CN106243054A - 一种三唑酰胺醇类杀菌剂及其合成方法 - Google Patents
一种三唑酰胺醇类杀菌剂及其合成方法 Download PDFInfo
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Abstract
本发明属于有机化工技术领域,特别是一种作为杀菌剂的三唑酰胺醇类化合物,所述杀菌剂化学结构式为:其中,取代基R1和R2为苯基或对氯苯基或对氟苯基或邻氯苯基或邻氟苯基或2,4‑二氯苯基或2,4‑二氟苯基或叔丁基或邻甲基苯基或间氟苯基或对三氟甲基苯基或邻甲基对氯苯基及其他取代基,取代基位置、个数以及共轭位置不固定。合成方法为以一类三唑酰胺酮类化合物,在甲醇作溶剂的条件下,经硼氢化钠还原,得到一类新型三唑酰胺醇类化合物。该发明关键点在于提供了一种步骤少、产率高的合成新方法以合成一类新型三唑酰胺醇类化合物,又因产物其表现出良好的抑菌活性,有利于作为杀菌剂的应用。
Description
技术领域
本发明涉及有机化工技术领域,特别是一种三唑酰胺醇类杀菌剂及其合成方法。
背景技术
粮食供应不足的问题长期制约着人类的发展,尤其在非洲等农业不发达地区。而由各种细菌和真菌引起的农作物病害造成的粮食减产,是导致粮食供应不足问题的主要原因之一。为了应对不断变异的细菌和真菌,以及各种不同条件下对杀菌剂使用限制的需求,研究开发出更多具有更好抑菌活性的新型杀菌剂,是促进杀菌剂发展的关键。目前商品化的三唑类杀菌剂主要特点为:大多数杀菌剂的药效团三唑环都连接在碳链上,且分子结构中含有酰胺键的杀菌剂有很多,但三唑类杀菌剂分子结构中含有酰胺键的却很少见报道。目前商业化的杀菌剂存在抑菌活性不够理想、半抑制浓度(IC50)较高等问题。
发明内容
本发明的主要目的在于提供一种三唑酰胺醇类杀菌剂及其合成方法。
本发明的技术方案如下:
一种三唑酰胺醇类杀菌剂,所述杀菌剂化学结构式为:
其中,取代基R1和R2为苯基或对氯苯基或对氟苯基或邻氯苯基或邻氟苯基或2,4-二氯苯基或2,4-二氟苯基或叔丁基或邻甲基苯基或间氟苯基或对三氟甲基苯基或邻甲基对氯苯基中的任意一种,取代基位置、个数以及共轭位置不固定。
进一步优选为化学结构式为:
合成所述的三唑酰胺醇类杀菌剂的方法,所述方法包括以下合成路径:
所述方法包括以下步骤:
(1)室温条件下,向反应瓶中加入甲醇,称取化合物1和硼氢化钠加入到甲醇中;
所述化合物1为三唑酰胺酮;
(2)将所述步骤(1)中的反应体系置于0~60℃下搅拌,反应瓶中即出现大量气泡,反应0.2~1小时;
(3)取所述步骤(2)的反应液TLC监测,反应完毕后,减压蒸馏除去溶剂甲醇,剩余物经硅胶柱进行柱层析分离纯化得到化合物2;
完成三唑酰胺醇类杀菌剂的合成。
所述步骤(1)化合物1与硼氢化钠的投料比为2:3。改变投料比,化合物2的收率会有较大提高;投料比的范围较大,有利于精细化学品的生产。
所述步骤(2)反应温度为0~60℃。在此反应温度下有利于反应平稳进行,减少副产物生成。高于此反应温度反应将加剧,副产物增多。
所述步骤(2)反应时间0.2~1小时。反应时间为0.2~1小时,少于0.2小时则反应不完全,多于1小时则副产物增多。
本发明有益效果如下:
1、本发明为以三唑酰胺酮衍生物在硼氢化钠作用下经还原反应,得到的三唑酰胺醇类杀菌剂,其抑菌活性较高,半抑制浓度(IC50)较低,适合作为杀菌剂应用在各种不同环境条件下;
2、本发明合成一类与传统商业化杀菌剂不同的新型三唑酰胺醇类杀菌剂,提供了一种制备成本低、操作简单且反应效率高的合成新方法。
3、本发明合成了一类三唑酰胺醇类杀菌剂,此类化合物在抑制意大利青霉菌、指状青霉菌和水稻纹枯菌等菌类方面有较广泛的研究与应用。
具体实施方式
下面结合实施例来进一步说明本发明,但本发明要求保护的范围并不局限于实施例表述的范围。
仪器及试剂:
熔点用X4型熔点仪(北京第三光学仪器厂生产)测定,温度计未经校正;1H NMR和13C NMR用Varian Mercury 400型400MHz核磁共振仪或者Varian Mercury 600型600MHz核磁共振仪测定,氘代氯仿(CDCl3)或者氘代二甲亚砜(DMSO-d6)为溶剂,TMS为内标;MS使用FinniganTrace质谱仪测定;元素分析使用Vario EL III元素分析仪测定;所用试剂为国产(或进口)化学纯或分析纯。溶剂甲苯是经过重蒸干燥过的,三乙胺也是通过重蒸处理过的。
实施例1
一种合成N-(2-(4-氯苯基)-2-羟基乙基)-N-(4-氟苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1a(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.5小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2a:
产率:97%
实施例2
一种合成N-(2-(4-氯苯基)-2-羟基乙基)-N-(2-氟苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1b(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2b:
产率:92%
实施例3
一种合成N-(4-氯苯基)-N-(2-(2,4-二氯苯基)-2-羟基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1c(0.43g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.5小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2c:
