CN117229172A - 一种二奎烷类化合物及其合成方法和应用 - Google Patents
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Abstract
本发明公开了一种二奎烷类化合物及其合成方法和应用,以芳基二氰基烯与烯丙基碳酸酯为反应原料,在有机膦催化剂的作用下,反应得到二奎烷类化合物。本发明优点包括:反应高效、收率高;有机膦催化剂便宜易得、稳定、并且无刺激性气味;反应中无需加入强酸或强碱,以及额外的氧化或还原剂,条件较为温和;反应中无需使用过渡金属作为催化剂,经济实用,对环境友好;反应底物容易制备。本发明式(III)所代表的化合物对指状青霉菌(Penicillium digitaum)、水稻纹枯菌(Rhizoctonia solani)具有较好的抑制活性,其中化合物11的效果最好,分别达到91%和83%。
Description
技术领域
本发明属于有机化合物工艺应用技术领域,具体涉及二奎烷类化合物及其高效简捷的合成方法,以及在抗指状青霉菌和/或水稻纹枯菌的药物上的应用。
背景技术
二奎烷是一种明显的广泛存在于碳环框架中的结构单元的一系列天然产品,如生物碱和萜类化合物。这些含有二奎烷类的分子不仅表现出特殊的五并五碳环结构,而且表现出具有广泛的生物活性,引起了来自全世界有机合成领域的广泛关注。此外,还发现了多种含有苯二奎烷类的天然化合物具有显著的生物活性及药理活性。另一种也含有五并五碳环的天然产物Canataxapropellane是具有重要药用的紫杉烷二萜科,最突出的紫杉醇是当今临床上最常用的抗癌药物之一,如下所示:
开发该类的简易合成策略一直是有机合成界非常关注的话题,然而很少报道合成该类的催化方法,合成该类仍具有很高的挑战性,本发明的目标是设计一种简单且实用的催化方法来构造该类。据我们所知,有机膦催化在环化反应方面是非常优秀的催化剂,经常被当做环合反应的高效催化剂。因此本发明将该母核结构拆分为原料芳基二氰基烯与烯丙基碳酸酯,通过有机膦催化的作用构建该母核结构。
发明内容
本发明创新性地实现一种高效构建二奎烷类的方法。本发明人经研究发现芳基二氰基烯是一类非常活泼的含吸电子基的芳基化合物,它具有稳定、易制备等特点。鉴于此,本发明设计了芳基二氰基烯与烯丙基碳酸酯进行反应来制备二奎烷类化合物的反应方法。
本发明提出的一种二奎烷类化合物的合成方法,在有机膦催化剂催化的条件下,以芳基二氰基烯与与烯丙基碳酸酯为反应原料,在反应溶剂中反应,有效地实现了相应转化,制备得到如图(III)所示的二奎烷类化合物。其中,所述反应过程如以下反应式a所示:
其中,R1是2-硝基、4-硝基、5-氟-2-硝基、5-氯-2-硝基、5-溴-2-硝基、4-氟-2-硝基、4-氯-2-硝基、4-溴-2-硝基、4-甲酸甲酯基中的任意一种。R2是乙基、异丙基、正丁基、叔丁基、苄基、环己基中的任意一种。
如以上反应式a所示,本发明利用(I)所示的芳基二氰基烯,与烯丙基碳酸酯为反应原料,在有机膦催化剂作用下,在反应溶剂中反应得到如图(III)所示的二奎烷类化合物。
本发明中,所述起始原料如图(I)所示的芳基二氰基烯和原料如图(II)所示的烯丙基碳酸酯的用量比例为1:2-3。
本发明中,所述溶剂是二氯甲烷、二氯乙烷、三氯甲烷、甲苯、乙腈、丙酮之中任意一种。从产物的反应效果来看,溶剂选择丙酮。
本发明合成反应包括以下步骤:
方程式a所述反应包括以下步骤:在反应容器中加入芳基二氰基烯、烯丙基碳酸酯、丙酮,在常温(常温一般为25℃左右)条件下搅拌反应,得到图(III)所示的二奎烷类化合物。
在一个具体实例中,如方程式a,本发明合成反应是在反应瓶A中,加入芳基二氰基烯(X mmol),烯丙基碳酸酯(Y mmol),溶剂(V mL),反应体系在25℃条件下搅拌12小时。反应完毕后,反应体系浓缩,经柱层析分离得到目标产物。
本发明还提出了按照本发明上述合成方法制备得到的如图(III)所示的二奎烷类化合物。
其中,R1是卤素原子取代;R2是烷基或芳基。
本发明还提出了上述(III)所示的二奎烷类化合物在合成含有二奎烷类相关潜在药物的应用方法。
本发明具有以下优点:1、反应高效,收率高;2、有机膦催化剂便宜易得、稳定、并且无刺激性气味;3、反应中无需加入强酸或强碱,以及额外的氧化或还原剂,条件较为温和;4、反应中无需使用过渡金属作为催化剂,经济实用,对环境友好;5、反应底物容易制备;6、反应放大后反应效率高,具有实用价值。
本发明以容易制备的芳基二氰基烯化合物和烯丙基碳酸酯化合物为反应原料,在有机膦催化剂作用下,反应得到二奎烷类化合物。反应操作简单,条件温和,适合大规模工业化生产。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
本发明芳基烷基硫醚化合物的合成反应,包括以下步骤:
如方程式a所示:在反应容器中加入邻硝基苯基二氰基烯、烯丙基碳酸酯、丙酮,在常温条件下搅拌反应,得到(III)所示的二奎烷类化合物。再经浓缩,柱层析分离得到目的产物。
如表1所示的二奎烷类化合物,均为通过本发明方法合成得到的产物,尚未见有公开文献揭示这些化合物。
表1本发明的新的二奎烷类化合物
实施例1
