CN106397254B - 手性8‑羟基升补身烷倍半萜酰胺类化合物及作为农用杀菌剂的用途 - Google Patents
手性8‑羟基升补身烷倍半萜酰胺类化合物及作为农用杀菌剂的用途 Download PDFInfo
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- CN106397254B CN106397254B CN201610762193.3A CN201610762193A CN106397254B CN 106397254 B CN106397254 B CN 106397254B CN 201610762193 A CN201610762193 A CN 201610762193A CN 106397254 B CN106397254 B CN 106397254B
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- methyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
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Abstract
本发明涉及手性8‑羟基升补身烷倍半萜酰胺类化合物及其抑制多种农作物病原菌的用途,该类化合物的化学结构式如下式(I)所示:
Description
技术领域
本发明涉及一类新的手性8-羟基升补身烷倍半萜酰胺类化合物及其作为农用杀菌剂的用途;特别是指该类化合物在植物真菌病害防治中的应用,属于农药技术领域。
背景技术
2016年中央一号文件强调加强农业供给侧改革、提高粮食等农产品的有效供给,农药作为农业生产不可缺少的重要物资,对控制病虫草害、调节植物生长以及农作物稳产、丰产起着十分重要的作用。据联合国粮农组织统计,全球每年因病害造成的损失在11%以上,如马铃薯晚疫病每年在全球造成的损失约67亿美元;另一方面农药残留残毒、对环境的负面影响及有害生物的抗药性等问题日趋严重(Thornton,J.Pure Appl.Chem.2001,73,1231~1236.)。从分子水平角度讲,农药分子在生物体内发挥药效是一个手性识别过程,配体和受体的匹配性将关系到活性大小和安全性,手性的重要性在现代农药开发中也越来越得到凸显,目前商品化手性农药在农药市场中已超过三分之一(Lamberth,C.,et al.,Science,2013,341,742-746.)。手性农药创制使化学品的精准高效使用成为可能,符合绿色新农药创制的要求。由于天然产物具有化学结构新颖,作用方式多样,环境相容性好等诸多优点,在新农药创制以及医药开发中占有重要的地位(吴文君.从天然产物到新农药创制-原理.方法.,2006,北京:化学工业出版社。Newman,D.J.et al.J.Med.Chem.2008,51,2589-2599.)。
Drimane类倍半萜是一类重要的天然产物,在自然界中广泛分布,具有广泛的生物活性,如抗肿瘤、拒食活性、植物生长调节性、神经毒性、抗疟活性、强心活性、抗菌活性、抗过敏、抗炎和镇痛、细胞毒性、植物性毒性、杀鱼和灭螺活性等(B.J.M.Jansen and Ae.deGroot,.Nat.Prod.Rep.,2004,21,449-477)。近年来,关于Drimane类倍半萜及其类似物的构效关系研究成为医药研究的热点之一,如MacKenzie,等人对此类化合物及其类似物的SHIP1调节活性进行了广泛的专利保护(MacKenzie,L.F.,WO 2014110036A1,2014)。Hayakawa最近进行Drimane生物碱的合成并发现其有较好的细胞毒活性。天然产物drimenal对番茄灰霉病菌和马铃薯晚疫病菌都表现出很好的抑制作用(Jochen M.Scheret al..Phytochemistry,2004,65,2583-2588),但文献调研发现此类化合物在农药领域的研究较少,未见手性8-羟基升补身烷倍半萜酰胺类化合物在农药研究领域的报道。本发明发现手性8-羟基升补身烷倍半萜酰胺类化合物具有较好的抑菌活性,这对开发绿色环境友好的新型杀菌剂具有重要意义。
