CN107721956B - 苯并丁内酯类衍生物、合成方法及其制备杀菌剂的应用 - Google Patents

苯并丁内酯类衍生物、合成方法及其制备杀菌剂的应用 Download PDF

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CN107721956B
CN107721956B CN201710807283.4A CN201710807283A CN107721956B CN 107721956 B CN107721956 B CN 107721956B CN 201710807283 A CN201710807283 A CN 201710807283A CN 107721956 B CN107721956 B CN 107721956B
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冯俊涛
吴永玲
王德龙
韩立荣
王智辉
周一万
张兴
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Abstract

本发明公开了苯并丁内酯类衍生物、合成方法及其制备杀菌剂的应用，以倍半萜内酯类药效团α‑亚甲基‑γ‑丁内酯为先导化合物，整合苯并呋喃酮药效团，在其α‑亚甲基位置进行修饰、定向衍生合成出一系列α‑亚烯基苯并丁内酯化合物，并测定了这类化合物的抑菌活性，在此构效基础上合成了2个具产业化开发前景的高活性化合物。用于防治小麦白粉病、小麦赤霉病、小麦全蚀病、小麦纹枯病、玉米大斑病、水稻纹枯病、水稻稻瘟病、棉花立枯病、辣椒疫霉病、番茄灰霉病、番茄叶霉病、番茄早晚疫病、黄瓜炭疽病、黄瓜枯萎病、油菜菌核病等病原菌引起的植物病害。

Description

苯并丁内酯类衍生物、合成方法及其制备杀菌剂的应用
技术领域
本发明属于化学的新化合物领域，具体涉及苯并丁内酯类衍生物、合成方法及其制 备杀菌剂的应用。
背景技术
寻找高效、低毒、低残留的生物源农药是目前国内外农药学领域研究的热点之一。α-亚甲基-γ-丁内酯是倍半萜内酯类化合物的主要药效团，在我们前期研究过程中， α-亚甲基-γ-丁内酯类化合物具有较好的抑菌活性，且苯并呋喃酮类化合物具有抗菌、 抗过敏、抗HIV和抗肿瘤等多种药理作用。因此本发明整合这两种药效团，在其α-亚 甲基位置进行修饰、定向衍生合成出一系列α-亚烯基苯并丁内酯化合物，为开发高活 性杀菌剂鉴定基础。
发明内容
本发明涉及一种具杀菌活性的苯并丁内酯衍生物，特别是，在此基础上得到的两种 具产业化开发前景的高活性化合物及其作为杀菌剂在防治植物病害方面的应用。本发明 的目的在于提供一类具杀菌活性的苯并丁内酯类衍生物作为杀菌剂在防治植物病害方应用。
为了实现上述任务，本发明采取如下的技术解决方案：
苯并丁内酯类衍生物，该类衍生物的结构通式如式(一)所示：
Figure BDA0001403008810000011
R基团选自单取代苯基、双取代芳基、饱和直连烷基、含S杂环芳基、含N杂环芳 基、含O杂环芳基和多环芳基中的一种。
具体的，R基团的结构如表1所示：
表1
Figure BDA0001403008810000012
Figure BDA0001403008810000021
苯并丁内酯类衍生物的合成方法，包括将邻羟基苯乙酸与对甲苯磺酸的摩尔比为10:1混合后在120～130℃下回流4h得到苯并呋喃酮；苯并呋喃酮与取代苯甲醛的摩尔 比为1:2混合后再加入10ml三乙胺和15ml乙酸酐于80℃下回流12h得到反应产物，反 应产物经萃取纯化后即得苯并丁内酯类衍生物。
还有，包括式(二)和式(三)的化合物：
Figure BDA0001403008810000031
所述的式(二)和式(三)的化合物的制备方法包括：
对R邻羟基苯甲酸50mmol、硫粉100mmol和对甲苯磺酸1.75mmol混合后在120～130℃下回流8h，再加入质量浓度是20％的氢氧化钠水溶液10ml和四丁基溴化胺1.25 mmol在100℃下水解反应8h，调节pH为7得到3-R邻羟基苯乙酸；
5mmol 3-R邻羟基苯乙酸与15mL氯氧化磷在50mL二氯甲烷中搅拌16h，得到的 产物经水洗干燥纯化后得到3-R苯并呋喃酮；
1.5mmol的3-R苯并呋喃酮与3mmol的对三氟苯甲醛在pH为8的环境中加入10mL 浓度为10mol/L氢氧化钾乙醇溶液并在室温下搅拌14h得到的粗产物，调节粗产物的 pH为7，再将粗产物依次经萃取、水洗、干燥和纯化后得到对三氟甲基苯(3-R)苯并丁 内酯；
R为氟或***。
所述的苯并丁内酯类衍生物用于制备植物杀菌剂的应用。
所述的苯并丁内酯类衍生物可用于制备防治由植物病原真菌引起的植物病害的农 药制剂。
所述的植物原病菌引起的植物病害包括：小麦白粉病、小麦赤霉病、小麦全蚀病、小麦纹枯病、玉米大斑病、水稻纹枯病、水稻稻瘟病、棉花立枯病、辣椒疫霉病、番茄 灰霉病、番茄叶霉病、番茄早晚疫病、黄瓜炭疽病、黄瓜枯萎病和油菜菌核病。
所述的农药制剂的形态包括可湿性粉剂、乳油、微乳剂、可溶性液剂、水剂、水分散粒剂、水乳剂、颗粒剂和悬浮剂。
所述的农药制剂与百菌清或其他商品化杀菌剂混配制成复合的可湿性粉剂、乳油、 微乳剂、可溶性液剂、水剂、水分散粒剂、水乳剂、颗粒剂或悬浮剂。
本发明的优点包括：
本发明的具杀菌活性的苯并丁内酯类衍生物具有较为谱的强杀菌活性，其α-亚烯基位取代基电负性强弱对该类化合物的杀菌活性具有重要影响，将α-亚甲基改造为α- 亚烯基，生成一系列衍生物，所得化合物的杀菌活性均有所提高，且当苯并丁内酯苯环 上改造为带含氟基团和具杀菌活性的***基团时，杀菌活性大大提高。
附图说明
图1为化合物4-氟苯基苯并丁内酯的1H NMR图谱；
图2为化合物4-氟苯基苯并丁内酯的13C NMR图谱；
图3为化合物4-氟苯基苯并丁内酯的HR-MS(ESI)图谱；
图4为化合物2-吡啶苯并丁内酯的1H NMR图谱；
图5为化合物2-吡啶苯并丁内酯的13C NMR图谱；
图6为化合物2-吡啶苯并丁内酯的HR-MS(ESI)图谱；
以下结合说明书附图和具体实施方式对本发明做具体说明。
具体实施方式
以药效团α-亚甲基-γ-丁内酯为先导化合物，利用药效团与骨架整合策略合成一系列苯并丁内酯类化合物，以番茄灰霉病菌和黄瓜炭疽病菌为供试菌种测定抑菌活性， 通过构效关系分析，推测高活性化合物的理想结构，并合成了2个具产业化开发前景的 高活性化合物。
具杀菌活性的苯并丁内酯类衍生物，该类衍生物的结构通式如式(一)所示，各化合物名称及取代基团(R基团)结构如表1所示。
Figure BDA0001403008810000041
表1
Figure BDA0001403008810000042
Figure BDA0001403008810000051
苯并丁内酯衍生物的合成:
苯并丁内酯类衍生物按以下路线合成：
Figure BDA0001403008810000052
即：取邻羟基苯乙酸3g(19.7mmol)，对甲苯磺酸1.75mmol，在120～130℃下回 流4h，得到苯并呋喃酮粗产物，选取石油醚/乙酸乙酯体系的硅胶柱层析技术对产物进 行分离纯化。再将苯并呋喃酮1.5mmol，取代苯甲醛3mmol，10ml三乙胺，15ml乙 酸酐加入圆底烧瓶中，80℃下回流12h。TLC跟踪监测至反应完成后，真空条件下将产 物旋干，乙酸乙酯萃取三次，收集乙酸乙酯相用无水硫酸钠干燥过夜，真空旋干产物。
根据反应粗产物极性大小选用石油醚/二氯甲烷、石油醚/乙酸乙酯、石油醚/丙酮、 石油醚/二氯甲烷/乙酸乙酯中的某一展开体系，调整至适当配比，综合运用重结晶、硅胶柱层析、制备薄层色谱等技术进行分离、纯化，分别得到一系列的苯并丁内酯类衍生 物，根据加入的不同的取代苯甲醛最终得到携带不同R基团的苯并丁内酯类衍生物。