将邻硝基取代的二氰基苯基烯(19.9mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物1(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:93%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.01(dd,J=8.4,1.2Hz,1H),7.84(d,J=7.6Hz,1H),7.77–7.73(m,1H),7.59–7.55(m,1H),6.69(dd,J=4.0,2.0Hz,1H),4.59(d,J=6.4Hz,1H),4.36(d,J=6.4Hz,1H),4.29(t,J=6.8Hz,2H),4.07–4.01(m,1H),3.90–3.84(m,1H),3.49(d,J=13.6Hz,1H),3.06(dt,J=19.6,1.6Hz,1H),2.92(dt,J=19.6,2.8Hz,1H),2.58(d,J=13.6Hz,1H),1.75–1.71(m,2H),1.47–1.40(m,2H),1.36–1.32(m,2H),1.20–1.14(m,2H),0.98(t,J=7.4Hz,3H),0.82(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.6,163.1,149.8,140.3,137.2,133.4,131.2,129.8,129.6,125.2,114.2,113.5,66.6,64.8,59.5,58.8,53.5,47.2,44.4,41.8,30.4,30.2,19.2,18.9,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H29N3O6H+(M+H)+514.1973,found 514.1978.
实施例2
将间硝基取代的二氰基苯基烯(19.9mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物2(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:51%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.36(t,J=2.0Hz,1H),8.29(dd,J=8.4,1.6Hz,1H),7.86(d,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),6.72(dd,J=4.0,2.0Hz,1H),4.52(dd,J=7.2,1.6Hz,1H),4.33–4.26(m,2H),4.00–3.94(m,1H),3.91–3.85(m,1H),3.74(d,J=7.2Hz,1H),3.57(d,J=13.6,1H),3.01(dt,J=19.6,2.0Hz,1H),2.86(dt,J=19.6,2.8Hz,1H),2.46(d,J=13.6Hz,1H),1.78–1.71(m,2H),1.47–1.41(m,2H),1.34–1.29(m,2H),1.20–1.14(m,2H),0.98(t,J=7.6Hz,3H),0.82(t,J=7.2Hz,3H).13CNMR(100MHz,CDCl3)δ173.3,163.1,148.4,140.5,137.6,137.1,134.4,130.0,124.0,123.5,114.4,112.8,66.7,64.8,61.0,59.0,57.0,46.6,44.4,42.6,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H29N3O6H+(M+H)+514.1973,found 514.1978.
实施例3
将对硝基取代的二氰基苯基烯(19.9mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物3(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:59%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.32(d,J=8.8Hz,2H),7.68(d,J=8.8Hz,2H),6.70(dd,J=4.0,2.0Hz,1H),4.53(dd,J=7.6,1.6Hz,1H),4.31–4.25(m,2H),4.00–3.85(m,2H),3.71(d,J=7.6Hz,1H),3.57(d,J=13.6Hz,1H),2.98(dt,J=19.6,2.4Hz,1H),2.85(dt,J=19.6,2.8Hz,1H),2.45(d,J=13.6Hz,1H),1.76–1.70(m,2H),1.47–1.41(m,2H),1.34–1.28(m,2H),1.22–1.15(m,2H),0.98(t,J=7.2Hz,3H),0.82(t,J=7.6Hz,3H).13C NMR(100MHz,CDCl3)δ173.3,163.1,148.2,142.5,140.2,137.2,129.5,124.1,114.3,112.8,66.7,64.9,61.1,59.1,56.8,46.7,44.4,42.6,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H29N3O6Na+(M+Na)+502.1949,found502.1960.
