CN107954937A - Naamine类衍生物及其制备方法和在治疗植物病毒和病菌病中的应用 - Google Patents
Naamine类衍生物及其制备方法和在治疗植物病毒和病菌病中的应用 Download PDFInfo
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- CN107954937A CN107954937A CN201610911058.0A CN201610911058A CN107954937A CN 107954937 A CN107954937 A CN 107954937A CN 201610911058 A CN201610911058 A CN 201610911058A CN 107954937 A CN107954937 A CN 107954937A
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- naamine
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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Abstract
本发明公开Naamine类衍生物及其制备方法和在治疗植物病毒和病菌病中的应用，Naamine类衍生物具体为Ⅰ‑1～Ⅰ～16所示的化合物，在每一反应过程中，参与反应的物质之间按照反应要求的摩尔比进行取料，为确保目标产物的反应进程会选择过量物质参与反应，并根据反应类型确定体系pH值，反应温度和时间，在进行制备之后进行提纯分离或者干燥，本发明的Naamine类衍生物表现出很好的治疗植物病毒和病菌病活性，能很好地抑制烟草花叶病毒(TMV)和黄瓜枯萎，花生褐斑，苹果轮纹，小麦纹枯，玉米小斑，西瓜炭疽，水稻恶苗，番茄早疫，小麦赤霉，马铃薯晚疫，辣椒疫霉，油菜菌核，黄瓜灰霉，水稻纹枯14种植物病菌。
Description
技术领域
本发明涉及Naamine类衍生物及其制备方法和在治疗植物病毒和病菌病中的应用，属于农业防护技术领域。
背景技术
植物病毒素有“植物癌症”之称,目前已知约有1000多种，分布广泛，农业生产中病毒病是仅次于真菌病害的第二大类植物病害。一种植物病毒可侵染多种植物，而同种植物又可以被多种病毒侵染。当植物病毒侵染寄主后，植物代谢异常，出现植物的叶片黄化，褪绿，皱缩，卷曲；植株矮化，坏死；果实减少或畸形，从而降低农作物的产量和品质。在病害流行期间，甚至对感病作物造成毁灭性的灾害。据统计，全世界每年因植物病毒病造成的直接损失达200亿美元以上，我国重要的经济作物如：蔬菜、花卉以及烟草，每年因植物病毒病造成的直接损失达10亿美元以上。我国主要的蔬菜病毒病有：黄瓜花叶病毒病、芜菁花叶病毒病、辣(甜)椒病毒病、甜瓜花叶病毒病、西瓜花叶病毒病、菜豆花叶病毒病。因受这些病毒的危害造成减产减收甚至绝收的现象普遍发生。水稻病毒病是一类系统性侵染病害，在我国发生的就有11种，近年经常遇到的主要是水稻矮缩病，水稻条纹叶枯病和水稻东格鲁病。中国稻区广阔，稻病广泛流行，病害严重时仅一个省就有数十万吨损失。玉米病毒病主要有玉米矮花叶病、玉米粗缩病和玉米条纹病，大多数玉米产区都是混合发病，病害发病率高，主要依靠昆虫传播，防控困难，是国内外玉米产区较难防治的病害之一。
烟草花叶病毒(简称:TMV)是发现最早，研究最为深入的植物病毒，而且作为模型系统研究已有110多年，评选为十大植物病毒之首。它是一种单链RNA病毒，可浸染38个科268种植物，能使受感染植物的叶片看来斑驳污损，因此得名。TMV在无菌条件下致病力可达数年，在干燥的病组织内可存活30年以上。该病毒有不同株系，我国主要有普通株系、番茄株系、黄斑株系和珠斑株系4个株系。植株感染病毒后，幼嫩叶片侧脉及支脉组织呈半透明状，叶脉两侧叶肉组织渐呈淡绿色，病毒在叶片组织内大量增殖，使部分叶肉细胞增大或增多，出现叶片薄厚不匀，颜色黄绿相间，呈花叶状，发病后期花叶斑驳程度加大，并出现大面积深褐色坏死斑，中下部老叶尤甚，发病重的叶片皱缩、畸形、扭曲。早期发病的植株节间缩短，严重矮化，生长缓慢，不能正常开花结实并易脱落。据统计，全世界每年仅烟草花叶病毒病一项危害造成的经济损失就高达一亿多美元。一般年份发病率约为25％，严重的达50％以上。由于植物本身没有动物那样完善的免疫系统，而病毒个体十分微小，病毒病原诊断鉴定的难度较大，再加上植物病毒病具有间歇性的暴发流行和无明显的周期性特征，因此植物病毒病的防治比较困难，一直是植物病害及病毒学研究的热点和难点。已发现的抗植物病毒药剂主要有：苯并噻二唑(BTH)、噻酰菌胺(TDL)、4-甲基-1,2,3-噻二唑-5-甲酸(TDLA)、DL-β-氨基丁酸(BABA)、病毒唑、宁南霉素、菲并吲哚里西啶生物碱安托芬、联三唑类化合物XY-13和XY-30、病毒A(有效成分为盐酸吗啉双胍和醋酸铜)、水杨酸、多羟基双萘醛、氨基寡糖素(几丁寡糖，学名为β-1，4-寡聚葡萄糖胺)。而现有的这些抗植物病毒剂中实用化品种并不多，而且防治效果差，一般低于60％，质量控制较为困难，长期使用都存在一定的环境风险。因此，开发以天然植物活性物质为有效成分的高效、低毒的绿色抗植物病毒农药新品种意义非常重大。
海洋是人类物质资源的天然宝库，已知海洋生物的物种总数占地球生物的80％以上(J Antibiot(Tokyo),1994,47,1425–1433)，目前从海绵、海兔、海鞘、海藻、鲨鱼、珊瑚等海洋生物中分离获得7000余种海洋天然产物，新发现的化合物还在以加速度递增。在已发现的化合物中包括萜类、多肽、甾体类、聚醚类、生物碱、大环内酯类、多糖等化合物，约50％具有各种生物活性，超过0.1％的化合物结构新颖，活性显著，极有可能开发成药(Chem.Rev.2015,115,9655-9706)。因此，从海洋天然产物中寻找新型活性药物先导已成为当今研究的热点。自1987年，以色列特拉维夫大学Kashman课题组首次从红海海绵Leucettachaqosensis中分离得到2-氨基咪唑生物碱Naamine A和Naamidine A(TetrahedronLett.1982,87,3003-3006.)以来，大量该类生物碱被分离报道。由于Naamine类生物碱天然含量较低，且合成较为困难，生物活性研究还不够深入，主要集中在抗癌活性方面，在抗人体病毒和病菌方面的研究还处于初级阶段，并且在抗植物病毒和病菌中的应用还没有报道，并且人体病毒病菌和植物病毒病菌有很大的区别，绝大多数情况下二者互不传染。
发明内容
本发明的目的是提供Naamine类衍生物及其制备方法和在治疗植物病毒和病菌病中的应用，本专利的Naamine类衍生物具有很好的抗植物病毒和病菌活性。
Naamine类衍生物具有化学式I所示的结构，具体为Ⅰ-1～Ⅰ～16所示的化合物，通式中R1-R4，n和X所指内容如Ⅰ-1～Ⅰ～16结构所示。
本发明的Naamine类衍生物I表现出很好的治疗植物病毒和病菌病活性，能很好地抑制烟草花叶病毒(TMV)和黄瓜枯萎，花生褐斑，苹果轮纹，小麦纹枯，玉米小斑，西瓜炭疽，水稻恶苗，番茄早疫，小麦赤霉，马铃薯晚疫，辣椒疫霉，油菜菌核，黄瓜灰霉，水稻纹枯14种植物病菌。
上述化合物采用如下不同方法进行制备(在每一反应过程中，参与反应的物质之间按照反应要求的摩尔比进行取料，为确保目标产物的反应进程会选择过量物质参与反应，并根据反应类型确定体系pH值，反应温度和时间，在进行制备之后进行提纯分离或者干燥，具体详见实施例记载)：