产率:94%
实施例4
一种合成N-(4-氟苯基)-N-(2-(2,4-二氯苯基)-2-羟基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1d(0.41g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2d:
产率:96%
实施例5
一种合成N-(4-氯苯基)-N-(2-(4-氟苯基)-2-羟基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1e(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.3小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2e:
产率:86%
实施例6
一种合成N-(2-(2,4-二氯苯基)-2-羟基乙基)-N-(2,4-二氟苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1f(0.43g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.4小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2f:
产率:93%
实施例7
一种合成N-(4-氯苯基)-N-(2-羟基-3,3-二甲基丁基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1g(0.34g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.7小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2g:
产率:87%
实施例8
一种合成N-(2-(4-氯苯基)-2-羟基乙基)-N-(邻甲苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1h(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.8小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2h:
产率:90%
实施例9
一种合成N-(2-(4-氯苯基)-2-羟基乙基)-N-(3-氟苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1i(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2i:
产率:91%
实施例10
一种合成N-(2-羟基-3,3-二甲基丁基)-N-苯基-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1j(0.30g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2j:
产率:85%
实施例11
一种合成N-(2-氯苯基)-N-(2-羟基-2-苯基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1k(0.36g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2k:
产率:84%
实施例12
一种合成N-(4-氟苯基)-N-(2-羟基-3,3-二甲基丁基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1l(0.32g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2l:
产率:88%
实施例13
一种合成N-(4-氟苯基)-N-(2-羟基-2-苯基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1m(0.34g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2m:
产率:86%
实施例14
一种合成N-(2-(4-氯苯基)-甲基)-2-(1H-1,2,4-三唑)-N-(4-(三氟甲基)苯基)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1n(0.42g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于20℃下搅拌,体系立即出现大量气泡,反应0.8小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2n:
产率:89%
实施例15
一种合成N-(4-氯-2-甲基苯基)-N-(2-羟基-2-苯基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1o(0.37g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.5小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2o:
产率:87%
实施例16
