)ppm.13C NMR(100MHz,CDCl3):δ167.6,167.5,151.9,151.6,151.2,143.8,134.4,131.8,119.5,82.4,82.4,56.6,50.5,32.8,27.8,27.8ppm.HRMS:calcd for C20H27ClN4O4Na[M+Na]+445.1613,found 445.1605.
dimethyl 2-(2-(6-iodo-9H-purin-9-yl)but-3-en-1-yl)malonate(5e)
1H NMR(400MHz,CDCl3):δ8.62(s,1H),8.12(s,1H),6.22–6.14(m,1H),5.39–5.24(m,3H),3.73(s,3H),3.63(s,3H),3.23(t,J＝7.4Hz,1H),2.74(t,J＝7.4Hz,2H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.5,152.0,147.8,143.1,138.7,134.0,122.4,119.8,56.6,53.0,52.9,48.3,32.8ppm.HRMS:calcd forC14H15IN4O4Na[M+Na]+453.0030,found 453.0029.
diethyl 2-(2-(6-ethoxy-9H-purin-9-yl)but-3-en-1-yl)malonate(5f)
1H NMR(400MHz,CDCl3):δ8.50(s,1H),7.90(s,1H),6.22-6.13(m,1H),5.33–5.21(m,3H),4.66(q,J＝7.2Hz,2H),4.22–4.03(m,4H),3.17(t,J＝7.2Hz,1H),2.70(t,J＝7.4Hz,2H),1.51(t,J＝7.2Hz,3H),1.21(dt,J＝19.9,7.1Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.3,160.9,152.1,151.8,140.6,134.8,121.6,118.8,63.1,61.9,61.9,55.8,48.6,32.9,14.5,14.0,13.9ppm.HRMS:calcdfor C18H24N4O5Na[M+Na]+399.1639,found 399.1642.
diethyl 2-(2-(2-chloro-6-(piperidin-1-yl)-9H-purin-9-yl)but-3-en-1-yl)malonate(5g)
1H NMR(400MHz,CDCl3):δ7.66(s,1H),6.15-6.06(m,1H),5.32-5.21(m,2H),
5.19-5.15(m,1H),4.28–4.01(m,8H),3.16(dd,J＝8.0,6.4Hz,1H),2.70–2.51(m,2H),1.72–1.69(m,6H),1.26(t,J＝7.4Hz,3H),1.19(t,J＝7.4Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.3,154.0,153.8,151.9,136.5,135.0,118.5,61.9,61.8,54.7,48.6,33.1,26.1,24.6,13.9,13.9ppm.HRMS:calcd forC21H28ClN5O4Na[M+Na+]472.1722,found 472.1713.
diethyl 2-(2-(6-cyclopentyl-9H-purin-9-yl)but-3-en-1-yl)malonate(5h)
1H NMR(400MHz,CDCl3):δ8.87(s,1H),8.00(s,1H),6.24–6.15(m,1H),5.35–5.25(m,3H),4.22–4.14(m,2H),4.11–3.99(m,2H),3.93-3.84(m,1H),3.22(t,J＝7.2Hz,1H),2.79–2.67(m,2H),2.17–1.76(m,8H),1.23(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.3,166.4,152.5,150.4,142.0,134.8,132.3,119.0,61.9,61.8,55.7,48.8,42.6,32.8,32.8,26.3,14.0,13.9ppm.HRMS:calcd for C21H28N4O4Na[M+Na]+423.2003,found 423.1996.
diethyl 2-(2-(6-(phenanthren-9-yl)-9H-purin-9-yl)but-3-en-1-yl)malonate(5i)
1H NMR(400MHz,CDCl3):δ9.16(s,1H),8.77(dd,J＝20.0,8.0Hz,2H),8.29–8.25(m,2H),8.12(s,1H),7.99(d,J＝7.6Hz,1H),7.73–7.56(m,4H),6.32-6.24(m,1H),5.44–5.35(m,3H),4.27–4.07(m,4H),3.33(t,J＝7.2Hz,1H),2.88–2.76(m,2H),1.29–1.20(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.3,158.2,152.3,151.9,143.3,143.3,134.6,132.9,131.3,131.2,131.2,131.0,131.0,129.6,127.8,126.8,126.8,126.7,126.5,122.9,122.6,119.4,62.0,61.9,56.0,48.8,32.8,14.0,14.0ppm.HRMS:calcd for C30H29N4O4[M+H]+509.2183,found 509.2174.