1.化合物Ⅰ-1，Ⅰ-2，Ⅰ-4和8按照下述方法制备：首先取代氨基酸1a—1d与Boc酸酐反应得物质2a—2d，与苄溴反应保护羟基得3a—3d，甲基化得4a—4d，缩合得5a—5d，再与格式试剂反应得6a—6d，脱保护得7a—7d，最后经氰胺关环得化合物Ⅰ-1，Ⅰ-2，Ⅰ-4和8，如下式所示：
2.化合物Ⅰ-3，Ⅰ-14，Naamine A及Naamidine A按照下述方法制备：将化合物Ⅰ-1，Ⅰ-2和8经钯碳氢气还原得化合物9，Ⅰ-3和Naamine A；甲基脲与草酰氯反应得关环产物10，与双三甲基硅基乙酰胺反应得11，再与化合物9和Naamine A反应得化合物Ⅰ-14和Naamidine A，如下式所示：
3.化合物Ⅰ-5～Ⅰ-8(Ⅰ-5、Ⅰ-6、Ⅰ-7、Ⅰ-8)按照下述步骤进行制备：将化合物8经酰化得化合物12，盐酸条件下脱除一个酰基得化合物13，钯碳条件下脱苄基得化合物Ⅰ-5、Ⅰ-6、Ⅰ-7、Ⅰ-8，如下式所示：
4.化合物Ⅰ-9和Ⅰ-10按照下述方法制备：化合物naamine A与相应的醛反应得化合物14，使用硼氢化钠进行还原得到化合物Ⅰ-9和Ⅰ-10，如下式所示：
5.化合物Ⅰ-11和Ⅰ-12按照下述方法制备：化合物naamine A与相应的酸反应得化合物Ⅰ-11和Ⅰ-12，如下式所示：
6.化合物Ⅰ-13按照下述方法制备：化合物naamine A与碘甲烷反应得化合物15，再进行水解后得到化合物Ⅰ-13，如下式所示：
7.化合物Ⅰ-15和Ⅰ-16按照下述方法制备：化合物naamidine A与相应的金属盐反应得化合物Ⅰ-15和Ⅰ-16，，如下式所示：
具体实施方式
下述的实施例和生测试验中使用的仪器和药品：X-4型显微熔点测定仪(北京泰克仪器有限公司)；Bruker AV400核磁共振波谱仪，以TMS为内标，CDCl3、CD3OD或DMSO-d6作溶剂；Varian 7.0T FTICR-MS高分辨质谱仪；药品购于百灵威，试剂购于天津试剂六厂。
实施例1：Naamine及Naamidine类衍生物Ⅰ-1，Ⅰ-2，Ⅰ-4和8的合成
2a：于100mL的圆底烧瓶中，依次加入1a(1.00g,4.03mmol)，水(20mL)，1,4-二氧六环(20mL)，三乙胺(1.68mL,12.1mmol)，二碳酸二叔丁酯(1.02mL,4.44mmol)，室温反应18h。脱溶，加入适量水、乙酸乙酯，以稀盐酸调pH为弱酸性，用乙酸乙酯萃取，有机相以饱和食盐水洗，有机相脱溶，加入少量甲醇，低温冰冻，析出固体，抽滤，得白色固体0.59g，收率47％。熔点106–108℃，1H NMR(400MHz,DMSO-d6)δ12.54(s,1H,COOH),8.74(s,1H,OH),7.03(d,J＝8.1Hz,1H,Ar-H),6.81(s,1H,NH),6.67–6.59(m,2H,Ar-H),4.07–3.90(m,1H,CH),3.74(s,3H,O-CH3),2.92–2.87(m,1H,CH2),2.75–2.56(m,1H,CH2),1.30(two s,9H,C-CH3).
2b～2c的合成同2a，原料为相应原料，未经提纯直接投下一步。
3a：于100mL的圆底烧瓶中，依次加入2a(0.59g,1.89mmol)，甲醇(50mL)，溴化苄(0.27mL,2.27mmol)，碳酸钾(0.60g,4.55mmol)，回流反应4h。脱溶，加入适量水，以稀盐酸调pH为弱酸性，以乙酸乙酯萃取，有机相以饱和食盐水洗，无水硫酸钠干燥，抽滤，脱溶，得淡黄色油状物0.67g，收率88％。久置固化，熔点128–130℃，1H NMR(400MHz,CDCl3)δ7.51–7.27(m,5H,Ar-H),6.81(d,J＝8.1Hz,1H,Ar-H),6.72(s,1H,Ar-H),6.65(d,J＝7.8Hz,1H,Ar-H),6.02 and 4.93(d,J＝7.3Hz,1H,NH),5.12(s,2H,O-CH2),4.55 and 4.34(s,1H,CH),3.85(s,3H,O-CH3),3.13–2.85(m,2H,CH2),1.42 and 1.32(two s,9H,C-CH3).
3b和3c的合成同3a，原料为相应原料。
3b:白色固体，三步收率53％。熔点143–145℃，1H NMR(400MHz,CDCl3)δ7.46–7.28(m,5H,Ar-H),6.81(d,J＝8.6Hz,1H,Ar-H),6.75–6.68(m,2H,Ar-H),5.84 and 4.89(twod,1H,NH),5.11(s,2H,O-CH2),4.59–4.46 and 4.35–4.25(two m,1H,CHCH2),3.85(s,3H,O-CH3),3.12–2.76(m,2H,CHCH2),1.42 and 1.35(two s,9H,C-CH3).
3c:棕色固体，三步收率23％。熔点123–125℃，1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.1Hz,2H,Ar-H),7.36–7.27(m,3H,Ar-H),6.38(s,2H,Ar-H),4.98(s,2H,O-CH2),4.94(d,J＝6.9Hz,1H,NH),4.59(s,1H,CH),3.79(s,6H,O-CH3),3.18–3.08(m,1H,CH2),3.05–2.96(m,1H,CH2),1.43 and 1.35(two s,9H,C-CH3).
3d:于2000mL的圆底烧瓶中依次加入L-酪氨酸(30.00g,0.17mol)，水(300mL)，1,4-二氧六环(300mL)，三乙胺(35mL,248.40mmol)，冰浴条件下，加入二碳酸二叔丁酯(41.70mL,182.40mmol)，搅拌30min后，室温反应18h。脱溶，固体以水、乙酸乙酯稀释，用稀盐酸调pH＝1，用适量乙酸乙酯萃取，有机相以饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，脱溶，得浅黄色透明油状物，包加部分Boc酸酐，未经提纯直接进行下一步。
于2000mL的圆底烧瓶中，加入上步生成的N-Boc-L-酪氨酸(理论0.16mol)，N,N-二甲基甲酰胺(890mL)，碳酸钾(114g,0.83mol)，四丁基碘化铵(7.6g,0.02mol)，溴化苄(59mL,0.49mol)，室温反应48h。加入水(900mL)，以乙酸乙酯(600mL*3)萃取。合并有机相，以无水硫酸钠干燥，抽滤，脱溶，直接投下一步。
于2000mL的圆底烧瓶中，加入上步生成的N-Boc-O-benzyl-L-tyrosine benzylester(理论0.16mol)，(500mL)，1,4-二氧六环(500mL)，加入氢氧化钠(22.00g,0.55mol)，室温搅拌24h。部分脱溶除去1,4-二氧六环，以适量乙醚洗，水相以稀盐酸调酸性，以乙酸乙酯萃取3次。合并有机相，以无水硫酸钠干燥，抽滤脱溶，得黄色油状物，以乙醇，石油醚重结晶得白色固体63.25g，理论61.55g，有部分溶剂包加，三步收率大于99％。1H NMR(400MHz,CDCl3)δ7.45–7.28(m,5H,Ar-H),7.10(d,J＝8.3Hz,2H,Ar-H),6.91(d,J＝8.4Hz,2H,Ar-H),6.11 and 4.92(two d,J＝6.6Hz,1H,NH),5.03(s,2H,O-CH2),4.57 and 4.36(two d,J＝5.4Hz,1H,CHCH2),3.06(m,2H,CHCH2),1.37(d,J＝38.4Hz,9H,CCH3).