以取代基R为苯基举例说明纯化过程：将得到的粗产物苯基苯并丁内酯分别用体积 比为10:1的石油醚/二氯甲烷、石油醚/乙酸乙酯和石油醚/丙酮三种溶剂体系在薄层层析板上展开，其中石油醚/二氯甲烷和石油醚/丙酮两种体系均无法分开产物和杂志斑点，而石油醚/乙酸乙酯溶剂体系则使产物点和杂质点完全分开，因此选择石油醚/乙酸乙酯溶剂作为硅胶柱层析洗脱剂。柱层析采用湿法装柱、上样，梯度洗脱，洗脱剂：石油醚： 乙酸乙酯(V/V)＝20:1→10:1，薄层层析法跟踪监测产物，旋转蒸发仪减压浓缩收集的洗 脱剂，得最终产物(产率90％，纯度90％)。为得到纯度较高的化合物，将得到的产物利 用石油醚：乙酸乙酯溶剂体系进行重结晶，挑取1g左右产物放入100mL烧杯中，加 入10mL乙酸乙酯溶液使其完全溶解，然后加入80mL左右石油醚并搅拌均匀，将烧杯 放在通风处晾置2d左右直至黄色晶体析出在烧杯壁上，用药勺轻轻刮下则可得纯度99％ 以上的终产物苯基苯并丁内酯，最终产率在80％左右。其他化合物可按照上述方法进行 纯化。
2、取代苯并丁内酯类衍生物的合成:
本发明的苯并丁内酯类衍生物还包括式(二)和式(三)的化合物；
Figure BDA0001403008810000061
取代苯并丁内酯类衍生物按以下路线合成：
Figure BDA0001403008810000062
即：取对R邻羟基苯甲酸50mmol，硫粉100mmol，对甲苯磺酸1.75mmol，在120～ 130℃下回流8小时，TLC跟踪监测至反应完成后，再加入质量浓度为20％的氢氧化钠水 溶液10ml和四丁基溴化胺1.25mmol，在100℃下水解反应8h，并用盐酸调节pH＝7 得到粗产物A(3-R邻羟基苯乙酸)。5mmol粗产物A与15mL氯氧化磷在50mL二氯甲 烷中搅拌16h，得到的产物用二氯甲烷、水分别水洗后干燥过夜，选取石油醚/乙酸乙 酯体系的硅胶柱层析技术对得到的产物进行分离纯化得到产物B(3-R苯并呋喃酮)。1.5 mmol的产物B与3mmol的对三氟苯甲醛在pH为8的环境中加入10mL浓度为10mol/L 氢氧化钾乙醇溶液并在室温下搅拌14h，得到的粗产物用盐酸调节pH为7，乙酸乙酯 萃取后用水、卤水(饱和氯化钠溶液)水洗。无水硫酸钠干燥过夜后选取石油醚/乙酸 乙酯体系的硅胶柱层析技术对产物进行分离纯化得到最终产物C(对三氟甲基苯(3-R) 苯并丁内酯)，R为氟原子或***基团。
3.化合物的理化性质及波谱数据
苯基苯并丁内酯：产率80％，黄色晶体；mp:116.1-117.3℃；1H NMR(500MHz,CDCl3)δ8.19(dd,J＝6.5,2.9Hz,2H),7.63(s,1H),7.55(d,J＝7.6Hz,1H), 7.51-7.47(m,3H),7.37-7.31(m,1H),7.19(t,J＝7.6Hz,1H),7.11(d,J＝ 8.0Hz,1H).13C NMR(126MHz,CDCl3):δ165.90,153.05,140.35,133.17,132.02, 131.19,129.91,128.75,125.42,123.75,120.84,119.45,111.06.HR-MS(ESI): m/z calcd for C15H10O2([M+Na]+)222.0681,found 245.0573.
2-氯苯基苯并丁内酯：产率86％，黄色晶体；mp:128.3-129.1℃；1H NMR(500 MHz,CDCl3)δ7.92(s,1H),7.75(dd,J＝7.5,1.6Hz,1H),7.54-7.50(m,1H), 7.46-7.42(m,2H),7.40-7.36(m,1H),7.34(ddd,J＝8.7,5.5,1.2Hz,1H),7.12 (d,J＝8.1Hz,1H),7.00(td,J＝7.7,0.9Hz,1H).13C NMR(126MHz,CDCl3): δ168.20,154.67,137.05,135.73,135.18,134.65,132.55,131.60,131.43, 129.79,126.83,122.98,121.47,120.23,111.31.HR-MS(ESI):m/z calcd for C15H9ClO2([M+H]+)256.0291,found 257.0364.
3-氯苯基苯并丁内酯：产率82％，黄色晶体；mp:131.2-132.2℃；1H NMR(500MHz,CDCl3)δ8.17(s,1H),8.08(d,J＝7.2Hz,1H),7.55(d,J＝6.0Hz,2H),7.45-7.40 (m,2H),7.39-7.35(m,1H),7.20(t,J＝7.4Hz,1H),7.13(d,J＝8.0Hz,1H). 13C NMR(126MHz,CDCl3):δ166.10,153.34,138.07,134.73，134.53，131.47,131.05, 130.46,129.81,129.76,124.97,123.93,122.88,119.64,111.21.HR-MS(ESI): m/z calcd for C15H9ClO2([M+H]+)256.0291,found 257.0364.
4-氯苯基苯并丁内酯：产率84％，黄色晶体；mp:127.4-128.7℃；1H NMR(500MHz,CDCl3)δ8.15(d,J＝8.6Hz,2H),7.58-7.53(m,2H),7.45(d,J＝8.6Hz,2H), 7.36(td,J＝7.9,1.1Hz,1H),7.22-7.17(m,1H),7.12(d,J＝8.0Hz,1H). 13C NMR(126MHz,CDCl3):δ165.88,153.14,138.57,137.41,133.26,131.61,130.94, 130.19,128.91,125.18,123.91,121.37,119.49,110.95,101.04.HR-MS(ESI): m/z calcd for C15H9ClO2([M+H]+)256.0291,found 257.0364.
2-溴苯基苯并丁内酯：产率88％，黄色晶体；mp:148.8-149.7℃；1H NMR(500 MHz,CDCl3)δ8.19(dd,J＝7.8,1.2Hz,1H),7.89(d,J＝4.0Hz,1H),7.67 (d,J＝8.0Hz,1H),7.62(d,J＝7.6Hz,1H),7.41(t,J＝6.5Hz,1H),7.38-7.34 (m,1H),7.33-7.28(m,1H),7.22(t,J＝7.6Hz,1H),7.13(t,J＝6.5Hz,1H). 13C NMR(126MHz,CDCl3):δ166.52,153.37,138.67,138.20,132.75,132.12,131.89, 130.64,129.87,127.25,125.42,124.56,123.89,120.23,111.03.HR-MS(ESI): m/z calcd for C15H9BrO2([M+Na]+)299.9786,found322.9678.
3-溴苯基苯并丁内酯：产率79％，黄色固体；mp:149.6-150.4℃；1H NMR(500MHz,CDCl3)δ8.29(s,1H),8.15(d,J＝7.9Hz,1H),7.60(d,J＝9.5Hz,1H),7.55 (d,J＝10.0Hz,2H),7.40-7.34(m,2H),7.20(t,J＝7.6Hz,1H),7.13(d,J ＝8.1Hz,1H).13C NMR(126MHz,CDCl3):δ166.84,154.13,138.02,135.40,134.42, 133.96,130.49,130.22,130.05,128.00,125.22,123.96,122.73,119.66,111.02. HR-MS(ESI):m/z calcd for C15H9BrO2([M+Na]+)299.9786,found 322.9678.
4-溴苯基苯并丁内酯：产率88％，黄色固体；mp:142.1-143.2℃；1H NMR(500MHz,CDCl3)δ8.07(d,J＝8.5Hz,2H),7.63-7.58(m,2H),7.55(d,J＝6.3Hz,2H), 7.36(td,J＝7.9,1.2Hz,1H),7.19(td,J＝7.6,0.8Hz,1H),7.12(d,J＝ 8.0Hz,1H).13C NMR(126MHz,CDCl3):δ166.50,153.15,138.62,133.35,132.00, 131.89,130.24,126.02,125.17,123.93,122.44,119.52,110.97.HR-MS(ESI): m/z calcd for C15H9BrO2([M+Na]+)299.9786,found 322.9678.