实施例4
将5-氟-2-硝基取代的二氰基苯基烯(21.7mg,0.1mmol,1.0equiv.)与溶剂丙酮(1.0mL)加入到反应管中,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物4(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:61%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.12(dd,J=9.2,5.2Hz,1H),7.58(dd,J=9.2,2.4Hz,1H),7.26–7.22(m,1H),6.69(d,J=2.0Hz,1H),4.71(d,J=6.4Hz,1H),4.30(t,J=6.8Hz,3H),4.08–4.01(m,1H),3.95–3.89(m,1H),3.47(d,J=14.0Hz,1H),3.11(d,J=19.6Hz,1H),2.93(dt,J=20.0,2.4Hz,1H),2.61(d,J=14.0Hz,1H),1.78–1.71(m,2H),1.46–1.39(m,4H),1.24–1.19(m,2H),0.98(t,J=7.2Hz,3H),0.85(t,J=7.2Hz,3H).13CNMR(100MHz,CDCl3)δ173.4,163.1(d,J=23.4Hz),140.5,136.9,135.1(d,J=8.7Hz),128.3(d,J=9.8Hz),117.4(d,J=24.8Hz),116.8(d,J=22.8Hz),114.1,113.3,66.8,59.6,58.8,53.4,47.3,44.3,41.7,30.4,30.3,19.2,19.0,13.6,13.6.HRMS(ESI)m/z:calcd.for C26H28FN3O6H+(M+H)+498.2040,found 498.2043.
实施例5
将5-氯-2-硝基取代的二氰基苯基烯(23.3mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物5(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:63%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.01(d,J=8.8Hz,1H),7.83(d,J=2.0Hz,1H),7.54(dd,J=8.4,2.0Hz,1H),6.69(dd,J=4.0,2.0Hz,1H),4.65(d,J=6.4Hz,1H),4.34–4.27(m,3H),4.28–4.02(m,1H),3.94–3.88(m,1H),3.48(d,J=14.0Hz,1H),3.11(dt,J=19.6,1.6Hz,1H),2.93(dt,J=19.6,2.8Hz,1H),2.59(d,J=13.6Hz,1H),1.79–1.72(m,2H),1.47–1.39(m,4H),1.23–1.19(m,2H),0.98(t,J=7.6Hz,3H),0.86(t,J=7.6Hz,3H).13C NMR(100MHz,CDCl3)δ173.4,163.1,147.9,140.1,136.9,133.4,130.1,129.8,126.8,114.1,113.3,66.8,64.9,59.5,58.8,53.3,47.3,44.4,41.7,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H28ClN3O6H+(M+H)+514.1740,found 514.1748.
实施例6
将5-溴-2-硝基取代的二氰基苯基烯(27.8mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物6(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:64%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ7.98(d,J=1.6Hz,1H),7.92(d,J=8.8Hz,1H),7.70(dd,J=8.8,2.0Hz,1H),6.69(d,J=2.0Hz,1H),4.62(d,J=6.4Hz,1H),4.35–4.28(m,3H),4.08–4.02(m,1H),3.94–3.88(m,1H),3.48(d,J=14.0Hz,1H),3.11(d,J=19.6Hz,1H),2.93(dt,J=19.6,2.4Hz,1H),2.59(d,J=14.0Hz,1H),1.80–1.72(m,2H),1.42–1.39(m,2H),1.28–1.21(m,4H),0.98(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.4,163.1,140.6,136.9,133.4,133.1,132.8,128.4,126.7,114.1,113.3,66.8,64.9,59.5,58.8,53.2,47.3,44.4,41.7,30.5,30.4,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H28BrN3O6H+(M+H)+558.1235,found 558.1246.