发明内容
本发明要解决的技术问题是提供手性8-羟基升补身烷倍半萜酰胺类化合物的制备方法及其在防治植物真菌病害中的应用。本发明的手性8-羟基升补身烷倍半萜酰胺类化合物表现出很好的抑制真菌病害的作用,并且8-羟基的手性(立体构型)对抑菌活性有显著的影响。
本发明提供的手性8-羟基升补身烷倍半萜酰胺类化合物具有如下通式(I)所示结构。
通式(I)中8位的立体构型为R或者S。
通式(I)中R代表:
(1)简单脂肪取代基:含有C1~C19的骨架的脂肪胺,具体是指如下所示的取代基:
(2)苄基类取代基:主要是指苄胺类化合物对应的酰胺,具体是指如下所示的取代基:
(3)苯乙基类取代基:主要是指苯乙胺类化合物对应的酰胺,具体是指如下式所示的取代基:
(4)苯基类取代基:主要是指苯胺类化合物对应的酰胺,具体是指如下式所示的取代基:
(5)吡啶取代基:主要是指氨基吡啶类化合物对应的酰胺,具体是指如下式所示的取代基:
2-吡啶取代基:
3-吡啶取代基:
4-吡啶取代基:
本发明还包括如通式(I)所示的手性8-羟基升补身烷倍半萜酰胺类化合物在农药化学上可以接受的盐。
本发明涉及的化合物可以根据如下合成路线来进行化学完成。
合成方法一:
当手性8-羟基升补身烷倍半萜酰胺类化合物8位的立体构型为R构型时,对应的胺试剂为廉价易得的液体脂肪胺时,可按照如下的合成路线来进行8-R-羟基-升补身烷倍半萜酰胺类化合物的制备。
该合成路线以廉价易得的天然产物香紫苏醇为起始原料,首先在高锰酸钾氧化条件下对其进行氧化降解,然后碱性条件下处理获得升补身烷羧酸盐,然后酸性条件下处理环化,制备香紫苏内酯。获得的香紫苏内酯在过量的胺溶液中进行胺解,获得酰胺化合物,即为目标化合物。
合成方法二:
当手性8-羟基-升补身烷倍半萜酰胺类化合物8位的立体构型为R构型时,对应的胺试剂为脂肪胺、苯乙胺、苄基胺类化合物、苯胺或取代苯胺以及氨基吡啶类化合物时,可按照如下的合成路线来进行8-R-
具体实施方式
通过下述实施例和生测实验结果,可进一步说明和理解本发明,但并不意味着限制本发明。
实施例一:N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺的合成
香紫苏内酯的((+)-sclareolide)的合成
将天然产物香紫苏醇(-)-sclareol(10.0g,32.4mmol,1.0equiv)溶于200mL无水丙酮中,将体系置于冰浴中,向其中加入乙酸酐60mL;随后分批加入高锰酸钾粉末(30.7g,194.5mol,6equiv)。体系逐渐回复至室温,磁力搅拌,薄层层析(TLC)跟踪检测反应进程。原料消耗完毕后,向其中缓慢加入碳酸钠水溶液(20.0g/150mL)淬灭反应,继续搅拌0.5小时,过滤,减压下蒸除丙酮,获得香紫苏内酯和升补身烷羧酸的混合物。向此混合物中加入2N氢氧化钠水溶液(50mL),回流反应2小时,恢复至室温,用2N盐酸酸化反应体系至pH=3。有沉淀析出,用冷水洗滤饼,将滤饼在真空下干燥获得浅黄色固体,硅胶柱层析(200-300m,PE/EtOAc=8∶1)分离后获得白色固体香紫苏内酯4.95g,产率61%。
N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺的合成
将香紫苏内酯(+)-sclareolide(100mg,0.4mmol,1.0equiv.)溶于正丁胺中(2.0mL),室温下搅拌。薄层层析(TLC)跟踪检测反应进程。反应完毕后,减压蒸除多余的正丁胺,残余物分散于水和乙酸乙酯中(20mL,20mL),水相用乙酸乙酯萃取2次(2×10mL)。合并有机相,无水硫酸钠干燥后,在减压下蒸除溶剂,硅胶柱层析分离(200-300m,PE/EtOAc=4∶1),获得N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺,白色固体90mg,产率70%)。