2-氟苯基苯并丁内酯：产率83％，黄色固体；mp:135.1-135.3℃；1H NMR(500MHz,CDCl3)δ8.22(m,1H),8.14(s,1H),7.59(s,1H),7.56(d,J＝7.7Hz,1H),7.36(m, 1H),7.22(d,J＝7.9Hz,1H),7.16(d,J＝2.3Hz,1H),7.13(s,1H),7.10(d, J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ165.34,165.25,163.15,153.32,137.55, 133.21,128.73,124.54,122.21,119.65,116.21,113.43,110.65.HR-MS(ESI): m/z calcd for C15H9FO2([M+H]+)240.0587,found 241.0659.
3-氟苯基苯并丁内酯：产率81％，黄色固体；mp:136.1-137.2℃；1H NMR(500 MHz,CDCl3)δ8.26(s,1H),8.16(s,1H),7.55(s,1H),7.52(d,J＝7.7Hz,1H), 7.34(m,1H),7.22(d,J＝7.9Hz,1H),7.32(d,J＝2.3Hz,1H),7.15(s,1H), 7.14(d,J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ165.72,164.52,163.16,151.23, 139.69,135.52,125.76,124.36,123.84,119.87,115.65,113.32,110.20.HR-MS (ESI):m/z calcd for C15H9FO2([M+H]+)240.0587,found 241.0659.
4-氟苯基苯并丁内酯：产率80％，黄色固体；mp:137.4-138.1℃；1H NMR(500MHz,CDCl3)δ8.30-8.17(m,2H),7.59(s,1H),7.54(d,J＝7.7Hz,1H),7.38-7.32 (m,1H),7.20(d,J＝7.9Hz,1H),7.18(d,J＝2.3Hz,1H),7.17(s,1H),7.12 (d,J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ166.62,165.52,163.36,153.03, 138.89,134.51,129.75,125.33,123.85,119.34,115.92,115.75,110.90.HR-MS (ESI):m/z calcd for C15H9FO2([M+H]+)240.0587,found 241.0659.其氢谱、碳谱 和质谱图分别见图1、2和3。
2-甲基苯基苯并丁内酯：产率81％，黄色油状物；1H NMR(500MHz,CDCl3)δ7.98 (s,1H),7.65(d,J＝7.6Hz,1H),7.43(t,J＝6.8Hz,1H),7.39(d,J＝7.5 Hz,1H),7.32(dd,J＝16.1,7.1Hz,3H),7.14(d,J＝8.1Hz,1H),6.99(t, J＝7.7Hz,1H),2.44(s,3H).13C NMR(126MHz,CDCl3):δ168.68,154.45,140.06, 137.80,133.22,130.88,130.82,130.58,128.26,125.85,123.77 122.93,121.99, 119.77,111.03,20.11.HR-MS(ESI):m/z calcdfor C16H12O2([M+H]+)236.0837, found 237.0910.
3-甲基苯基苯并丁内酯：产率87％，黄色晶体；mp:155.2-156.2℃；1H NMR(500MHz,CDCl3)δ8.04(d,J＝7.8Hz,1H),7.98(s,1H),7.61(s,1H),7.54(d, J＝7.6Hz,1H),7.38(t,J＝7.7Hz,1H),7.36-7.31(m,1H),7.30(d,J＝7.6 Hz,1H),7.18(t,J＝7.6Hz,1H),7.11(d,J＝8.0Hz,1H),2.44(s,3H).13C NMR(126MHz,CDCl3):δ165.90,153.00,140.63,138.22,133.14,132.65,132.30, 129.77,129.19,128.52,125.54,123.70,120.57,119.35,111.02,21.41.HR-MS (ESI):m/z calcd for C16H12O2([M+H]+)236.0837,found237.0910.
4-甲基苯基苯并丁内酯：产率75％，黄色固体；mp:156.8-157.7℃；1H NMR(500MHz,CDCl3)δ8.13(d,J＝8.2Hz,1H),7.86(s,1H),7.80(d,J＝7.7Hz,1H), 7.64-7.59(m,2H),7.34(d,J＝7.7Hz,2H),7.15(t,J＝6.1Hz,1H),7.06(td, J＝7.7,0.9Hz,1H),2.46(s,3H).13C NMR(126MHz,CDCl3):δ169.18,154.42, 141.31,140.55,132.26,131.25,130.66,129.57,123.65,122.73,122.09,119.21, 111.19,21.75.HR-MS(ESI):m/z calcd forC16H12O2([M+H]+)236.0837,found 237.0910.
2-甲氧基苯基苯并丁内酯：产率86％，黄色固体；mp:176.4-177.5℃；1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.72(d,J＝7.6Hz,1H),7.63(d,J＝7.7Hz,1H), 7.49-7.43(m,1H),7.32-7.27(m,1H),7.09(d,J＝8.0Hz,1H),7.06-7.03(m, 1H),7.01(d,J＝7.9Hz,1H),6.98(d,J＝8.3Hz,1H),3.87(s,3H).13C NMR (126MHz,CDCl3):δ169.00,158.44,153.54,137.41,132.63,130.56,129.52, 123.65,122.76,122.10,121.59,120.61,119.74,111.19,110.78,55.67.HR-MS (ESI):m/z calcd for C16H12O3([M+Na]+)252.0786,found275.0679.
3-甲氧基苯基苯并丁内酯：产率81％，黄色固体；mp:172.1-172.2℃；1H NMR(500MHz,CDCl3)δ7.87(s,1H),7.80(d,J＝7.8Hz,1H),7.62(s,1H),7.45(t, J＝7.9Hz,1H),7.32-7.28(m,1H),7.24-7.19(m,1H),7.17(d,J＝8.0Hz,1H), 7.09(t,J＝6.0Hz,1H),7.06(dd,J＝8.8,2.1Hz,1H),3.89(s,3H).13C NMR (126MHz,CDCl3):δ168.93,159.70,154.56,140.83,135.29,130.99,129.94, 125.32,123.75,123.03,121.81,119.44,116.41,114.41,111.24,55.44.HR-MS (ESI):m/z calcd for C16H12O3([M+Na]+)252.0786,found275.0679.
4-甲氧基苯基苯并丁内酯：产率83％，黄色固体；mp:174.5-175.4℃；1H NMR(500MHz,CDCl3)δ8.31(d,J＝8.8Hz,2H),7.57(s,1H),7.53(d,J＝7.6Hz,1H), 7.36(dd,J＝13.3,5.3Hz,1H),7.20(d,J＝7.6Hz,1H),7.17(d,J＝8.0Hz, 1H),7.01(d,J＝8.9Hz,2H),3.92(s,3H).13C NMR(126MHz,CDCl3):δ166.43, 162.02,152.60,140.32,134.71,131.78,130.38,129.02,126.48,126.01,123.60, 122.34,118.90,114.24,110.63,55.51.HR-MS(ESI):m/z calcd for C16H12O3([M+ Na]+)252.0786,found 275.0679.
2-羟基苯基苯并丁内酯：产率66％，黄色固体；mp:167.2-168.2℃；1H NMR(500MHz,CDCl3)δ7.82(s,1H),7.79(d,J＝7.7Hz,1H),7.51(d,J＝5.5Hz,2H), 7.42(s,1H),7.42(m,1H),7.21(dd,J＝3.3,2.1Hz,1H),7.16(d,J＝8.0 Hz,1H),7.08(t,J＝7.7Hz,1H).13C NMR(126MHz,CDCl3):δ168.27,155.67, 152.93,137.48,135.44,132.29,130.55,127.53,124.62,123.54,121.25,120.41, 120.11,119.68,114.03.HR-MS(ESI):m/z calcdfor C15H10O3([M+H]+)238.0630, found 239.0703.
3-羟基苯基苯并丁内酯：产率61％，黄色固体；mp:172.4-173.6℃；1H NMR(500MHz,CDCl3)δ7.81(s,1H),7.75(d,J＝7.4Hz,1H),7.45(d,J＝5.5Hz,2H), 7.41(s,1H),7.27(m,1H),7.21(dd,J＝3.3,2.1Hz,1H),7.15(d,J＝8.0 Hz,1H),7.10(t,J＝7.7Hz,1H).13C NMR(126MHz,CDCl3):δ168.65,156.45, 152.96,138.98,135.42,132.29,131.65,128.86,123.92,123.81,123.05,122.41, 121.55,118.58,110.09.HR-MS(ESI):m/z calcdfor C15H10O3([M+H]+)238.0630, found 239.0703.