4d:氩气保护下，于100mL的圆底烧瓶中，加入3d(3.72g,10.02mmol)，无水四氢呋喃(30mL)，冰浴下，缓慢加入70％含量的氢化钠(1.13g,30.06mmol)，再加入碘甲烷(5.00mL,20.04mmol)，室温搅拌24h。加入水(100mL)，以乙醚洗，水相以稀盐酸调酸性，部分脱溶，除去四氢呋喃，以乙酸乙酯(50mL*3)萃取，合并有机相，以硫代硫酸钠溶液，饱和碳酸氢钠溶液，饱和氯化钠溶液洗，无水硫酸钠干燥，抽滤，脱溶，得白色固体3.78g，收率98％。熔点126–127℃，1H NMR(400MHz,CDCl3)δ7.47–7.29(m,5H,Ar-H),7.14–7.08(m,2H,Ar-H),6.91(d,J＝8.0Hz,2H,Ar-H),5.04(s,2H,O-CH2),4.71–4.66 and 4.60–4.53(two m,1H,CHCH2),3.33–3.17(m,1H,CHCH2),3.16–2.92(m,1H,CHCH2),2.75 and 2.67(two s,3H,N-CH3),1.41 and 1.35(two s,9H,C-CH3).
4a、4b和4c的合成同4d，原料为相应原料。
4a，淡黄色液体，收率88％。1H NMR(400MHz,CDCl3)δ7.47–7.27(m,5H,Ar-H),6.83–6.62(m,3H,Ar-H),5.12(s,2H,O-CH2),4.73 and 4.52(two d,J＝5.9Hz,1H,CH),3.87(s,3H,O-CH3),3.26–3.19(m,1H,CH2),3.12–2.92(m,1H,CH2),2.74 and 2.37(two s,3H,N-CH3),1.41 and 1.33(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ176.3,156.3,155.1,149.6,146.9,137.2,130.6,130.3,128.5,127.8,127.3,121.1,121.0,114.2,112.7,112.5,80.7,80.6,71.1,61.8,60.3,56.0,34.8,34.3,32.8,28.3,28.2.HRMS(ESI)calcdfor C23H29NNaO6 +[M+Na]+438.1887,found 438.1880.
4b，棕色液体，收率76％。1H NMR(400MHz,CDCl3)δ7.44–7.27(m,5H,Ar-H),6.83–6.67(m,3H,Ar-H),5.11(s,2H,O-CH2),4.72–4.66 and 4.45–4.35(two m,1H,CHCH2),3.84(s,3H,O-CH3),3.25–3.10(m,1H,CHCH2),3.04–2.84(m,1H,CHCH2),2.64 and 2.57(two s,3H,N-CH3),1.39 and 1.33(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ176.4,156.4,155.0,148.6,148.5,148.0,137.2,137.1,130.0,129.6,127.9,127.4,127.4,121.8,121.7,115.1,114.8,112.1,111.9,80.7,77.31,71.2,71.0,61.8,60.6,60.5,56.1,34.8,34.2,33.0,14.2.HRMS(ESI)calcd for C23H29NNaO6 +[M+Na]+438.1887,found 438.1883.
4c，棕色液体，收率79％。1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.0Hz,2H,Ar-H),7.36–7.27(m,3H,Ar-H),6.42 and 6.37(two s,2H,Ar-H),4.98(s,2H,O-CH2),4.80–4.70and 4.55–4.45(two m,1H,CH),3.80(s,6H,O-CH3),3.33–3.17(m,1H,CH2),3.15–2.95(m,1H,CH2),2.73 and 2.67(two s,3H,N-CH3),1.43 and 1.36(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ176.0,156.2,154.9,153.5,153.4,137.8,137.7,135.7,135.5,133.3,132.9,130.2,128.5,128.1,127.8,106.0,105.8,80.7,75.0,61.8,60.3,56.1,35.5,34.9,33.1,33.0,28.3,28.2.HRMS(ESI)calcd for C24H31NNaO7 +[M+Na]+468.1993,found468.1989.
5d:于500mL的反应瓶中，依次加入4d(28.95g,0.75mol)，二氯甲烷(200mL)，二异丙基乙基胺(40.40mL,232.87mmol)，1-羟基苯并三唑(11.15g,82.63mmol)，加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(15.80g,82.63mmol)，加入N,O-二甲基羟胺盐酸盐(8.03g,82.63mmol)，室温搅拌12h。以稀盐酸调弱酸性，有固体析出，抽滤，滤液以适量二氯甲烷萃取，合并有机相，以饱和氯化钠溶液洗，无水硫酸钠干燥，抽滤，脱溶，柱层析分离(PE：EA＝10:1 to PE：EA＝1:1)，得27.24g淡黄色油状物，收率85％。1H NMR(400MHz,CDCl3)δ7.43–7.30(m,5H,Ar-H),7.16 and 7.08(two d,J＝8.2Hz,2H,Ar-H),6.93–6.85(m,2H,Ar-H),5.50 and 5.12(two s,1H,CHCH2),5.03(s,2H,O-CH2),3.63 and 3.60(two s,3H,O-CH3),3.19 and 3.16(two s,3H,N-CH3),3.10–2.89(m,2H,CHCH2),2.84(s,3H,N-CH3),1.36and 1.25(two s,9H,CCH3).
5a、5b和5c的合成同5d，原料为相应原料。
5a黄色液体，收率73％。1H NMR(400MHz,CDCl3)δ7.45–7.28(m,5H,Ar-H),6.83–6.61(m,3H,Ar-H),5.52 and 5.09(two s,1H,CH),5.12(s,2H,O-CH2),3.87(s,3H,O-CH3),3.62 and 3.59(two s,3H,O-CH3),3.18 and 3.15(two s,3H,N-CH3),3.15–2.86(m,2H,CH2),2.84(s,3H,N-CH3),1.37 and 1.24(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ155.6,154.9,149.5,149.4,146.8,146.7,137.3,131.2,130.6,128.5,127.7,127.2,121.3,114.2,114.1,113.1,112.9,79.7,71.1,61.3,60.4,57.3,55.9,54.4,34.5,32.3,30.2,29.9,28.3,28.1,21.0,14.2.HRMS(ESI)calcd for C25H35N2O6 +[M+H]+459.2490,found459.2498.