一种合成N-(2-(4-溴苯基)-羟基乙基)-N-(邻甲苯基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1p(0.42g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.5小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2p:
产率:89%
实施例17
一种合成N-(2-(4-溴苯基)-羟基乙基)-N-苯基-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1q(0.40g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于30℃下搅拌,体系立即出现大量气泡,反应0.6小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2q:
产率:93%
实施例18
一种合成N-(2,4-二氟苯基)-N-(2-羟基-2-苯基乙基)-2-(1H-1,2,4-三唑)乙酰胺的方法,包括以下实验步骤:
称取三唑酰胺酮1r(0.36g,1mmol)和硼氢化钠(0.06g,1.5mmol)加入到5mL甲醇中,于40℃下搅拌,体系立即出现大量气泡,反应0.5小时,TLC监测,反应完毕后,减压蒸馏掉溶剂甲醇,剩余物经硅胶柱进行柱层析分离(洗脱剂:V乙酸乙酯/V石油醚=2:1),即可得到三唑酰胺醇2r:
产率:90%
上述的实施例仅为本发明的优选技术方案,而不应视为对于本发明的限制,本申请中的实施例及实施例中的特征在不冲突的情况下,可以相互任意组合。本发明的保护范围应以权利要求记载的技术方案,包括权利要求记载的技术方案中技术特征的等同替换方案为保护范围。即在此范围内的等同替换改进,也在本发明的保护范围之内。
化合物波普性质:
2a:N-(2-(4-chlorophenyl)-2-hydroxyethyl)-N-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 152-153℃;1H NMR(CDCl3,600MHz)δ(ppm)8.17(s,1H,Ar-H),7.91(s,1H,Ar-H),7.31–7.22(m,6H,Ar-H),7.17(t,J=7.8Hz,2H,Ar-H),4.99(d,J=9.0Hz,1H,CH2),4.81–4.64(m,2H,COCH2),4.04–3.93(m,1H,CH),3.74(d,J=2.4Hz,1H,CH2),3.72(d,J=2.4Hz,1H,OH);13C NMR(CDCl3,100MHz)δ(ppm)166.8,163.7,161.2,151.7,144.8,140.0,136.8,133.6,129.9,129.8,128.6,127.3,117.5,117.2,71.0,58.4,51.1;MS(EI,70eV):m/z(%)=374(1)[M+],251(8),234(83),165(38),123(100).Anal.Calcd for C18H16ClFN4O2:C,57.68;H,4.30;N,14.95.Found:C,57.54;H,4.37;N,14.70.
2b:N-(2-(4-chlorophenyl)-2-hydroxyethyl)-N-(2-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 98-100℃;1H NMR(CDCl3,600MHz)δ(ppm)8.20–7.90(m,2H,Ar-H),7.53–7.14(m,8H,Ar-H),5.16–4.92(m,1H,CH),4.87–4.68(m,2H,COCH2),4.18–3.56(m,3H,CH2,OH);13C NMR(CDCl3,100MHz)δ(ppm)167.0,158.5,156.8,151.8,144.8,140.0,133.5,131.1,130.3,129.9,128.6,128.6,127.3,127.2,125.8,117.1,117.0,71.7,71.5,59.0,57.6,50.7;MS(EI,70eV):m/z(%)=374(2)[M+],251(15),234(33),165(20),124(100).Anal.Calcd for C18H16ClFN4O2:C,57.68;H,4.30;N,14.95.Found:C,57.57;H,4.34;N,14.72.
2c:N-(4-chlorophenyl)-N-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 157-159℃;1H NMR(CDCl3,600MHz)δ(ppm)8.19(s,1H,Ar-H),7.94(s,1H,Ar-H),7.57(d,J=8.4Hz,1H,Ar-H),7.46(d,J=8.4Hz,2H,Ar-H),7.32–7.13(m,4H,Ar-H),5.25(d,J=9.0Hz,1H,CH),4.86–4.68(m,2H,COCH2),4.66–4.52(m,1H,OH),4.22–3.72(m,2H,CH2);13C NMR(CDCl3,150MHz)δ(ppm)167.4,151.8,144.8,138.8,137.4,135.4,134.1,132.0,130.6,129.1,129.0,128.6,127.5,69.0,56.6,51.0;MS(EI,70eV):m/z(%)=424(2)[M+],356(2),285(3),250(100).Anal.Calcd for C18H15Cl3N4O2:C,50.79;H,3.55;N,13.16.Found:C,50.67;H,3.60;N,13.00.
