CN115124486B - 苯并噁唑衍生物及其制备方法与应用 - Google Patents

苯并噁唑衍生物及其制备方法与应用 Download PDF

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CN115124486B
CN115124486B CN202210803794.XA CN202210803794A CN115124486B CN 115124486 B CN115124486 B CN 115124486B CN 202210803794 A CN202210803794 A CN 202210803794A CN 115124486 B CN115124486 B CN 115124486B
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吴迪
秦啸天
陈宬
桑微
樊广高
江民
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Abstract

本发明提供一种苯并噁唑衍生物及其制备方法与应用，所述苯并噁唑衍生物具有以下三种结构：其中，R1为R2选自H，2‑甲基，3‑甲基，4‑甲基，4‑甲氧基，4‑异丙基，4‑叔丁基，4‑氟，4‑氯，4‑溴，4‑碘、4‑氰基中的一种；R3选自H，同时R4选自H、2,4‑Cl2、2,4‑Me2、2‑Cl‑4‑CF3、2‑F‑4‑Cl中的一种；R3选自3,5‑Cl2时，同时R4选自2,4‑Cl2、2,4,6‑Cl3中的一种。本发明提供的新型苯并噁唑衍生物可作为较高活性的琥珀酸‑细胞色素c氧化还原酶复合物抑制剂，且具有良好的杀菌活性。

Description

苯并噁唑衍生物及其制备方法与应用
技术领域
本发明属于芳基或取代的芳基杂环化合物技术领域，具体涉及一种苯并噁唑衍生物及其制备方法与应用。
背景技术
琥珀酸脱氢酶，也称为线粒体呼吸链复合体Ⅱ，可以催化电子由琥珀酸转至辅Q的传递；线粒体细胞色素bc1复合物，也叫细胞色素c还原酶，同时称为线粒体呼吸链复合体III，是线粒体以及大多数细菌呼吸作用电子传递链中的重要组成部分，催化电子从泛醌传递到细胞色素 c(细菌中是细胞色素c2)的反应。琥珀酸-细胞色素c氧化还原酶(SCR)就是指复合物Ⅱ和 III的混合物，由两者共同组成。研究表明复合体Ⅱ和复合体Ⅲ均可作为理想的农用杀菌剂作用靶标，具有重要的农学意义和应用价值。
以猪心来源的SCR为靶标的杀菌剂已成为当前最重要的一类杀菌剂品种，是各大农药公司研究的热点。然而，这类杀菌剂因长期使用而产生严重抗性问题，导致防效效果明显下降。因此，设计合成出结构新颖、活性高的SCR抑制剂极为重要。
发明内容
针对现有技术中存在的上述不足，本发明的目的之一在于提供一种新型苯并噁唑衍生物，该新型苯并噁唑衍生物可作为高活性的琥珀酸-细胞色素c氧化还原酶复合物抑制剂，具有一定的杀菌活性。
为了实现上述发明目的，具体技术方案如下：
苯并噁唑衍生物，所述苯并噁唑衍生物具有以下三种结构，如式(Ⅰ)、式(Ⅱ)、式(Ⅲ) 所示：
其中，R1为
R2选自H，2-甲基，3-甲基，4-甲基，4-甲氧基，4-异丙基，4-叔丁基，4-氟，4-氯，4-溴， 4-碘、4-氰基中的一种；
R3选自H或3,5-Cl2；
R3为H时，R4选自H、2,4-Cl2、2,4-Me2、2-Cl-4-CF3、2-F-4-Cl中的一种；
R3为3,5-Cl2时，R4选自2,4-Cl2、2,4,6-Cl3中的一种。
R1为时，则该类化合物结构为：
若R1为则该类化合物结构为：
在本发明中，基团上的虚线表示该基团的连接键，指明了该基团的连接位点。
本发明的目的之二在于提供一种上述苯并噁唑衍生物的制备方法。
具体技术方案如下：
一种上述苯并噁唑衍生物的制备方法，步骤如下：将2-氯苯并噁唑与胺类化合物在无水无氧的条件下进行亲核取代反应，然后纯化得到式(Ⅰ)、式(Ⅱ)或式(Ⅲ)所示的苯并噁唑衍生物；
所述胺类化合物结构式为R1-NH2，其中
R1选自
R2选自H，2-甲基，3-甲基，4-甲基，4-甲氧基，4-异丙基，4-叔丁基，4-氟，4-氯，4-溴， 4-碘、4-氰基中的一种；
R3选自H或3,5-Cl2；
R3为H时，R4选自H、2,4-Cl2、2,4-Me2、2-Cl-4-CF3、2-F-4-Cl中的一种；
R3为3,5-Cl2时，R4选自2,4-Cl2、2,4,6-Cl3中的一种。
按上述方案，所述式(Ⅰ)苯并噁唑衍生物的制备条件为：所述2-氯苯并噁唑与胺类化合物摩尔比为0.25-1.25：1，优选为0.5-1.25：1，更优选为1：1，于50-100℃下反应1-24h时，优选为80-100℃下反应10-20h，所得产物为式(Ⅰ)化合物。
按上述方案，所述式(Ⅱ)苯并噁唑衍生物的制备条件为：所述2-氯苯并噁唑与胺类化合物摩尔比为2.5-5：1，优选为2.5-4：1，更优选为3：1，于110-150℃下反应1-24h时，优选为110-130℃下反应10-20h，所得产物为式(Ⅱ)化合物。
按上述方案，所述式(Ⅲ)苯并噁唑衍生物的制备条件为：所述2-氯苯并噁唑与胺类化合物摩尔比为2.5-5：1，优选为4-5：1，更优选为4：1，在碱和溶剂存在条件下，110-150℃下加热回流反应1-24h时，优选为110-130℃下加热回流反应10-20h，所得产物为式(Ⅲ)化合物。
按上述方案，所述碱为Na2CO3，K2CO3，Cs2CO3，NaH，4-二甲氨基吡啶(DMAP)，吡啶中的一种，优选为NaH，所述碱与胺类化合物的摩尔比为0.5-1.5：1，优选为1-1.5：1。
按上述方案，所述溶剂为1,4-二氧六环，甲苯，间二甲苯，均三甲苯，氯苯中的一种，优选为甲苯，所述胺类化合物与有机溶剂的摩尔体积比为0.2-2mmol/mL，优选为 0.25-0.4mmol/mL。
该方法所用的合成路线如下式所示：
本发明的目的之三在于提供一种上述苯并噁唑衍生物的应用。
具体技术方案如下：
一种上述苯并噁唑衍生物在制备抑制琥珀酸-细胞色素c氧化还原酶(SCR)活性药物方面的应用。
进一步地，其在制备防治恶苗菌，松枯梢病，水稻纹枯病，油茶炭疽病农用杀菌剂方面的应用。
本发明的有益效果在于：
本发明提供的新型苯并噁唑衍生物可作为高活性的琥珀酸-细胞色素c氧化还原酶(SCR) 抑制剂，且具有良好的杀菌活性(对恶苗菌，松枯梢病，水稻纹枯病，油茶炭疽病均有较好的防治效果)。
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。
具体实施方式
以下对本发明的具体实施方式进行详细说明，应当理解的，此处所描述的具体实施方式仅用于解释和说明本发明，并不用于限制本发明。
以下实施例中，在没有特别说明的情况下，所使用的各种原料均来自于商购。
实施例1-19
一种新型苯并噁唑衍生物，其结构式如下：
其制备方法为：将2-氯苯并噁唑与胺类化合物R1-NH2(R1的选择见表1)在无水无氧的条件下进行反应，然后纯化得到苯并噁唑衍生物。
若底物胺类化合物为液体，将预先烘干的25mL的Schlenk反应管进行抽真空和通氩气三次后，用微量进样器将2-氯苯并噁唑(0.4mmol，46μL)和胺类化合物(0.4mmol)依次加入Schlenk反应管中，在无水无氧环境下，搅拌加热至100℃，反应16h后停止反应，经柱层析纯化得到式(Ⅰ)化合物；若底物胺类化合物为固体，将称好的胺类化合物(0.4mmol)加至预先烘干的25mL的Schlenk反应管，进行抽真空和通氩气三次后，用微量进样器将2-氯苯并噁唑(0.4mmol，46μL)加入反应体系中，搅拌加热至100℃，反应16h后停止反应，经柱层析纯化得到式(Ⅰ)化合物。
本实施例1-19用于说明采用反应式(1)的合成方法制备式(Ⅰ)所示的目标化合物，制备得到的苯并噁唑衍生物分别标记为Ⅰ-1～Ⅰ-19，产物取代基及其收率如表1所示：
表1
本实施例中a均代表分离收率；
另外实施例1-19所制备的苯并噁唑衍生物的结构表征数据如下：
化合物Ⅰ-1：白色固体，熔点175.7-176.4℃；1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.61(d,J ＝8.0Hz,2H),7.49(d,J＝7.8Hz,1H),7.40(t,J＝7.6Hz,2H),7.35(d,J＝8.0Hz,1H),7.24(d,J＝7.0Hz,1H),7.12(q,J＝7.6Hz,2H).13C NMR(126MHz,CDCl3)δ158.4,147.9,142.2,137.8, 129.3,124.3,123.4,121.8,118.5,117.1,109.1.HRMS(APCI)calcd.forC13H11N2O[M+H]+: 211.08659；Found:211.08627.
