CN112375123B - 噁唑基甾体衍生物及其合成方法与应用 - Google Patents

噁唑基甾体衍生物及其合成方法与应用 Download PDF

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CN112375123B
CN112375123B CN202011458037.0A CN202011458037A CN112375123B CN 112375123 B CN112375123 B CN 112375123B CN 202011458037 A CN202011458037 A CN 202011458037A CN 112375123 B CN112375123 B CN 112375123B
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师宝君
马世闯
李奇
蒋伟奇
吴文君
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Abstract

本发明提供一种噁唑基甾体衍生物，其具有通式(1)表示的化学结构，取代基R表示烷基、苯基或取代苯基中的一种。本发明还进一步给出了所述噁唑基甾体衍生物的合成方法。经生物测定证实，所述噁唑基甾体衍生物对苹果绵蚜、桃蚜和黄蚜以及粉虱等刺吸式昆虫表现出良好的毒杀活性，可用于植物虫害防治。
Figure DDA0002830008740000011

Description

噁唑基甾体衍生物及其合成方法与应用
技术领域
本发明属于药物合成技术领域，涉及一种噁唑基甾体衍生物，具体涉及一种噁唑基甾体衍生物的制备以及在病虫害防治中的应用。
背景技术
杂环化合物在自然界中普遍存在且用途广泛，在人们的现实生活中占有非常重要的地位。绝大多数药物和半数以上的有机化合物都为杂环化合物。杂环化合物的合成及其生物活性的探究是有机化学、药物化学及农药开发的重要研究领域之一，尤其是某些含有N、O杂原子的杂环化合物，表现出了良好的杀菌活性，在农药、医药等领域得到了广泛的应用。
含氮杂环中的噁唑类化合物由于具有广谱生物活性，是近年来研究开发较为活跃的领域之一，其应用领域主要是：在医药方面可用来做抗癌、消炎、退热等药物；在农药方面可用来做除草剂、抗菌剂、植物生长调节剂、杀虫剂等；在工业方面可做电子传输材料，用于有机电致发光器，也可作发光材料，用于分辨活细胞的荧光成像情况；同时，这类化合物还可作为重要的有机合成中间体。
刺吸式害虫是农业上为害最为严重的害虫之一，例如蚜虫、粉虱等都可以为害大多数农作物，对其产量和质量造成了严重的损失，但目前有效的防治药剂经过长期使用，大多数都对刺吸式害虫产生了很严重的抗药性。因此，需要迫切的筛选出新的防治药剂。甾体类化合物是广泛存在于自然界中的一类天然化学成分，包括植物甾醇、胆汁酸、C21甾类、昆虫变态激素、强心苷、甾体皂苷、甾体生物碱、蟾毒配基等。基于甾体类药物的毒性低，利用率高，不易产生耐药性等优点，越来越多的甾体类药物被开发出来。
发明内容
本发明的目的在于提供一系列结构新颖的噁唑基甾体衍生物，并探讨该噁唑基甾体衍生物对刺吸式害虫(蚜虫)的毒杀活性。本发明所述噁唑基甾体衍生物，具有通式(1)表示的化学结构，其中，取代基R表示烷基、苯基或取代苯基中的一种。
Figure BDA0002830008720000021
通式(1)所示的噁唑基甾体衍生物，其中，取代基R为式(6g)-(31g)中的一种。
Figure BDA0002830008720000031
本发明还给出了所述噁唑基甾体衍生物的制备方法，所述通式(1)的合成路线为：
Figure BDA0002830008720000041
具体地，所述步骤h的反应条件为：向溶有化合物(3)的二氯甲烷中，分别加入4-二甲氨基吡啶、二氯乙烷和化合物(2)，常温反应6h。
具体地，所述步骤i的反应条件为：以四氢呋喃为溶剂，加入四丁基氟化铵，常温反应2h。
进一步地，上述通式(1)的合成路线中，所述化合物(2)的合成路线为：