2d:N-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)-N-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 99-101℃;1H NMR(CDCl3,600MHz)δ(ppm)8.21(s,1H,Ar-H),7.91(s,1H,Ar-H),7.55(d,J=8.4Hz,1H,Ar-H),7.36–7.20(m,4H,Ar-H),7.17(t,J=7.8Hz,2H,Ar-H),5.23(d,J=8.4Hz,1H,CH2),4.98(d,J=1.2Hz,1H,OH),4.86–4.62(m,2H,COCH2),4.11(q,J=9.0Hz,1H,CH),3.70(d,J=14.4Hz,1H,CH2);13C NMR(CDCl3,150MHz)δ(ppm)167.3,163.2,161.5,151.6,144.9,137.5,136.2,133.9,132.0,129.8,129.7,128.9,128.5,127.4,117.4,117.2,68.3,56.4,51.0;MS(EI,70eV):m/z(%)=408(8)[M+],285(12),234(82),165(25),124(100).Anal.Calcd for C18H15Cl2FN4O2:C,52.83;H,3.69;N,13.69.Found:C,52.81;H,3.82;N,13.46.
2e:N-(4-chlorophenyl)-N-(2-(4-fluorophenyl)-2-hydroxyethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 239-242℃;1H NMR(CDCl3,600MHz)δ(ppm)8.14(d,J=11.4Hz,1H,Ar-H),7.95(s,1H,Ar-H),7.50–7.44(m,2H,Ar-H),7.42–7.34(m,2H,Ar-H),7.31–7.28(m,2H,Ar-H),7.08–7.00(m,2H,Ar-H),5.12–4.99(m,1H,CH),4.94–4.71(m,2H,COCH2),4.15–3.72(m,3H,CH2,OH);13C NMR(CDCl3,100MHz)δ(ppm)167.0,163.7,161.3,151.8,144.8,140.0,136.5,133.5,130.3,129.9,128.6,127.3,127.2,117.1,71.7,59.0,50.7;MS(EI,70eV):m/z(%)=374(51)[M+],302(64),231(49),181(49),144(36),107(100).Anal.Calcd for C18H16ClFN4O2:C,57.68;H,4.30;N,14.90.Found:C,57.44;H,4.35;N,14.66.
2f:N-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)-N-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 142-144℃;1H NMR(CDCl3,600MHz)δ(ppm)8.20(d,J=7.8Hz,1H,Ar-H),7.93(s,1H,Ar-H),7.58(d,J=7.8Hz,1H,Ar-H),7.48–6.94(m,5H,Ar-H),5.41–5.18(m,1H,CH),4.92–4.65(m,2H,COCH2),4.51–3.47(m,3H,CH2,OH);13C NMR(CDCl3,150MHz)δ(ppm)167.4,163.4,158.9,151.6,144.9,137.5,137.1,133.9,132.0,131.2,129.0,128.5,127.5,127.4,124.8,113.0,105.9,68.6,56.9,55.3,50.6;MS(EI,70eV):m/z(%)=426(100)[M+],109(96),79(62).Anal.Calcd for C18H14Cl2F2N4O2:C,50.60;H,3.30;N,13.11.Found:C,50.43;H,3.37;N,13.02.
2g:N-(4-chlorophenyl)-N-(2-hydroxy-3,3-dimethylbutyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 156-157℃;1H NMR(CDCl3,600MHz)δ(ppm)8.18(s,1H,Ar-H),7.92(s,1H,Ar-H),7.47(d,J=7.2Hz,2H,Ar-H),7.35(d,J=7.8Hz,2H,Ar-H),4.86–4.57(m,2H,COCH2),4.03(t,J=12.0Hz,1H,CH),3.60–3.32(m,2H,CH2),3.02(d,J=3.0Hz,1H,OH),0.88(s,9H,3CH3);13C NMR(CDCl3,150MHz)δ(ppm)166.5,151.6,144.8,139.1,134.9,130.4,129.5,76.4,52.8,51.0,34.3,25.5;MS(EI,70eV):m/z(%)=336(1)[M+],168(100),90(99).Anal.Calcd for C16H21ClN4O2:C,57.06;H,6.28;N,16.63.Found:C,56.99;H,6.32;N,16.48.