diethyl 2-(2-(1H-benzo[d]imidazol-1-yl)but-3-en-1-yl)malonate(5j)
1H NMR(400MHz,CDCl3):δ7.93(s,1H),7.83–7.80(m,1H),7.42-7.40(m,1H),7.31–7.28(m,2H),6.12–6.04(m,1H),5.35(dd,J＝10.4,1.2Hz,1H),5.23(dd,J＝17.2,1.2Hz,1H),5.06–5.01(m,1H),4.21–4.03(m,4H),3.18(dd,J＝8.0,6.4Hz,1H),2.73–2.59(m,2H),1.24-1.18(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.4,144.0,141.4,135.0,133.1,123.0,122.4,120.6,118.7,110.5,61.9,61.8,56.1,48.5,32.6,14.0,13.9ppm.HRMS:calcd for C18H22N2O4Na[M+Na]+353.1472,found 353.1467.
diethyl 2-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)but-3-en-1-yl)malonate(5k)
1H NMR(400MHz,CDCl3):δ7.79(s,1H),7.55(s,1H),7.13(s,1H),6.09-6.01(m,1H),5.30(dd,J＝10.4,1.2Hz,1H),5.18(dd,J＝17.2,1.2Hz,1H),4.98–4.93(m,1H),4.21–4.05(m,4H),3.16-3.13(m,1H),2.69–2.56(m,2H),2.36-2.35(m,6H),1.23-1.16(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.5,168.3,142.4,140.6,135.1,132.0,131.4,131.3,120.3,118.2,110.5,61.7,61.7,55.9,48.4,32.4,20.5,20.1,13.8,13.8ppm.HRMS:calcd for C20H27N2O4[M+H+]359.1965,found 359.1957
diethyl 2-(2-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-yl)malonate(5l)
1H NMR(400MHz,CDCl3):δ8.06(d,J＝8.4Hz,1H),7.52-7.44(m,2H),7.39-7.35(m,1H),6.22-6.14(m,1H),5.50-5.44(m,1H),5.32(d,J＝10.4Hz,1H),5.23(dd,J＝16.8,0.8Hz,1H),4.20–4.03(m,4H),3.22(dd,J＝8.4,6.4Hz,1H),2.96-2.88(m,1H),2.80-2.73(m,1H),1.22-1.17(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.4,146.1,134.8,132.5,127.3,124.1,120.1,118.9,109.7,61.7,61.7,59.7,48.4,32.4,13.9ppm.HRMS:calcd for C17H21N3O4Na[M+Na]+354.1424,found 354.1419.
dimethyl 2-(2-(6-chloro-7H-purin-7-yl)but-3-en-1-yl)malonate(6a)
1H NMR(400MHz,CDCl3):δ8.93(s,1H),8.36(s,1H),6.13-6.05(m,1H),5.76(d,J＝7.6Hz,1H),5.44(dd,J＝10.4,1.2Hz,1H),5.25(dd,J＝17.2,1.2Hz,1H),3.75(s,3H),3.68(s,3H),3.38(t,J＝7.2Hz,1H),2.78-2.67(m,2H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.3,161.6,152.5,146.8,142.8,134.7,122.1,120.0,57.3,53.1,53.0,48.2,33.7ppm.HRMS:calcd for C14H15ClN4O4Na[M+Na]+361.0674,found361.0668.
diethyl 2-(2-(6-chloro-7H-purin-7-yl)but-3-en-1-yl)malonate(6b)
1H NMR(400MHz,CDCl3):δ8.90(s,1H),8.35(s,1H),6.12–6.03(m,1H),5.74(q,J＝7.2Hz,1H),5.41(d,J＝10.4Hz,1H),5.22(d,J＝17.2Hz,1H),4.23–4.05(m,4H),3.31(t,J＝7.2Hz,1H),2.77–2.68(m,2H),1.25–1.19(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.0,167.9,161.6,152.3,146.9,142.7,134.8,122.1,119.8,62.1,62.0,57.3,48.5,33.5,13.8ppm.HRMS:calcd for C16H19ClN4O4Na[M+Na]+389.0987,found 389.0978.
diisopropyl 2-(2-(6-chloro-7H-purin-7-yl)but-3-en-1-yl)malonate(6c)
1H NMR(400MHz,CDCl3):δ8.90(s,1H),8.36(s,1H),6.11-6.03(m,1H),5.76-5.07(m,1H),5.40(dd,J＝10.4,1.2Hz,1H),5.20(dd,J＝16.8,1.2Hz,1H),5.07–4.91(m,2H),3.24(t,J＝7.2Hz,1H),2.76–2.63(m,2H),1.22-1.15(m,12H)ppm.13C NMR(100MHz,CDCl3):δ167.6,161.7,152.5,146.9,142.8,135.0,122.2,119.7,69.9,69.9,57.5,48.9,33.4,21.5,21.5,21.4ppm.HRMS:calcd for C18H23ClN4O4Na[M+Na]+417.1300,found 417.1290.