Figure BDA0002830008720000042
具体地，所述步骤d和e的反应条件为：酰氯(2a)与无水乙醇混合，以浓硫酸为催化剂，60℃反应6h；所得产物溶于无水乙醇中，加入水合肼，50℃反应12h。
具体地，所述步骤f的反应条件为：以二氯甲烷为溶剂，加入三乙胺和乙基乙二酰氯酯，-10℃反应1h，在常温条件下反应8h后，再加入三乙胺和对甲苯磺酰氯，继续反应12h。
具体地，所述步骤g的反应条件为：以无水乙醇为溶剂，加入氢氧化钾水溶液，冰浴反应1h。
进一步地，上述通式(1)的合成路线中，所述化合物(3)的合成路线为：
Figure BDA0002830008720000051
具体地，所述步骤a和b的反应条件为：以N,N-二甲基甲酰胺为溶剂，加入咪唑和叔丁基二甲基氯硅烷，冰浴30min后常温反应12h，所得产物加入磷叶立德盐反应体系中常温搅拌24h。
具体地，所述步骤c的反应条件为：以AD-mix-β为催化剂，甲基磺酰胺和化合物(3b)0℃反应2d，常温反应3d，反应完成后加入亚硫酸钠固体，反应1h。
基本本发明的生物测定结果，本发明还进一步保护所述噁唑基甾体衍生物在植物虫害防治中的应用，具体可用于蚜虫的防治。
为了在农业和植保领域施用所述噁唑基甾体衍生物，本领域普通技术人员可以将所述噁唑基甾体衍生物中的一种或几种作为杀虫活性成分，与农药学上可接受的载体，或者是其他的农用活性成分组合使用，制备成便于施用的制剂，比如水分散粒剂、可湿性粉剂或可分散油悬浮剂等多种剂型。在配制上述不同剂型时，对本领域的普通技术人员来说，除需要使用含有供选的杀菌活性成分外，还需要选用多种助剂，可以根据需要选择使用不同的农药制剂辅助成分(助剂)。所述辅助成分可以为分散介质、分散剂、乳化剂、润湿剂、增稠剂、消泡剂、防冻剂、崩解剂、粘结剂、填料等中的一种或几种。关于含所述噁唑基甾体衍生物的单剂或组合物制剂的配制方法，本发明不作陈述。
与现有技术相比，本发明具有以下有益效果：
(1)所述噁唑基甾体衍生物为一系列全新的化合物，本发明属首次提出。另外，本发明还给出所述噁唑基甾体衍生物的合成方法，其使用酰氯和去氢表雄酮为基础原料，通过取代、不对称双羟基化等反应得到本发明的噁唑基甾体衍生物。所述合成方法制备产率高，所得产物易于分离。
(2)经生物测定证实，所述噁唑基甾体衍生物对苹果绵蚜、桃蚜和黄蚜以及粉虱等刺吸式昆虫表现出良好的毒杀活性，可用于制备农用杀虫剂单剂或含所述噁唑基甾体衍生物的混合制剂。
附图说明
图1为目标化合物18g的单晶衍射图。
具体实施方式
下面，结合实施例对本发明的技术方案进行说明，但是，本发明并不限于下述的实施例。
本发明所述噁唑基甾体衍生物的合成制备。其合成思路可分为三部分：第一部分，先将去氢表雄酮1与N,N-二甲基甲酰胺、叔丁基二甲基氯硅烷反应保护1的三位羟基，然后以四氢呋喃作溶剂，加入乙基三苯基溴化膦和叔丁醇钾得到化合物3，最后在AD-mix-bata的催化下发生不对称双羟基化反应得到化合物4；第二部分，以各种酰氯为反应原料，在乙醇作溶剂的情况下发生肼解反应得到6c-31c，然后以二氯甲烷作溶剂，在三乙胺和对甲苯磺酰氯的存在下关环得到具有噁唑环的化合物6d-31d，再以无水乙醇作溶剂，加入氢氧化钾水溶液得到钾盐6e-31e；第三部分；将6e-31e和化合物4以酯键相连得到6f-31f，然后脱掉3位羟基的保护得到化合物6g-31g。
Figure BDA0002830008720000081
上述为噁唑基甾体衍生物的合成制备路线，反应试剂和条件：
(a)imidazole,TBSCl,0℃-rt；
(b)t-BuOK,EtPh3PBr,0℃-rt；
(c)t-BuOH:H2O(V/V),CH2Cl2,0℃2d,rt 3d；
(d)EtOH,60℃；
(e)hydrazine hydrate,50℃；
(f)CH2Cl2,Et3N,PTSCl,rt；
(g)EtOH,KOH,0℃；
(h)CH2Cl2,DMAP,EDC,rt；
(i)TBAF,THF,rt.