化合物Ⅰ-2：白色固体，熔点103.1-103.8℃；1H NMR(500MHz,CDCl3)δ8.07(d,J＝8.0Hz,1H), 7.46(d,J＝7.8Hz,1H),7.32(t,J＝9.2Hz,2H),7.22(t,J＝8.1Hz,2H),7.17–7.05(m,2H),2.36(s,3H).13C NMR(126MHz,CDCl3)δ158.6,148.0,142.5,135.9,130.7,127.4,127.3,124.2,121.8, 120.5,120.4,117.3,109.0,17.7.HRMS(APCI)calcd.forC14H13N2O[M+H]+:225.10224；Found: 225.10194.
化合物Ⅰ-3：白色固体，熔点144.1-144.8℃；1H NMR(500MHz,CDCl3)δ8.49(s,1H),7.48(d,J ＝7.7Hz,1H),7.42(d,J＝13.7Hz,2H),7.35(d,J＝7.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(d,J＝7.6Hz,1H),7.12(t,J＝7.6Hz,1H),6.93(d,J＝7.3Hz,1H),2.39(s,3H).13C NMR(126MHz, CDCl3)δ158.6,147.9,142.2,139.3,137.8,129.2,124.3,124.2,121.7,119.2,116.9,115.7,109.2, 21.6.HRMS(APCI)calcd.for C14H13N2O[M+H]+:225.10224；Found:225.10211.
化合物Ⅰ-4：白色固体，熔点183.3-184.1℃；1H NMR(500MHz,CDCl3)δ8.14(s,1H),7.47(t,J ＝8.4Hz,3H),7.34(d,J＝7.9Hz,1H),7.23(d,J＝7.6Hz,1H),7.20(d,J＝8.1Hz,2H),7.11(t,J＝7.7Hz,1H),2.35(s,3H).13C NMR(126MHz,CDCl3)δ157.0,145.5,136.5,131.8,131.0,130.2, 126.5,124.2,121.0,114.2,110.7,21.0.HRMS(APCI)calcd.forC14H13N2O[M+H]+:225.10224； Found:225.10196.
化合物Ⅰ-5：白色固体，熔点137.5-138.4℃；1H NMR(500MHz,CDCl3)δ8.50(s,1H),7.49(d,J ＝8.6Hz,2H),7.42(d,J＝7.7Hz,1H),7.32(d,J＝7.9Hz,1H),7.21(t,J＝7.6Hz,1H),7.09(t,J＝7.7Hz,1H),6.94(d,J＝8.6Hz,2H),3.81(s,3H).13C NMR(126MHz,CDCl3)δ159.3,156.1, 148.0,142.3,131.0,124.2,121.4,121.0,116.7,114.6,109.1,55.6.HRMS(APCI)calcd.for C14H13N2O2[M+H]+:241.09715；Found:241.09688.
化合物Ⅰ-6：白色固体，熔点157.1-158.4℃；1H NMR(500MHz,CDCl3)δ8.88(s,1H),7.53–7.43 (m,3H),7.34(d,J＝7.9Hz,1H),7.28–7.19(m,3H),7.10(t,J＝7.7Hz,1H),2.96–2.84(m,1H), 1.26(d,J＝6.8Hz,6H).13C NMR(126MHz,CDCl3)δ159.1,148.0,144.2,142.2,135.6,127.2, 124.3,121.5,119.0,116.8,109.1,33.6,24.1.HRMS(APCI)calcd.for C16H17N2O[M+H]+: 253.13354；Found:253.13335.
化合物Ⅰ-7：白色固体，熔点160.4-161.2℃；1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.52(d, J＝8.3Hz,2H),7.47(d,J＝7.8Hz,1H),7.41(d,J＝8.3Hz,2H),7.34(d,J＝7.9Hz,1H),7.22(d,J＝7.7Hz,1H),7.11(t,J＝7.7Hz,1H),1.33(s,9H).13C NMR(126MHz,CDCl3)δ158.8,147.9, 146.4,142.2,135.2,126.2,124.2,121.6,118.6,116.9,109.1,34.3,31.4.HRMS(APCI)calcd.for C17H19N2O[M+H]+:267.14919；Found:267.14902.
化合物Ⅰ-8：白色固体，熔点178.7-179.2℃；1H NMR(500MHz,CDCl3)δ8.44(s,1H),7.56(dd, J＝8.8,4.5Hz,2H),7.44(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.23(d,J＝7.7Hz,1H),7.11(dt,J＝17.3,8.2Hz,3H).13C NMR(126MHz,CDCl3)δ160.0(d,J＝242.6Hz),158.7,147.9,142.0, 133.9(d,J＝2.7Hz),124.4,121.9,120.5(d,J＝8.0Hz),116.9,116.0(d,J＝22.7Hz),109.2.HRMS(APCI)calcd.for C13H10FN2O[M+H]+:229.07717；Found:229.07704.
化合物Ⅰ-9：白色固体，熔点196.1-196.8℃；1H NMR(500MHz,DMSO-d6)δ10.77(s,1H),7.79 (d,J＝7.9Hz,2H),7.51–7.45(m,2H),7.43(d,J＝8.1Hz,2H),7.23(t,J＝7.6Hz,1H),7.14(t,J＝7.7Hz,1H).13C NMR(126MHz,DMSO-d6)δ158.1,147.4,142.6,138.2,129.3,126.1,124.5, 122.3,119.5,117.2,109.5.HRMS(APCI)calcd.for C13H10ClN2O[M+H]+:245.04762；Found: 245.04735.