4-羟基苯基苯并丁内酯：产率61％，黄色固体；mp:173.4-174.2℃；1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.82(d,J＝7.7Hz,1H),7.56(d,J＝5.5Hz,2H), 7.48(s,1H),7.42-7.37(m,1H),7.24(dd,J＝3.3,2.1Hz,1H),7.18(d,J＝ 8.0Hz,1H),7.12(t,J＝7.7Hz,1H).13C NMR(126MHz,CDCl3):δ169.25,154.65, 150.91,139.08,135.42,131.29,130.05,126.83,123.92,123.51,123.25,122.41, 119.58,111.09.HR-MS(ESI):m/z calcdfor C15H10O3([M+H]+)238.0630,found 239.0703.
2-硝基苯基苯并丁内酯：产率66％，黄色固体；mp:187.6-188.2℃；1H NMR(500MHz,CDCl3)δ8.27(d,J＝8.9Hz,1H),8.03(d,J＝8.5Hz,1H),7.79(s,1H), 7.75(d,J＝2.9Hz,2H),7.56(d,J＝7.8Hz,1H),7.42(t,J＝7.8Hz,2H), 7.19(d,J＝8.1Hz,1H),7.09(dd,J＝11.2,4.2Hz,1H).13C NMR(126MHz,CDCl3): δ156.07,142.50,138.15,136.44,135.32,134.12,132.26,130.00,126.34, 124.54,124.38,123.23,122.94,122.57,110.69.HR-MS(ESI):m/z calcd for C15H9NO5 ([M-H]+)283.0481,found 282.0408.
3-羟基苯基苯并丁内酯：产率63％，黄色固体；mp:189.4-189.2℃；1H NMR(500MHz,CDCl3)δ8.25(d,J＝8.9Hz,1H),8.23(d,J＝8.9Hz,1H),7.79(s,1H), 7.73(d,J＝2.3Hz,2H),7.56(d,J＝7.8Hz,1H),7.42(t,J＝7.8Hz,2H), 7.19(d,J＝7.1Hz,1H),7.01(dd,J＝10.2,4.2Hz,1H).13C NMR(126MHz,CDCl3): δ156.57,143.59,138.34,136.84,132.76,132.43,131.04,130.00,126.75, 124.71,124.48,123.64,122.64,122.54,112.65.HR-MS(ESI):m/z calcd for C15H9NO5 ([M-H]+)283.0481,found 282.0408.
4-羟基苯基苯并丁内酯：产率64％，黄色固体；mp:186.4-187.2℃；1H NMR(500MHz,CDCl3)δ8.31(d,J＝8.9Hz,1H),8.26(d,J＝8.9Hz,1H),7.85(s,1H), 7.84(d,J＝2.9Hz,2H),7.56(d,J＝7.8Hz,1H),7.42(t,J＝7.8Hz,2H), 7.19(d,J＝8.1Hz,1H),7.08(dd,J＝11.2,4.2Hz,1H).13C NMR(126MHz,CDCl3): δ155.07,140.50,139.12,136.84,132.26,130.00,124.35,124.21,124.08, 123.64,122.94,120.17,111.74.HR-MS(ESI):m/z calcd for C15H9NO5([M-H]+) 283.0481,found 282.0408.
2-氰基苯基苯并丁内酯：产率62％，黄色固体；mp:134.5-135.2℃；1H NMR(500MHz,CDCl3)δ7.80(d,J＝8.2Hz,3H),7.78-7.71(m,2H),7.56(d,J＝7.8Hz, 1H),7.42(m,1H),7.13(d,J＝8.1Hz,1H),7.07(t,J＝7.7Hz,1H).13C NMR (126MHz,CDCl3):δ169.44,155.65,138.21,135.21,132.66,132.70,129.80, 128.86,124.90,124.02,122.79,121.07,118.28,115.65,110.69.HR-MS(ESI): m/z calcd for C16H9NO2([M-H]+)247.0633,found 246.0561.
3-氰基苯基苯并丁内酯：产率65％，黄色固体；mp:132.2-133.5℃；1H NMR(500MHz,CDCl3)δ7.81(d,J＝8.2Hz,3H),7.82-7.27(m,2H),7.52(d,J＝7.8Hz, 1H),7.42(m,1H),7.14(d,J＝8.1Hz,1H),7.09(t,J＝7.7Hz,1H).13C NMR (126MHz,CDCl3):δ169.11,156.99,139.62,137.65,137.21,132.66,132.10, 129.80,124.40,124.02,123.89,121.07,118.87,113.45,111.32.HR-MS(ESI): m/z calcd for C16H9NO2([M-H]+)247.0633,found 246.0561.
4-氰基苯基苯并丁内酯：产率62％，黄色固体；mp:137.6-138.6℃；1H NMR(500MHz,CDCl3)δ7.81(d,J＝8.2Hz,3H),7.79-7.75(m,2H),7.56(d,J＝7.8Hz, 1H),7.44-7.38(m,1H),7.18(d,J＝8.1Hz,1H),7.07(t,J＝7.7Hz,1H).13C NMR(126MHz,CDCl3):δ168.11,154.99,138.62,137.38,132.66,132.10,129.80, 124.90,124.02,122.89,121.07,118.18,113.65,111.68.HR-MS(ESI):m/z calcd for C16H9NO2([M-H]+)247.0633,found246.0561.
4-乙基苯基苯并丁内酯：产率84％，黄色固体；mp:111.6-112.7℃；1H NMR(500MHz,CDCl3)δ8.16(d,J＝8.2Hz,2H),7.62(s,1H),7.54(dd,J＝7.6,0.6 Hz,1H),7.33(s,2H),7.31(s,1H),7.18(td,J＝7.6,0.8Hz,1H),7.11(d, J＝8.0Hz,1H),2.75-2.70(m,2H),1.28(d,J＝7.6Hz,3H).13C NMR(126MHz, CDCl3):δ166.10,152.88,148.06,140.57,132.38,130.77,129.53,128.22,125.70, 123.65,119.72,119.22,110.98,29.04,15.22.HR-MS(ESI):m/z calcd for C17H14O2 ([M+Na]+)250.0994,found 273.0886.
4-三氟甲基苯基苯并丁内酯：黄色油状物；1H NMR(500MHz,CDCl3)δ8.23(d, J＝7.9Hz,2H),7.72(d,J＝7.8Hz,2H),7.65(d,J＝11.5Hz,1H),7.58(d, J＝7.1Hz,1H),7.41-7.37(m,1H),7.22(t,J＝7.1Hz,1H),7.14(d,J＝8.0 Hz,1H).13C NMR(126MHz,CDCl3):δ165.55,153.45,137.71,136.19,131.77, 130.83,127.31,127.27,125.43,124.73,124.07,123.28,119.89,111.10.HR-MS (ESI):m/z calcd for C16H9F3O2([M+Na]+)290.0555,found 313.0447.
甲基苯并丁内酯：产率86％，灰色固体；mp:89.3-90.5℃；1H NMR(500MHz,CDCl3) δ7.61-7.58(m,2H),7.26(td,J＝7.8,1.3Hz,1H),7.14(td,J＝7.6,0.9 Hz,1H),7.09(d,J＝7.8Hz,1H),4.15(s,3H).13C NMR(126MHz,CDCl3):δ169.68, 160.03,151.46,128.02,124.46,122.64,122.48,110.20,103.47,63.67.HR-MS (ESI):m/z calcd for C10H8O2([M+Na]+)160.0524,found 183.0416.
乙基苯并丁内酯：产率82％，灰色固体；mp:86.6-87.9℃；1H NMR(500MHz,CDCl3) δ7.66(s,1H),7.59(t,J＝6.3Hz,1H),7.24(td,J＝7.8,1.3Hz,1H),7.13 (td,J＝7.6,0.8Hz,1H),7.08(d,J＝8.0Hz,1H),4.36(q,J＝7.1Hz,2H), 1.50(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3):δ169.85,158.78,151.57, 127.89,123.65,122.69,122.65,110.12,103.30,72.85,15.50.HR-MS(ESI):m/z calcd for C11H10O2([M+Na]+)174.0681,found197.0573.
2-萘基苯并丁内酯：产率84％，黄色固体；mp:188.2-189.7℃；1H NMR(500MHz,CDCl3)δ8.66(s,1H),8.35(dd,J＝8.7,1.6Hz,1H),7.95(d,J＝7.9Hz,1H), 7.93-7.88(m,1H),7.86(d,J＝8.0Hz,1H),7.75(d,J＝9.0Hz,1H),7.58(d, J＝7.7Hz,2H),7.55(dd,J＝4.3,1.4Hz,1H),7.39-7.32(m,1H),7.23-7.17 (m,1H),7.13(d,J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ166.03,153.06, 140.33,134.57,133.51,133.00,130.90,129.84,129.30,128.15,128.12,128.07, 127.71,126.64,125.62,123.81,120.78,119.40,110.85.HR-MS(ESI):m/z calcd for C19H12O2([M+H]+)272.0837,found 273.0910.