甾体衍生物的合成：将4.33g去氢表雄酮(15mmol)溶解于有40mLN,N-二甲基甲酰胺的250mL茄型烧瓶中，搅拌待完全溶解，在冰浴下依次加入3.06g咪唑(45mmol)和2.71g叔丁基二甲基氯硅烷(18mmol)冰浴30min后反应12h。然后用1mol/L的盐酸水和乙酸乙酯萃取，用甲醇洗涤得5.60g白色固体。将2.24g叔丁醇钾(20mmol)和7.43g乙基三苯基溴化膦(20mmol)加入干燥的1000mL的茄型烧瓶，以15mL无水四氢呋喃作溶剂，冰浴1h，常温3h，将2.01g上述制备的白色固体(5mmol)溶解于5mL四氢呋喃中加入反应体系常温搅拌24h，然后用1mol/L的盐酸水和乙酸乙酯萃取，以石油醚和乙酸乙酯50:1(v/v)纯化得2.00g产物(3b)。在不对称双羟基化反应中，将18.6g催化剂AD-mix-β溶于叔丁醇和水的混合溶剂中(v/v＝80mL/80mL)，然后在0℃下加入3.44g甲基磺酰胺(36.2mmol)和5.0g产物3(12.1mmol)的二氯甲烷(40mL)溶液，然后在0℃下反应2d，常温下反应3d，反应完成后加入13g亚硫酸钠固体，反应1h后用1mol/L的氢氧化钾水溶液和1mol/L的盐酸水溶液各萃取三次，用二氯甲烷和乙酸乙酯10:1(v/v)纯化得4.57g白色固体(3)。
噁唑环的制备：取干燥的圆底烧瓶，以各种酰氯(20mmol)为原料，向内加入15mL无水乙醇溶液，以浓硫酸为催化剂60℃反应6h，反应完成后减压旋蒸用饱和碳酸氢钠水溶液和乙酸乙酯萃取，得油状液体，无须纯化直接进行下一步反应。将上述油状液体溶于无水乙醇中加入水合肼在50℃反应12h，直接过滤得滤液，减压旋干得黄色固体(2b)，无须纯化直接进行下一步反应。在关环反应的实验中，先将(2b)(15mmol)溶于二氯甲烷(40mL)中，然后加入3.04g三乙胺(30mmol)和3.07g乙基乙二酰氯酯(22.5mmol)反应在-10℃反应1h，在常温条件下反应8h后再加入1.52g三乙胺(15mmol)和2.86g对甲苯磺酰氯(15mmol)继续反应12h，反应完成后用乙酸乙酯和1mol/L的盐酸水溶液萃取，用石油醚和乙酸乙酯10:1(v/v)纯化得白色或黄色固体(2c)。将化合物6d-31d(10mmol)溶于无水乙醇中，然后加入0.56g氢氧化钾(10mol)的水溶液，冰浴反应1h，过滤得白色固体(2)。
噁唑基甾体衍生物的合成：将化合物(3)溶于二氯甲烷中，加入2,4-二甲氨基吡啶，EDC和化合物(2)，常温反应6h，反应完成后，用二氯甲烷和1mol/L的盐酸水溶液萃取，以石油醚和乙酸乙酯5:1(v/v)纯化得白色固体(4)。再以四氢呋喃为溶剂，加入TBAF常温反应2h，用水和乙酸乙酯萃取，以二氯甲烷和甲醇79:1(v/v)纯化得白色固体产物(1)。
将通过上述方法制得的所述噁唑基甾体衍生物通过1H-NMR、13C-NMR进行确认，其中目标化合物18g的结构通过单晶衍射的方法予以确认，其结果如下。
化合物6g
Figure BDA0002830008720000111
1H NMR(500MHz,Chloroform-d)δ＝8.14–8.12(m,2H),7.62–7.58(m,1H),7.55–7.52(m,1H),5.44(q,J＝6.3Hz,1H),5.36–5.34(m,1H),3.58–3.51(m,1H),2.78(s,1H),2.33–2.22(m,2H),2.05–1.72(m,11H),1.67–1.50(m,5H),1.46(d,J＝6.4Hz,3H),1.25–1.06(m,2H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝166.74,156.70,153.78,140.91,133.04,129.39,127.75,122.78,121.59,84.19,80.92,71.80,51.11,49.71,46.38,42.34,37.85,37.39,36.60,32.01,31.97,31.71,31.09,23.63,20.70,19.53。
化合物7g
Figure BDA0002830008720000112
1H NMR(500MHz,Chloroform-d)δ＝8.12–8.08(m,1H),7.62–7.57(m,1H),7.33–7.25(m,2H),5.43(q,J＝6.3Hz,1H),5.35–5.33(m 1H),3.57–3.51(m,1H),2.79(s,1H),2.34–2.19(m,4H),2.00–1.73(m,8H),1.65–1.49(m,5H),1.45(d,J＝6.4Hz,3H),1.27–1.08(m,3H),1.02(s,3H),0.83(s,3H).