实施例7
将4-氟-2-硝基取代的二氰基苯基烯(21.7mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物7(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:63%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ7.89(dd,J=8.8,5.2Hz,1H),7.75(dd,J=8.0,2.4Hz,1H),7.49–7.45(m,1H),6.66(d,J=1.6Hz,1H),4.58(d,J=6.8Hz,1H),4.28(t,J=6.8Hz,1H),4.08–4.02(m,1H),3.93–3.87(m,1H),3.49(d,J=14.0Hz,1H),3.03(d,J=19.6Hz,1H),2.89(d,J=19.6Hz,1H),2.56(d,J=13.6Hz,1H),1.76–1.69(m,2H),1.46–1.37(m,4H),1.24–1.19(m,2H),0.98(t,J=7.2Hz,3H),0.85(t,J=7.6Hz,1H).13C NMR(100MHz,CDCl3)δ173.5,163.2(d,J=13.3Hz),160.5,150.4,140.1,137.1,131.9(d,J=8.2Hz),127.3(d,J=4.1Hz),120.9(d,J=21.1Hz),114.0(d,J=53.3Hz),113.1(d,J=26.4Hz),66.7,64.9,59.5,58.8,53.1,47.2,44.3,41.8,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C26H28FN3O6H+(M+H)+498.2040,found498.2046.
实施例8
将4-氯-2-硝基取代的二氰基苯基烯(23.3mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物8(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:64%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.00(d,J=2.4Hz,1H),7.83(d,J=8.8Hz,1H),7.71(dd,J=8.4,2.0Hz,1H),6.66(dd,J=4.0,2.0Hz,1H),4.55(d,J=6.8Hz,1H),4.28(t,J=6.8Hz,3H),4.09–4.03(m,1H),3.93–3.87(m,1H),3.50(d,J=13.6Hz,1H),3.02(dt,J=19.6,2.0Hz,2H),2.89(dt,J=19.6,2.4Hz,1H),2.56(d,J=13.6Hz,1H),1.76–1.69(m,2H),1.46–1.37(m,4H),1.24–1.18(m,2H),0.98(t,J=7.2Hz,3H),0.85(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.5,163.1,150.1,140.0,137.1,135.6,133.5,131.2,129.6,125.3,113.9,113.4,66.7,64.9,59.3,58.8,53.1,47.3,44.2,41.7,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.forC26H28ClN3O6Na+(M+Na)+536.1560,found 536.1559.
实施例9
将4-溴-2-硝基取代的二氰基苯基烯(27.8mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物9(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:68%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.86(dd,J=8.8,2.4Hz,1H),7.75(d,J=8.8Hz,1H),6.66(dd,J=4.0,2.0Hz,1H),4.53(d,J=6.8Hz,1H),4.28(t,J=6.8Hz,3H),4.08–4.02(m,1H),3.93–3.87(m,1H),3.50(d,J=13.6Hz,1H),3.02(dt,J=19.6,2.0Hz,1H),2.89(dt,J=19.6,2.4Hz,1H),2.55(d,J=13.6Hz,1H),1.74–1.69(m,2H),1.44–1.37(m,4H),1.24–1.18(m,2H),0.98(t,J=7.6Hz,3H),0.86(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.5,163.1,150.1,140.0,137.1,136.5,131.4,130.1,128.2,123.1,113.9,113.4,66.7,65.0,59.3,58.8,53.2,47.3,44.2,41.6,30.4,30.3,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.forC26H28BrN3O6H+(M+H)+558.1235,found 558.1246.
实施例10
将邻硝基胡椒醛取代的二氰基苯基烯(24.3mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物10(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:73%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ7.53(s,1H),7.23(s,1H),6.69(dd,J=4.0,2.4Hz,1H),6.17(s,2H),4.71(d,J=6.0Hz,1H),4.28(t,J=6.8Hz,2H),4.08–4.01(m,1H),3.98–3.92(m,1H),3.41(d,J=14.0Hz,1H),3.12(ddd,J=19.6,3.6,1.2Hz,1H),2.93(dt,J=19.6,2.4Hz,1H),2.60(d,J=13.6Hz,1H),1.75–1.70(m,2H),1.47–1.40(m,4H),1.26–1.23(m,2H),0.97(t,J=7.2Hz,4H),0.86(t,J=7.2Hz,4H).13C NMR(100MHz,CDCl3)δ173.6,163.2,152.0,148.0,144.1,140.5,137.1,127.8,114.4,113.7,108.3,106.2,103.4,66.7,64.9,59.5,58.8,53.8,47.0,44.3,41.8,30.4,30.6,27.4,19.2,19.0,13.7.HRMS(ESI)m/z:calcd.for C27H29N3O8Na+(M+Na)+546.1848,found 546.1847.