2h:N-(2-(4-chlorophenyl)-2-hydroxyethyl)-N-(o-tolyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 68-69℃;1H NMR(CDCl3,600MHz)δ(ppm)8.22–7.88(m,2H,Ar-H),7.58–6.92(m,8H,Ar-H),5.24–4.86(m,1H,CH),4.80–4.48(m,2H,COCH2),4.44–3.04(m,3H,CH2,OH),2.32(d,J=18.6Hz,3H,CH3);13C NMR(CDCl3,150MHz)δ(ppm)161.3,151.3,144.8,139.9,138.2,135.3,133.4,132.2,129.7,128.9,128.5,127.4,127.1,71.0,58.4,55.9,50.8,17.3;MS(EI,70eV):m/z(%)=370(4)[M+],230(30),161(25),132(11),120(100).Anal.Calcd for C19H19ClN4O2:C,61.54;H,5.16;N,15.11.Found:C,61.39;H,5.33;N,14.90.
2i:N-(2-(4-chlorophenyl)-2-hydroxyethyl)-N-(3-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 131-132℃;1H NMR(CDCl3,600MHz)δ(ppm)8.16(s,1H,Ar-H),7.90(s,1H,Ar-H),7.46(q,J=7.8Hz,1H,Ar-H),7.34–7.20(m,4H,Ar-H),7.17(t,J=7.8Hz,1H,Ar-H),7.08(t,J=7.8Hz,2H,Ar-H),5.12–4.95(m,1H,CH2),4.88–4.66(m,2H,COCH2),4.10–3.36(m,3H,CH2,OH);13C NMR(CDCl3,100MHz)δ(ppm)166.4,164.3,161.8,151.6,144.9,142.2,140.0,133.5,131.6,121.6,127.3,123.8,116.5,115.5,70.7,58.2,51.0;MS(EI,70eV):m/z(%)=374(2)[M+],251(17),124(100).Anal.Calcd forC18H16ClFN4O2:C,57.68;H,4.30;N,14.95.Found:C,57.40;H,4.25;N,14.82.
2j:N-(2-hydroxy-3,3-dimethylbutyl)-N-phenyl-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 142-143℃;1H NMR(CDCl3,600MHz)δ(ppm)8.19(d,J=11.4Hz,1H,Ar-H),7.94(s,1H,Ar-H),7.59(d,J=8.4Hz,1H,Ar-H),7.50–7.27(m,2H,Ar-H),7.14–6.92(m,2H,Ar-H),5.42–5.14(m,1H,CH),4.92–4.66(m,2H,COCH2),4.38–3.50(m,3H,CH2,OH);13C NMR(CDCl3,100MHz)δ(ppm)166.4,151.6,144.9,140.0,133.5,131.6,116.5,70.7,58.2,51.0,34.2,25.6;MS(EI,70eV):m/z(%)=302(1)[M+],285(15),252(46),183(10),142(100).Anal.Calcd for C16H22N4O2:C,63.55;H,7.33;N,18.53.Found:C,63.44;H,7.40;N,18.46.
2k:N-(2-chlorophenyl)-N-(2-hydroxy-2-phenylethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 44-45℃;1H NMR(CDCl3,600MHz)δ(ppm)8.16(d,J=15.6Hz,1H,Ar-H),7.90(d,J=7.2Hz,1H,Ar-H),7.66–7.50(m,1H,Ar-H),7.50–7.15(m,8H,Ar-H),5.34–4.84(m,1H,CH),4.76–3.26(m,5H,COCH2,CH2,OH);13C NMR(CDCl3,150MHz)δ(ppm)166.8,151.6,144.8,141.7,141.3,132.6,130.9,130.7,128.5,128.4,127.7,126.0,125.7,72.2,58.9,56.5,51.0;MS(EI,70eV):m/z(%)=356(2)[M+],250(54),215(50),181(16),139(100).Anal.Calcd for C18H17ClN4O2:C,60.59;H,4.80;N,15.70.Found:C,60.45;H,4.85;N,15.55.