di-tert-butyl 2-(2-(6-chloro-7H-purin-7-yl)but-3-en-1-yl)malonate(6d)
1H NMR(400MHz,CDCl3):δ8.90(s,1H),8.36(s,1H),6.10–6.01(m,1H),5.70(q,J＝7.2Hz,1H),5.38(dd,J＝10.4,0.8Hz,1H),5.17(dd,J＝17.2,0.8Hz,1H),3.15(t,J＝7.2Hz,1H),2.68-2.59(m,2H),1.44(s,3H),1.40(s,3H)ppm.13C NMR(100MHz,CDCl3):δ167.5,167.4,161.7,152.4,146.9,142.9,135.3,122.3,119.5,82.7,57.7,50.5,33.4,27.9,27.8ppm.HRMS:calcd for C20H27ClN4O4Na[M+Na]+445.1613,found 445.1606.
dimethyl 2-(2-(6-iodo-7H-purin-7-yl)but-3-en-1-yl)malonate(6e)
1H NMR(400MHz,CDCl3):δ8.77(s,1H),8.37(s,1H),6.09-6.03(m,2H),5.40(d,J＝9.2Hz,1H),5.16(d,J＝15.6Hz,1H),3.75(s,3H),3.65(s,3H),3.39(t,J＝7.2Hz,1H),2.83–2.71(m,2H)ppm.13C NMR(100MHz,CDCl3):δ168.4,168.4,159.0,152.7,146.9,135.0,127.6,119.6,108.3,55.0,53.2,53.1,48.2,33.5ppm.HRMS:calcd for C14H15IN4O4Na[M+Na]+453.0030,found 453.0023.
dimethyl 2-(2-(2,6-dichloro-7H-purin-7-yl)but-3-en-1-yl)malonate(6f)
1H NMR(400MHz,CDCl3):δ8.35(s,1H),6.10–6.01(m,1H),5.68(q,J＝6.8Hz,1H),5.44(dd,J＝9.2,1.2Hz,1H),5.23(dd,J＝15.6,1.2Hz,1H),3.73(s,3H),3.68(s,3H),3.35(t,J＝7.2Hz,1H),2.74–2.69(m,2H)ppm.13C NMR(100MHz,CDCl3):δ168.3,168.3,163.3,153.3,148.1,143.6,134.4,121.4,120.3,57.6,53.2,53.1,48.1,33.6ppm.HRMS:calcd for C14H14Cl2N4O4Na[M+Na]+395.0284,found 395.0277.diethyl 2-(2-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-yl)malonate(6g)
1H NMR(400MHz,CDCl3):δ8.06(d,J＝8.4Hz,1H),7.52-7.44(m,2H),7.39-7.35(m,1H),6.22-6.14(m,1H),5.50-5.44(m,1H),5.32(d,J＝10.4Hz,1H),5.23(dd,J＝16.8,0.8Hz,1H),4.20–4.03(m,4H),3.22(dd,J＝8.4,6.4Hz,1H),2.96-2.88(m,1H),2.80-2.73(m,1H),1.22-1.17(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.4,146.1,134.8,132.5,127.3,124.1,120.1,118.9,109.7,61.7,61.7,59.7,48.4,32.4,13.9ppm.HRMS:calcd for C17H21N3O4Na[M+Na]+354.1424,found 354.1419.
diethyl 2-(2-(1H-benzo[d]imidazol-1-yl)but-3-en-1-yl)malonate(6h)
1H NMR(400MHz,CDCl3):δ7.93(s,1H),7.83–7.80(m,1H),7.42-7.40(m,1H),7.31–7.28(m,2H),6.12–6.04(m,1H),5.35(dd,J＝10.4,1.2Hz,1H),5.23(dd,J＝17.2,1.2Hz,1H),5.06–5.01(m,1H),4.21–4.03(m,4H),3.18(dd,J＝8.0,6.4Hz,1H),2.73–2.59(m,2H),1.24-1.18(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.4,144.0,141.4,135.0,133.1,123.0,122.4,120.6,118.7,110.5,61.9,61.8,56.1,48.5,32.6,14.0,13.9ppm.HRMS:calcd for C18H22N2O4Na[M+Na]+353.1472,found 353.1467.