13C NMR(125MHz,Chloroform-d)δ＝163.38,160.36(JCF＝258.75Hz),156.81,153.48,140.89,134.76(JCF＝7.5Hz),130.20,124.87(JCF＝3.75Hz),121.39,117.20(JCF＝20Hz),111.27(JCF＝11.25Hz),83.98,81.02,71.62,50.97,49.62,46.27,42.19,37.56,37.32,36.49,31.90,31.87,31.55,30.97,23.51,20.60,19.41,15.55,14.51。
化合物8g
Figure BDA0002830008720000121
1H NMR(500MHz,Chloroform-d)δ＝7.93(d,J＝7.8Hz,1H),7.83(d,J＝8.9Hz,1H),7.54–7.50(m,1H),7.32–7.28(m,1H),5.44(q,J＝6.4Hz,1H),5.36–5.34(m,1H),3.57–3.51(m,1H),2.33–2.23(m,4H),2.01–1.72(m,9H),1.66–1.50(m,6H),1.46(d,J＝6.6Hz,3H),1.25–1.19(m,1H),1.12–1.06(m,1H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.66,163.95,161.97,155.26(JCF＝403.75Hz),140.94,131.31(JCF＝7.5Hz),124.65(JCF＝8.75Hz),123.54(JCF＝3.75Hz),121.56,120.17(JCF＝21.25Hz),114.78(JCF＝25Hz),84.22,81.07,71.81,51.12,49.74,46.43,42.36,37.84,37.42,36.61,32.03,31.99,31.72,31.10,23.62,20.72,19.53,15.69,14.65。
化合物9g
Figure BDA0002830008720000131
1H NMR(500MHz,Chloroform-d)δ＝8.19–8.15(m,2H),7.25–7.22(m,2H),5.45(q,J＝6.3Hz,1H),5.37–5.35(m,1H),3.57–3.51(m,1H),2.52(s,1H),2.33–2.21(m,2H),2.04–1.95(m,2H),1.90–1.83(m,3H),1.78–1.74(m,6H),1.67–1.50(m,5H),1.46(d,J＝6.3Hz,3H),1.26–1.19(m,1H),1.13–1.05(m,1H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.91,165.65(JCF＝253.75Hz),156.72,153.71,140.92,130.21(JCF＝8.75Hz),121.58,119.12(JCF＝3.75Hz),116.88(JCF＝22.5Hz),84.20,81.00,71.81,51.12,49.73,46.41,42.35,37.83,37.40,36.61,32.02,31.98,31.72,31.10,23.63,20.71,19.53,15.69,14.64。
化合物10g
Figure BDA0002830008720000141
1H NMR(500MHz,Chloroform-d)δ＝8.04–8.01(m,1H),7.57(d,J＝8.1Hz,1H),7.53–7.50(m,1H),7.44–7.41(m,1H),5.42(q,J＝6.4Hz,1H),5.34(d,J＝4.9Hz,1H),3.57–3.51(m,1H),2.33–2.22(m,3H),2.00–1.49(m,15H),1.45(d,J＝6.3Hz,4H),1.25–1.05(m,3H),1.01(s,3H),0.82(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.04,156.99,153.56,140.91,133.84,133.50,131.71,131.60,127.35,122.08,121.54,84.11,81.13,71.76,51.07,49.69,46.35,42.30,37.78,37.38,36.58,31.98,31.96,31.66,31.07,23.61,20.68,19.51,15.66,14.61。
化合物11g
Figure BDA0002830008720000142
1H NMR(500MHz,Chloroform-d)δ＝8.11–8.10(m,1H),8.01(d,J＝7.8Hz,1H),7.57–7.55(m,1H),7.49–7.45(m,1H),5.44(q,J＝6.2Hz,1H),5.35–5.34(m,1H),3.57–3.51(m,1H),2.33–2.22(m,2H),2.03–1.74(m,10H),1.63–1.50(m,6H),1.46(d,J＝6.5Hz,4H),1.25–1.19(m,1H),1.11–1.06(m,1H),1.02(s,4H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.51,156.89,153.61,140.93,135.64,133.08,130.76,127.64,125.80,124.38,121.56,84.22,81.13,71.80,51.12,49.73,46.42,42.35,37.85,37.41,36.60,32.02,31.98,31.72,31.09,23.62,20.71,19.53,15.70,14.64。
化合物12g
Figure BDA0002830008720000151
1H NMR(500MHz,Chloroform-d)δ＝8.07(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),5.44(q,J＝6.3Hz,1H),5.35–5.34(m,1H),3.56–3.51(m,1H),2.54(d,J＝125.6Hz,1H),2.33–2.22(m,2H),2.07–1.74(m,10H),1.64–1.50(m,5H),1.45(d,J＝6.4Hz,3H),1.38–1.06(m,3H),1.02(s,2H),0.84(s,1H)；