化合物Ⅰ-10：白色固体，熔点226.2-227.1℃；1H NMR(500MHz,DMSO-d6)δ10.78(s,1H),7.74 (d,J＝8.4Hz,2H),7.56(d,J＝8.2Hz,2H),7.52–7.44(m,2H),7.23(t,J＝7.6Hz,1H),7.15(t,J＝7.7Hz,1H).13C NMR(126MHz,DMSO)δ158.1,147.4,142.6,138.6,132.2,124.6,122.4,119.9, 117.2,114.0,109.5.HRMS(APCI)calcd.for C13H10BrN2O[M+H]+:288.99710；Found:288.99689. 化合物Ⅰ-11：白色固体，熔点230.2-231.0℃；1H NMR(500MHz,Acetone-d6)δ9.68(s,1H),7.73 (s,4H),7.46(d,J＝7.8Hz,1H),7.40(d,J＝7.9Hz,1H),7.24(t,J＝7.6Hz,1H),7.15(t,J＝7.7Hz, 1H).13C NMR(126MHz,Acetone-d6)δ158.6,148.5,143.6,139.9,138.7,124.9,122.9,120.8,118.0, 109.7,85.1.HRMS(APCI)calcd.for C13H8IN2O[M-H]-:334.96868；Found:334.96896.
化合物Ⅰ-12：白色固体，熔点186.4-187.1℃；1H NMR(500MHz,Acetone-d6)δ8.07(d,J＝8.7 Hz,2H),7.78(d,J＝8.7Hz,2H),7.51(d,J＝7.7Hz,1H),7.43(d,J＝7.9Hz,1H),7.28(t,J＝7.6Hz,1H),7.19(t,J＝7.7Hz,1H).13C NMR(126MHz,Acetone-d6)δ157.2,147.5,142.9,142.1, 133.2,124.3,122.6,118.8,117.9,117.3,109.2,104.8.HRMS(APCI)calcd.for C14H10N3O[M+H]+: 236.08184；Found:236.08154.
化合物Ⅰ-13：白色固体，熔点154.0-154.7℃；1H NMR(500MHz,CDCl3)δ8.27(s,1H),7.58(d, J＝8.8Hz,2H),7.46(d,J＝7.8Hz,1H),7.37–7.30(m,3H),7.23(t,J＝7.8Hz,1H),7.15–7.05(m,4H),7.01(d,J＝8.0Hz,2H).13C NMR(126MHz,CDCl3)δ158.7,157.7,152.9,147.9,142.2, 133.4,129.7,124.3,123.0,121.8,120.4,120.1,118.3,116.9,109.1.HRMS(APCI)calcd.for C19H15N2O2[M+H]+:303.11280；Found:303.11246.
化合物Ⅰ-14：白色固体，熔点256.6-257.1℃；1H NMR(500MHz,DMSO-d6)δ11.16(s,1H),8.03 (s,2H),7.77(d,J＝2.5Hz,1H),7.56(dd,J＝7.9,4.0Hz,2H),7.35–7.23(m,2H),7.20(t,J＝7.6Hz,1H),6.66(d,J＝8.9Hz,1H).13C NMR(126MHz,DMSO)δ157.5,151.5,147.4,142.2,140.2, 138.5,130.6,128.9,128.9,127.4,124.8,122.9,122.6,118.2,117.7,116.1,109.8.HRMS(APCI)calcd.for C19H11Cl4N2O2[M+H]+:438.95691；Found:438.95673.
化合物Ⅰ-15：白色固体，熔点155.5-156.2℃；1H NMR(500MHz,CDCl3)δ8.45(s,1H),7.55– 7.46(m,2H),7.43(d,J＝7.8Hz,1H),7.32(d,J＝7.9Hz,1H),7.21(t,J＝7.6Hz,1H),7.14–7.04(m,2H),6.95(dd,J＝19.5,8.5Hz,3H),6.81(d,J＝8.1Hz,1H),2.31(s,3H),2.21(s,3H).13C NMR(126MHz,CDCl3)δ159.0,154.4,152.3,147.9,142.2,133.5,132.3,132.1,129.6,127.6, 124.2,121.6,120.6,119.6,117.9,116.8,109.1,20.7,16.1.HRMS(APCI)calcd.for C21H19N2O2[M+H]+:331.14410；Found:331.14377.
化合物Ⅰ-16：白色固体，熔点196.5-197.1℃；1H NMR(500MHz,CDCl3)δ7.90(s,1H),7.74(d, J＝1.7Hz,1H),7.67(d,J＝8.9Hz,2H),7.48(d,J＝7.8Hz,1H),7.42(d,J＝8.6Hz,1H),7.36(d,J＝8.0Hz,1H),7.24(d,J＝7.8Hz,1H),7.15(t,J＝7.3Hz,1H),7.10(d,J＝8.9Hz,2H),6.94(d,J ＝8.6Hz,1H).13C NMR(126MHz,CDCl3)δ158.0,156.4,150.9,147.8,142.1,134.8,128.1(q,J＝ 3.8Hz),126.0(q,J＝33.3Hz),125.0(q,J＝3.6Hz),124.8,124.4,123.4(q,J＝271.7Hz),122.1,120.6,120.2,118.0,117.2,109.1.HRMS(APCI)calcd.for C20H13ClF3N2O2[M+H]+:405.06122； Found:405.06094.
化合物Ⅰ-17：白色固体，熔点173.2-173.7℃；1H NMR(500MHz,CDCl3)δ7.79(s,1H),7.59(d, J＝8.9Hz,2H),7.47(d,J＝7.7Hz,1H),7.34(d,J＝8.0Hz,1H),7.24–7.18(m,2H),7.13(t,J＝7.7Hz,1H),7.08(d,J＝8.5Hz,1H),7.03(d,J＝8.9Hz,2H),6.96(t,J＝8.7Hz,1H).13C NMR (126MHz,CDCl3)δ158.5,153.7(d,J＝252.5Hz),152.6,147.9,143.3(d,J＝11.3Hz),142.1, 133.8,128.9(d,J＝8.7Hz),124.8(d,J＝3.8Hz),124.3,121.8,121.7(d,J＝1.8Hz),120.4,118.7,117.8(d,J＝21.4Hz),116.9,109.1.HRMS(APCI)calcd.forC19H13ClFN2O2[M+H]+:355.06441； Found:355.06406.
化合物Ⅰ-18：白色固体，熔点164.6-165.4℃；1H NMR(500MHz,CDCl3)δ7.61(d,J＝8.4Hz, 2H),7.48(d,J＝6.0Hz,2H),7.34(d,J＝8.0Hz,1H),7.23(d,J＝7.7Hz,1H),7.20–7.09(m,2H),7.02(d,J＝8.7Hz,2H),6.89(d,J＝8.8Hz,1H).13C NMR(126MHz,CDCl3)δ158.1,152.2,151.9, 147.9,142.2,133.9,130.5,128.8,128.0,126.1,124.3,122.0,120.5,120.2,119.4,117.2,109.1.HRMS(APCI)calcd.for C19H13Cl2N2O2[M+H]+:371.03486；Found:371.03455.
化合物Ⅰ-19：白色固体，熔点209.5-209.9℃；1H NMR(500MHz,CDCl3)δ7.82(s,1H),7.68(s, 2H),7.53(d,J＝7.9Hz,1H),7.39(d,J＝8.1Hz,1H),7.32(d,2H),7.28(s,1H),7.18(t,J＝7.8Hz, 1H).13C NMR(126MHz,CDCl3)δ157.0,147.8,147.6,143.8,141.6,134.8,129.2,129.1,127.3, 127.1,124.6,122.6,118.4,117.5,109.4.HRMS(APCI)calcd.for C19H10Cl5N2O2[M+H]+: 472.91794；Found:472.91766.