9-蒽基苯并丁内酯：产率86％，黄色固体；mp:187.3-188.2℃；1H NMR(500MHz,CDCl3)δ8.69(d,J＝8.7Hz,1H),8.58(s,1H),8.10(d,J＝8.4Hz,2H),8.02 (t,J＝6.3Hz,2H),7.56-7.51(m,2H),7.48(dt,J＝11.9,9.2Hz,2H),7.24-7.17 (m,1H),7.13(d,J＝8.0Hz,1H),6.61(t,J＝7.6Hz,1H),6.00(d,J＝7.7 Hz,1H).13C NMR(126MHz,CDCl3):δ168.01,154.64,137.02,131.21,130.85, 129.37,129.20,128.91,127.25,127.07,126.65,125.80,125.34,124.39,123.72, 121.97,110.74.HR-MS(ESI):m/z calcd forC23H14O2([M+H]+)322.0994,found 323.1067.
4-异丙基苯基苯并丁内酯：产率73％，黄色固体；mp:162.4-163.5℃；1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.84(d,J＝7.7Hz,1H),7.65(d,J＝8.1Hz,2H), 7.36(dd,J＝12.3,8.3Hz,4H),7.14(d,J＝8.0Hz,1H),3.01-2.96(m,1H), 1.33(d,J＝6.9Hz,6H).13CNMR(126MHz,CDCl3):δ169.24,154.41,152.19, 141.35,132.45,130.85,129.67,126.91,123.67,122.78,122.09,119.26,111.18, 34.32,23.76.HR-MS(ESI):m/z calcd forC18H16O2([M+Na]+)264.1150,found 287.1043.
2,4二氯苯苯并丁内酯：产率83％，黄色固体；mp:145.2-146.2℃；1H NMR(500MHz,CDCl3)δ7.84(s,1H),7.71(d,J＝8.3Hz,1H),7.55(d,J＝1.9Hz,1H), 7.42(d,J＝7.7Hz,1H),7.38(dd,J＝8.5,2.3Hz,2H),7.14(t,J＝8.5Hz, 1H),7.03(t,J＝7.7Hz,1H).13C NMR(126MHz,CDCl3):δ167.96,154.80,136.83, 135.54,131.70,131.08,130.53,130.26,127.99,127.17,124.42,123.87,122.92, 121.25,111.27.HR-MS(ESI):m/z calcdfor C15H8Cl2O2([M+H]+)289.9910,found 290.9974.
3,5二氟苯苯并丁内酯：产率82％，黄色固体；mp:156.3-157.2℃；1H NMR(500MHz,CDCl3)δ7.75(d,J＝6.8Hz,2H),7.55(d,J＝7.6Hz,1H),7.49(s,1H), 7.39(t,J＝7.8Hz,1H),7.21(t,J＝7.6Hz,1H),7.13(d,J＝8.0Hz,1H), 6.93(t,J＝8.5Hz,1H).13C NMR(126MHz,CDCl3):δ163.75,161.77,153.51, 136.73,135.71,130.92,124.60,124.06,119.82,114.45,114.29,111.10,106.59, 106.39,106.19.HR-MS(ESI):m/z calcd forC15H8F2O2([M+H]+)258.0492,found 259.0565.
2-溴-4氟苯苯并丁内酯：产率76％，黄色固体；mp:153.5-154.2℃；1H NMR(500MHz,CDCl3)δ7.78(s,1H),7.74(dd,J＝8.6,5.9Hz,1H),7.46(dd,J＝8.1, 2.5Hz,1H),7.38(dd,J＝7.9,2.9Hz,2H),7.20-7.15(m,1H),7.14-7.11(m, 1H),7.01(td,J＝7.7,0.8Hz,1H).13C NMR(126MHz,CDCl3):δ168.02,164.23, 162.20,153.98,137.85,131.53,131.14,130.69,123.86,122.79,121.27,121.03, 120.84,115.11,111.23.HR-MS(ESI):m/z calcdfor C15H8BrFO2([M+H]+)317.9692, found 318.9765.
3-氯-4氟苯苯并丁内酯：产率74％，黄色固体；mp:152.2-153.5℃；1H NMR(500MHz,CDCl3)δ8.32(dd,J＝7.1,1.9Hz,1H),8.12(ddd,J＝8.3,4.5,2.0Hz, 1H),7.53(d,J＝7.6Hz,1H),7.51-7.46(m,1H),7.35(d,J＝7.7Hz,1H), 7.25-7.17(m,2H),7.11(d,J＝8.2Hz,1H).13C NMR(126MHz,CDCl3):δ165.78, 158.41,153.20,137.08,134.22,132.29,130.44,124.90,123.98,122.65,121.78, 119.57,116.89,116.72,111.01.HR-MS(ESI):m/z calcd for C15H8ClFO2([M+H]+) 274.0197,found 275.0270.
2-噻吩苯并丁内酯：产率86％，黄色固体；mp:167.2-168.2℃；1H NMR(500MHz,CDCl3)δ7.89(d,J＝3.7Hz,1H),7.76(s,1H),7.70(d,J＝5.1Hz,1H),7.50 (dd,J＝7.6,0.6Hz,1H),7.30(td,J＝7.9,1.2Hz,1H),7.17(ddd,J＝15.7, 6.3,2.3Hz,2H),7.10(d,J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ166.47, 152.72,137.69,137.41,134.74,131.04,129.34,127.93,125.12,123.75,119.05, 116.11,110.81.HR-MS(ESI):m/z calcd forC13H8O2S([M+H]+)228.0245,found 229.0318.
2-糠醛苯并丁内酯：产率75％，黄色固体；mp:153.5-154.6℃；1H NMR(500MHz,CDCl3)δ8.26(d,J＝3.7Hz,1H),7.66(d,J＝1.5Hz,1H),7.52(s,1H),7.50 (d,J＝7.7Hz,1H),7.32(td,J＝7.9,1.1Hz,1H),7.17(td,J＝7.6,0.6Hz, 1H),7.12(d,J＝8.0Hz,1H),6.71-6.64(m,1H).13C NMR(126MHz,CDCl3):δ 166.10,152.87,150.78,146.27,129.52,125.04,124.52,123.76,120.77,119.18, 116.20,114.16,110.82.HR-MS(ESI):m/z calcdfor C13H8O3([M+H]+)212.0473, found 213.0546.
2-吡咯苯并丁内酯：产率65％，灰色固体；mp:177.2-178.5℃；1H NMR(500MHz,CDCl3)δ12.46(s,1H),7.44(s,2H),7.27-7.22(m,2H),7.16(t,J＝7.5Hz, 1H),7.11(d,J＝7.9Hz,1H),6.84(s,1H),6.43(d,J＝1.2Hz,1H).13C NMR (126MHz,CDCl3):δ170.09,151.98,129.78,128.48,127.58,126.96,125.97, 123.80,122.61,118.17,112.29,110.57.HR-MS(ESI):m/z calcd for C13H9NO2([M +H]+)211.0633,found 212.0706.
3-吲哚苯并丁内酯：产率63％，黄色固体；mp:162.1-163.4℃；1H NMR(500MHz,CDCl3)δ9.40(d,J＝5.3Hz,1H),8.44(dd,J＝7.3,4.6Hz,1H),7.81-7.70 (m,2H),7.60-7.53(m,1H),7.43-7.35(m,2H),7.30(td,J＝12.4,7.3Hz,1H), 7.21-7.12(m,1H),7.11-7.03(m,1H).13C NMR(126MHz,CDCl3):δ169.54,167.30, 152.47,135.33,132.10,129.75,129.42,127.51,126.06,125.18,124.49,123.82, 119.06,117.65,116.94,115.66,110.72.HR-MS(ESI):m/z calcd for C17H11NO2([M +H]+)261.0790,found 262.0863.