2l:N-(4-fluorophenyl)-N-(2-hydroxy-3,3-dimethylbutyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 131-312℃;1H NMR(CDCl3,600MHz)δ(ppm)8.16(s,1H,Ar-H),7.93(s,1H,Ar-H),7.38(q,J=4.8Hz,2H,Ar-H),7.19(t,J=7.8Hz,2H,Ar-H),4.85–4.61(m,2H,COCH2),4.16–3.97(m,1H,CH),3.57–3.35(m,2H,CH2),2.76(d,J=6.6Hz,1H,OH),0.89(s,9H,3CH3);13C NMR(CDCl3,150MHz)δ(ppm)166.7,163.1,161.4,151.5,144.8,136.6,130.0,117.3,117.1,76.4,52.9,51.0,34.3,25.5;MS(EI,70eV):m/z(%)=320(9)[M+],302(8),263(14),234(51),165(27),123(100).Anal.Calcd for C16H21FN4O2:C,59.99;H,6.61;N,17.49.Found:C,59.88;H,6.85;N,17.35.
2m:N-(4-fluorophenyl)-N-(2-hydroxy-2-phenylethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 161-162℃;1H NMR(CDCl3,600MHz)δ(ppm)8.15(s,1H,Ar-H),7.91(s,1H,Ar-H),7.36–7.19(m,7H,Ar-H),7.15(t,J=7.8Hz,2H,Ar-H),5.08–4.95(m,1H,CH),4.78–4.63(m,2H,COCH2),4.10–3.74(m,2H,CH2),3.71(d,J=4.6Hz,1H,OH);13C NMR(CDCl3,150MHz)δ(ppm)166.7,163.1,161.5,151.6,144.8,141.5,136.8,129.9,128.5,127.9,125.9,117.3,117.1,71.5,58.4,51.0;MS(EI,70eV):m/z(%)=340(4)[M+],234(51),212(40),165(20),124(100).Anal.Calcd for C18H17FN4O2:C,65.52;H,5.03;N,16.46.Found:C,65.40;H,5.25;N,16.22.
2n:N-(2-(4-chlorophenyl)-2-hydroxyethyl)-2-(1H-1,2,4-triazol-1-yl)-N-(4-(trifluoromethyl)phenyl)acetamide
Colourless oil;1H NMR(CDCl3,600MHz)δ(ppm)8.24–8.14(m,2H,Ar-H),8.02–7.90(m,2H,Ar-H),7.75(d,J=7.8Hz,1H,Ar-H),7.52–7.43(m,2H,Ar-H),7.29–7.23(m,3H,Ar-H),5.05(d,J=2.4Hz,1H,OH),5.00(s,2H,COCH2),4.75(d,J=0.6Hz,1H,CH),3.81(s,2H,CH2);13C NMR(CDCl3,150MHz)δ(ppm)166.9,166.2,152.0,151.7,144.3,139.9,133.7,132.0,128.7,128.6,127.4,127.2,112.0,70.9,58.4,53.0,51.0,50.2;MS(EI,70eV):m/z(%)=424(2)[M+],296(37),251(39),174(100).Anal.Calcd for C19H16ClF3N4O2:C,53.72;H,3.80;N,13.19.Found:C,53.46;H,9.85;N,13.02.