实施例20-38
一种新型苯并噁唑衍生物，其结构式如下：
其制备方法为：将2-氯苯并噁唑与胺类化合物R1-NH2(R1的选择见表2)在无水无氧的条件下进行反应，然后纯化得到苯并噁唑衍生物。
若底物胺类化合物为液体，将预先烘干的25mL的Schlenk反应管进行抽真空和通氩气三次后，用微量进样器将2-氯苯并噁唑(1.2mmol，137μL)和胺类化合物(0.4mmol)依次加入Schlenk反应管中，在无水无氧环境下，搅拌加热至120℃，反应16h后停止反应，经柱层析纯化得到式(Ⅱ)化合物；若底物胺类化合物为固体，将称好的胺类化合物(0.4mmol)加至预先烘干的25mL的Schlenk反应管，进行抽真空和通氩气三次后，用微量进样器将2-氯苯并噁唑(1.2mmol，137μL)加入反应体系中，搅拌加热至120℃，反应16h后停止反应，经柱层析纯化得到式(Ⅱ)化合物。
本实施例20-38用于说明采用反应式(2)的合成方法制备式(Ⅱ)所示的目标化合物，制备得到的苯并噁唑衍生物分别标记为Ⅱ-1～Ⅱ-19，产物取代基及其收率如表2所示：
表2
本实施例中a均代表分离收率；
另外实施例20-38所制备的苯并噁唑衍生物的结构表征数据如下：
化合物Ⅱ-1：白色固体，熔点199.0-199.6℃；1H NMR(500MHz,CDCl3)δ7.69(d,J＝7.8Hz,2H), 7.63–7.56(m,2H),7.56–7.50(m,3H),7.46(d,J＝8.0Hz,2H),7.34(t,J＝7.6Hz,2H),7.31– 7.27(m,2H).13C NMR(126MHz,CDCl3)δ156.6,149.0,141.2,138.5,130.0,129.0,127.4,124.7, 123.9,119.3,110.1.HRMS(APCI)calcd.for C20H14N3O2[M+H]+:328.10805；Found:328.10773. 化合物Ⅱ-2：白色固体，熔点195.0-195.5℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,2H), 7.47–7.38(m,6H),7.29(t,J＝7.7Hz,2H),7.23(t,J＝7.9Hz,2H),2.26(s,3H).13C NMR(126 MHz,CDCl3)δ156.3,149.0,141.3,137.1,136.6,131.8,129.8,128.7,127.7,124.6,123.6,119.2, 110.1,17.5.HRMS(APCI)calcd.for C21H16N3O2[M+H]+:342.12370；Found:342.12329.
化合物Ⅱ-3：白色固体，熔点185.5-186.2℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,2H), 7.44(t,J＝7.9Hz,3H),7.35–7.28(m,5H),7.28–7.22(m,2H),2.44(s,3H).13CNMR(126MHz, CDCl3)δ156.7,149.0,141.3,140.2,138.3,129.8,129.8,128.0,124.7,124.5,123.8,119.3,110.2, 21.4.HRMS(APCI)calcd.for C21H16N3O2[M+H]+:342.12370；Found:342.12341.
化合物Ⅱ-4：白色固体，熔点202.4-203.3℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,2H), 7.42(t,J＝7.3Hz,3H),7.37(t,J＝8.7Hz,3H),7.30(t,J＝7.6Hz,2H),7.27–7.21(m,2H),2.46(s,3H).13C NMR(126MHz,CDCl3)δ156.7,149.0,141.3,139.3,135.8,130.7,127.3,124.6,123.7, 119.2,110.1,21.3.HRMS(APCI)calcd.for C21H16N3O2[M+H]+:342.12370；Found:342.12357. 化合物Ⅱ-5：白色固体，熔点231.8-232.7℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,2H), 7.44(t,J＝7.8Hz,4H),7.30(t,J＝7.6Hz,2H),7.24(t,2H),7.07(d,J＝8.6Hz,2H),3.89(s,3H).13C NMR(126MHz,CDCl3)：δ160.0,156.9,149.0,141.3,131.0,129.1,124.7,123.7,119.2,115.2, 110.1,55.6.HRMS(APCI)calcd.for C21H16N3O3[M+H]+:358.11862；Found:358.11829.
化合物Ⅱ-6：白色固体，熔点207.6-208.1℃；1H NMR(500MHz,CDCl3)：δ7.66(d,J＝7.8Hz, 2H),7.42(t,6H),7.30(t,J＝7.6Hz,2H),7.25(t,2H),3.07–2.96(m,1H),1.32(d,J＝6.8Hz,6H).13C NMR(126MHz,CDCl3)：δ156.8,149.7,149.1,141.3,136.1,128.1,127.1,124.7,123.8,119.2, 110.2,33.9,23.9.HRMS(APCI)calcd.for C23H20N3O2[M+H]+:370.15500；Found:370.15488. 化合物Ⅱ-7：白色固体，熔点194.7-195.3℃；1H NMR(500MHz,CDCl3)：δ7.66(d,J＝7.8Hz, 2H),7.55(d,J＝8.2Hz,2H),7.42(t,J＝7.1Hz,4H),7.30(t,J＝7.6Hz,2H),7.24(t,J＝7.7Hz,2H),1.39(s,9H).13C NMR(126MHz,CDCl3)：δ156.8,151.9,149.0,141.2,135.8,127.0,126.7, 124.6,123.8,119.2,110.1,34.8,31.3.HRMS(APCI)calcd.for C24H22N3O2[M+H]+:384.17065； Found:384.17038.
化合物Ⅱ-8：白色固体，熔点217.6-218.8℃；1H NMR(500MHz,CDCl3)：δ7.65(d,J＝7.8Hz, 2H),7.54–7.49(m,2H),7.44(d,J＝8.0Hz,2H),7.31(t,J＝7.7Hz,2H),7.25(q,J＝8.1Hz, 4H).13C NMR(126MHz,CDCl3)：δ162.5(d,J＝249.7Hz),156.4,149.0,141.1,134.3,134.3,129.6 (d,J＝9.0Hz),124.4(d,J＝106.5Hz),119.3,117.1(d,J＝23.2Hz),110.1.HRMS(APCI)calcd.for C20H13FN3O2[M+H]+:346.09863；Found:346.09833.
化合物Ⅱ-9：白色固体，熔点241.1-241.8℃；1H NMR(500MHz,CDCl3)δ7.65(d,J＝7.8Hz,2H), 7.53(d,J＝7.5Hz,2H),7.45(t,4H),7.36–7.25(m,4H).13C NMR(126MHz,CDCl3)δ156.3, 149.1,141.1,137.0,134.9,130.3,128.8,124.8,124.0,119.3,110.2.HRMS(APCI)calcd.for C20H13ClN3O2[M+H]+:362.06908；Found:362.06863.
化合物Ⅱ-10：白色固体，熔点259.0-259.9℃；1H NMR(500MHz,CDCl3)δ7.71–7.64(m,4H), 7.45(d,J＝7.9Hz,2H),7.39(d,J＝8.2Hz,2H),7.35–7.25(m,4H).13C NMR(126MHz, CDCl3)δ156.2,149.1,141.1,137.6,133.2,129.0,124.8,124.1,123.0,119.3,110.2.HRMS(APCI) calcd.for C20H13BrN3O2[M+H]+:406.01857；Found:406.01825.