实施例11
将对甲酸甲酯取代的二氰基苯基烯(21.2mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物11(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:51%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.11(d,J=8.0Hz,2H),7.55(d,J=8.0Hz,2H),6.70(d,J=1.6Hz,1H),4.53(d,J=6.0Hz,1H),4.30–4.23(m,2H),3.93(s,3H),3.84–3.78(m,1H),3.65(d,J=7.6Hz,1H),3.55(d,J=13.6Hz,1H),2.98(dt,J=19.6,2.0Hz,1H),2.83(dt,J=19.6,2.8Hz,1H),2.43(d,J=13.6Hz,1H),1.74–1.69(m,2H),1.47–1.41(m,2H),1.23–1.19(m,2H),1.14–1.09(m,2H),0.97(t,J=7.6Hz,3H),0.79(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.5,166.5,163.2,140.2,137.5,130.7,130.2,128.4,114.7,113.0,85.2,66.5,64.7,61.4,59.0,56.8,52.2,46.7,44.6,42.7,30.4,30.1,27.4,19.2,18.9,13.7,13.5.HRMS(ESI)m/z:calcd.forC28H32N2O6Na+(M+Na)+515.2153,found 515.2158.
实施例12
将对甲氧基取代的二氰基苯基烯(18.4mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物12(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:43%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ7.38(d,J=8.8Hz,2H),6.94(d,J=8.4Hz,2H),6.69(d,J=2.0Hz,1H),4.45(d,J=7.6Hz,1H),4.29–4.22(m,2H),3.98–3.92(m,1H),3.87–3.84(m,1H),3.82(s,3H),3.57(d,J=7.6Hz,1H),3.51(d,J=13.6Hz,1H),2.98(dt,J=19.2,1.6Hz,1H),2.81(dt,J=19.2,2.4Hz,1H),2.40(d,J=13.6Hz,1H),1.73–1.68(m,2H),1.46–1.40(m,2H),1.29–1.25(m,2H),1.17–1.11(m,2H),0.97(t,J=7.2Hz,3H),0.81(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ173.8,163.4,160.0,140.1,137.9,129.4,127.3,115.1,114.2,113.4,66.4,64.7,61.1,58.8,57.1,55.2,46.4,44.7,43.1,30.4,30.2,19.2,19.0,13.7,13.6.HRMS(ESI)m/z:calcd.for C27H32N2O5H+(M+H)+465.2389,found 465.2394.
实施例13
将邻硝基取代的二氰基苯基烯(19.9mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基叔丁基碳酸酯(77.4mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物13(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:63%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ8.00(dd,J=8.0,1.2Hz,1H),7.88(dd,J=8.0,0.8Hz,1H),7.77–7.73(m,1H),7.58–7.53(m,1H),6.56(dd,J=4.4,2.4Hz,1H),4.58(d,J=6.4Hz,1H),4.31(d,J=6.0Hz,1H),3.43(d,J=13.2Hz,1H),2.96(ddd,J=19.6,4.0,1.6Hz,1H),2.84(dt,J=19.6,2.8Hz,1H),2.52(d,J=14.0Hz,1H),1.56(s,9H),1.24(s,9H).13C NMR(100MHz,CDCl3)δ172.6,162.5,149.8,139.1,139.0,133.4,131.4,129.9,129.5,125.2,114.4,113.6,83.3,81.6,59.7,58.7,53.7,47.4,44.6,41.8,27.9,27.7.HRMS(ESI)m/z:calcd.for C26H29N3O6Na+(M+Na)+502.1949,found502.1950.
