CN103755718B - 木霉菌素c8不饱和酸酯衍生物及其用途 - Google Patents
木霉菌素c8不饱和酸酯衍生物及其用途 Download PDFInfo
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- CN103755718B CN103755718B CN201410018923.XA CN201410018923A CN103755718B CN 103755718 B CN103755718 B CN 103755718B CN 201410018923 A CN201410018923 A CN 201410018923A CN 103755718 B CN103755718 B CN 103755718B
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- trichodermin
- unsaturated acids
- acids ester
- ester derivant
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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Abstract
本发明公开了一种木霉菌素C8不饱和酸酯衍生物,该木霉菌素C8不饱和酸酯衍生物的结构通式为:
Description
技术领域
本发明属于新农药创制中的杀菌剂创制领域,具体涉及一系列对植物病原真菌具有抑菌活性的木霉菌素C8不饱和酸酯衍生物。
背景技术
自21世纪以来,杀菌剂的发展迅速,杀虫剂所占比例已逐渐被杀菌剂追上,特别是嘧菌酯,已经成为杀菌剂品种的代表,销售额成倍增长。当前,以天然产物为母体的、广谱高效、作用机理独特的杀菌剂已成为国际上近期开发的重点。
内生真菌及其天然产物在现代生物药物开发中具有重要的应用潜力,单端孢霉烯类化合物是一类著名的真菌毒素,为镰刀菌属(Fusarium)、单端孢霉属(Trichothecene)、木霉属(Trichoderma)、漆斑霉属(Myrothecium)等真菌的代谢产物,这些化合物都有一个相似的倍半萜骨架,分子中通常含有一个稳定的环氧和烯双键结构。单端孢霉烯类化合物具有抑制或杀死真菌(包括许多植物病原菌)以及抑制植物生长等值得关注的功能。如Trichodermin(式III化合物)可抑制Aspergillus flavus、A.niger、Cladosporiumcucumerium、Rhizoctonia solani、R.bataticola、Candida albicans以及Rhizopusstolonifer等多种植物病原菌菌丝生长,trichodermin对烟草、豆类植物、麦类等的胚芽鞘生长具明显抑制作用,并可以从根部吸收,导致上述植株死亡。
Trichodermol(式II化合物)是结构最为简单的单端孢霉烯类化合物,在检索大量国内外文献并通过项目组对部分单端孢霉烯类活性物质的初步研究后发现,以Trichodermol为基本骨架的化合物不但具有高效的抑制真菌和抑制植物生长的活性,而且其毒性低,对哺乳动物较为安全,具有巨大的开发潜力。
木霉菌素(Trichodermin,式Ⅲ化合物)是浙江大学农学院生物技术研究所从一种新发现的内生真菌―紫杉木霉的次生代谢产物中分离的一种化合物,研究发现该化合物对重要植物病原真菌立枯丝核菌和灰葡萄孢菌有很强的抑制作用,对水稻稻瘟病及纹枯病也有良好的抑制作用。经室内生物测定、温室田间药效试验及急性试验,表明木霉菌素在植物病害生物防治中具有良好的发展前景。