化合物Ⅱ-11：白色固体，熔点284.1-284.8℃；1H NMR(500MHz,CDCl3)δ7.88(d,J＝8.1Hz,2H), 7.66(d,J＝7.7Hz,2H),7.45(d,J＝7.9Hz,2H),7.35–7.26(m,6H).13C NMR(126MHz,CDCl3)δ156.2,149.1,141.1,139.2,138.3,129.2,124.9,124.1,119.3,110.2,94.5.HRMS(APCI)calcd.for C20H13IN3O2[M+H]+:454.00470；Found:454.00427.
化合物Ⅱ-12：白色固体，熔点219.5-220.1℃；1H NMR(500MHz,Acetone-d6)δ8.01(d,J＝8.2 Hz,2H),7.91(d,J＝8.2Hz,2H),7.61(s,4H),7.40(s,4H).13C NMR(126MHz,Acetone-d6)δ 156.0,149.4,143.3,141.0,133.7,127.1,125.0,124.6,119.0,117.8,111.4,110.3.HRMS(APCI)calcd.for C21H13N4O2[M+H]+:353.10330；Found:353.10294.
化合物Ⅱ-13：白色固体，熔点235.9-236.6℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.8Hz,2H), 7.48–7.38(m,6H),7.31(t,J＝7.5Hz,2H),7.27(s,1H),7.24(s,1H),7.19(t,J＝7.4Hz,1H),7.14(t,J＝8.6Hz,4H).13C NMR(126MHz,CDCl3)δ158.2,156.7,155.9,149.0,141.2,132.8,130.0, 129.1,124.7,124.3,123.8,120.0,119.2,119.0,110.1.HRMS(APCI)calcd.for C26H18N3O3[M+H]+: 420.13427；Found:420.13403.
化合物Ⅱ-14：白色固体，熔点216.1-216.8℃；1H NMR(500MHz,CDCl3)δ7.68(d,J＝7.3Hz,2H), 7.61(s,2H),7.55–7.47(m,3H),7.34(dt,J＝19.7,7.5Hz,4H),7.15(dd,J＝8.8,2.3Hz,1H),6.59(d,J＝8.8Hz,1H).13C NMR(126MHz,CDCl3)δ155.6,150.7,149.2,147.1,140.8,136.5,130.6, 130.5,128.3,128.0,127.6,125.1,124.5,123.8,119.5,115.5,110.4.HRMS(APCI)calcd.for C26H14Cl4N3O3[M+H]+:555.97838；Found:555.97821.
化合物Ⅱ-15：白色固体，熔点236.0-236.6℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.9Hz, 2H),7.46–7.37(m,4H),7.30(td,J＝7.7,1.1Hz,2H),7.26(d,J＝1.3Hz,1H),7.23(dd,1H),7.09 (s,1H),7.05–6.98(m,3H),6.95(d,J＝8.2Hz,1H),2.33(s,3H),2.23(s,3H).13C NMR(126MHz, CDCl3)δ158.8,156.8,151.1,149.0,141.2,134.5,132.2,132.0,130.1,128.9,127.8,124.7,123.8, 120.7,119.2,117.5,110.1,20.8,16.1.HRMS(APCI)calcd.for C28H22N3O3[M+H]+:448.16557； Found:448.16516.
化合物Ⅱ-16：白色固体，熔点202.5-203.2℃；1H NMR(500MHz,CDCl3)δ7.77(d,J＝1.6Hz, 1H),7.65(d,J＝7.7Hz,2H),7.55–7.50(m,3H),7.44(d,J＝8.0Hz,2H),7.31(t,J＝7.2Hz,2H),7.27(d,J＝1.1Hz,1H),7.25–7.22(m,1H),7.21–7.14(m,3H).13C NMR(126MHz,CDCl3)δ 156.5,156.1,154.9,149.1,141.1,134.4,129.3,128.3(q,J＝3.7Hz),127.2(q,J＝33.6Hz),126.3,125.2(q,J＝3.7Hz),124.8,124.0,123.2(q,J＝272.1Hz),120.4,119.6,119.2,110.2.HRMS(APCI) calcd.for C27H16ClF3N3O3[M+H]+:522.08268；Found:522.08246.
化合物Ⅱ-17：白色固体，熔点229.1-229.6℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.6Hz, 2H),7.46(dd,J＝12.0,8.5Hz,4H),7.31(t,J＝7.6Hz,2H),7.27(d,J＝2.1Hz,2H),7.25(d,J＝2.7Hz,1H),7.16(d,J＝5.4Hz,2H),7.10(d,J＝6.9Hz,2H).13C NMR(126MHz,CDCl3)δ157.5, 156.6,154.4(d,J＝253.5Hz),149.0,141.5(d,J＝12.0Hz),141.2,133.3,130.4(d,J＝8.7Hz), 129.2,125.2(d,J＝3.9Hz),124.7,123.9,123.5(d,J＝1.6Hz),119.2,118.1(d,J＝21.6Hz),117.8,110.2.HRMS(APCI)calcd.for C26H16ClFN3O3[M+H]+:472.08587；Found:472.08557.
化合物Ⅱ-18：白色固体，熔点238.1-238.5℃；1H NMR(500MHz,CDCl3)δ7.66(d,J＝7.4Hz, 2H),7.51(d,J＝2.5Hz,1H),7.49–7.43(m,4H),7.31(td,J＝7.7,1.1Hz,2H),7.29–7.26(m,2H),7.25(d,J＝1.2Hz,1H),7.13–7.07(m,3H).13C NMR(126MHz,CDCl3)δ157.1,156.6,150.3, 149.0,141.1,133.5,130.7,130.3,129.2,128.3,127.4,124.7,123.9,122.6,119.2,118.4, 110.2.HRMS(APCI)calcd.for C26H16Cl2N3O3[M+H]+:488.05632；Found:488.05603.
化合物Ⅱ-19：白色固体，熔点205.4-206.8℃；1H NMR(500MHz,CDCl3)δ7.67(d,J＝8.6Hz, 2H),7.57–7.40(m,4H),7.38–7.28(m,6H).13C NMR(126MHz,CDCl3)δ155.7,149.1,148.5, 147.2,140.9,134.5,129.9,129.0,128.3,127.5,127.3,125.0,124.3,119.4,110.3.HRMS(APCI)calcd.for C26H13Cl5N3O3[M+H]+:589.93941；Found:589.93903.
实施例39-57
一种新型苯并噁唑衍生物，其结构式如下：
其制备方法为：
在手套箱中将2-氯苯并噁唑(1.6mmol，183μL)、胺类化合物R1-NH2(R1的选择见表3) (0.4mmol)、NaH(0.4mmol，16mg)和甲苯(1mL)加入25mL的Schlenk反应管中，在无水无氧环境下加热至回流，反应16h，反应结束后通过柱层析纯化得到式(Ⅲ)化合物。
本实施例39-57用于说明采用反应式(3)的合成方法制备式(Ⅲ)所示的目标化合物，制备得到的苯并噁唑衍生物分别标记为Ⅲ-1～Ⅲ-19，产物取代基及其收率如表3所示：
表3
本实施例中a均代表分离收率；
另外实施例39-57所制备的苯并噁唑衍生物的结构表征数据如下：
化合物Ⅲ-1：白色固体，熔点144.2-144.6℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝8.3Hz,1H), 7.76(d,J＝7.9Hz,1H),7.63(d,J＝7.9Hz,1H),7.42–7.35(m,3H),7.35–7.28(m,3H),7.26(d,J＝7.6Hz,1H),7.21–7.11(m,3H).13C NMR(126MHz,CDCl3)δ152.0,148.7,144.7,144.5,143.3, 140.4,128.9,128.3,124.9,124.4,124.4,124.3,124.1,123.1,119.4,113.6,110.7,109.6.HRMS(APCI)calcd.for C20H14N3O2[M+H]+:328.10805；Found:328.10773.