5b，黄色液体，收率80％。1H NMR(400MHz,CDCl3)δ7.50–7.28(m,5H,Ar-H),6.87–6.70(m,3H,Ar-H),5.49 and 5.06(two s,1H,CHCH2),5.12(s,2H,O-CH2),3.85(s,3H,O-CH3),3.62 and 3.57(two s,3H,O-CH3),3.17 and 3.14(two s,3H,N-CH3),3.11–2.81(m,2H,CHCH2),2.79 and 2.78(two s,3H,N-CH3),1.38 and 1.28(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ155.7,155.0,148.5,148.3,148.2,148.0,137.3,137.2,130.6,129.9,128.6,127.8,127.4,127.3,122.1,122.0,115.4,115.1,112.1,111.9,79.8,79.7,77.3,71.1,71.0,61.6,61.3,57.4,56.2,56.1,54.5,34.5,32.4,32.1,30.2,30.0,28.3,28.2.HRMS(ESI)calcd for C25H35N2O6 +[M+H]+459.2490,found 459.2490.
5c，棕色液体，收率67％。1H NMR(400MHz,CDCl3)δ7.53–7.45(m,2H,Ar-H),7.38–7.28(m,3H,Ar-H),6.46 and 6.37(two s,2H,Ar-H),5.57 and 5.12(two s,1H,CH),4.96(s,2H,O-CH2),3.80(s,6H,O-CH3),3.63 and 3.60(two s,3H,O-CH3),3.20 and 3.16(twos,3H,N-CH3),3.14–3.07(m,1H,CH2),2.96–2.88(m,1H,CH2),2.85 and 2.84(two s,3H,N-CH3),1.39 and 1.27(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ155.6,154.9,153.4,153.2,137.9,137.8,135.6,135.4,134.0,133.1,128.5,128.1,128.1,127.8,127.7,106.3,106.1,79.8,75.0,75.0,61.5,61.3,60.8,60.4,57.4,56.1,56.0,53.9,35.3,32.3,32.0,30.2,30.0,28.3,28.15,21.0,14.2.HRMS(ESI)calcd for C26H37N2O7 +[M+H]+489.2595,found 489.2603.
6d:氩气保护下，于1000mL的圆底烧瓶中，加入镁(0.54g,22.50mmol)，加入无水四氢呋喃(20mL)，4-甲氧基苄氯(1.8mL,13.58mmol)溶于无水四氢呋喃(10mL)和无水乙醚(5mL)中，冰浴下，以恒压滴液漏斗滴加到反应瓶中，滴毕，室温反应1h。5d(2.91g,6.79mmol)溶解到无水四氢呋喃(50mL)中，冰浴下，以恒压滴液漏斗加入到反应瓶中，滴毕，室温反应3h。反应瓶中加入饱和氯化铵水溶液(30mL)，水(20mL)，用乙醚(50mL*3)萃取。合并有机相，以饱和氯化钠溶液(75mL)洗，无水硫酸钠干燥，抽滤，脱溶。柱层析(DCM to PE:EA＝2:1)得浅色透明液体3.06g，收率92％。1H NMR(400MHz,CDCl3,exists as a 1:1mixture of two rotamers)δ7.45–7.27(m,5H,Ar-H),7.10–6.98(m,4H,Ar-H),6.89–6.79(m,4H,Ar-H),5.02(s,2H,O-CH2),4.76–4.70 and 4.35–4.25(two m,1H,CH),3.78 and3.79(two s,3H,O-CH3),3.73–3.61(m,2H,CH2CO),3.15–3.07(m,1H,CHCH2),2.87–2.75(m,1H,CHCH2),2.58 and 2.52(two s,3H,N-CH3),1.43 and 1.34(two s,9H,CCH3).
6a、6b和6c的合成同6d，原料为相应原料。
6a:淡黄色液体，收率85％。1H NMR(400MHz,CDCl3)δ7.45–7.28(m,5H,Ar-H),7.12–7.04(m,2H,Ar-H),6.88–6.80(m,2H,Ar-H),6.77–6.74(m,1H,Ar-H),6.68–6.52(m,2H,Ar-H),5.11(s,2H,O-CH2),4.78–4.70 and 4.30–4.20(two m,1H,CH),3.83(s,3H,O-CH3),3.79and 3.78(two s,3H,O-CH3),3.74–3.61(m,2H,C-CH2),3.19–3.01(m,1H,CH2),2.85–2.76(m,1H,CH2),2.58 and 2.51(two s,3H,N-CH3),1.43 and 1.34(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ206.0,205.9,158.7,158.6,155.8,154.9,149.6,149.5,146.8,146.6,137.3,137.2,131.2,130.8,130.5,130.5,128.5,127.8,127.3,127.3,125.8,125.7,121.2,121.1,114.3,114.2,114.1,114.0,112.8,112.7,80.8,80.3,71.1,66.8,65.9,64.4,56.0,55.9,55.3,55.2,46.2,45.7,33.4,32.9,32.3,28.4,28.2.HRMS(ESI)calcdfor C31H37NNaO6 +[M+Na]+542.2513,found 542.2515.
6b:淡黄色液体，收率91％。1H NMR(400MHz,CDCl3)δ7.48–7.27(m,5H,Ar-H),7.07(dd,J＝8.5,3.1Hz,2H,Ar-H),6.91–6.73(m,3H,Ar-H),6.71–6.58(m,2H,Ar-H),5.15–5.01(m,2H,O-CH2),4.70–4.60 and 4.19–4.09(two m,1H,CHCH2),3.84(s,3H,O-CH3),3.79–3.76(m,3H,O-CH3),3.73–3.58(m,2H,CO-CH2),3.14–3.00(m,1H,CHCH2),2.83–2.70(m,1H,CHCH2),2.48 and 2.43(two s,3H,N-CH3),1.44 and 1.36(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ205.9,158.7,154.8,148.5,148.1,137.1,130.5,130.5,130.1,128.6,127.8,127.4,127.3,125.8,125.7,121.9,115.2,115.0,114.2,114.0,112.0,111.9,80.9,80.3,71.0,70.9,67.0,64.5,56.1,55.3,46.2,45.7,33.4,32.8,32.3,28.4,28.3.HRMS(ESI)calcd for C31H37NNaO6 +[M+Na]+542.2513,found 542.2517.
6c:淡黄色液体，收率85％。1H NMR(400MHz,CDCl3)δ7.46(d,J＝7.4Hz,2H,Ar-H),7.35–7.26(m,3H,Ar-H),7.16–7.05(m,2H,Ar-H),6.92–6.81(m,2H,Ar-H),6.33 and 6.26(two s,2H,Ar-H),4.96(s,2H,O-CH2),4.76–4.70 and 4.25–4.15(two m,1H,CH),3.79and 3.78(two s,3H,O-CH3),3.76(s,6H,O-CH3),3.74–3.61(m,2H,CO-CH2),3.17–3.05(m,1H,CHCH2),2.89–2.72(m,1H,CHCH2),2.56 and 2.51(two s,3H,N-CH3),1.46 and 1.37(two s,9H,C-CH3).13C NMR(100MHz,CDCl3)δ205.9,205.8,158.8,158.6,155.8,154.8,153.6,153.4,138.0,137.8,135.5,135.4,134.0,133.5,130.6,130.5,128.6,128.6,128.2,127.9,127.8,125.8,125.7,114.2,114.1,113.9,113.6,106.1,106.1,80.9,80.4,75.0,67.0,64.9,64.3,56.2,56.1,56.0,55.3,55.3,55.2,46.2,45.7,34.2,33.7,28.4,28.3.HRMS(ESI)calcd for C32H39NNaO7 +[M+Na]+572.2619,found 572.2614.