13C NMR(125MHz,Chloroform-d)δ＝165.90,156.77,153.70,140.93,139.56,129.85,129.00,121.57,121.26,84.22,81.01,71.81,51.12,49.73,46.42,42.36,37.85,37.41,36.61,32.02,31.98,31.72,31.10,23.62,20.71,19.53,15.70,14.64。
化合物13g
Figure BDA0002830008720000161
1H NMR(500MHz2,Chloroform-d)δ＝8.02–7.86(m,2H),7.47–7.35(m,2H),5.44(q,J＝6.4Hz,1H),5.35–5.34(m,1H),3.58–3.51(m,1H),2.71(s,1H),2.43(s,3H),2.33–2.18(m,4H),2.01–1.74(m,8H),1.67–1.48(m,5H),1.45(d,J＝6.5Hz,3H),1.24–1.06(m,3H),1.02(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝166.93,156.64,153.80,140.90,139.40,133.88,129.29,128.19,124.92,122.61,121.59,84.15,80.93,71.80,51.10,49.71,46.37,42.33,37.80,37.39,36.59,32.01,31.97,31.70,31.09,23.63,21.42,20.70,19.53,15.69,14.63。
化合物14g
Figure BDA0002830008720000162
1H NMR(500MHz,Chloroform-d)δ＝7.91–7.89(m,2H),7.41–7.34(m,2H),5.43(q,J＝6.3Hz,1H),5.34–5.33(m,1H),3.57-3.51(m,1H),2.42(s,3H),2.33–2.23(m,2H),1.99-1.73(m,9H),1.62–1.49(m,6H),1.45(d,J＝6.4Hz,4H),1.24–1.06(m,3H),1.01(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝166.87,156.63,153.77,140.95,139.34,133.83,129.24,128.13,124.88,122.57,121.51,84.11,80.96,71.73,51.07,49.71,46.36,42.29,37.67,37.40,36.58,31.99,31.96,31.65,31.06,23.61,21.38,20.69,19.51,15.68,14.61。
化合物15g
Figure BDA0002830008720000171
1H NMR(500MHz,DMSO-d6)δ＝7.99(d,J＝8.2Hz,2H),7.45(d,J＝8.0Hz,2H),5.30–5.25(m,2H),4.43(s,1H),3.38–3.23(m,7H),2.41(s,3H),2.17–2.06(m,2H),1.95–1.85(m,2H),1.77–1.66(m,5H),1.61–1.50(m,3H),1.46–1.40(m,2H),1.33(d,J＝6.4Hz,3H),0.94(s,3H),0.75(s,3H)；
13C NMR(125MHz,DMSO-d6)δ＝165.54,156.37,153.83,143.26,141.26,130.10,127.17,120.33,119.81,82.85,78.76,69.98,50.36,49.54,46.09,42.21,36.97,36.08,35.33,31.57,31.44,31.42,30.65,23.01,21.22,20.17,19.13,15.39,14.45。
化合物16g
Figure BDA0002830008720000181
1H NMR(500MHz,Chloroform-d)δ＝8.15–8.13(m,1H),7.96–7.94(m,1H),7.84–7.81(m,2H),5.42(q,J＝6.2Hz,1H),5.35(d,J＝5.0Hz,1H),3.57–3.51(m,1H),2.33–2.22(m,2H),2.11–1.81(m,9H),1.78–1.50(m,7H),1.45(d,J＝6.4Hz,3H),1.33–1.06(m,3H),1.02(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝163.51,157.54,153.31,148.27,140.87,133.60,133.53,132.25,125.19,121.59,118.04,84.22,81.22,71.81,51.10,49.70,46.40,42.35,37.96,37.39,36.59,32.00,31.97,31.71,31.08,23.60,20.69,19.53,15.65,14.64。
化合物17g
Figure BDA0002830008720000182
1H NMR(500MHz,Chloroform-d)δ＝8.96–8.95(m,1H),8.49–8.44(m,2H),7.78(t,J＝8.0Hz,1H),5.46(q,J＝6.3Hz,1H),5.35–5.34(m,1H),3.57–3.51(m,1H),2.63–2.21(m,5H),2.05–1.72(m,8H),1.65–1.50(m,5H),1.46(d,J＝6.3Hz,3H),1.33–1.06(m,3H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.70,157.18,153.43,148.82,140.91,133.12,130.83,127.36,124.44,122.63,121.53,84.14,81.40,71.77,51.08,49.69,46.43,42.31,37.74,37.38,36.58,31.98,31.96,31.67,31.06,23.60,20.68,19.52,15.69,14.64。
化合物18g
Figure BDA0002830008720000191