熔点:180.6-181.1℃.1H NMR(400MHz,CDCl3)δ5.86(s,br,1H,NH),3.22(dd,J1=13.3Hz,J2=6.68Hz,2H,CH2-CO),2.92(s,br,1H,OH),2.37(dd,J1=15.4Hz,J2=5.36Hz,1H),2.11(dd,J1=15.4Hz,J2=3.96Hz,1H),1.93(dt,J1=12.48Hz,J2=3.16Hz,1H),1.77(t,J=4.64Hz,2H),1.67(m,1H),1.56~1.62(m,2H),1.44~1.50(m,4H),1.31~1.38(m,3H),1.27(m,1H),1.13(s,3H,CH3),1.13(m,1H),0.98(m,1H),0.92(t,J=7.32Hz,3H,CH3),0.87(s,3H,CH3),0.78(s,6H,2 X CH3).LC-MS(ESI+)m/z:Calcd.for[M+Na:C20H37NNaO2]:346.27,Found:346.41;Calcd.for[M-H2O+H:C20H36NO]:306.28,Found:306.42。
实施例二:2-((1R,2R,4aS,8aS)-2-羟基-2,5,5,8a-四甲基十氢化萘-1-基)-N-(o-甲苯基)乙酰胺的合成
具体实施方式
通过下述实施例和生测实验结果,可进一步说明和理解本发明,但并不意味着限制本发明。
实施例一:N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺的合成
香紫苏内酯的((+)-sclareolide)的合成
将天然产物香紫苏醇(-)-sclareol(10.0g,32.4mmol,1.0equiv)溶于200mL无水丙酮中,将体系置于冰浴中,向其中加入乙酸酐60mL;随后分批加入高锰酸钾粉末(30.7g,194.5mol,6equiv)。体系逐渐回复至室温,磁力搅拌,薄层层析(TLC)跟踪检测反应进程。原料消耗完毕后,向其中缓慢加入碳酸钠水溶液(20.0g/150mL)淬灭反应,继续搅拌0.5小时,过滤,减压下蒸除丙酮,获得香紫苏内酯和升补身烷羧酸的混合物。向此混合物中加入2N氢氧化钠水溶液(50mL),回流反应2小时,恢复至室温,用2N盐酸酸化反应体系至pH=3。有沉淀析出,用冷水洗滤饼,将滤饼在真空下干燥获得浅黄色固体,硅胶柱层析(200-300m,PE/EtOAc=8∶1)分离后获得白色固体香紫苏内酯4.95g,产率61%。
N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺的合成
将香紫苏内酯(+)-sclareolide(100mg,0.4mmol,1.0equiv.)溶于正丁胺中(2.0mL),室温下搅拌。薄层层析(TLC)跟踪检测反应进程。反应完毕后,减压蒸除多余的正丁胺,残余物分散于水和乙酸乙酯中(20mL,20mL),水相用乙酸乙酯萃取2次(2×10mL)。合并有机相,无水硫酸钠干燥后,在减压下蒸除溶剂,硅胶柱层析分离(200-300m,PE/EtOAc=4∶1),获得N-丁基-2((1R,2R,4aS,8aS)-2-羟基--2,5,5,8a-四甲基十氢化萘-1-基)乙酰胺,白色固体90mg,产率70%)。熔点:180.6-181.1℃.1H NMR(400MHz,CDCl3)δ5.86(s,br,1H,NH),3.22(dd,J1=13.3Hz,J2=6.68Hz,2H,CH2-CO),2.92(s,br,1H,OH),2.37(dd,J1=15.4Hz,J2=5.36Hz,1H),2.11(dd,J1=15.4Hz,J2=3.96Hz,1H),1.93(dt,J1=12.48Hz,J2=3.16Hz,1H),1.77(t,J=4.64Hz,2H),1.67(m,1H),1.56~1.62(m,2H),1.44~1.50(m,4H),1.31~1.38(m,3H),1.27(m,1H),1.13(s,3H,CH3),1.13(m,1H),0.98(m,1H),0.92(t,J=7.32Hz,3H,CH3),0.87(s,3H,CH3),0.78(s,6H,2 X CH3).LC-MS(ESI+)m/z:Calcd.for[M+Na:C20H37NNaO2]:346.27,Found:346.41;Calcd.for[M-H2O+H:C20H36NO]:306.28,Found:306.42。