化合物Ⅲ-2：白色固体，熔点115.5-116.2℃；1H NMR(500MHz,CDCl3)δ8.14(d,J＝7.9Hz,1H), 7.75(d,J＝7.8Hz,1H),7.61(d,J＝7.9Hz,1H),7.34(dt,J＝22.3,7.6Hz,2H),7.24(q,J＝7.0Hz, 4H),7.16(t,J＝7.8Hz,1H),7.11(d,J＝7.9Hz,1H),7.06(t,J＝7.0Hz,1H),2.35(s,3H).13C NMR(126MHz,CDCl3)δ152.3,148.8,144.6,143.5,142.4,140.4,130.9,130.4,128.5,126.2, 124.9,124.4,124.3,124.2,124.0,121.9,119.3,113.6,110.6,109.6,18.2.HRMS(APCI)calcd.for C21H16N3O2[M+H]+:342.12370；Found:342.12354.
化合物Ⅲ-3：白色固体，熔点126.3-126.9℃；1H NMR(500MHz,CDCl3)δ8.12(d,J＝7.9Hz,1H), 7.76(d,J＝8.4Hz,1H),7.64(d,J＝7.9Hz,1H),7.41–7.32(m,2H),7.28(d,J＝8.0Hz,2H),7.22–7.13(m,2H),7.10(d,J＝5.7Hz,2H),6.97(d,J＝7.5Hz,1H),2.38(s,3H).13C NMR(126MHz, CDCl3)δ152.1,148.7,144.6,144.5,143.2,140.4,138.7,128.7,128.4,124.9,124.8,124.4,124.4, 124.2,123.7,119.9,119.4,113.6,110.7,109.6,21.5.HRMS(APCI)calcd.for C21H16N3O2[M+H]+: 342.12370；Found:342.12335.
化合物Ⅲ-4：白色固体，熔点142.2-143.0℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.8Hz,1H), 7.76(d,J＝7.3Hz,1H),7.64(d,J＝7.7Hz,1H),7.40–7.32(m,2H),7.29–7.25(m,1H),7.23– 7.14(m,6H),2.37(s,3H).13C NMR(126MHz,CDCl3)δ152.1,148.7,144.6,143.1,142.0,140.4, 133.5,129.5,128.4,124.9,124.3,124.3,124.2,122.9,119.4,113.6,110.7,109.5,21.0.HRMS(APCI)calcd.for C21H16N3O2[M+H]+:342.12370；Found:342.12323.
化合物Ⅲ-5：白色固体，熔点164.3-165.1℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.9Hz,1H), 7.75(d,J＝7.7Hz,1H),7.64(d,J＝7.8Hz,1H),7.40–7.32(m,2H),7.32–7.26(m,3H),7.19(q,J＝7.8Hz,2H),6.93(d,J＝8.7Hz,2H),3.83(s,3H).13C NMR(126MHz,CDCl3)δ156.3,152.1, 148.7,144.6,142.8,142.8,140.4,137.6,128.4,124.9,124.3,124.3,124.2,119.3,114.1,113.6,110.7,109.5,55.4.HRMS(APCI)calcd.for C21H16N3O3[M+H]+:358.11862；Found:358.11804.
化合物Ⅲ-6：白色固体，熔点155.6-156.0℃；1H NMR(500MHz,CDCl3)δ8.12(d,J＝7.9Hz,1H), 7.75(d,J＝7.3Hz,1H),7.63(d,J＝7.8Hz,1H),7.36(dt,J＝21.0,7.5Hz,2H),7.27–7.24(m, 5H),7.22–7.14(m,2H),2.94(p,J＝6.8Hz,1H),1.29(d,J＝6.9Hz,6H).13CNMR(126MHz, CDCl3)δ152.1,148.7,144.6,144.6,143.0,142.1,140.4,128.4,126.8,124.9,124.3,124.3,124.2, 122.9,119.3,113.6,110.7,109.5,33.6,24.1.HRMS(APCI)calcd.for C23H20N3O2[M+H]+: 370.15500；Found:370.15457.
化合物Ⅲ-7：白色固体，熔点171.2-172.2℃；1H NMR(500MHz,CDCl3)δ8.13(d,J＝7.8Hz,1H), 7.75(d,J＝7.7Hz,1H),7.63(d,J＝7.8Hz,1H),7.44–7.31(m,4H),7.25(t,J＝3.9Hz,3H),7.23–7.14(m,2H),1.35(s,9H).13C NMR(126MHz,CDCl3)δ152.1,148.7,146.9,144.6,143.0,141.8, 140.4,128.4,125.7,124.9,124.3,124.3,124.2,122.6,119.3,113.6,110.7,109.6,34.4,31.5.HRMS(APCI)calcd.for C24H22N3O2[M+H]+:384.17065；Found:384.17026.
化合物Ⅲ-8：白色固体，熔点181.5-182.2℃；1H NMR(500MHz,CDCl3)δ8.12(d,J＝7.8Hz,1H), 7.77(d,J＝7.4Hz,1H),7.65(d,J＝7.7Hz,1H),7.43–7.33(m,2H),7.28(dd,J＝8.7,5.0Hz,3H),7.20(dt,J＝14.8,7.8Hz,2H),7.07(t,J＝8.6Hz,2H).13C NMR(126MHz,CDCl3)δ159.6(d,J＝242.4Hz),151.9,148.7,144.4,143.4,δ140.6(d,J＝2.8Hz),140.4,128.3,125.0,124.5,124.5,124.4, 124.4,119.4,115.5(d,J＝22.4Hz).113.6,110.6,109.6.HRMS(APCI)calcd.for C20H13FN3O2[M+H]+:346.09863；Found:346.09833.
化合物Ⅲ-9：白色固体，熔点176.8-177.4℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.8Hz,1H), 7.76(d,J＝6.9Hz,1H),7.64(d,J＝7.5Hz,1H),7.41–7.31(m,4H),7.28(t,J＝7.7Hz,2H),7.23(d,J＝3.6Hz,1H),7.20(d,J＝7.5Hz,1H),7.17(d,J＝7.9Hz,1H).13C NMR(126MHz,CDCl3)δ 151.8,148.7,144.4,143.7,143.3,140.3,129.2,128.9,128.3,125.0,124.6,124.5,124.5,124.5,119.5,113.6,110.7,109.6.HRMS(APCI)calcd.forC20H13ClN3O2[M+H]+:362.06908；Found: 362.06876.
化合物Ⅲ-10：白色固体，熔点178.1-178.5℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.9Hz,1H), 7.76(d,J＝7.4Hz,1H),7.64(d,J＝7.6Hz,1H),7.48(d,J＝8.7Hz,2H),7.41–7.33(m,2H),7.28(td,J＝7.8,1.3Hz,1H),7.24–7.16(m,4H).13C NMR(126MHz,CDCl3)δ151.8,148.7,144.4, 143.8,143.7,140.3,131.9,128.3,125.0,125.0,124.6,124.5,124.5,119.5,117.0,113.6,110.7,109.6.HRMS(APCI)calcd.for C20H13BrN3O2[M+H]+:406.01857；Found:406.01846.