8:于100mL的圆底烧瓶中，加入乙醚(11.4mL)，加入乙醇(8.7mL)，零下30℃，以恒压滴液漏斗滴加乙酰氯(7.9mL)，滴毕，室温反应10min。加入6d(0.70g,1.43mmol)，室温搅拌1h后，脱溶，加入适量乙醚，析出白色固体，抽滤得白色固体(0.51g,1.19mmol)，直接投下一步反应。白色固体(0.51g,1.19mmol)于100mL圆底烧瓶中，加入水(30mL)，加入氰胺(0.06g,1.32mmol)，加热至90℃，反应1h，冷却，析出固体，抽滤，晾干得0.41g白色固体，收率70％。熔点120–122℃，1H NMR(400MHz,CDCl3)δ7.43–7.30(m,5H,Ar-H),7.16(d,J＝8.3Hz,2H,Ar-H),6.98(d,J＝8.3Hz,2H,Ar-H),6.87(d,J＝8.4Hz,2H,Ar-H),6.79(d,J＝8.4Hz,2H,Ar-H),5.03(s,2H,O-CH2),3.85(s,2H,NH2),3.81(s,2H,CH2),3.75(s,3H,O-CH3),3.74(s,2H,CH2),3.07(s,3H,N-CH3).
目标化合物I-1、I-2和I-4的合成同8，原料为相应原料。
I-1:棕色固体，收率73％。分解温度95℃，1H NMR(400MHz,CDCl3)δ7.44–7.29(m,5H,Ar-H),7.18(d,J＝8.4Hz,2H,Ar-H),6.79–6.76(m,3H,Ar-H),6.55–6.48(m,2H,Ar-H),5.64(s,2H,NH2),5.12(s,2H,O-CH2),3.80(s,2H,CH2),3.77(s,2H,CH2),3.75(s,3H,O-CH3),3.71(s,3H,O-CH3),3.08(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ157.8,149.9,147.0,146.8,137.2,132.9,132.1,131.8,129.4,128.5,127.8,127.3,120.8,119.8,114.1,113.8,111.6,71.1,55.9,55.2,32.1,29.2,29.1.HRMS(ESI)calcd for C27H30N3O3 +[M+H]+444.2282,found 444.2289.
I-2:棕色固体，收率88％。熔点56–58℃，1H NMR(400MHz,CDCl3)δ7.35–7.24(m,5H,Ar-H),7.19(d,J＝8.4Hz,2H,Ar-H),6.85–6.75(m,3H,Ar-H),6.64(d,J＝7.8Hz,1H,Ar-H),6.40(s,1H,Ar-H),5.11(brs,2H,NH2),4.93(s,2H,O-CH2),3.86(s,3H,O-CH3),3.74(s,2H,CH2),3.73(s,2H,CH2),3.71(s,3H,O-CH3),2.87(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ158.0,148.3,148.1,146.9,137.1,132.8,131.6,130.9,129.6,129.6,128.6,127.8,127.4,120.8,120.4,113.9,111.9,70.6,56.1,55.2,32.0,29.1,28.9.HRMS(ESI)calcdfor C27H30N3O3 +[M+H]+444.2282,found 444.2291.
I-4:棕色固体，收率77％。熔点90–92℃，1H NMR(400MHz,CDCl3)δ7.46(d,J＝7.0Hz,2H,Ar-H),7.36–7.27(m,3H,Ar-H),7.19(d,J＝8.3Hz,2H,Ar-H),6.78(d,J＝8.3Hz,2H,Ar-H),6.22(s,2H,Ar-H),4.96(s,2H,O-CH2),4.69(brs,2H,NH2),3.81(s,2H,CH2),3.76(s,2H,CH2),3.75(s,3H,O-CH3),3.67(s,6H,O-CH3),3.07(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ158.0,153.7,147.0,137.8,135.5,134.2,132.5,129.5,128.5,128.1,127.8,120.6,113.9,104.9,75.0,56.1,55.3,31.9,29.8,29.3.HRMS(ESI)calcd for C28H32N3O4 +[M+H]+474.2387,found 474.2389.
实施例2：Naamine类衍生物Ⅰ-3和Ⅰ-14的合成
Naamine A:于1000mL的圆底烧瓶中，加入8(4.32g,10.45mmol)，加入甲醇(400mL)，加入钯碳(10％wt)(0.56g,0.13wt)，加入醋酸(4mL)，通入氢气，室温搅拌24h。抽滤，脱溶，得油状物，加入少量丙酮，析出灰白色固体，抽滤得2.95g。收率87％。熔点202–204℃，1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.6Hz,2H,Ar-H),6.85(d,J＝8.4Hz,2H,Ar-H),6.77(d,J＝8.6Hz,2H,Ar-H),6.65(d,J＝8.4Hz,2H,Ar-H),3.78(s,2H,CH2),3.73(s,3H,O-CH3),3.71(s,2H,CH2),3.09(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ160.0,157.5,148.4,131.5,130.5,130.2,129.0,125.2,123.8,116.6,115.1,55.7,30.2,29.8,28.5.HRMS(ESI)calcdfor C19H22N3O2 +[M+H]+324.1707,found 324.1707.
目标化合物9和I-3的合成同Naamine，原料为相应原料。
9:砖红色固体，收率95％。熔点163–165℃，1H NMR(400MHz,CD3OD)δ7.14(d,J＝8.5Hz,2H,Ar-H),6.77(d,J＝8.5Hz,2H,Ar-H),6.66(d,J＝8.0Hz,1H,Ar-H),6.53(dd,J＝8.0,1.4Hz,1H,Ar-H),6.45(d,J＝1.4Hz,1H,Ar-H),3.80(s,2H,CH2),3.73(s,3H,O-CH3),3.72(s,2H,CH2),3.58(s,3H,O-CH3),3.09(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ159.4,149.7,149.2,146.1,134.7,132.7,131.8,130.5,122.6,121.6,116.1,114.7,112.6,56.2,55.7,32.8,29.7,29.5.HRMS(ESI)calcd for C20H24N3O3 +[M+H]+354.1812,found 354.1818.
I-3，棕色固体，收率99％。熔点80–82℃，1H NMR(400MHz,CD3OD)δ7.13(d,J＝8.5Hz,2H,Ar-H),6.88–6.83(m,3H,Ar-H),6.61–6.58(m,2H,Ar-H),3.88(s,2H,CH2),3.84(s,2H,CH2),3.82(s,3H,O-CH3),3.75(s,3H,O-CH3),3.20(s,3H,N-CH3).13C NMR(100MHz,CD3OD)δ160.2,148.2,148.1,147.8,130.8,130.8,130.6,124.0,123.8,120.3,116.1,115.3,113.1,56.5,55.8,30.1,29.8,28.5.HRMS(ESI)calcd for C20H24N3O3 +[M+H]+354.1812,found 354.1818.
10:氩气保护下，于250mL的圆底烧瓶中，加入N-甲基脲(2.96g,0.04mol)，加入乙醚(100mL)，加入草酰氯(3.3mL,0.04mol)，加热回流2h。脱溶，加入少量二氯甲烷洗，抽滤，得白色固体2.87g，收率59％。熔点147–149℃，1H NMR(400MHz,DMSO-d6)δ11.99(s,1H,NH),2.92(s,3H,N-CH3).