在已经授权的中国发明专利ZL200810162582.8木霉菌素衍生物及其用途中,提到木霉菌素发酵来源的菌株和制备方法。在章初龙、林福呈等在2007年首次报道了产生木霉菌素的一种新型的从内生真菌南方红豆杉中分离到的新内生真菌紫杉木霉Trichodermataxi菌株ZJUF0986,其代谢产物就是木霉菌素(Trichodermin,式Ⅲ化合物)。(Chu-longZhang,Shu-peng Liu,Fu-cheng Lin,Christian P.Kubicek&Irina S.Druzhinina,Trichoderma taxi sp.nov.,an endophytic fungus from ChineseyewTaxusmairei.FEMSMicrobiol Lett270(2007)90–96.)陈邵媛、章初龙、林福呈等在2008年首次报道了木霉菌素的晶体结构(Shao-Yuan Chen,a*Chu-Long Zhang,a Yu-Zhe Chenb and Fu-ChengLin.Trichodermin(4b-acetoxy-12,13-epoxytrichothec-9-ene.ActaCrystallographica Section E2008,E64,o702)。
本课题组在此基础上,结合切实可行的化学合成方法,展开trichodermin系列衍生物的化学合成及其抑菌和抑制植物生长的构效关系研究,从而为创制以trichodermin为母体的新型农药产品奠定基础。
正是由于木霉素作为农用抗菌素具有高效性和广谱性的特点,且在许多木霉菌发酵产物中能分离到,所以如果研究进一步深入,如进行原始菌株改造、发酵工艺、构效关系、衍生化,结合田间效果及其安全性等,一旦获得性价比较高的木霉素衍生物,则极具产业化前景。
发明人所在课题组前期对木霉菌素C4位进行各种酯的衍生化,发现不同酯基对化合物的抑菌率明显不同。具体的是,芳香酯基比直链烷基酯活性高,不饱和酯基比饱和酯基活性高,在专利CN101429203A中有详述。
后来,发明人又对C8位进行修饰,发现将木霉菌素(II)中C8位接上酯基结构,其对稻瘟病菌的抑制效果明显增加。尤其是当接上的是肉桂酸酯时,其EC50值达到1.96mg/L,而木霉菌素原药对稻瘟病菌的EC50值为39.26mg/L。很明显,C8位上的酯基能够显著提高化合物的抑菌率,具体的在专利CN200810162582.8中有详述。
考虑到不饱和酸酯结构是一个比较好的活性结构片段,是很多商品化农药中的一个活性基团,比如杀菌剂--嘧菌酯、啶氧菌酯等,结构中不饱和酸酯结构的存在对防治农业与园林上重要的植物病原菌等具有良好的贡献作用。
发明内容
本发明要解决的技术问题是提供一种具有杀菌活性的木霉菌素C8不饱和酸酯衍生物及其制备方法和用途。
为了解决上述技术问题,本发明提供一种木霉菌素C8不饱和酸酯衍生物,该木霉菌素C8不饱和酸酯衍生物的结构通式为:
R为以下任意一种:
被卤素取代或被烷氧基取代或非取代的烯基;
被卤素、烷基、烷氧基、硝基、卤代烷基取代的或非取代的苯丙烯基;
被卤素取代或烷基取代或被烷氧基取代的或非取代的杂芳基。
作为本发明的木霉菌素C8不饱和酸酯衍生物的改进:结构通式中的R为以下任意一种:
乙烯基、正丙烯基、异丙烯基、正丁烯基、叔丁烯基;
甲氧基乙烯基、甲氧基丙烯基、乙氧基乙烯基(乙氧乙烯基)、甲氧基丙烯基;
被F取代的C2-C4-烯基、被Cl取代的C2-C4-烯基;
被F取代的苯丙烯基、被Cl取代的苯丙烯基、被Br取代的苯丙烯基、被硝基取代的苯丙烯基、被氰基取代的苯丙烯基、被甲基取代的苯丙烯基、被乙基取代的苯丙烯基、被甲氧基取代的苯丙烯基、被三氟甲基取代的苯丙烯基;
被F取代的吡啶基、被Cl取代的吡啶基、被甲基取代的吡啶基。
作为本发明的木霉菌素C8不饱和酸酯衍生物的进一步改进:结构通式中的R为下表中所示的任意一种:
表1木霉菌素C8不饱和酸酯衍生物
本发明还同时提供了上述木霉菌素C8不饱和酸酯衍生物的用途,用于抑制植物病原真菌,作为农业和/或园艺上的杀菌剂。