实施例二:2-((1R,2R,4aS,8aS)-2-羟基-2,5,5,8a-四甲基十氢化萘-1-基)-N-(o-甲苯基)乙酰胺的合成
所用的香紫苏内酯(+)-Sclareolide按照实施例二所描述的方法制备。
氮气保护下,称取邻甲基苯胺(0.430g,2.5mmol,2.5equiv)溶于无水四氢呋喃(1.7mL)中,将混合体系置于冰浴中,向其中加入二异丁基氢化铝的甲苯溶液(1.5M,2.0mL,3.0equiv)。体系自然恢复至室温,继续搅拌反应2小时,获得二异丁基氢化铝-邻甲基苯胺的复合物的甲苯溶液(浓度约为0.88M),将其直接用于下一步的胺解。
氮气保护下,向香紫苏内酯(+)-Sclareolide(0.250g,1.0mmol,1.0equiv)的无水四氢呋喃溶液中加入上述制备的二异丁基氢化铝-邻甲基苯胺的复合物的甲苯溶液。室温下搅拌反应至香紫苏内酯消耗完毕。冰浴条件下,向其中缓慢加入1.5mL水和4mL硫酸氢钾水溶液淬灭反应。反应体系用二氯甲烷萃取(3×10mL)。合并的有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压蒸除溶剂,硅胶柱层析分离(200-300m,PE/EtOAc=6∶1),2-((1R,2R,4aS,8aS)-2-羟基-2,5,5,8a-四甲基十氢化萘-1-基)-N-(o-甲苯基)乙酰胺。白色固体,熔点182.2-182.9℃.1H NMR(500MHz,CDCl3)δ8.30(s,br,1H,NH),7.85(d,J=8.0Hz,1H,aromatic H),7.13~7.18(m,2H,aromatic H),7.02(t,J=7.3Hz,1H,aromatic H),2.78(s,br,1H,OH),2.61(dd,J1=15.0,J2=4.2Hz,1H,CH2-CO),2.32(dd,J1=15.0,J2=3.8Hz,1H,CH2-CO),2.23(s,3H,Ph-CH3),1.93(dt,J1=12.5,J2=3.2Hz,1H),1.77~1.82(m,2H),1.68~1.70(m,1H),1.49~1.57(m,2H),1.43~1.45(m,1H),1.24~1.38(m,2H),1.21(s,3H,CH3),1.13(td,J1=13.5,J2=4.1Hz,1H),0.97(dd,J1=12.3,J2=2.1Hz,2H),0.87(s,3H,CH3),0.81(s,3H,CH3),0.80(s,3H,CH3).13C-NMR(125MHz,CDCl3)δ174.12,136.49,130.55,128.84,126.81,124.79,122.76,74.17,58.66,56.30,44.40,42.01,39.64,39.10,34.37,33.49,24.52,21.60,20.69,18.48,18.24,15.56.Elemental anal.calcd forC32H35NO2:C,77.27;H,9.87;N,3.92;found C,77.31;H,9.79;N,3.98;LC-MS(ESI+)m/z:Calcd.for[M+Na:C23H35NO2Na]:380.26,Found:380.39;Calcd.for[M-H2O+H:C23H34NO]:340.26,Found:340.40.
将2-((1R,2R,4aS,8aS)-2-羟基-2,5,5,8a-四甲基十氢化萘-1-基)-N-(o-甲苯基)乙酰胺溶于二氯甲烷中,缓慢挥发掉溶剂,获得化合物的单晶,结构经X-单晶衍射证实。
实施例三:手性8-羟基-升补身烷倍半萜酰胺类化合物的抑菌活性测定