2o:N-(4-chloro-2-methylphenyl)-N-(2-hydroxy-2-phenylethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 151-152℃;1H NMR(CDCl3,600MHz)δ(ppm)8.20–7.86(m,2H,Ar-H),7.48–6.98(m,8H,Ar-H),5.26–4.82(m,1H,CH),4.72–4.45(m,2H,COCH2),4.30–3.00(m,3H,CH2,OH),2.78(s,3H,CH3);13C NMR(CDCl3,100MHz)δ(ppm)166.4,151.5,144.8,141.8,138.8,137.4,135.2,132.0,130.3,128.5,128.4,127.8,126.0,125.6,71.4,58.4,56.0,50.7,17.3;MS(EI,70eV):m/z(%)=370(9)[M+],264(32),243(7),195(13),153(100).Anal.Calcd for C19H19ClN4O2:C,61.54;H,5.16;N,15.11.Found:C,61.27;H,5.00;N,15.02.
2p:N-(2-(4-bromophenyl)-2-hydroxyethyl)-N-(o-tolyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 118-119℃;1H NMR(CDCl3,600MHz)δ(ppm)8.15(d,J=10.2Hz,1H,Ar-H),7.90(d,J=5.4Hz,1H,Ar-H),7.46–7.33(m,4H,Ar-H),7.30–7.09(m,4H,Ar-H),5.26–4.84(m,1H,CH),4.79–4.16(m,3H,COCH2,OH),4.16–3.02(m,2H,CH2),2.29(s,3H,CH3);13C NMR(CDCl3,100MHz)δ(ppm)167.2,151.3,144.8,141.1,138.3,135.2,132.1,131.4,131.3,129.6,127.6,127.4,121.5,71.0,58.2,55.9,50.8,17.5;MS(EI,70eV):m/z(%)=414(5)[M+],230(51),212(67),161(57),120(100).Anal.Calcd for C19H19BrN4O2:C,54.95;H,4.61;N,13.49.Found:C,54.70;H,4.71;N,13.27.
2q:N-(2-(4-bromophenyl)-2-hydroxyethyl)-N-phenyl-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 168-169℃;1H NMR(CDCl3,600MHz)δ(ppm)8.14(s,1H,Ar-H),7.93(s,1H,Ar-H),7.52–7.41(m,5H,Ar-H),7.24(d,J=7.2Hz,2H,Ar-H),7.19(d,J=8.4Hz,2H,Ar-H),5.04–4.96(m,1H,CH),4.82–4.68(m,2H,COCH2),4.14–4.04(m,1H,OH),3.82–3.71(m,2H,CH2);13C NMR(CDCl3,150MHz)δ(ppm)167.0,151.7,144.8,140.7,140.6,131.5,130.4,129.2,127.8,127.6,121.6,71.4,58.4,51.1;MS(EI,70eV):m/z(%)=400(5)[M+],272(10),216(25),147(22),106(100).Anal.Calcd for C18H17BrN4O2:C,53.88;H,4.27;N,13.96.Found:C,53.66;H,4.31;N,14.20.
2r:N-(2,4-difluorophenyl)-N-(2-hydroxy-2-phenylethyl)-2-(1H-1,2,4-triazol-1-yl)acetamide
White solid,mp 156-159℃;1H NMR(CDCl3,600MHz)δ(ppm)8.17(d,J=7.8Hz,1H,Ar-H),7.92(d,J=3.0Hz,1H,Ar-H),7.36–7.20(m,6H,Ar-H),7.08–6.90(m,2H,Ar-H),5.21–4.90(m,1H,CH),4.84–4.64(m,2H,COCH2),4.20–3.22(m,3H,OH,CH2);13C NMR(CDCl3,150MHz)δ(ppm)166.6,163.3,151.6,144.8,141.5,131.8,131.2,128.5,128.4,128.0,127.8,125.9,125.7,112.9,110.3,71.7,58.9,57.1,50.6;MS(EI,70eV):m/z(%)=358(2)[M+],252(29),217(11),183(14),141(100).Anal.Calcd for C18H16F2N4O2:C,60.33;H,4.50;N,15.64.Found:C,60.20;H,4.66;N,15.48.