实施例14
将邻硝基取代的二氰基苯基烯(19.9mg,0.1mmol,1.0equiv.)与反应溶剂丙酮(1.0mL)加入到反应管中后,加入Boc保护的烯丙基苄基碳酸酯(87.6mg,0.3mmol,3.0equiv.),然后加入有机膦催化剂PPh3(7.9mg,30mol%),在25℃反应温度下搅拌12小时。然后将反应液减压除去溶剂,经柱层析分离后得到产物14(洗脱剂极性:石油醚/二氯甲烷/乙酸乙酯=60:40:1)。收率:81%,>20:1d.r.;1H NMR(400MHz,CDCl3)δ7.90(d,J=8.0Hz,1H),7.67(d,J=7.6Hz,1H),7.54(t,J=7.2Hz,1H),7.46(d,J=7.6Hz,1H),7.41(s,5H),7.28(d,J=2.0Hz,2H),7.11(dd,J=5.2,1.6Hz,2H),6.73(d,J=1.6Hz,1H),5.29(dd,J=32.4,12.0Hz,2H),5.08(d,J=12.4Hz,1H),4.87(d,J=12.4Hz,1H),4.63(d,J=6.4Hz,1H),4.35(d,J=5.6Hz,1H),3.48(d,J=13.6Hz,1H),3.06(d,J=19.2Hz,1H),2.91(dt,J=19.6,2.4Hz,1H),2.57(d,J=13.6Hz,1H).13C NMR(100MHz,CDCl3)δ173.2,162.8,149.6,141.0,136.9,135.1,134.7,133.3,131.0,129.7,129.5,128.9,128.9,128.8,128.5,128.3,128.2,125.2,114.2,113.5,68.5,66.7,59.5,58.8,53.5,47.1,44.3,41.8.HRMS(ESI)m/z:calcd.for C32H25N3O6Na+(M+Na)+570.1636,found570.1629.
实施例15
杀菌活性试验
化合物的浓度为100ppm,用打孔器(5mm)取菌种琼脂片,菌丝面朝下接种要含有待测化合物的PDA培养基上,置于圆形培养基的正中心,每个待测样品接种三个。空白对照组为不含待测化合物但含有相同浓度DMSO的培养基。放置在生化培养箱内于25℃下培养3~5天后,测定培养基上的菌落的直径。通过和上述空白对照组的比较来观察待测样品对菌丝生长的影响,计算待测样品在100mg/L下对菌落生长的抑制率。抑制率(%)=[(空白对照菌落直径-待测样品菌落直径)/(空白菌落直径-打孔器直径)]×100%。下表为部分化合物的测定结果:
从上述的表格中可以发现,化合物11的效果最好,在指状青霉菌及水稻纹枯病上分别达到91%和83%的抑菌效果。其他化合物也具有显著的抑菌效果。本申请的上述实施例中,化合物2、3与化合物1具有结构相似性;化合物5、6、7、8、9、10与化合物4具有结构相似性;化合物12与化合物11具有结构相似性;化合物13与化合物14具有结构相似性,因此,对本领域技术人员来说也能预测到具有与相似化合物在指状青霉菌及水稻纹枯病上具有显著的抑菌效果。
Claims (7)
1.一种二奎烷类化合物的合成方法,其特征在于,以芳基二氰基烯与烯丙基碳酸酯为反应原料,在有机膦催化剂的作用下,在反应溶剂中反应得到如式(Ⅲ)所示的二奎烷类化合物;所述反应过程如反应式a所示:
其中,R1是卤素原子取代;R2是烷基或芳基取代。
2.如权利要求1所述的合成方法,其特征在于,所述反应溶剂选自二氯甲烷、二氯乙烷、三氯甲烷、甲苯、乙腈、丙酮之中任意一种。
3.如权利要求1所述的合成方法,其特征在于,所述反应中,芳基二氰基烯R1选自2-硝基、4-硝基、5-氟-2-硝基、5-氯-2-硝基、5-溴-2-硝基、4-氟-2-硝基、4-氯-2-硝基、4-溴-2-硝基、4-甲酸甲酯基;R2是自乙基、异丙基、正丁基、叔丁基、苄基、环己基。
4.如权利要求1所述的合成方法,其特征在于,所述反应中,原料芳基二氰基烯与烯丙基碳酸酯的摩尔比例为1:2-3。
5.一种按权利要求1所述合成方法制备得到的二奎烷类化合物,其特征在于,其结构如(Ⅲ)所示:
其中,R1是卤素原子取代;R2是烷基或芳基取代。
6.根据权利要求5所述的二奎烷类化合物,其特征在于,其结构如(Ⅲ)所示:
其中,R1选自2-硝基、4-硝基、5-氟-2-硝基、5-氯-2-硝基、5-溴-2-硝基、4-氟-2-硝基、4-氯-2-硝基、4-溴-2-硝基、4-甲酸甲酯基中的任意一种;R2选自乙基、异丙基、正丁基、叔丁基、苄基、环己基中的任意一种。
7.如权利要求5或6所述的二奎烷类化合物在制备抗指状青霉菌和/或水稻纹枯菌的药物上的应用。
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