化合物Ⅲ-11：白色固体，熔点182.8-183.4℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝8.4Hz,1H), 7.79–7.75(m,1H),7.70–7.62(m,3H),7.42–7.34(m,2H),7.29(td,J＝7.7,1.3Hz,1H),7.22(td,J＝7.8,1.2Hz,1H),7.18(dd,J＝8.0,1.3Hz,1H),7.07(d,J＝8.6Hz,2H).13C NMR(126MHz, CDCl3)δ151.8,148.7,144.5,144.4,143.7,140.3,137.9,128.3,125.4,125.1,124.6,124.6,124.5, 119.5,113.7,110.7,109.7,87.7.HRMS(APCI)calcd.for C20H13IN3O2[M+H]+:454.00470；Found: 454.00430.
化合物Ⅲ-12：白色固体，熔点197.1-197.7℃；1H NMR(500MHz,CDCl3)δ8.13(d,J＝7.9Hz, 1H),7.79(d,J＝8.2Hz,1H),7.66(t,J＝8.1Hz,3H),7.45–7.29(m,5H),7.25–7.17(m,2H).13C NMR(126MHz,CDCl3)δ151.5,149.2,148.8,144.4,144.2,140.2,133.1,128.1,125.2,124.8, 124.8,124.8,124.1,119.7,119.3,113.8,110.7,109.8,107.1.HRMS(APCI)calcd.for C21H13N4O2[M+H]+:353.10330；Found:353.10278.
化合物Ⅲ-13：白色固体，熔点147.2-148.1℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.9Hz,1H), 7.75(d,J＝7.5Hz,1H),7.63(d,J＝7.7Hz,1H),7.41–7.29(m,6H),7.29–7.25(m,1H),7.19(q,J＝8.3,7.7Hz,2H),7.06(dt,J＝16.1,7.4Hz,5H).13C NMR(126MHz,CDCl3)δ157.8,153.3, 152.0,148.7,144.5,143.1,140.4,140.1,129.6,128.3,124.9,124.5,124.4,124.4,124.3,122.8,119.7,119.4,118.3,113.6,110.7,109.5.HRMS(APCI)calcd.for C26H18N3O3[M+H]+:420.13427； Found:420.13397.
化合物Ⅲ-14：白色固体，熔点199.4-200.5℃；1H NMR(500MHz,CDCl3)δ8.13(d,J＝7.9Hz,1H), 7.79(d,J＝7.3Hz,1H),7.66(d,J＝8.0Hz,1H),7.48(d,J＝2.4Hz,1H),7.41(d,J＝7.0Hz,4H), 7.34(dt,J＝8.0,4.3Hz,1H),7.28(d,J＝4.0Hz,2H),7.11(dd,J＝8.8,2.5Hz,1H),6.48(d,J＝8.8 Hz,1H).13C NMR(126MHz,CDCl3)δ151.4,151.4,148.8,144.6,144.2,143.3,142.8,140.2,130.4, 129.2,128.1,127.7,127.5,125.2,124.9,124.8,124.8,124.2,123.5,119.7,115.1,113.8,110.7,109.9.HRMS(APCI)calcd.forC26H14Cl4N3O3[M+H]+:555.97838；Found:555.97797.
化合物Ⅲ-15：白色固体，熔点176.7-177.3℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.9Hz, 1H),7.75(d,J＝8.0Hz,1H),7.63(d,J＝7.6Hz,1H),7.40–7.31(m,2H),7.27(d,J＝8.9Hz,3H),7.22–7.15(m,2H),7.06(s,1H),6.97(d,J＝8.1Hz,1H),6.91(d,J＝8.7Hz,2H),6.84(d,J＝8.1 Hz,1H),2.32(s,3H),2.22(s,3H).13C NMR(126MHz,CDCl3)δ154.7,152.5,152.0,148.7,144.5, 142.9,140.4,138.9,133.2,132.0,129.5,128.3,127.5,124.9,124.4,124.3,124.3,124.2,119.6,119.3,117.5,113.6,110.6,109.5,20.7,16.1.HRMS(APCI)calcd.for C28H22N3O3[M+H]+: 448.16557；Found:448.16525.
化合物Ⅲ-16：白色固体，熔点141.9-142.3℃；1H NMR(500MHz,CDCl3)δ8.12(d,J＝7.8Hz, 1H),7.80–7.71(m,2H),7.64(d,J＝8.2Hz,1H),7.46–7.33(m,5H),7.32–7.26(m,1H),7.24–7.17(m,2H),7.09–7.04(m,2H),6.97(d,J＝8.6Hz,1H).13C NMR(126MHz,CDCl3)δ156.6, 151.9,151.5,148.7,144.4,143.5,141.6,140.4,128.3,128.0(q,J＝3.7Hz),125.6(q,J＝33.4Hz),125.0,125.0,125.0,124.9,124.7,124.5,124.5,122.3,120.2,119.5,118.0,113.7,110.7, 109.6.HRMS(APCI)calcd.for C27H16ClF3N3O3[M+H]+:522.08268；Found:522.08240.
化合物Ⅲ-17：白色固体，熔点188.1-189.2℃；1H NMR(500MHz,CDCl3)δ8.12(d,J＝7.9Hz, 1H),7.76(d,J＝7.3Hz,1H),7.64(d,J＝7.5Hz,1H),7.42–7.33(m,2H),7.33–7.26(m,3H),7.24–7.17(m,3H),7.08(dt,J＝8.8,1.8Hz,1H),7.00(dd,J＝8.6,6.4Hz,3H).13CNMR(126 MHz,CDCl3)δ153.7(d,J＝252.5Hz),153.1,151.9,148.7,144.5,143.6(d,J＝11.3Hz),143.3, 140.4,140.4,128.6(d,J＝8.7Hz),128.3,125.0,124.7(d,J＝4.0Hz),124.6,124.5,124.5,124.4,121.6(d,J＝2.0Hz),119.4,118.3,117.7(d,J＝21.4Hz),113.6,110.7,109.6.HRMS(APCI)calcd. for C26H16ClFN3O3[M+H]+:472.08587；Found:472.08566.
化合物Ⅲ-18：白色固体，熔点203.6-204.3℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.8Hz, 1H),7.76(d,J＝8.5Hz,1H),7.64(d,J＝7.6Hz,1H),7.46(d,J＝2.5Hz,1H),7.41–7.30(m,4H),7.30–7.26(m,1H),7.24–7.15(m,3H),7.02–6.98(m,2H),6.91(d,J＝8.8Hz,1H).13C NMR (126MHz,CDCl3)δ152.7,152.1,151.9,148.7,144.4,143.3,140.7,140.4,130.4,128.5,128.3, 127.9,126.0,125.0,124.7,124.5,124.4,120.5,119.4,119.0,113.6,110.7,109.6.HRMS(APCI)calcd.for C26H16Cl2N3O3[M+H]+:488.05632；Found:488.05615.
化合物Ⅲ-19：白色固体，熔点219.3-220.1℃；1H NMR(500MHz,CDCl3)δ8.11(d,J＝7.9Hz, 1H),7.78(d,J＝8.1Hz,1H),7.65(d,J＝7.7Hz,1H),7.44–7.35(m,2H),7.32(s,5H),7.27(s, 2H).13C NMR(126MHz,CDCl3)δ151.5,148.7,147.7,144.6,144.4,144.3,141.5,140.2,129.0, 128.1,127.2,126.5,125.1,124.8,124.8,124.7,124.2,119.6,113.7,110.7,109.9.HRMS(APCI)calcd.for C26H13Cl5N3O3[M+H]+:589.93941；Found:589.93872.