1H NMR(500MHz,Chloroform-d)δ＝8.41(d,J＝8.5Hz,2H),8.36(d,J＝8.7Hz,2H),5.47(q,J＝6.3Hz,1H),5.36–5.35(m,1H),3.57–3.551(m,1H),2.41(s,1H),2.33–2.22(m,2H),2.02–1.72(m,11H),1.64–1.50(m,5H),1.47(d,J＝6.5Hz,3H),1.25–1.06(m,2H),1.03(s,3H),0.85(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.84,157.35,153.50,150.44,140.93,128.81,128.25,124.68,121.56,84.28,81.32,71.83,51.16,49.74,46.48,42.38,37.94,37.41,36.62,32.04,31.99,31.75,31.12,23.62,20.71,19.55,15.71,14.68。
化合物19g
Figure BDA0002830008720000201
1H NMR(500MHz,Chloroform-d)δ＝7.95–7.93(m,1H),7.75(d,J＝7.8Hz,1H),7.47–7.39(m,2H),5.41(q,J＝6.2Hz,1H),5.33–5.32(m,1H),3.57–3.50(m,1H),2.94–2.86(m,2H),2.33–2.20(m,2H),1.98–1.72(m,10H),1.64–1.48(m,5H),1.45(d,J＝6.2Hz,3H),1.24–1.03(m,3H),1.00(s,3H),0.81(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.48,156.99,153.51,140.93,134.88,133.48,132.07,127.81,124.10,122.08,121.45,84.05,81.14,71.68,51.02,49.66,46.32,42.24,37.66,37.37,36.54,31.94,31.93,31.59,31.03,23.58,20.66,19.48,15.62,14.58。
化合物20g
Figure BDA0002830008720000202
1H NMR(500MHz,Chloroform-d)δ＝7.99(d,J＝8.3Hz,2H),7.67(d,J＝8.2Hz,2H),5.44(q,J＝6.3Hz,1H),5.35(d,J＝4.9Hz,1H),3.57–3.51(m,1H),2.73(s,1H),2.33–2.22(m,2H),2.08–1.72(m,10H),1.66–1.50(m,5H),1.45(d,J＝6.4Hz,3H),1.25–1.06(m,2H),1.02(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.99,156.78,153.68,140.94,132.81,129.07,128.06,121.68,121.56,84.21,81.04,71.80,51.12,49.73,46.41,42.35,37.82,37.42,36.61,32.02,31.98,31.72,31.09,23.62,20.71,19.53,15.70,14.64。
化合物21g
Figure BDA0002830008720000211
1H NMR(500MHz,Chloroform-d)δ＝8.36(s,1H),8.31(d,J＝7.8Hz,1H),7.84(d,J＝7.8Hz,1H),7.68(t,J＝7.9Hz,1H),5.45(q,J＝6.3Hz,1H),5.34(d,J＝5.0Hz,1H),3.58–3.51(m,1H),2.98(s,1H),2.36–2.23(m,3H),2.03–1.72(m,8H),1.66–1.49(m,5H),1.46(d,J＝6.3Hz,3H),1.24–1.04(m,3H),1.02(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.40,157.01,153.57,140.95,132.17(JCF＝33.75Hz),130.78,130.13,129.50(JCF＝3.75Hz),124.57(JCF＝3.75Hz),123.64,122.32,121.52,84.13,81.28,71.76,51.08,49.70,46.41,42.30,37.71,37.41,36.59,31.99,31.96,31.67,31.06,23.61,20.70,19.51,15.68,14.63。
化合物22g
Figure BDA0002830008720000221
1NMR(500MHz,Chloroform-d)δ＝8.29(d,J＝8.1Hz,2H),7.82(d,J＝8.2Hz,2H),5.47(q,J＝6.3Hz,1H),5.36–5.35(m,1H),3.58–3.51(m,1H),2.33–2.22(m,3H),2.01–1.82(m,6H),1.78–1.72(m,4H),1.66–1.50(m,5H),1.47(d,J＝6.5Hz,3H),1.27–1.07(m,3H),1.03(s,3H),0.85(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝165.43,157.08,153.61,140.94,134.58(JCF＝32.5Hz),128.12,126.47,126.44,126.03,124.56,122.40,121.56,84.23,81.19,71.81,51.12,49.73,46.44,42.35,37.86,37.41,36.61,32.02,31.98,31.72,31.09,23.61,20.71,19.53,15.70,14.65。
化合物23g
Figure BDA0002830008720000222
1H NMR(500MHz,DMSO-d6)δ＝7.67(d,J＝7.6Hz,1H),7.57–7.54(m,2H),7.28–7.26(m,1H),5.30–5.26(m,2H),4.43(s,1H),3.87(s,3H),3.34–3.23(m,3H),2.17–2.06(m,2H),1.96–1.86(m,2H),1.78–1.66(m,5H),1.61–1.38(m,6H),1.34(d,J＝6.3Hz,4H),1.14–1.06(m,1H),0.95(s,3H),0.89–0.83(m,1H),0.76(s,3H)；
13C NMR(125MHz,DMSO-d6)δ＝165.24,159.68,156.55,153.75,141.25,130.87,123.69,120.28,119.49,118.75,111.99,82.80,78.85,69.95,55.50,50.33,49.52,46.07,42.19,36.95,36.05,35.30,31.54,31.41,31.39,30.62,22.97,20.14,19.09,15.36,14.42。