Naamidine A:氩气保护下，于100mL四口瓶中，加入10(1.28g,10mol)，加入乙腈(3mL)，加入N,O-双三甲基硅基乙酰胺(2.52g,12.4mmol)，加热回流45min。脱溶，加入甲苯(16mL)，加入Naamine A(0.65g,2mmol)，氩气保护下，回流18h。加入乙酸乙酯(180mL)，分别以水、饱和氯化钠溶液洗，有机相以无水硫酸钠干燥，抽滤脱溶，以少量二氯甲烷溶解，湿法上样，柱层析(Toluene:MeOH＝85:15,加1％三乙胺)。有机相脱溶，以适量二氯甲烷溶解，以稀盐酸、饱和氯化钠洗，无水硫酸钠干燥，抽滤，脱溶，得黄色粉末状固体0.74g，收率85％。熔点188–190℃，1H NMR(400MHz,CDCl3)δ7.11(d,J＝8.5Hz,2H,Ar-H),6.85–6.79(m,4H,Ar-H),6.74(d,J＝8.4Hz,2H,Ar-H),3.88(s,2H,CH2),3.87(s,2H,CH2),3.77(s,3H,O-CH3),3.37(s,3H,N-CH3),3.17(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ163.5,158.3,157.7,155.2,148.5,146.4,133.7,130.9,129.3,129.0,128.1,126.8,115.8,114.1,55.3,31.7,29.7,28.6,24.8.HRMS(ESI)calcd for C23H24N5O4 +[M+H]+434.1823,found 434.1826.
目标化合物I-14的合成同Naamidine A，原料为相应原料。
I-14，黄色固体，收率54％。熔点162–164℃，1H NMR(400MHz,CDCl3)δ7.14(d,J＝8.6Hz,2H,Ar-H),6.84–6.77(m,3H,Ar-H),6.54(dd,J＝8.1,1.8Hz,1H,Ar-H),6.34(d,J＝1.8Hz,1H,Ar-H),3.90(s,4H,CH2),3.77(s,3H,O-CH3),3.65(s,3H,O-CH3),3.49(s,3H,N-CH3),3.18(s,3H,N-CH3).13C NMR(100MHz,CDCl3)δ162.2,158.2,155.4,146.8,146.4,144.6,144.5,135.8,131.6,129.3,128.8,126.9,120.7,114.5,114.0,110.2,55.8,55.3,32.2,30.0,29.2,24.7.HRMS(ESI)calcd for C24H26N5O5 +[M+H]+464.1928,found 464.1932.
实施例3：Naamine类衍生物Ⅰ-5～Ⅰ-8的合成
I-5：于250mL的圆底烧瓶中，加入8(2.0g,4.84mmol)，加入二氯甲烷(120mL)，加入三乙胺(1.34mL,9.68mmol)，特戊酰氯(1.2mL,9.68mmol)溶于二氯甲烷(10mL)，以恒压滴液漏斗滴加到反应瓶中，20min后，TLC监测反应完全，反应液加入浓盐酸，搅拌20min，分液，有机相以饱和碳酸氢钠溶液，饱和氯化钠溶液洗，以无水硫酸钠干燥，抽滤，脱溶，得黄色油状物，直接投下一步，加入100mL甲醇，加入钯碳(10％wt)(0.3g,0.13wt)，通入氢气，室温搅拌24h。抽滤，脱溶，得暗白色固体1.91g，三步收率97％。熔点161–163℃，1H NMR(400MHz,CDCl3)δ13.41(s,1H),11.03(s,1H),7.13(d,J＝8.1Hz,2H,Ar-H),6.85–6.77(m,6H,Ar-H),3.90(s,2H,CH2),3.86(s,2H,CH2),3.76(s,3H,O-CH3),3.38(s,3H,N-CH3),1.37(s,9H,CCH3).13C NMR(100MHz,DMSO-d6)δ178.2,158.1,156.2,136.3,129.7,129.5,129.0,127.4,127.0,126.3,115.5,114.0,55.1,31.5,28.0,26.8,26.6.HRMS(ESI)calcd for C24H30N3O3 +[M+H]+408.2282,found 408.2282.
Ⅰ-6～Ⅰ-8的合成同Ⅰ-5。
Ⅰ-6：暗白色固体，收率：87％。熔点162–164℃，1H NMR(400MHz,CDCl3)δ7.09(d,J＝8.5Hz,2H,Ar-H),6.85–6.77(m,4H,Ar-H),6.63(d,J＝8.3Hz,2H,Ar-H),3.85(s,2H,CH2),3.79(s,2H,CH2),3.76(s,3H,O-CH3),3.13(s,3H,N-CH3),2.39(t,J＝7.5Hz,2H,COCH2),1.68–1.59(m,2H,CH2),1.30–1.25(m,4H,CH2CH2),0.84(t,J＝6.6Hz,3H,CH3).13C NMR(100MHz,CDCl3)δ158.3,156.0,130.5,129.4,128.7,127.7,123.1,115.9,114.1,55.2,37.7,31.5,30.8,30.0,28.2,25.6,22.5,14.0.HRMS(ESI)calcd for C25H32N3O3 +[M+H]+422.2438,found 422.2440.
Ⅰ-7：灰白色固体，收率68％。熔点172–174℃，1H NMR(400MHz,CDCl3)δ9.57(s,1H,NH),7.84(d,J＝7.3Hz,2H,Ar-H),7.48–7.35(m,3H,Ar-H),7.03(d,J＝8.6Hz,2H,Ar-H),6.91(d,J＝8.5Hz,2H,Ar-H),6.85(d,J＝8.6Hz,2H,Ar-H),6.78(d,J＝8.6Hz,2H,Ar-H),3.81(s,3H,O-CH3),3.76(s,4H,CH2),3.07(s,3H,N-CH3).13C NMR(100MHz,DMSO-d6)δ157.7,156.0,145.2,144.8,131.3,130.9,129.1,128.9,128.5,127.3,125.5,121.5,121.4,115.3,113.7,55.0,28.7,27.8,27.0.HRMS(ESI)calcd for C25H26N3O4S+[M+H]+464.1639,found 464.1632.
Ⅰ-8：柱层析(PE:EA＝2:1 to 1:4)。黄白色固体，收率59％。熔点153–154℃，1HNMR(400MHz,CDCl3)δ10.47(s,1H),7.08(d,J＝8.0Hz,2H,Ar-H),6.91(d,J＝7.9Hz,2H,Ar-H),6.84(d,J＝8.0Hz,2H,Ar-H),6.80(d,J＝7.9Hz,2H,Ar-H),3.80(s,4H,CH2),3.79(s,3H,O-CH3),3.15(s,3H,N-CH3),3.02(s,3H,S-CH3).13C NMR(100MHz,CDCl3)δ158.7,155.4,145.5,129.3,128.9,128.8,127.5,121.7,121.2,116.0,114.4,100.0,55.4,42.4,29.3,28.0.HRMS(ESI)calcd for C20H24N3O4S+[M+H]+402.1482,found 402.1481.
实施例4：Naamine类衍生物Ⅰ-9和Ⅰ-10的合成
I-9：于250mL圆底烧瓶中，加入Naamine A(1.00g,3.00mmol)，加入乙醇(120mL)，滴加几滴醋酸，加入苯甲醛(1.2mL,12.36mmol)，加热回流12h。脱溶部分溶剂，抽滤，得淡黄色滤饼(0.58g,1.41mmol)，黄色滤饼加入到250mL圆底烧瓶中，加入乙醇(100mL)，加入硼氢化钠(0.25g,6.5mmol)，加热至65℃，反应2h。TLC监测不再变化，加入少量水淬灭反应，以乙醇作淋洗剂，柱层析。脱溶后以丙酮重结晶，得0.2g白色固体，两步收率16％。分解温度226℃，1H NMR(400MHz,DMSO-d6)δ9.18(s,1H,OH),7.37(d,J＝7.6Hz,2H,Ar-H),7.33–7.19(m,3H,Ar-H),7.12(d,J＝8.2Hz,2H,Ar-H),6.84(d,J＝7.9Hz,2H,Ar-H),6.77(d,J＝8.2Hz,2H,Ar-H),6.62(d,J＝7.9Hz,2H,Ar-H),5.88(t,J＝5.8Hz,1H,NH CH2),4.32(d,J＝5.8Hz,2H,NHCH2),3.71(s,2H,CH2),3.69(s,3H,O-CH3),3.63(s,2H,CH2),3.03(s,3H,N-CH3).13CNMR(101MHz,DMSO-d6)δ157.1,155.5,148.8,140.7,133.8,131.5,129.7,129.3,128.8,128.0,127.7,126.5,120.6,115.1,113.3,54.9,46.5,31.9,28.6,27.8.HRMS(ESI)calcdfor C26H28N3O2 +[M+H]+414.2176,found414.2167.