2-吡啶苯并丁内酯：产率64％，灰色固体；mp:187.7-188.7℃；1H NMR(500MHz,CDCl3)δ9.12(d,J＝7.8Hz,1H),8.94-8.87(m,1H),7.84(td,J＝7.7,1.8 Hz,1H),7.74(s,1H),7.63(d,J＝7.8Hz,1H),7.45-7.40(m,1H),7.37(ddd, J＝7.6,4.7,0.9Hz,1H),7.22(td,J＝7.7,0.9Hz,1H),7.15(d,J＝8.0Hz, 1H).13C NMR(126MHz,CDCl3):δ169.89,155.19,153.15,149.89,137.87,136.87, 131.73,128.51,128.35,124.44,124.32,123.99,122.45,110.55.HR-MS(ESI): m/z calcd for C14H9NO2([M+H]+)223.0633,found224.0706.其氢谱、碳谱和质谱图 分别见图4、5和6。
肉桂醛苯并丁内酯：产率56％，黄色固体；mp:151.4-152.8℃；1H NMR(500MHz,CDCl3)δ8.35(dd,J＝15.5,11.7Hz,1H),7.60(d,J＝7.0Hz,2H),7.46(d, J＝7.6Hz,1H),7.42-7.33(m,4H),7.29(dd,J＝12.1,4.4Hz,1H),7.14(t, J＝7.6Hz,1H),7.08(t,J＝11.2Hz,2H).13C NMR(126MHz,CDCl3):δ166.91, 153.08,144.92,139.09,135.98,129.95,129.66,128.97,128.13,124.52,123.86, 123.80,119.65,119.51,110.81.HR-MS(ESI):m/z calcd for C17H12O2([M+Na]+) 248.0837,found 271.0370.
α-溴肉桂醛：产率53％，黄色固体；mp:152.3-153.7℃；1H NMR(500MHz,CDCl3) δ7.84(d,J＝8.2Hz,2H),7.50-7.45(m,3H),7.32-7.27(m,3H),7.16-7.13 (m,1H),7.12-7.09(m,1H),7.09-7.07(m,1H).13C NMR(126MHz,CDCl3):δ154.89, 154.66,139.89,135.32,134.86,132.12,129.73,128.88,128.77,128.68,126.60, 124.59,114.93,111.56,111.03.HR-MS(ESI):m/z calcd for C17H11BrO2([M+Na]+) 325.9942,found348.9834.
α-甲基肉桂醛：产率58％，黄色固体；mp:151.3-152.5℃；1H NMR(500MHz,CDCl3) δ7.64(d,J＝8.1Hz,3H),7.54(m,2H),7.35-7.26(m,3H),7.19(m,1H), 7.17-7.03(m,1H),7.1(m,1H)，2.53(s,3H).13C NMR(126MHz,CDCl3):δ167.67, 155.83,153.52,145.31,142.99,140.85,130.06,129.77,129.45,129.09,128.64, 128.47,123.60,119.18,110.79,22.93.HR-MS(ESI):m/z calcd for C18H14O2([M+ Na]+)262.0994,found285.0886.
对三氟甲基苯(3-氟)苯并丁内酯：产率68％，黄色固体；mp:176.3-177.2℃；1HNMR(500MHz,CDCl3)δ8.10(d,J＝7.9Hz,1H),7.73(d,J＝7.8Hz,2H),7.45 (d,J＝11.5Hz,1H),7.35(d,J＝7.1Hz,2H),7.32(t,J＝7.1Hz,1H),6.78 (d,J＝8.0Hz,1H).13C NMR(126MHz,CDCl3):δ165.55,153.45,137.71,136.19, 131.77,130.83,127.31,127.27,125.43,124.73,124.07,123.28,119.89,111.10. HR-MS(ESI):m/z calcd for C16H8F4O2([M+H]+)308.0460,found 309.0530.
对三氟甲基苯(3-***)苯并丁内酯：产率62％，黄色固体；mp:182.1-183.6℃； 1HNMR(500MHz,CDCl3)δ7.73(s,1H),7.45(d,J＝7.6Hz,2H),7.32(d,J＝ 7.1Hz,2H),7.28(t,J＝7.1Hz,1H),6.93(d,J＝8.0Hz,2H),3.03-2.94(m, 2H),2.13(s,1H).13C NMR(126MHz,CDCl3):δ162.20,150.92,139.83,138.65, 134.61,130.21,129.41,126.55,126.31,125.43,125.01,124.61,120.78,119.31, 67.98,64.52.HR-MS(ESI):m/z calcd forC18H12F3N3O2([M+H]+)359.0882,found 360.0952.
4化合物的生物活性测定实例
实验例1：生长速率法测定苯并丁内酯类衍生物对番茄灰霉病菌和黄瓜炭疽病菌的 抑制毒力
1.材料与方法
1.1供试材料
番茄灰葡萄病菌(Botrytis cinerea)、黄瓜炭疽病菌(Colletotrichumlagenarium) 均由西北农林科技大学无公害农药研究服务中心提供。所合成的苯并丁内酯类衍生物、 96％多菌灵原药、吐温-20(乳化剂)
1.2试验方法
马铃薯葡萄糖琼脂培养基(PDA培养基)的配制：将马铃薯去皮后400g，切为小 块后加入蒸馏水煮沸30分钟，过滤后滤液加入葡萄糖40g，琼脂粉26～30g，蒸馏水 定容至2000mL，pH＝7，121℃高压灭菌30分钟。
采用抑制菌丝生长速率法将不同的α-亚甲基-γ-丁内酯类衍生物药剂配成10000mg/L浓度母液，取1mL母液与冷却至45℃左右的PDA培养基混合均匀后倒入培养皿 中制成浓度为100mg/L的含药平板，待培养基冷却后分别接种不同的供试菌菌饼(直 径为4mm)，每处理3次重复，同时设置空白对照及多菌灵药剂对照，置于适宜的条 件下培养72～96h后，采用十字交叉法测量各个供试菌的菌落生长直径，用公式1计 算抑制率。以供试药剂质量浓度的对数值为自变量(x)，以抑制率的几率值为因变量(y)， 采用最小二乘法求出供试药剂的毒力回归方程，并计算出各供试化合物的IC50值。
Figure BDA0001403008810000141
2.结果与分析
苯并丁内酯衍生物通过抑制菌丝生长速率法对番茄灰霉病菌和黄瓜炭疽病菌的抑 制作用结果见表1。
表1:苯并丁内酯衍生物对番茄灰霉病菌和黄瓜炭疽病菌菌丝生长的抑制毒力
Figure BDA0001403008810000142
Figure BDA0001403008810000151
从表1中可以看出，对三氟甲基苯苯并丁内酯和4-氟苯苯并丁内酯EC50值分别为2.02μg/mL和2.41μg/mL，与对照药剂多菌灵相当。含吸电子基团的衍生物活性略高 于含给电子基团的化合物，如2-氯苯苯并丁内酯化合物对番茄灰霉病菌的抑菌活性(EC50值为5.65μg/mL)高于化合物2-甲氧基苯苯并丁内酯(EC50值为15.64μg/mL)。经过 构效关系研究后设计的两个化合物对三氟甲基苯(3-氟)苯并丁内酯(EC50值为 1.32μg/mL)和对三氟甲基苯(3-***)苯并丁内酯(EC50值为1.14μg/mL)对番茄灰霉 的的抑菌活性明显高于对照药剂多菌灵(EC50值为1.6μg/mL)。