化合物24g
Figure BDA0002830008720000231
1H NMR(500MHz,DMSO-d6)δ＝8.04(d,J＝8.8Hz,2H),7.18(d,J＝8.4Hz,2H),5.30–5.26(m,2H),4.57(d,J＝4.4Hz,1H),4.41(s,1H),3.87(s,3H),3.31(s,6H),2.17–2.06(m,2H),1.95–1.86(m,2H),1.78–1.67(m,5H),1.62–1.43(m,5H),1.33(d,J＝6.4Hz,3H),0.95(s,3H),0.76(s,3H)；
13C NMR(125MHz,DMSO-d6)δ＝165.40,162.73,156.13,153.84,141.25,129.14,120.29,115.01,114.77,82.83,78.63,69.95,55.60,50.33,49.52,46.07,42.19,36.94,36.05,35.27,31.54,31.41,31.40,30.62,22.97,20.13,19.10,15.38,14.43。
化合物25g
Figure BDA0002830008720000241
1H NMR(500MHz,Chloroform-d)δ＝5.35–5.28(m,2H),3.52–3.37(m,1H),3.37(s,1H),3.12(s,1H),2.58(s,3H),2.28–2.17(m,2H),1.95–1.64(m,10H),1.60–1.43(m,6H),1.36(d,J＝6.4Hz,3H),1.05–1.02(m,1H),0.96(s,3H),0.76(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝166.30,157.13,153.52,140.93,121.29,83.81,80.84,71.49,50.90,49.58,46.23,42.11,37.31,36.46,31.87,31.85,31.85,31.46,30.93,23.48,20.58,19.39,15.51,14.49,11.22。
化合物26g
Figure BDA0002830008720000242
1H NMR(500MHz,Chloroform-d)δ＝5.39(q,J＝6.3Hz,1H),5.34(d,J＝5.0Hz,1H),3.56–3.50(m,1H),2.96(q,J＝7.6Hz,2H),2.41(s,2H),2.32–2.21(m,2H),2.00–1.81(m,6H),1.77–1.70(m,2H),1.65–1.57(m,2H),1.55–1.47(m,4H),1.43–1.40(m,6H),1.24(s,2H),1.10–1.05(m,1H),1.01(s,3H),0.81(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝170.46,157.07,153.81,140.93,121.54,84.13,80.76,71.76,51.08,49.69,46.35,42.31,37.80,37.39,36.59,32.00,31.96,31.68,31.07,23.59,20.68,19.52,19.43,15.65,14.61,10.74。
化合物27g
Figure BDA0002830008720000251
1H NMR(500MHz,Chloroform-d)δ＝5.36–5.29(m,2H),3.53–3.47(m,1H),3.11(s,2H),2.87(t,J＝7.5Hz,2H),2.30–2.19(m,2H),1.96–1.66(m,11H),1.61–1.41(m,6H),1.38(d,J＝6.4Hz,3H),1.21–1.03(m,2H),1.01–0.97(m,6H),0.77(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝169.49,157.03,153.65,140.97,121.34,83.88,80.83,71.55,50.95,49.63,46.27,42.16,37.44,37.35,36.51,31.92,31.89,31.52,30.98,27.35,23.51,20.62,19.94,19.42,15.54,14.53,13.57。
化合物28g
Figure BDA0002830008720000252
1H NMR 1H NMR(500MHz,Chloroform-d)δ＝8.02(d,J＝8.5Hz,1H),7.61(d,J＝2.1Hz,1H),7.44–7.42(m,1H),5.44(q,J＝6.3Hz,1H),5.36–5.35(m,1H),3.57–3.51(m,1H),2.33–2.22(m,2H),2.02–1.50(m,17H),1.46(d,J＝6.4Hz,3H),1.25–1.06(m,2H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.30,157.00,153.55,140.94,139.45,134.67,132.40,131.59,127.94,121.55,120.68,84.25,81.09,71.80,51.13,49.74,46.41,42.36,37.93,37.41,36.61,32.02,31.98,31.72,31.09,23.61,20.70,19.53,15.68,14.64。
化合物29g
Figure BDA0002830008720000261
1H NMR(500MHz,Chloroform-d)δ＝8.08–8.06(m,1H),7.33–7.31(m,1H),7.18–7.14(m,1H),5.43(q,J＝6.4Hz,1H),5.35–5.34(m,1H),3.57–3.51(m,1H),2.33–2.22(m,5H),2.01–1.72(m,9H),1.66–1.50(m,5H),1.45(d,J＝6.6Hz,3H),1.25–1.08(m,2H),1.02(s,3H),0.83(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.57(JCF＝256.25Hz),164.22,156.87,153.42,140.83,135.41(JCF＝10Hz),133.35(JCF＝10Hz),121.43,119.13(JCF＝25Hz),118.55(JCF＝3.75Hz),115.14(JCF＝22.5Hz),84.06,81.04,71.68,51.00,49.63,46.29,42.23,37.73,37.30,36.49,31.91,31.87,31.59,30.99,23.51,20.59,19.41,15.55,14.51。