作为本发明的木霉菌素C8不饱和酸酯衍生物的用途的改进:所述植物病原真菌为小麦赤霉病菌(Gibberella zeae)、小麦白粉病(Blumeria graminis)、黄瓜灰霉病菌(Botrytis cinerea)、水稻纹枯病菌(Rhizoctonia solani)、水稻稻瘟病菌(Pyriculariaoryzae)或水稻稻曲病菌(Ustilaginoidea oryzae)。
本发明所述的结构通式I的木霉菌素C8不饱和酸酯衍生物,可单一使用或者与另外的生物活性化合物组合使用,对许多植物病原真菌具有防治效果。
发明人在化合物II的衍生化发明过程中,发现若C8位上所连接的酯为不饱和酸酯,如烯酸酯,肉桂酸酯时,化合物具有更好的活性,该内容未见文献报道。具体结构式如通式I所示:
(I)
当本发明的木霉菌素C8不饱和酸酯衍生物用于农业或园艺业,可有各种剂型的制剂,例如它可被配制成微粒剂,细微粒剂,可湿性粉剂,稀乳剂,水或油基悬浮液或者水或油溶液(它可直接喷雾或稀释后使用),烟雾剂或聚合物胶囊。所用载体可以是天然的或合成的,可以是有机的或无机的,它通常用来帮助活性化合物到达被处理的部位,并有助于贮藏,运输或使用活性化合物。固体,液体及气体载体可选自本领域已知的用于该类制剂的载体。
这样的制剂可按常规方法,如通过将活性成分与载体或稀释剂(溶剂)以及,任意选择的,一种或多种表面活性剂紧密混合和/或研磨。
合适的溶剂的实例包括:芳烃,特别石油中C8到C12的馏分,如二甲苯混合物或取代的萘;脂族或脂环烃,如环己烷或石蜡;醇,如乙醇,1,2-亚乙基二醇,1,2-亚乙基二醇单甲醚或1,2-亚乙基单***;二元醇或其醚;酮,如环己酮;极性溶剂,如N-甲基-2-吡咯烷酮,二甲基亚砜或二甲基甲酰胺;任意选择的环氧化的植物油,如环氧化椰子油或大豆油,以及水。
用于诸如粒剂和分散性可湿性粉剂中的载体实例包括:天然矿物填充剂,如方解石,滑石,高岭土,蒙脱石或活性白土。为了改善组合物的物理性质,也可加入高分散的硅酸或高分散的吸附聚合物。合适的颗粒化吸附载体的实例包括;多孔物质,如浮石,磨碎的砖,海泡石和膨润土;及非多孔性物质,如方解石和沙子。可使用种类广泛的,有机或无机的粒化物质,其实例包括白云石和磨碎的植物残渣。
可使用一种或多种农业化学品等制剂中的常规的,具有良好乳化,分散和湿润性质的阳离子,阳离子和非离子化合物作为表明活性剂。可使用单一的上述表面活性剂或上述表面活性剂的混合物。
可使用的非离子表面活性剂包括:聚氧乙烯烷基醚;聚氧乙烯烷基酯;聚氧乙烯烷基芳基醚;聚氧乙烯芳基芳基醚;聚氧乙烯脱水山梨糖醇烷基酯;脱水山梨糖醇烷基酯;脂肪酸糖酯;脂肪酸甘油酯或季戊四醇酯;普卢兰尼克型表面活性剂;炔属醇,乙炔二醇,以及它们的环氧乙烷加成物;硅氧烷表面活性剂;和烷基葡糖苷。
可使用的阴离子表面活性剂包括;烷基苯磺酸盐;二烷基硫代琥珀酸盐;烷基硫酸盐;烷基甲基牛磺酸盐;硫酸或磷酸被上述非离子表面活性物质环氧乙烷加成物酯化,如果需要,用合适的碱中和,而制备的阴离子表面活性剂;木素磺酸盐;烷基萘磺酸盐及其缩合物;苯酚磺酸盐及其缩合物;盐形式的聚羧酸或聚磺酸聚皂或其与诸如丙烯酸,马来酸,苯乙烯磺酸或与乙烯基的缩合物形式的聚皂;由淀粉或糊精与1-(2-辛酰基)-琥珀酸钠添加剂组成的淀粉型表面活性剂;羧甲基纤维素盐;皂类如高级脂肪酸的钠盐或钾盐,以及α-烯属磺酸盐。
可使用的阳离子表面活性剂包括胺盐或季铵盐表面活性剂,以及高级脂族胺或脂肪酰胺的环氧乙烷加成物。
可使用的两性表面活性剂包括氨基酸型或内铵盐型表面活性剂,或卵磷脂。
已经发现其中一个或更多氢原子被氟取代的上述各类表面活性剂的衍生物具有强的降低表明张力的作用,有利于在本发明中使用。
利用本发明的木霉菌素C8不饱和酸酯衍生物制备而得的组合物也可含一种或多种添加剂,选自稳定剂,消泡剂,粘度调节剂,交联剂或粘合剂或其组合,及肥料和其他活性物质以达到特殊效果。
杀菌组合物通常含有0.01到99%,优选0.1到95%的活性化合物(即,本发明的木霉菌素C8不饱和酸酯衍生物);含有1到99.99%的固体或液体添加剂;以及含有0到25%,优选0.1到25%的表面活性剂。当商品产品以浓缩组合物形式出售时,最终使用者通常将其稀释成0.001到0.0001%的重量比的浓度(10到1ppm)。