实验例2:活体组织法测定部分苯并丁内酯化合物对番茄灰霉病的保护毒力
1.材料与方法
1.1供试材料
番茄灰葡萄病菌(Botrytis cinerea)由西北农林科技大学无公害农药研究服务中心 提供；番茄灰霉果实，采自杨凌杨村乡大棚温室。部分苯并丁内酯类衍生物、96％多菌灵原药、吐温-20(乳化剂)。
1.2试验方法
对番茄灰霉病的保护药效试验采用番茄幼果法进行(方法参考方仲达，植病研究方 法[M].北京:农业出版社.第三版.1995)。具体操作为：将从田间采集的未施任何杀菌药剂的番茄果实，先用清水洗涤干净、晾干，再用脱脂棉醮取75％的乙醇擦拭果实表面， 进行灭菌处理。在番茄表面采用喷雾法将稀释好的药剂直接喷洒在果实表面，待药液晾 干后即开始接菌。接菌时，用接种针在番茄果实表面刺出直径约0.5cm的侵染区域， 以利灰霉病菌的侵染，将直径0.4cm的菌饼倒扣在番茄果实表面。接菌后的番茄幼果 23℃保湿培养6d，测量菌落直径，采用以下公式计算抑菌率。
菌落生长直径(cm)＝实测菌落直径－0.4
Figure BDA0001403008810000161
2.结果与分析
采用活体组织法(番茄幼果法)测定了20种苯并丁内酯类衍生物对番茄灰霉病的保护作用，结果见表2所示。
表2苯并丁内酯类衍生物对番茄灰霉病的保护毒力
Figure BDA0001403008810000162
从表中可以看出，引入杂环和不饱和键能明显提高对番茄灰霉的保护作用效果；同 样，引入双取代基也能明显提高活性。例如：本实验中2-噻吩苯并丁内酯的EC50值为6.98μg/mL，含不饱和双键化合物肉桂醛苯并丁内酯的EC50值为3.78μg/mL，明显高于 无取代基的化合物苯基苯并丁内酯的EC50值为12.65μg/mL。双取代基化合物2-溴-4氟 苯苯并丁内酯的EC50值为3.84μg/mL对番茄灰霉病菌的保护作用也明显提高；经结构 改造后的化合物对三氟甲基苯(3-氟)苯并丁内酯和对三氟甲基苯(3-***)苯并丁内酯 (EC50值分别为1.46μg/mL和1.23μg/mL)对番茄灰霉病菌的保护作用明显高于对 照药剂多菌灵。
实验例3：8种苯并丁内酯化合物防治小麦白粉病的盆栽实验
1.材料与方法
1.1供试材料
小麦白粉病菌(Erysiphe graminis)，由西北农林科技大学无公害农药研究服务中心提供；供试植物寄主材料为小麦陕-451感病品种，由西北农林科技大学小麦中心提供。部分苯并丁内酯类衍生物、50％速克灵WP、吐温-20(乳化剂)。
1.2试验方法
在每营养钵播种10～15粒已催芽的小麦种子，在温室培养至待小麦长至两叶期时进行治疗和保护作用试验。以常量喷雾进行施药，每个处理设3次重复，设溶剂对照和 清水对照。
采用孢子抖动法进行小麦白粉病接种，处理后的小麦置于温度为18±1℃，光照/黑暗＝8h/16h条件下培养，依据病害发生情况分级调查，计算各处理病情指数和防治效果。
治疗作用，先接菌，24h后再进行喷药处理、培养；保护作用，先喷药处理，24h 后再接菌，培养8d后检查叶片发病情况并记录，按以下公式统计、计算结果。
Figure RE-GDA0001508732130000171
Figure RE-GDA0001508732130000172
小麦白粉病的分级标准(以叶片为单位)(方仲达.植病研究方法[M].北京:农业出版社.第三版.1995)：
0级：叶面无病斑；
1级：叶片上只有少量有限的菌丝体，无孢子；
2级：叶面菌丝体量中等，有一些孢子，组织轻微坏死和褪绿；
3级：菌丝体的量中等或很多，孢子产生的量有限，有一些坏死和褪绿；
4级：孢子堆很大，产生大量孢子，没有坏死。
2.结果与分析
采用盆栽法测试了8种苯并丁内酯类衍生物对小麦白粉病的防治作用效果，结果见表 3所示。
表3 8种苯并丁内酯类衍生物对小麦白粉病的盆栽药效试验结果(8d)
Figure BDA0001403008810000173
Figure BDA0001403008810000181
注：①表中数据为3次重复的平均值；②苯并丁内酯类衍生物的药效计算采用溶剂对照，速克灵的 药效计算使用清水对照；③防效栏中，同列数字后标不同小写字母者表示在方差分析(Duncan's法) 中于0.05水平上差异显著。
5、含苯并丁内酯类衍生物的各种制剂的制备
含苯并丁内酯类衍生物的各种制剂均按农药标准加工方法进行，各种剂型中所含成 分的重量百分比如下：
剂型 苯并丁内酯类衍生物％ 填料或溶剂％ 表面活性剂％
可湿性粉剂 10～90 0～70 1～10
乳油 5～50 30～95 5～35
微乳剂 10～50 30～80 1～30
可溶性液剂 1～70 0～80 1～35
水剂 1～80 0～80 1～35
水分散粒剂 1～90 0～80 1～35
水乳剂 1～80 0～80 1～35
悬浮剂 1～80 0～80 1～35
其中的填料可以是粘土、陶土、高岭土、滑石粉、白炭黑、膨润土和硅澡土等本领域技术人员公知的物质中的一种或一种以上的混合物；
溶剂可以是水、甲醇、乙醇、正(异)丙醇，乙酸乙酯，苯、甲苯和其他芳香烃等 本领域技术人员公知的物质中的一种或一种以上的混合物；
表面活性剂可以是本领域技术人员公知的且常用的各类表面活性物质的一种或一 种以上的混合物。如十二烷基苯磺酸钙，苯乙烯酸聚氧乙烯醚，月桂醇聚氧乙烯醚，辛基酚聚氧乙基醚，拉开粉、皂素、木质素、磺酸盐类物质、烷基磺酸盐类物质和月桂醇 等表面活性剂的一种或一种以上的混合物。
其他助剂包括湿润剂、乳化剂、分散剂、粘着剂、稳定剂和增效剂。
其中湿润剂可以是茶枯、纸浆废液、洗衣粉和拉开粉等本领域技术人员公知的物质 中的一种或一种以上的混合物；
乳化剂可以是烷基苯磺酸盐类、烷基酚聚氧乙烯醚类、苯乙基酚聚氧乙烯醚类、斯潘系列、吐温等本领域技术人员公知的物质中的一种或一种以上的混合物；
分散剂可以是废糖蜜、纸浆废液浓缩物等本领域技术人员公知的物质中的一种或一 种以上的混合物；
黏着剂可以是淀粉糊、明胶等本领域技术人员公知的物质中的一种或一种以上的混 合物；
稳定剂可以是环氧氯丙烷、乙二醇、丙三醇等本领域技术人员公知的物质中的一种 或一种以上的混合物；
增效剂可以是有机硅、增效醚、增效胺、碳酸烷基酯、月桂氮酮等本领域技术人员公知的物质中的一种或一种以上的混合物。
以下是发明人给出的具体实施例。
制备实施例1：20％对氯苯基苯并丁内酯乳油的制备
室温下，称取2g对氯苯基苯并丁内酯，加入2mL丙酮溶解，加入2mL吐温-20， 加水定容至10mL，充分搅拌、摇匀。即得20％对氯苯基苯并丁内酯乳油。
制备实施例2：5％肉桂醛苯并丁内酯可湿性粉剂的制备
称取1g的肉桂醛苯并丁内酯，物理粉碎，过200目筛。加入0.2g十二烷基苯磺酸钠、0.5g羟甲基纤维素钠和18.3g过200目筛滑石粉，充分混匀。即制得5％肉桂醛苯 并丁内酯可湿性粉剂。
制备实施例3：5％3,5二氟苯苯并丁内酯微乳剂的制备
称取1g3,5二氟苯苯并丁内酯，加入2mL丙酮搅拌使其充分溶解，然后加入5mL OP-10,1mL吐温-20，余量用水补齐，800-1000转/分钟搅拌20-30分钟，即可制得 5％3,5二氟苯苯并丁内酯微乳剂。
制备实施例4：5％对氟苯苯并丁内酯可溶性液剂的制备
称取1g对氟苯苯并丁内酯，在20-25℃下，加入2mL丙酮溶解后，加入2mL吐温 -20，10mL甲醇和5mL环己酮，充分摇匀。即可制得5％对氟苯苯并丁内酯可溶性液 剂。
制备实施例5：10％2-吡咯苯基苯并丁内酯水剂的制备
称取1g 2-吡咯苯基苯并丁内酯，加入1mL丙酮溶解后，加入1mL吐温-20，1mL OP-10和6mL水，充分摇匀。即可制得10％2-吡咯苯基苯并丁内酯水剂。
制备实施例6：5％对三氟甲基苯基苯并丁内酯水分散粒剂的制备
称取1g对三氟甲基苯基苯并丁内酯，加入1mL丙酮溶解后，加入1mL吐温-20， 和7mL水，充分摇匀。加入0.2g十二烷基苯磺酸钠、6g白炭黑和12.6g明胶，挤块， 干燥。即可制得5％对三氟甲基苯基苯并丁内酯水分散粒剂。