化合物30g
Figure BDA0002830008720000271
1H NMR(500MHz,Chloroform-d)δ＝8.01(d,J＝2.1Hz,2H),7.58–7.57(m,1H),5.45(q,J＝6.3Hz,1H),5.36–5.35(m,1H),3.57–3.51(m,1H),2.51(d,J＝72.3Hz,1H),2.33–2.22(m,2H),2.06–1.50(m,15H),1.46(d,J＝6.5Hz,3H),1.26–1.06(m,3H),1.02(s,3H),0.84(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.44,157.04,153.49,140.93,136.48,132.89,125.90,125.39,121.56,84.24,81.24,71.81,51.12,49.73,46.45,42.36,37.85,37.41,36.60,32.02,31.98,31.73,31.09,23.61,20.71,19.54,15.71,14.66。
化合物31g
Figure BDA0002830008720000272
1H NMR(500MHz,Chloroform-d)δ＝8.59(s,2H),8.10(s,1H),5.48(q,J＝6.4Hz,1H),5.36–5.35(m,1H),3.58–3.52(m,1H),2.57(s,2H),2.34–2.23(m,2H),2.00–1.75(m,8H),1.66–1.51(m,5H),1.47(d,J＝6.4Hz,4H),1.25–1.07(m,2H),1.03(s,4H),0.85(s,3H)；
13C NMR(125MHz,Chloroform-d)δ＝164.20,157.30,153.43,140.92,133.24(JCF＝35Hz),127.69,126.32,124.98,123.75,121.56,84.24,81.51,71.83,51.13,49.73,46.49,42.33,37.83,37.41,36.61,32.02,31.98,31.70,31.09,23.61,20.71,19.53,15.71,14.67。
本发明探究了部分所述噁唑基甾体衍生物对蚜虫的生物学活性。
采用玻片浸渍法测定表1所列噁唑基甾体衍生物对桃蚜、苹果绵蚜和苹果黄蚜的抑制活性。具体方法：准确称量一定量待测化合物，以丙酮为溶剂，将化合物溶解，用0.1％Tween-80水溶液配制成浓度为12.5，25，50，100和200μg/mL的溶液，室温下静置半小时待样品完全溶解后保存待用。将待测蚜虫粘贴到含有双面胶的载玻片上，然后将含有蚜虫的玻片在配置的药液中浸渍5s取出，用吸水纸吸干残余的药液，阳性对照为噻虫嗪和毒死蜱，阴性对照为0.1％Tween-80水溶液。在培养皿中保湿培养24h后观察其死亡数并计算LC50值，结果见表1。
表1部分噁唑基甾体衍生物对蚜虫活性的LC50(μg/mL)
Figure BDA0002830008720000281
Figure BDA0002830008720000291
其中，a表示化合物的杀虫活性LC50>100μg/mL。
本发明进一步探究了部分所述噁唑基甾体衍生物对粉虱的生物学活性。
采用叶面喷雾法测定表2所列的噁唑基甾体衍生物对粉虱的毒杀活性。具体方法：准确称量一定量待测化合物，以丙酮溶解，用0.1％吐温80水溶液配制成浓度为1000μg/mL的溶液保存待用。将药液喷施于黄瓜叶片的背面，待其自然晾干将待测粉虱放入生测装置内，将装置夹在叶片背面使粉虱接触叶片。阳性对照为螺虫乙酯，阴性对照为丙酮。观察其在7d后的死亡数并计算LC50值，结果见表2。
表2部分噁唑基甾体衍生物对粉虱的抑制活性的LC50
Figure BDA0002830008720000292
Figure BDA0002830008720000301
表2室内生物测定结果表明，测试化合物对粉虱具有很好的生物活性，与阳性对照具有相似的杀虫效果。
本发明通过具体的实例对所述噁唑基甾体衍生物及其制备方法应用进行了描述，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技术方案范围之内。

Claims (9)

1.一种噁唑基甾体衍生物，其特征在于，具有通式1表示的化学结构，
Figure FDA0003859447690000011
其中，取代基R为式6g-31g中的一种；
Figure FDA0003859447690000012
Figure FDA0003859447690000021
2.如权利要求1所述的噁唑基甾体衍生物的合成路线为：
Figure FDA0003859447690000022
3.根据权利要求2所述的合成路线，其特征在于，所述步骤h的反应条件为：向溶有化合物3的二氯甲烷中，分别加入4-二甲氨基吡啶、二氯乙烷和化合物2，常温反应6h；
所述步骤i的反应条件为：以四氢呋喃为溶剂，加入四丁基氟化铵，常温反应2h。
4.根据权利要求2所述的合成路线，其特征在于，所述化合物2的合成路线为：
Figure FDA0003859447690000031
5.根据权利要求4所述的合成路线，其特征在于，所述步骤d和e的反应条件为：酰氯2a与无水乙醇混合，以浓硫酸为催化剂，60℃反应6h；所得产物溶于无水乙醇中，加入水合肼，50℃反应12h；
所述步骤f的反应条件为：以二氯甲烷为溶剂，加入三乙胺和乙基乙二酰氯酯，-10℃反应1h，在常温条件下反应8h后，再加入三乙胺和对甲苯磺酰氯，继续反应12h；
所述步骤g的反应条件为：以无水乙醇为溶剂，加入氢氧化钾水溶液，冰浴反应1h。
6.根据权利要求2所述的合成路线，其特征在于，所述化合物3的合成路线为：
Figure FDA0003859447690000032
7.根据权利要求6所述的合成路线，其特征在于，所述步骤a和b的反应条件为：以N,N-二甲基甲酰胺为溶剂，加入咪唑和叔丁基二甲基氯硅烷，冰浴30min后常温反应12h，所得产物加入磷叶立德盐反应体系中常温搅拌24h；
所述步骤c的反应条件为：以AD-mix-β为催化剂，甲基磺酰胺和化合物3b 0℃反应2d，常温反应3d，反应完成后加入亚硫酸钠固体，反应1h。
8.如权利要求1所述的噁唑基甾体衍生物在植物虫害防治中的应用。
9.根据权利要求8所述的应用，其特征在于，用于蚜虫和粉虱的防治。
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