上述百分比都按重量计。
本发明的木霉菌素C8不饱和酸酯衍生物,实际用法和用量为:通常稀释成0.001到0.0001%的重量比的浓度进行喷洒,每公顷的有效用量(即木霉菌素C8不饱和酸酯衍生物)的用量为50-200g。
本发明化合物可以与其他活性化合物,例如,杀虫剂、杀菌剂、杀螨剂、杀线虫剂、抗真菌剂、植物生长调节剂或除草剂混合配制或协同使用。
本发明化合物也可与增效剂混合配制或协同使用。这样的化学品的制备及所使用的形式是商业用途所需的。增效剂无独立活性,本身为可提高活性化合物活性的化合物。
本发明进一步通过下列非限制性实施例,制备例及制剂实施例加以说明,它们分别说明本发明某些化合物,用来制备本发明化合物的原料,以及含有本发明化合物的某些农用制剂的制备。
本发明化合物由前述表1所指定的编号表示。
本发明的优点在于:合成了系列未见报道的不同于木霉菌素的新型衍生物,因为其母体结构是天然内生真菌的代谢产物,经高效菌株发酵,经过提取分离得到,活性很好,所以此母体结构为先导化合物设计合成的系列衍生物都具有一定的生物活性,对小麦赤霉病菌(Gibberella zeae)、小麦白粉病(Blumeria graminis)、黄瓜灰霉病菌(Botrytiscinerea)、水稻纹枯病菌(Rhizoctonia solani)、水稻稻瘟病菌(Pyricularia oryzae)、水稻稻曲病菌(Ustilaginoidea oryzae)都有不同程度的杀菌活性。其中化合物I-1、I-2和I-3对水稻纹枯病菌,I-1、I-2、I-3、I-7和I-8对小麦白粉病菌,I-1、I-2和I-3对小麦赤霉病菌表现出良好的抑制活性。
本发明采用木霉菌素(式III化合物)为原料,通过二氧化硒氧化得到通式IV化合物,式IV化合物进一步进行衍生化反应,得到木霉菌素C8不饱和酸酯衍生物,并进行杀菌活性测定,从普筛中选出50mg/L浓度下抑制率80%以上的进行初筛评价。
反应式主原料IV的合成
其中a)SeO2,aq.二氧六环,回流,18h;32%
在室温下,往100mL的反应瓶中依次加入2.92g(10mmol)木霉菌素(III)和80mL二氧六环,待木霉菌素(III)溶解后,往体系中再加入1.44g(13mmol)SeO2,最后加入8mL水。反应液在回流下反应18个小时后,TLC跟踪点板,原料点反应完全。过滤掉反应液中的固体,然后无水Na2SO4(约4.0g)干燥,减压(5-50MPa)脱二氧六环,得到粘稠液体,采用200~300目的硅胶柱分离,淋洗剂为乙酸乙酯:石油醚=1:5,(体积比),得到目标化合物0.98g的4-β-乙酰基-8-羟基-12,13-环氧单端胞霉-9-烯毒素(IV),95%(体积%)的乙醇重结晶,过滤得化合物IV(0.90g),收率为32%。具体结构确证数据如下:
IV:Rf=0.55(silica gel,ethyl acetate/petroleum ether1:3);[α]D 18=47.5556(c0.010,CH3OH);MS ES+m/z:309.12(M+H)+(100%);1H NMR(500MHz,CDCl3):δ5.52(dd,J=3.5,7.5Hz,1H,H-4),4.345.48-5.46(m,1H,H-10),4.06(d,J=7.5Hz,1H,H-8),3.84(d,J=5.0Hz,1H,H-2),3.63(d,J=5.5Hz,1H,H-11),3.13(d,J=4.0Hz,1H,H-13),2.85(d,J=4.0Hz,1H,H-13),2.53-2.49(m,1H,H-3),2.08(s,3H,AcH),2.02-1.98(m,1H,H-3),1.86-1.84(m,1H,H-7),1.70(s,3H,H-16),1.53-1.52(m,1H,H-7),0.98(s,3H,H-14),0.73(s,3H,H-15).