制备实施例7：5％2-噻吩苯基苯并丁内酯水乳剂的制备
称取1g 2-噻吩苯基苯并丁内酯，加入3mL丙酮溶解后，加入1mL吐温-20，5mL OP-10和1mL丙三醇，搅拌后余量用水补齐，800-1000转/分钟搅拌20-30分钟，即可 制得5％2-噻吩苯基苯并丁内酯水乳剂。
制备实施例8：5％间氟苯基苯并丁内酯悬浮剂的制备
称取1g间氟苯基苯并丁内酯，加入2mL丙酮溶解后，加入2mL吐温-20，0.5g 羟甲基纤维素钠，1.5mL丙三醇，13mL水，800-1000转/分钟搅拌20-30分钟，即可 制得5％间氟苯基苯并丁内酯悬浮剂。
制备实施例9：20％对三氟甲基苯基苯并丁内酯·多菌灵(1:1)乳油的制备
室温下，分别称取0.5g对三氟甲基苯基苯并丁内酯和0.52g 96％多菌灵原药，加入 2mL丙酮溶解后，加入2mL吐温-20，加入1g十二烷基苯磺酸钠，加水定容至10mL， 充分摇匀。即可制得20％对三氟甲基苯基苯并丁内酯·百菌清(1:1)乳油。
应用实验例1.4种苯并丁内酯类衍生物乳油防治番茄灰霉病田间药效实验
1.材料与方法
1.1供试材料
10％间氯苯并丁内酯乳油、10％2-噻吩苯并丁内酯乳油、10％3-氯-4氟苯苯并丁内 酯乳油、10％对三氟甲基苯(3-氟)苯并丁内酯乳油、80％多菌灵可湿性粉剂；番茄温室大 棚种植；番茄灰葡萄病菌(Botrytis cinerea)由西北农林科技大学无公害农药研究服务 中心提供。
1.2试验方法
二次稀释法进行药液配置；每小区用水1.85L。
治疗作用，先接种，24h后再进行喷药处理；保护作用，先喷药处理，24h后再接 种。
第8d检查叶片发病情况并记录。根据番茄灰霉病情分级标准调查记录，计算病情指数和防治效果。
病情分级按以下标准：
叶部被害分级方法(以叶片为单位)
0级：无病斑；
1级：单叶片病斑有3个；
3级：单叶片病斑有4-6个；
5级：单叶片病斑有7-10个；
7级：单叶片病斑有11-20个，部分密集成片。
9级：单叶片有病斑密集占叶面1/4以上。
病情指数计算公式和防治效果计算公式如下：
Figure BDA0001403008810000201
Figure BDA0001403008810000202
式中：CK0、CK1为空白对照区施药前、后病情指数，PT0、PT1为处理区施药前、后病情指数。
2.结果与分析
采用盆栽法测试了4种苯并丁内酯类衍生物对番茄灰霉病大田药效实验效果，结果 见表4所示。
表4. 4种苯并丁内酯类衍生物对番茄灰霉病大田药效实验结果(7d)
Figure BDA0001403008810000203
Figure BDA0001403008810000211
注：①表中数据为3次重复的平均值；②防效栏中，同列数字后标不同小写字母者表示 在方差分析(Duncan's法)中于0.05水平上差异显著。
由上表可以看出四种苯并丁内酯类衍生物对番茄灰霉叶片均具有较高的田间防效。 10％3-氯-4氟苯苯并丁内酯EC、10％对三氟甲基苯(3-氟)苯并丁内酯EC稀释500倍田间防效与商品药剂80％多菌灵可湿性粉剂1000倍液对番茄灰霉病的防效相当。
应用实验例2：8种苯并丁内酯类衍生物制剂防治小麦赤霉病田间药效实验
1.材料与方法
1.1供试材料
20％对氟苯并丁内酯乳油(编号ZX-1)、5％对硝基苯并丁内酯可湿性粉剂(编号ZX-2)、 5％2-萘基苯并丁内酯微乳剂(编号ZX-3)、5％肉桂醛苯并丁内酯可溶性液剂(编号ZX-4)、 10％对三氟甲基苯苯并丁内酯(编号ZX-5)、5％3,5二氟苯苯并丁内酯(编号ZX-6)、5％ 对三氟甲基苯(3-氟)苯并丁内酯(编号ZX-7)、20％对三氟甲基苯(3-***)苯并丁内酯· 百菌清(1:1)乳油(编号ZX-8)、80％多菌灵可湿性粉剂；黄瓜津杂4号，温室大棚种植；小麦赤霉病菌。
1.2试验方法
A、小区设置
设18个处理，3次重复，共54个小区，随机区组排列，各小区面积：6.2m×1.0m ＝6.2m2。
B、调查方法
每小区十字交叉取四点调查，每点调查两株，每株调查全部叶片，计算公式如下：
Figure RE-GDA0001508732130000212
Figure RE-GDA0001508732130000213
小麦赤霉病的分级标准(以叶片为单位)：
0级：叶面无病斑；
1级：叶片上只有少量有限的菌丝体，无孢子；
2级：叶面菌丝体量中等，有一些孢子，组织轻微坏死和褪绿；
3级：菌丝体的量中等或很多，孢子产生的量有限，有一些坏死和褪绿；
4级：孢子堆很大，产生大量孢子，没有坏死。
2.结果与分析
8种苯并丁内酯类衍生物制剂防治小麦赤霉病田间药效实验结果见表5.
表5. 8种苯并丁内酯类衍生物制剂防治小麦赤霉病田间药效实验
Figure BDA0001403008810000214
Figure BDA0001403008810000221
注：①表中数据为3次重复的平均值；②防效栏中，同列数字后标不同小写字母者表示 在方差分析(Duncan's法)中于0.05水平上差异显著。
由上表可以看出，8种苯并丁内酯类衍生物制剂对小麦赤霉病均具有较高的田间防 效。其中混配制剂--20％对三氟甲基苯(3-***)苯并丁内酯·百菌清(1:1)乳油(编号ZX-8)稀释1000倍、20％对氟苯并丁内酯乳油(编号ZX-1)稀释500倍田间防效与商品 药剂80％多菌灵可湿性粉剂稀释1000倍对小麦赤霉病的防效相当，差异不显著，而20％ 对三氟甲基苯(3-***)苯并丁内酯·百菌清(1:1)乳油(编号ZX-8)稀释500倍田间防 效高于商品药剂80％多菌灵可湿性粉剂稀释1000倍对小麦赤霉病的防效，差异显著。

Claims (6)

1.苯并丁内酯类衍生物，其特征在于，结构如式(二)所示,
Figure FDA0002737006360000011
其中，R为氟或
Figure FDA0002737006360000012
2.权利要求1所述的苯并丁内酯类衍生物的合成方法，其特征在于，化合物的制备方法包括：
对R邻羟基苯甲酸50mmol、硫粉100mmol和对甲苯磺酸1.75mmol混合后在120～130℃下回流8h，再加入质量浓度是20％的氢氧化钠水溶液10ml和四丁基溴化铵1.25mmol在100℃下水解反应8h，调节pH为7得到3-R邻羟基苯乙酸；
5mmol 3-R邻羟基苯乙酸与15mL氯氧化磷在50mL二氯甲烷中搅拌16h，得到的产物经水洗干燥纯化后得到3-R苯并呋喃酮；
1.5mmol的3-R苯并呋喃酮与3mmol的对三氟苯甲醛在pH为8的环境中加入10mL浓度为10mol/L氢氧化钾乙醇溶液并在室温下搅拌14h得到的粗产物，调节粗产物的pH为7，再将粗产物依次经萃取、水洗、干燥和纯化后得到所述苯并丁内酯衍生物。
3.权利要求1所述的苯并丁内酯类衍生物或式(一)中所示的化合物用于制备防治由植物病原真菌引起的植物病害的农药制剂的应用；
Figure FDA0002737006360000013
表1
Figure FDA0002737006360000021
Figure FDA0002737006360000031
Figure FDA0002737006360000041
R选自如表1所示的任一结构。
4.如权利要求3所述的应用，其特征在于，所述的植物原病菌引起的植物病害包括：小麦白粉病、小麦赤霉病、小麦全蚀病、小麦纹枯病、玉米大斑病、水稻纹枯病、水稻稻瘟病、棉花立枯病、辣椒疫霉病、番茄灰霉病、番茄叶霉病、番茄早晚疫病、黄瓜炭疽病、黄瓜枯萎病和油菜菌核病。
5.如权利要求3所述的应用，其特征在于，所述的农药制剂的形态包括可湿性粉剂、乳油、微乳剂、可溶性液剂、水剂、水分散粒剂、水乳剂、颗粒剂和悬浮剂。
6.如权利要求3所述的应用，其特征在于，所述的农药制剂与百菌清或其他商品化杀菌剂混配制成复合的可湿性粉剂、乳油、微乳剂、可溶性液剂、水剂、水分散粒剂、水乳剂、颗粒剂或悬浮剂。
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