I-10：合成同I-9，反应完毕脱溶，加入丙酮，抽滤得灰白色滤饼，收率60％。熔点226–228℃，1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),7.12(d,J＝7.9Hz,2H,Ar-H),6.83(d,J＝7.8Hz,2H,Ar-H),6.77(d,J＝7.9Hz,2H,Ar-H),6.61(d,J＝7.8Hz,2H,Ar-H),5.02(t,J＝6.1Hz,1H,NH),3.69(s,5H,O-CH3 and CH2),3.62(s,2H,CH2),3.02(s,3H,N-CH3),2.96(d,J＝6.1Hz,2H,NHCH2),0.88(s,9H,CCH3).13C NMR(100MHz,DMSO-d6)δ157.1,155.4,149.5,133.8,131.2,129.8,129.2,128.8,120.4,115.0,113.3,54.9,54.3,31.8,31.8,28.6,27.8,27.4.HRMS(ESI)calcd for C24H32N3O2 +[M+H]+394.2489,found 394.2483.
实施例5：Naamine类衍生物Ⅰ-11和Ⅰ-12的合成
I-11：于250mL圆底烧瓶中，依次加入Naamine(0.35g,1.08mmol)，甲醇(100mL)，三氟乙酸(0.16mL,2.16mmol)，50℃反应2h，脱溶，得泡沫状灰色固体0.46g，收率98％。熔点123–125℃，1H NMR(400MHz,DMSO-d6)δ12.21(s,1H,OH),9.36(s,1H,NH),7.47(s,2H,NH2),7.14(d,J＝8.5Hz,2H,Ar-H),6.92(d,J＝8.3Hz,2H,Ar-H),6.86(d,J＝8.5Hz,2H,Ar-H),6.68(d,J＝8.3Hz,2H,Ar-H),3.87(s,2H,CH2),3.81(s,2H,CH2),3.72(s,3H,O-CH3),3.15(s,3H,N-CH3).13C NMR(101MHz,DMSO-d6)δ158.8(q,J＝32.7Hz),158.0,156.1,146.2,130.1,129.3,129.0,127.1,122.2,121.7,118.2,115.4,113.9,55.0,29.3,28.0,26.6.
I-12：-30℃于250mL圆底烧瓶中，加入乙醇(5mL)，缓慢加入乙酰氯(0.33mL,4.64mmol)，搅拌5min，室温搅拌10min，Naamine(0.5g,1.54mmol)溶于乙醇(100mL)，加入到反应瓶中，50℃反应2h，脱溶，得泡沫状白色固体0.54g，收率98％。熔点45–47℃，1H NMR(400MHz,DMSO-d6)δ12.14(s,1H,OH),9.37(s,1H,NH),7.47(s,2H,NH2),7.15(d,J＝8.7Hz,2H,Ar-H),6.91(d,J＝8.5Hz,2H,Ar-H),6.86(d,J＝8.7Hz,2H,Ar-H),6.69(d,J＝8.5Hz,2H,Ar-H),3.86(s,2H,CH2),3.81(s,2H,CH2),3.72(s,3H,O-CH3),3.15(s,3H,N-CH3).13CNMR(101MHz,DMSO-d6)δ157.9,156.1,146.1,130.2,129.4,128.9,127.1,122.2,121.7,115.4,113.9,55.1,29.5,27.9,26.6.
实施例6：Naamine类衍生物Ⅰ-13的合成
I-13：氩气保护下，于250mL圆底烧瓶中，依次加入Naamine(0.50g,1.54mmol)，无水四氢呋喃(100mL)，冰浴下加入70％含量的氢化钠(0.42g,12.36mmol)，碘甲烷(0.77mL,12.36mmol)。70℃反应24h。加入少量水淬灭反应，脱溶，以稀盐酸调pH为酸性，以二氯甲烷萃取，有机相分别以饱和碳酸氢钠溶液、饱和氯化钠溶液洗，以无水硫酸钠干燥，抽滤。以二氯甲烷上样，柱层析(EA)。脱溶，以甲醇重结晶，得白色固体0.37g，收率68％。熔点157–159℃，1H NMR(400MHz,DMSO-d6)δ7.08(d,J＝8.6Hz,4H,Ar-H),6.86(d,J＝8.6Hz,4H,Ar-H),3.84(s,4H,CH2),3.72(s,6H,O-CH3),2.89(s,6H,N-CH3).13C NMR(100MHz,CDCl3)δ158.4,153.8,129.9,128.8,117.5,114.1,55.3,28.3,27.8.HRMS(ESI)calcd for C21H25N2O3 +[M+H]+353.1860,found 353.1879.
实施例7：Naamine类衍生物Ⅰ-15和Ⅰ-16的合成
I-16：于500mL的圆底烧瓶中，加入Naamidine A(0.50g,1.15mmol)，加入二氯甲烷(100mL)，七水硫酸锌(19.9g,69mmol)溶于水(200mL)，加入到反应瓶中，室温搅拌3h，抽滤，晾干，得黄色固体0.20g，收率38％。熔点185–187℃，1H NMR(400MHz,DMSO-d6)δ9.30(s,2H,OH),6.95(d,J＝8.2Hz,4H,Ar-H),6.69(d,J＝8.2Hz,4H,Ar-H),6.50(s,8H,Ar-H),4.04–3.90(m,4H,CH2),3.82(d,J＝16.7Hz,2H,CH2),3.62(s,6H,O-CH3),3.57(s,6H,N-CH3),3.26(d,J＝16.7Hz,2H,CH2),2.80(s,6H,N-CH3).13C NMR(101MHz,DMSO-d6)δ163.7,160.5,157.3,155.9,153.2,146.8,132.0,129.9,129.0,128.4,128.3,127.7,115.4,113.0,54.7,30.2,29.9,27.4,24.0.HRMS(ESI)calcd for C46H45N10O8Zn+[M+H]+929.2708,found929.2709.
化合物I-15由Naamidine A与五水硫酸铜反应，合成方法同I-16。黑色固体，收率75％。熔点大于300℃，HRMS(ESI)calcd for C46H45N10O8Cu+[M+H]+928.2712,found928.2712.