木霉菌素C8不饱和酸酯衍生物的合成通用步骤:
4-β-乙酰基-8-羟基-12,13-环氧单端胞霉-9-烯毒素(IV)(1当量)、三乙胺(1~10当量,相对于IV而言)和催化剂量的DMAP催化剂溶于干燥的二氯甲烷中,冰水浴下慢慢滴加需要的各种不饱和酸的酰氯(1.1当量,相对于IV而言)。反应混合物在室温下反应至原料基本上完全消失(通过TLC检测跟踪反应)。反应液稀释后用1M HCl、饱和食盐水分别洗涤,用无水Na2SO4干燥。浓缩得到粗产物,用硅胶柱层析纯化得到目标化合物。
具体实施方式
下面分别列出代表性的具体实施例:
实施例1、一种木霉菌素C8位不饱和酸酯衍生物(I-1)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的丙烯酰氯,室温下搅拌反应,TLC检测反应进程(反应时间约为3.0小时)。反应结束后,先用10ml二氯甲烷作为溶剂进行稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,溶剂旋干(浓缩至干)。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-1。
1H NMR(500MHz,CDCl3):δ6.45(dd,J=1.5,17.5Hz,1H,H-18),6.16(dd,J=10.5,17.5Hz,1H,H-17),5.88(dd,J=10.5,1.0Hz,1H,H-18),5.60-5.58(m,1H,H-8),5.55(q,J=4.0,3.5Hz,1H,H-4),5.45(dd,J=6.0,10.0Hz,1H,H-10),3.86(d,J=5.5Hz,1H,H-2),3.66(d,J=5.5Hz,1H,H-11),3.14(d,J=4.0Hz,1H,H-13),2.38(d,J=4.0Hz,1H,H-13),2.55(dd,J=8.0,15.5Hz,1H,H-3),2.08(s,3H,CH3COO-),2.03-1.86(m,3H,H-3&H-7),1.71(s,3H,H-16),1.07(s,3H,H-14),0.72(s,3H,H-15),MS ES+m/z:362.17(M+H)+(100%)。
实施例2、化合物(I-2)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的3-甲基丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-2。
1H NMR(500MHz,CDCl3):δ6.09(s,1H,CH=C-Me2),5.53(m,2H,H-4&H-8),5.41-5.39(1H,m,H-10),3.83(d,J=5.5Hz,1H,H-2),3.62(d,J=5.5Hz,1H,H-11),3.09(d,J=4.0Hz,1H,H-13),2.78(d,J=4.0Hz,1H,H-13),2.53(dd,J=7.5,15.5Hz,1H,H-3),2.18(s,3H,-CH=C-CH3),2.08(s,3H,-COCH3),2.01-1.97(m,3H,1H-3&2H-7),1.91(s,3H,-CH=C-CH3),1.88(s,3H,H-16),1.05(s,3H,H-14),0.70(s,3H,H-15),MS ES+m/z:391.20(M+H)+(100%).
实施例3、化合物(I-3)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的3,3-二甲基丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,饱和食盐水洗涤2次,无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3),得到目标化合物I-3,1H NMR(500MHz,CDCl3):δ6.09(s,1H,CH=C-Me2),5.53(m,2H,H-4&H-8),5.41-5.39(1H,m,H-10),3.83(d,J=5.5Hz,1H,H-2),3.62(d,J=5.5Hz,1H,H-11),3.09(d,J=4.0Hz,1H,H-13),2.78(d,J=4.0Hz,1H,H-13),2.53(dd,J=7.5,15.5Hz,1H,H-3),2.18(s,3H,-CH=C-CH3),2.08(s,3H,-COCH3),2.01-1.97(m,3H,1H-3&2H-7),1.91(s,3H,-CH=C-CH3),1.88(s,3H,H-16),1.05(s,3H,H-14),0.70(s,3H,H-15),MS ES+m/z:391.20(M+H)+(100%)。
实施例4、化合物(I-8)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-对甲基苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-8.1H-NMR(500MHz,CDCl3):δ7.68-7.65(d,J=15.5Hz,1H,C=CH-Ar),7.41-7.39(d,J=8.0Hz,2H,H-2,6-Ar),7.18-7.16(d,J=8.0Hz,2H,H-3,5-Ar),6.39-6.35(d,J=15.5Hz,1H,O=C-CH=),5.58-5.57(d,J=5.5Hz,1H,H-10),5.53-5.51(dd,J1=J2=3.5Hz,1H,H-4),5.49-5.45(dd,J1=J2=1.5Hz,1H,H-8),,3.84-3.83(d,J=5.0Hz,1H,H-2),3.65-3.64(d,J=5.0Hz,1H,H-11),3.11-3.10(d,J=4.0Hz,1H,H-13),2.81-2.80(d,J=4.0Hz,1H,H-13),2.53-2.48(dd,J1=J2=8.0Hz,1H,H-3endo),2.35-2.34(d,J=5.0Hz,3H,H-4-CH3-Ar),2.13(s,3H,O=CCH3),2.05-1.95(m,2H,H-7exo,3exo),1.91-1.87(dd,J1=J2=1.5Hz,1H,H-7endo),1.72(s,3H,H-16),1.06(s,3H,H-14),0.70(s,3H,H-15);MS ESI+m/z:453.34(M+H)+(100%).