采用平板抑制菌丝生长速率法进行离体抑菌活性评价,选取测试菌株于PDA平板进行活化,包括水稻纹枯病菌(Rhizoctonia solani),小麦纹枯病菌(Rhizoctoniacerealis),油菜菌核病菌(Sclerotinia scleotiorum),小麦赤霉病菌(Fusariumgraminearum),小麦全蚀病菌(Gaeumanomyce graminis),番茄灰霉病菌(Botrytiscinerea),马铃薯晚疫病菌(Phytophthora infestans),辣椒疫霉病菌(Phytophthoracapsici),番茄早疫病菌(Alternaria solani),水稻恶苗病菌(Fusarium fujikuroi),马铃薯干腐病菌(Fusarium sulphureum),黄瓜炭疽病菌(Colletotrichum lagenarium),水稻稻瘟病菌(Phyricularia cerealis)。将化合物配置成系列梯度浓度的PDA含药平板,将测试菌株制成5mm直径菌饼置于含药培养皿中央,25℃恒温培养至空白对照皿的测试菌株长至接近培养皿边缘时,用十字交叉法测量各含药平板的菌落直径,计算化合物对菌丝生长的抑制率,对病害的抑制率按照如下公式计算:
使用统计软件SPSS20.0计算抑制率为50%时化合物的浓度,即EC50值。重复3次取平均值。以多菌灵(carbendazim)为阳性对照,各化合物对植物病原菌的EC50值(mg/L)。
表1 手性8-羟基-升补身烷倍半萜酰胺类化合物的抑菌活性
表2 手性8-羟基-升补身烷倍半萜酰胺8-位羟基的立体构型对抑菌活性的影响
从表1和表2中可以看出,手性8-羟基-升补身烷倍半萜酰胺类化合物(8位为R构型)对植物病害有较好的抑制作用。4-氟取代酰胺化合物对油菜菌核病菌(Sclerotiniasclerotiorum)、和番茄灰霉病菌(Botrytis cinerea)均表现出了强烈的抑制作用,抑制中浓度分别为3.33mg/L和2.45mg/L;其对番茄灰霉病菌的活性明显高于阳性对照多菌灵。
结合表1数据,从表2中可以看出,8位羟基的手性对活性有显著的影响,4-氟取代酰胺化合物中8位由原来的R构型变为S构型后,对小麦赤霉病菌的抑制活性有显著的提高(提高接近9倍),抑制中浓度为4.10mg/L。
本发明所涉及的手性8-羟基-升补身烷酰胺类化合物作为农用杀菌剂的用途已经通过具体的实例进行了描述,本领域技术人员可借鉴本发明内容,适当改变原料、工艺条件等环节来实现相应的其它目的,其相关改变都没有脱离本发明的内容,所有类似的替换和改动对于本领域技术人员来说是显而易见的,都被视为包括在本发明的范围之内。
Claims (6)
1.如下通式(I)所示的酰胺类化合物及其农药化学上可以接受的盐,
其中,
通式(I)中8位的立体构型为R或者S,
取代基R选自:C1~C19的开链或环状脂肪取代基;苄基;苯环上有甲基,羟基,甲氧基,卤素,二氟甲基或三氟甲基取代的苄基;苄位有C1~C6烃基取代的苄基;苯乙基;苯环上有甲基,羟基,甲氧基,卤素,硝基,二氟甲基或三氟甲基取代的苯乙基;3-吲哚乙基;苯环上有甲基,羟基,甲氧基,卤素,硝基,二氟甲基或三氟甲基取代的3-吲哚乙基;苯基;苯环上有甲基,羟基,甲氧基,卤素,硝基,二氟甲基或三氟甲基取代的苯基;2-吡啶基以及吡啶环上有甲基,羟基,氰基,卤素,硝基或三氟甲基取代的2-吡啶基;3-吡啶基以及吡啶环上有甲基,羟基,氰基,卤素,硝基或三氟甲基取代的3-吡啶基;4-吡啶基以及吡啶环上有甲基,羟基,氰基,卤素,硝基或三氟甲基取代的4-吡啶基。
2.一种酰胺类化合物,其特征在于,选自以下化合物:
3.权利要求1所示的通式(I)所示的酰胺类化合物在防治农业植物病原菌上的应用,选自如下病原菌:水稻纹枯病菌,小麦纹枯病菌,油菜菌核病菌,小麦赤霉病菌,小麦全蚀病菌,番茄灰霉病菌,马铃薯晚疫病菌,辣椒疫霉病菌,番茄早疫病菌,水稻恶苗病菌,马铃薯干腐病菌,黄瓜炭疽病菌,水稻稻瘟病菌。
4.如权利要求3所要求的应用,其特征在于,所述的农业病害为油菜菌核病菌,小麦赤霉病菌和番茄灰霉病菌。
5.根据权利要求3或4的用途,所述化合物加工成乳油、水乳剂、微乳剂、可湿性粉剂、水分散粒剂或悬浮剂。
6.权利要求1或2所述的酰胺类化合物在防治植物病害中的应用,其特征在于它作为抑菌剂和商品化杀菌剂中的一种或多种组合在制备复配杀菌剂中的用途;商品化杀菌剂选自嘧菌酯、吡唑醚菌酯、丙硫菌唑、肟菌酯、环菌唑、代森锰锌、氟环唑、戊唑醇、啶酰菌胺、甲霜灵、啶氧菌酯、苯醚甲环唑、丙环唑、百菌清、噻酰菌胺、甲噻诱胺、异噻菌胺、宁南霉素、烯丙异噻唑、氟吗啉、烯酰吗啉。
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