实施例8：抗烟草花叶病毒活性的测定，测定程序如下：
1、病毒提纯及浓度测定：
病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。病毒粗提液经2次聚乙二醇离心处理后，测定浓度，4℃冷藏备用。
2、化合物溶液配制：
称量后，原药加入DMF溶解，制得1×105μg/mL母液，后用含1wt‰吐温80水溶液稀释至所需浓度；宁南霉素制剂直接兑水稀释。
3、离体作用：
摩擦接种珊西烟适龄叶片，用流水冲洗，病毒浓度10μg/mL。收干后剪下，沿叶中脉对剖，左右半叶分别浸于1‰吐温水及药剂中，30min后取出，于适宜光照温度下保湿培养，每3片叶为1次重复，重复3次。3d后记录病斑数，计算防效。
4、活体保护作用：
选长势均匀一致的3–5叶期珊西烟，全株喷雾施药，每处理3次重复，并设1‰吐温80水溶液对照。24h后，叶面撒布金刚砂(500目)，用毛笔蘸取病毒液，在全叶面沿支脉方向轻擦2次，叶片下方用手掌支撑，病毒浓度10μg/mL，接种后用流水冲洗。3d后记录病斑数，计算防效。
5、活体治疗作用：
选长势均匀一致的3–5叶期珊西烟，用毛笔全叶接种病毒，病毒浓度为10μg/mL，接种后用流水冲洗。叶面收干后，全株喷雾施药，每处理3次重复，并设1‰吐温80水溶液对照。3d后记录病斑数，计算防效。
6、活体钝化作用：
选长势均匀一致的3–5叶期珊西烟，将药剂与等体积的病毒汁液混合钝化30min后，摩擦接种，病毒浓度20μg/mL，接种后即用流水冲洗，重复3次，设1‰吐温80水溶液对照。3d后数病斑数，计算结果。
抑制率(％)＝[(对照枯斑数-处理枯斑数)/对照枯斑数]×100％
表1Naamine类衍生物I-1～I-16的抗TMV活性测试结果：
从表1中可见Naamine类衍生物I-1～I-3，I-7和I-15表现出很好的抗TMV活性，与商品化品种病毒唑相当，具备极大的开发价值。
实施例9：抗菌活性测试，测定程序如下：
A.离体杀菌测试，菌体生长速率测定法(平皿法)：
将一定量药剂溶解在适量丙酮内，然后用含有200μg/mL乳化剂水溶液稀释至所需浓度，然后各吸取1mL药液注入培养皿内，再分别加入9mL培养基，摇匀后制成50μg/mL的含药平板，以添加1mL灭菌水的平板做空白对照。用直径4mm的打孔器沿菌丝外缘切取菌盘，移至含药平板上。每处理重复三次。将培养皿放在24±1℃恒温培养箱内培养。48小时后调查各处理菌盘扩展直径，求平均值，与空白对照比较计算相对抑菌率。
表2Naamine类衍生物I-1～I-16的离体杀菌活性测试结果：
由表2中数据可以看出，Naamine类衍生物I-1～I-16在离体模式下对14种菌(黄瓜枯萎、花生褐斑、苹果轮纹、小麦纹枯、玉米小斑、西瓜炭疽、水稻恶苗、番茄早疫、小麦赤霉、马铃薯晚疫、辣椒疫霉、油菜菌核、黄瓜灰霉、水稻纹枯)均有不同程度的抑制活性。其中I-4对苹果轮纹和辣椒疫霉的抑制率达到了65％。I-3对苹果轮纹的抑制率达到了67％。I-14对小麦赤霉的抑制率达到了68％。I-9对小麦纹枯的抑制率达到了70％。I-12对小麦纹枯的抑制率达到了71％。I-11对油菜菌核的抑制率达到了66％，具备极大的开发价值。
B.活体杀菌测试，植株喷雾法：
称量各化合物，定量DMSO溶解后加入1‰吐温80水溶液，配制成所需浓度待测液。供试黄瓜、小麦幼苗培养于南开大学生测楼日光温室。黄瓜第一片真叶完全展开后，喷雾处理，喷液量1mL/处理，喷雾压力0.7kg/cm2，喷雾距离15cm。小麦一叶一心期处理，方法与黄瓜处理过程相同。药剂处理后24h，黄瓜灰霉与黄瓜霜霉均采用喷雾接种5×105个/mL的孢子囊悬浮液于药剂处理后的黄瓜真叶叶背，至叶片呈水浸状止。暗环境保湿培养24h，后移至温室环境下正常培养。48h后调查结果。小麦苗则采用沉降接种法，接菌后7d调查结果。结果调查采用分级方法，以“100”级代表无病，即抑制率100％；“0”级代表最严重的发病程度，抑制率为0，记录。
表3Naamine类衍生物I-1～I-16的活体杀菌活性测试结果：
从表3中数据可以看出，Naamine类衍生物I-1～I-16同样表现出不错的活体杀菌活性。
以上对本发明做了示例性的描述，应该说明的是，在不脱离本发明的核心的情况下，任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (8)
1.Naamine类衍生物，其特征在于，具有化学式I所示的结构，具体为Ⅰ-1～Ⅰ～16所示的化合物，通式中R1-R4，n和X所指内容如Ⅰ-1～Ⅰ～16结构所示。
2.如权利要求1所述的Naamine类衍生物在治疗植物病毒中的应用。
3.根据权利要求2所述的应用，其特征在于，植物病毒为烟草花叶病毒。
4.根据权利要求2所述的应用，其特征在于，Naamine类衍生物处理剂量为100—500μg/mL。
5.如权利要求1所述的Naamine类衍生物在治疗植物病菌中的应用。
6.根据权利要求5所述的应用，其特征在于，植物病菌为黄瓜枯萎，花生褐斑，苹果轮纹，小麦纹枯，玉米小斑，西瓜炭疽，水稻恶苗，番茄早疫，小麦赤霉，马铃薯晚疫，辣椒疫霉，油菜菌核，黄瓜灰霉，水稻纹枯14种植物病菌。
7.根据权利要求5所述的应用，其特征在于，Naamine类衍生物处理剂量为50—200μg/mL。
8.Naamine类衍生物的制备方法，其特征在于，化合物Ⅰ-1～Ⅰ～16采用如下不同方法进行制备：
(1)化合物Ⅰ-1，Ⅰ-2，Ⅰ-4和8按照下述方法制备：首先取代氨基酸1a—1d与Boc酸酐反应得物质2a—2d，与苄溴反应保护羟基得3a—3d，甲基化得4a—4d，缩合得5a—5d，再与格式试剂反应得6a—6d，脱保护得7a—7d，最后经氰胺关环得化合物Ⅰ-1，Ⅰ-2，Ⅰ-4和8，如下式所示：
(2)化合物Ⅰ-3，Ⅰ-14，Naamine A及Naamidine A按照下述方法制备：将化合物Ⅰ-1，Ⅰ-2和8经钯碳氢气还原得化合物9，Ⅰ-3和Naamine A；甲基脲与草酰氯反应得关环产物10，与双三甲基硅基乙酰胺反应得11，再与化合物9和Naamine A反应得化合物Ⅰ-14和Naamidine A，如下式所示：
(3)化合物Ⅰ-5～Ⅰ-8(Ⅰ-5、Ⅰ-6、Ⅰ-7、Ⅰ-8)按照下述步骤进行制备：将化合物8经酰化得化合物12，盐酸条件下脱除一个酰基得化合物13，钯碳条件下脱苄基得化合物Ⅰ-5、Ⅰ-6、Ⅰ-7、Ⅰ-8，如下式所示：
(4)化合物Ⅰ-9和Ⅰ-10按照下述方法制备：化合物naamine A与相应的醛反应得化合物14，使用硼氢化钠进行还原得到化合物Ⅰ-9和Ⅰ-10，如下式所示：
(5)化合物Ⅰ-11和Ⅰ-12按照下述方法制备：化合物naamine A与相应的酸反应得化合物Ⅰ-11和Ⅰ-12，如下式所示：
(6)化合物Ⅰ-13按照下述方法制备：化合物naamine A与碘甲烷反应得化合物15，再进行水解后得到化合物Ⅰ-13，如下式所示：
(7)化合物Ⅰ-15和Ⅰ-16按照下述方法制备：化合物naamidine A与相应的金属盐反应得化合物Ⅰ-15和Ⅰ-16，，如下式所示：
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