实施例5、化合物(I-9)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-对甲氧基苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-9.1H-NMR(500MHz,CDCl3):δ7.69-7.66(d,J=15.5Hz,1H,C=CH-Ar),7.51-7.48(dd,J1=9.0Hz,J2=3.0Hz,2H,H-2,6-Ar),6.93-6.91(dd,J1=8.5Hz,J2=2.5Hz,2H,H-3,5-Ar),6.33-6.30(d,J=16.0Hz,1H,O=C-CH=),5.61-5.60(dd,J1=J2=1.5Hz,1H,H-8),5.55-5.54(dd,J1=J2=3.5Hz,1H,H-4),5.51-5.48(d,J=5.5Hz,1H,H-10),3.88-3.87(d,J=5.0Hz,1H,H-2),3.85(s,3H,H-Ar-OCH3),3.68-3.67(d,J=5.0Hz,1H,H-11),3.15-3.14(d,J=4.0Hz,1H,H-13),2.84-2.83(d,J=4.0Hz,1H,H-13),2.57-2.52(dd,J1=J2=9.0Hz,1H,H-3endo),2.09(s,3H,O=CCH3),2.04-1.98(m,2H,H-7exo,3exo),1.93-1.90(dd,J1=J2=1.5Hz,1H,H-7endo),1.75(s,3H,H-16),1.09(s,3H,H-14),0.73(s,3H,H-15);MS ESI+m/z:469.34(M+H)+(100%).
实施例6、化合物(I-10)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-(3,4,5-三甲氧基)苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-10.1H-NMR(500MHz,CDCl3):δ7.64-7.61(d,J=16.0Hz,1H,C=CH-Ar),6.78-6.76(s,2H,H-2,6-Ar),6.36-6.33(d,J=16.0Hz,1H,O=C-CH=),5.61-5.60(dd,J1=J2=1.5Hz,1H,H-8),5.55-5.53(dd,J1=J2=3.5Hz,1H,H-4),5.51-5.48(d,J=5.5Hz,1H,H-10),3.89(s,6H,Ar-3,5-OCH3),3.88(s,3H,Ar-4-OCH3),3.86-3.85(d,J=5.0Hz,1H,H-2),3.68-3.67(d,J=5.5Hz,1H,H-11),3.14-3.13(d,J=4.0Hz,1H,H-13),2.84-2.83(d,J=4.0Hz,1H,H-13),2.56-2.51(dd,J1=J2=9.0Hz,1H,H-3endo),2.17(s,3H,O=CCH3),2.08-1.97(m,2H,H-7exo,3exo),1.93-1.75(dd,J1=J2=1.5Hz,1H,H-7endo),1.75(s,3H,H-16),1.08(s,3H,H-14),0.73(s,3H,H-15);MS ESI+m/z:529.38(M+H)+(100%).
实施例7、化合物(I-15)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-邻溴苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-15.1H-NMR(500MHz,CDCl3):δ8.10-8.07(d,J=16.0Hz,1H,C=CH-Ar),7.64-7.62(m,2H,H-3,5-Ar),7.36-7.33(dd,J1=J2=8.0Hz,1H,H-6-Ar),7.27-7.23(m,1H,H-4-Ar),6.42-6.38(d,J=16.0Hz,1H,O=C-CH=),5.62-5.61(dd,J1=J2=1.5Hz,1H,H-8),5.57-5.54(dd,J1=J2=3.5Hz,1H,H-4),5.51-5.48(dd,J1=J2=6.0Hz,1H,H-10),3.89-3.88(d,J=5.0Hz,1H,H-2),3.69-3.68(d,J=5.5Hz,1H,H-11),3.16-3.15(d,J=4.0Hz,1H,H-13),2.85-2.84(d,J=4.0Hz,1H,H-13),2.57-2.52(dd,J1=J2=9.0Hz,1H,H-3endo),2.09(s,3H,O=CCH3),2.05-1.99(m,2H,H-7exo,3exo),1.96-1.93(dd,J1=J2=1.5Hz,1H,H-7endo),1.77(s,3H,H-16),1.10(s,3H,H-14),0.74(s,3H,H-15);MS ESI+m/z:517.36(M+H)+(100%).