diethyl 2-(2-(2-methyl-1H-benzo[d]imidazol-1-yl)but-3-en-1-yl)malonate(6i)
1H NMR(400MHz,CDCl3):δ7.70-7.67(m,1H),7.35-7.33(m,1H),7.23–7.16(m,2H),6.14-6.06(m,1H),5.29(dd,J＝10.4,1.2Hz,1H),5.13–5.06(m,2H),4.23–4.06(m,2H),3.98(q,J＝7.2Hz,2H),3.12-3.01(m,1H),2.84-2.76(m,1H),2.72–2.64(m,1H),2.57(s,3H),1.20(t,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ168.6,168.3,151.6,142.7,1346,133.5,122.1,122.0,119.3,118.0,111.1,61.8,61.8,55.6,48.5,31.2,14.6,13.9,13.8ppm.HRMS:calcdfor C19H25N2O4[M+H+]345.1809,found 345.1800.
diethyl 2-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)but-3-en-1-yl)malonate(6j)
1H NMR(400MHz,CDCl3):δ7.79(s,1H),7.55(s,1H),7.13(s,1H),6.09-6.01(m,1H),5.30(dd,J＝10.4,1.2Hz,1H),5.18(dd,J＝17.2,1.2Hz,1H),4.98–4.93(m,1H),4.21–4.05(m,4H),3.16-3.13(m,1H),2.69–2.56(m,2H),2.36-2.35(m,6H),1.23-1.16(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.5,168.3,142.4,140.6,135.1,132.0,131.4,131.3,120.3,118.2,110.5,61.7,61.7,55.9,48.4,32.4,20.5,20.1,13.8,13.8ppm.HRMS:calcd for C20H27N2O4[M+H+]359.1965,found 359.1957.
diethyl 2-(2-(4-nitro-1H-imidazol-1-yl)but-3-en-1-yl)malonate(6k)
1H NMR(400MHz,CDCl3):δ7.79(s,1H),7.48(s,1H),5.99-5.91(m,1H),5.44(d,J＝10.4Hz,1H),5.30(d,J＝17.2Hz,1H),4.83-4.77(m,1H),4.23–4.17(m,4H),3.21(t,J＝7.2Hz,1H),2.53-2.48(m,2H),1.29-1.25(m,6H)ppm.13C NMR(100MHz,CDCl3):δ168.1,168.0,135.1,134.1,120.4,117.6,62.2,62.2,59.1,48.2,33.4,14.0,14.0ppm.HRMS:calcd for C14H219N3O6Na[M+Na+]348.1166,found 348.1165.
按照本发明方法，共合成出38个化合物，具体如下:
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (5)

1.一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，其特征在于，反应方程式如下： 
其中：R1选自下列基团中的一种：F、Cl、Br、I、H、甲氧基、乙氧基、哌啶、吗啉、二甲胺基、丙硫基、苯基、萘基； 
R2选自下列基团中的一种：H、NH2、Cl、F； 
R3选自下列基团中的一种：甲基、乙基、异丙基、叔丁基、苄基。 
2.根据权利要求1所述的一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，其特征在于，所述反应方程中两个X相同。 
3.根据权利要求1所述的一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，其特征在于，所述反应方程中两个X不同，虚线表示的键为单键或者双键，并且虚线所在的环为芳环。 
4.根据权利要求1所述的一种通过嘌呤对乙烯基环丙烷的选择性开环构建非环核苷的方法，其特征在于，所述的方法具体为： 
(a)以二恶烷作溶剂，氮气保护下以加入Pd2(dba)3·CHCl3和配体L，然后依次加入两种反应物，30摄氏度反应18小时； 
其中：配体L的结构式为：
(b)以二恶烷作溶剂，氮气保护下以加入AlCl3，然后依次加入两种反应物，85摄氏度 反应18小时； 
(c)以二恶烷作溶剂，氮气保护下以加入MgI2，然后依次加入两种反应物，85摄氏度反应18小时。 
5.根据权利要求1所述的方法，所述的非环核苷及其类似物选自下列38个具体化合物中： 
。
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CN105037366A (zh) * 2015-07-30 2015-11-11 河南师范大学 一种不对称[3+2]环加成合成手性五元碳环核苷类似物的方法
CN107602559A (zh) * 2017-09-29 2018-01-19 河南师范大学 一种通过迈克尔加成引发的不对称环丙化合成手性三元碳环核苷的方法
CN109912601A (zh) * 2019-04-11 2019-06-21 河南师范大学 一种合成喷昔洛韦类似物的方法
CN109912601B (zh) * 2019-04-11 2020-09-01 河南师范大学 一种合成喷昔洛韦类似物的方法
CN112778224A (zh) * 2021-01-29 2021-05-11 河南师范大学 一种合成更昔洛韦类似物的方法
CN112778224B (zh) * 2021-01-29 2023-03-21 河南师范大学 一种合成更昔洛韦类似物的方法

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