为更加准确地确定化合物组成，制备得到化合物Ⅱ-1和Ⅲ-1的单晶结构(长单晶方法：将乙醇加入纯产品中使之完全溶解，然后通过乙醚缓慢的向乙醇溶液中扩散得到相应的单晶)，测得单晶结构如下式所示：
测试例1
本测试例用于说明本发明实施例所制备的苯并噁唑衍生物Ⅰ-1～14、Ⅱ-1～14和Ⅲ-1～14对琥珀酸-细胞色素c氧化还原酶(SCR)的抑制活性，对照药剂为吡噻菌胺和嘧菌酯。
本测试例中使用的酶为琥珀酸-细胞色素c氧化还原酶(SCR)，从猪心中分离制得。SCR 的抑制活性测试方法为：总体积1.8mL，体系中含100mM的Na2HPO4-NaH2PO4缓冲液(pH7.2) (苯并噁唑衍生物加在缓冲液中使其最终浓度为10μM)、0.3mM的乙二胺四乙酸(EDTA)、 20mM的琥珀酸钠、60μM的细胞色素c、0.08nM的SCR，在温度为30℃恒温水浴及600rpm 磁力搅拌下进行反应。在波长为550nm处监测底物细胞色素c光吸收的增加，采集线性范围内的实验点，即控制底物SCR的消耗不超过5％的实验点。根据细胞色素c的摩尔消光系数 18.5mM-1cm-1，可以计算在反应时间内细胞色素c的还原产量并拟合线性斜率，再扣掉基线斜率即为反应的初速度。该测试结果反映出所制备的苯并噁唑衍生物Ⅰ-1～14、Ⅱ-1～14和Ⅲ-1～14 对琥珀酸脱氢酶(简称复合物II)与细胞色素bc1复合物(简称复合物Ⅲ)的总体抑制结果。
所制备的苯并噁唑衍生物对SCR(复合物II+复合物III)的抑制活性数据如下表4所示。
表4
从表4所示的活性结果可以得知，本发明提供的苯并噁唑衍生物对SCR体系均有较好的抑制效果，说明这些化合物对复合物II+复合物III的混合酶的活性有一定的抑制效果。与现有市售药剂相比，对SCR抑制活性接近，但制备过程容易，成本低，产物结构稳定。
测试例2
本测试例用于测定部分实施例制得的苯并噁唑衍生物的杀菌活性。
本测试例中对四种试验靶标的测试方法一样，以水稻纹枯病菌为例，具体实验方法如下：按照《农药生物活性测试标准操作规范(SOP)》，采用盆栽活体法测定，评价这些化合物在220 mg/L剂量下对试验靶标的杀菌活性。
(1)供试药的配制
将苯并噁唑衍生物配制成5重量％的乳油(以下简称5％EC)，试验均采用活体盆栽，普筛浓度采用220mg/L，初、复筛根据化合物生物活性情况确定药剂浓度。
(2)供试病原菌
活体试验对象：恶苗菌、松枯梢病菌、水稻纹枯病菌、油茶炭疽菌。
(3)供试作物:将盆栽黄瓜幼苗培养至2片真叶期时供试验用。
(4)试验方法(盆栽活体测定)
选择二片真叶期长势一致的盆栽黄瓜苗，待药剂喷雾晾干后，将菌饼有菌丝的一面接贴于叶片上，22-26℃暗光保湿24h后，恢复自然光照培养约4d，并以未喷药剂的作为对照样。待对照充分发病后用卡尺计量每个接种点病斑直径，计算防效％。
(5)测试方法：
分级标准采用《农药田间药效试验准则》，以病情指数计算防治效果％。
病情指数＝∑(各级病叶数×相对级数值)×100/(总叶数×9)；
防治效果(％)＝(对照病情指数-处理病情指数)×100/对照病情指数。
部分实施例制得的苯并噁唑衍生物对该试验靶标普筛结果如下表5所示：
表5
从表5可以看出，在220mg/L浓度下，本发明实施例制备的苯并噁唑衍生物对恶苗病、松枯梢病、水稻纹枯病、油茶炭疽病均有一定的防效，其中Ⅰ-2对恶苗病的防效达到了69.59％，Ⅲ-4对松枯梢病的防效达到了63.73％，Ⅲ-13对水稻纹枯病的防效达到了69.26％，Ⅱ-7对油茶炭疽病的防效达到了67.91％。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。

Claims (7)

1.一种苯并噁唑衍生物，其特征在于，所述苯并噁唑衍生物具有以下结构，如式(Ⅲ)所示：
其中，R1为
R2选自H，2-甲基，3-甲基，4-甲基，4-甲氧基，4-异丙基，4-叔丁基，4-氟，4-氯，4-溴，4-碘、4-氰基中的一种；
R3选自H或3,5-Cl2；
R3为H时，R4选自H、2,4-Cl2、2,4-Me2、2-Cl-4-CF3、2-F-4-Cl中的一种；
R3为3,5-Cl2时，R4选自2,4-Cl2、2,4,6-Cl3中的一种。
2.一种权利要求1所述的苯并噁唑衍生物的制备方法，其特征在于，具体步骤如下：将2-氯苯并噁唑与胺类化合物在无水无氧的条件下进行亲核取代反应，然后纯化得到式(Ⅲ)苯并噁唑衍生物；
所述胺类化合物结构式为R1-NH2，其中
R1选自
R2选自H，2-甲基，3-甲基，4-甲基，4-甲氧基，4-异丙基，4-叔丁基，4-氟，4-氯，4-溴，4-碘、4-氰基中的一种；
R3选自H或3,5-Cl2；
R3为H时，R4选自H、2,4-Cl2、2,4-Me2、2-Cl-4-CF3、2-F-4-Cl中的一种；
R3为3,5-Cl2时，R4选自2,4-Cl2、2,4,6-Cl3中的一种。
3.根据权利要求2所述的苯并噁唑衍生物的制备方法，其特征在于，所述式(Ⅲ)苯并噁唑衍生物的制备条件为：所述2-氯苯并噁唑与胺类化合物摩尔比为2.5-5：1，在碱和溶剂存在条件下，于110-150℃下加热回流反应1-24h时，所得产物为式(Ⅲ)苯并噁唑衍生物。
4.根据权利要求3所述的苯并噁唑衍生物的制备方法，其特征在于，所述碱为Na2CO3，K2CO3，Cs2CO3，NaH，4-二甲氨基吡啶，吡啶中的一种，所述碱与胺类化合物的摩尔比为0.5-1.5：1。
5.根据权利要求3所述的苯并噁唑衍生物的制备方法，其特征在于，所述溶剂为1,4-二氧六环，甲苯，间二甲苯，均三甲苯，氯苯中的一种，所述胺类化合物与有机溶剂的摩尔体积比为0.2-2mmol/mL。
6.权利要求1所述的苯并噁唑衍生物在抑制琥珀酸-细胞色素c氧化还原酶活性方面的应用，所述应用为非治疗目的的。
7.根据权利要求6所述的应用，其特征在于，其在防治恶苗菌，松枯梢病，水稻纹枯病，油茶炭疽病的农用杀菌剂方面的应用。
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