实施例8、化合物(I-18)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-对氟苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-18.1H-NMR(500MHz,CDCl3):δ7.68-7.65(d,J=16.0Hz,1H,C=CH-Ar),7.54-7.51(dd,J1=J2=5.5Hz,2H,H-2,6-Ar),7.11-7.07(dd,J1=J2=8.5Hz,2H,H-3,5-Ar),6.37-6.34(d,J=16.0Hz,1H,O=C-CH=),5.61-5.60(dd,J1=J2=1.0Hz,1H,H-8),5.55-5.53(dd,J1=J2=3.5Hz,1H,H-4),5.50-5.47(dd,J1=J2=6.5Hz,1H,H-10),3.87-3.86(d,J=5.5Hz,1H,H-2),3.68-3.67(d,J=5.5Hz,1H,H-11),3.14-3.13(d,J=4.0Hz,1H,H-13),2.83-2.82(d,J=4.0Hz,1H,H-13),2.56-2.54(dd,J1=J2=9.0Hz,1H,H-3endo),2.17(s,3H,O=CCH3),2.03-1.97(m,2H,H-7exo,3exo),1.93-1.91(dd,J1=J2=1.5Hz,1H,H-7endo),1.74(s,3H,H-16),1.08(s,3H,H-14),0.72(s,3H,H-15);MS ESI+m/z:457.25(M+H)+(100%).
实施例9、化合物(I-19)的合成方法,其反应式为:
具体反应过程如下:
在双口烧瓶中加入二氯甲烷10mL,4-β-乙酰基-8-羟基-12,13-环氧单端胞酶-9-烯毒素(IV)0.5g,加入三乙胺1.0g,10mg DMAP催化剂,冰水浴下慢慢滴入1.1当量摩尔量的β-间三氟甲基苯丙烯酰氯,室温下搅拌反应,TLC检测反应进程。反应结束后,先用10ml二氯甲烷稀释,再用1M的稀盐酸洗涤3次,每次约10ml,饱和食盐水洗涤2次,每次约10ml,3-5g无水硫酸钠干燥,浓缩至干。然后经硅胶柱层析分离(洗脱剂,乙酸乙酯:石油醚=1:3的体积比),得到目标化合物I-19.1H-NMR(500MHz,CDCl3):δ7.77(s,1H,H-2-Ar),7.74-7.71(d,J=16.0Hz,1H,C=CH-Ar),7.71-7.70(dd,J1=8.0Hz,J2=0.5Hz,1H,H-6-Ar),7.65-7.64(d,J=7.5Hz,1H,H-4-Ar),7.55-7.52(m,1H,H-5-Ar),6.52-6.49(d,J=16.0Hz,1H,O=C-CH=),5.62-5.61(dd,J1=J2=1.5Hz,1H,H-8),5.55-5.53(dd,J1=J2=3.5Hz,1H,H-4),5.51-5.49(dd,J1=J2=6.0Hz,1H,H-10),3.88-3.87(d,J=5.0Hz,1H,H-2),3.68-3.67(d,J=5.5Hz,1H,H-11),3.15-3.14(d,J=4.0Hz,1H,H-13),2.83-2.82(d,J=4.0Hz,1H,H-13),2.56-2.52(dd,J1=J2=9.0Hz,1H,H-3endo),2.08(s,3H,O=CCH3),2.04-1.99(m,2H,H-7exo,3exo),1.93-1.90(dd,J1=J2=1.5Hz,1H,H-7endo),1.75(s,3H,H-16),1.09(s,3H,H-14),0.73(s,3H,H-15).13C NMR(100MHz,CDCl3):170.89(O=CCH3),166.05(O=CCH),143.44(CH-Ar),138.71(C9),135.07(C-1-Ar),131.13(C-2-Ar),129.51(C-3-Ar),126.83,126.81(C-4,5-Ar),124.62(Ar-CF3),124.59(C10),119.90(O=CCH),79.38,74.31,71.41,69.89(C2,C11,C8,C4),65.29(C12),49.14,47.70(C5,C6),42.19(C3),36.65(C13),30.95(C7),21.07(C16),18.78(O=CCH3),16.95(C15),5.81(C14);MS ESI+m/z:507.36(M+H)+(100%).
农药制剂实施例
当本发明化合物作农业或园艺应用时,可以是多种形式或剂型,在下面的制剂实施例中举例说明。其中,所用的本发明化合物是列于表1的各个化合物。所有百分数都是重量级的,本发明化合物与前面表1给的号码一致。
制剂实施例1
可湿性粉剂
含10%本发明化合物I-10,2.5%十二烷基苯磺酸钠,2.5%木素磺酸钠,1%分散剂NNO和84%硅藻土的混合物充分混合并磨成粉制成可湿性粉剂。
制剂实施例2
乳油
20%本发明化合物I-1,2%农乳500,3%农乳602,3%乳化剂PE6200,3%PE2520和69%二甲苯的混合物充分混合并制成可乳化的乳油。
制剂实施例3
粒剂
含3%本发明化合物I-8,1%分散剂REAX88A,3%分散剂Wgwin6100,5%木素磺酸钠和88%粘土的混合物充分混合并磨成粉,与水捏合好,然后成粒并干燥制成粒剂。
制剂实施例4
水乳剂
10%本发明化合物I-3,5%乳化剂PE6200,5%农乳603和1%乳化剂REAXWL,1.0%BHT(一种抗氧化剂)溶于20%环己酮中。将溶液与10.0%的防冻剂乙二醇和20.0%醇类溶剂以及28%的水的混合液均匀地乳化剪切制成可乳化的水乳剂。
生物测定实施例
参照《农药生物活性评价SOP》。
小麦赤霉病菌(Gibberella zeae)、小麦白粉病(Blumeria graminis)、黄瓜灰霉病菌(Botrytis cinerea)、水稻纹枯病菌(Rhizoctonia solani)、水稻稻瘟病菌(Pyricularia oryzae)、水稻稻曲病菌(Ustilaginoidea oryzae):参照生测标准方法NY/T1156.2-2006,采用含药培养基法:取表1中的各化合物药液,加入冷却至45℃的PDA中,制成含药培养基平板,浓度为50mg/L。然后从培养好的试验病菌菌落边缘取6.5mm直径菌丝块,移至含药培养基上,每处理4次重复。处理完毕,置于28℃的恒温生化培养箱中培养,4天后测量菌落直径,计算生长抑制率。
试验设药剂对照和溶剂对照。
处理后定期观察记录叶片、植株的发病情况和菌丝生长情况,根据病情指数和菌丝直径,计算防效和抑制率。
生长抑制率(%)=(对照菌落直径-处理菌落直径)×100/(对照菌落直径-6mm)。
具体试验结果与数据(浓度为50mg/L,抑制率≥85%)见表2:
表2.所有新化合物杀菌活性毒力普筛测定结果
在50mg/L的浓度下大部分新化合物对黄瓜灰霉病菌、小麦赤霉病菌、小麦白粉病、水稻纹枯病菌及水稻稻曲病菌都有不同程度的杀菌活性。其中化合物I-1、I-2和I-3对水稻纹枯病菌,I-1、I-2、I-3、I-7和I-8对小麦白粉病菌,I-1、I-2和I-3对赤霉病菌表现出良好的抑制活性,配制成制剂后活性会更高,可以进一步开发为商品杀菌剂。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (3)
1.木霉菌素C8不饱和酸酯衍生物,其特征是该木霉菌素C8不饱和酸酯衍生物的结构通式为:
所述结构通式中的R为下表中所示的任意一种:
2.根据权利要求1所述的木霉菌素C8不饱和酸酯衍生物的用途,其特征是:用于抑制植物病原真菌,作为农业和/或园艺上的杀菌剂。
3.根据权利要求2所述的木霉菌素C8不饱和酸酯衍生物的用途,其特征是:所述植物病原真菌为小麦赤霉病菌(Gibberella zeae)、小麦白粉病(Blumeria graminis)、黄瓜灰霉病菌(Botrytis cinerea)、水稻纹枯病菌(Rhizoctonia solani)、水稻稻瘟病菌(Pyricularia oryzae)或水稻稻曲病菌(Ustilaginoidea oryzae)。
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CN101787031A (zh) * | 2010-03-04 | 2010-07-28 | 建德市大洋化工有限公司 | 木霉菌素类衍生物及其防治病原菌的用途 |
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