目标化合物三唑酰胺醇2的生物活性测试
设备和材料:
台式压力高温蒸汽灭菌箱(YXQ.DY型),感量万分之一的电子天平(SartoriusBT25S),无菌操作台(志诚,ZHJH-C1109B),接种针,玻璃棒,刻度尺,打火机,封口膜、三角瓶(75mL),量筒(20mL),微量进样器(100μL,200μL,500μL,1000μL),培养皿(直径6cm),霉菌培养箱(MJX-250型),细纱布,酒精灯,直径5mm打孔器。
PDA粉(青岛海洋化工),蒸馏水,DMSO,吐温-80,小麦赤霉菌(Gibberellasaubinetii),稻瘟菌(Magnaporthe grisea),指状青霉菌(Penicillium digitatum),意大利青霉菌(Penicillium italicum),水稻纹枯菌(Rhizoctonia solani)。
实验方法(采用含毒介质法)
PDA培养基的制备
称取PDA粉46g,加入蒸馏水1000mL,摇匀配置成溶液,用棉纱布盖上瓶口。把此培养基放到高压灭菌锅内采用湿热法于125℃下灭菌0.5h。
试样的配制(50mg/L)
用分析天平称取2~3mg待测样品放于已消毒的样品管中,加入几滴DMSO溶解该样品,加入适量蒸馏水和一滴吐温-80,配置成均匀的浓度为1000mg/L的溶液,取此溶液1000μL,迅速加入到9.0mL热的(40~50℃)培养基内,摇匀即配置成待测样品浓度为100mg/L的培养基,水平放置在无菌操作台内紫外杀菌15min。
抑菌活性测定
用直径5mm打孔器取菌种琼脂片,菌丝面朝下接种要含有待测药品的PDA培养基上,置于圆形培养基的正中心,切不要滑动菌种琼脂片,以免污染培养基。每个待测样品接种三个,以不含药品但含有相同浓度DMSO的培养基为对空白照,以含相同浓度的商品化药物烯唑醇、三唑酮的作为对照,放置在生化培养箱内于25℃下培养3~5天后,测定培养基上的菌落的直径。通过和上述空白对照组以及商品化药物对照组的比较来观察待测样品对菌丝生长的影响,计算待测样品在100mg/L下对菌落生长的抑制率。
抑制率(%)=[(空白对照菌落直径-待测样品菌落直径)/(空白菌落直径-打孔器直径)]×100%
目标化合物三唑酰胺醇2的抑菌活性测试结果
表1:化合物2的抑菌活性测试结果
注:化合物浓度均为100mg/L;数据为三次重复的平均值。
从上述表1可以看出,该系列化合物三唑酰胺醇2在100mg/L下对意大利青霉菌、指状青霉菌和水稻纹枯菌均表现出了一定的抑制活性,其中大部分化合物的抑菌活性一般,抑菌率为90%左右,个别化合物抑菌活性较好,如化合物2e对水稻纹枯菌的抑菌率高达100%,同时该化合物对指状青霉菌和稻瘟菌也分别有99%和91%的抑菌率。该系列化合物对小麦赤霉菌的抑菌活性普遍不理想,大部分化合物的抑菌率都在50%以下。通过化合物的抑菌活性和结构的关系总结我们可知,当化合物的取代基R1和R2含有氯和氟时,抑菌活性普遍要比含有甲基和氢时要好一些,且氯和氟处在邻位时的活性要比处在对位时的活性稍好。
Claims (5)
1.一种三唑酰胺醇类杀菌剂,其特征在于,所述杀菌剂的化学结构式为:
其中,取代基R1和R2为苯基或对氯苯基或对氟苯基或邻氯苯基或邻氟苯基或2,4-二氯苯基或2,4-二氟苯基或叔丁基或邻甲基苯基或间氟苯基或对三氟甲基苯基或邻甲基对氯苯基中的任意一种,取代基位置、个数以及共轭位置不固定。
2.权利要求1所述的三唑酰胺醇类杀菌剂,其特征在于,化学结构式为:
3.合成权利要求1或2所述的三唑酰胺醇类杀菌剂的方法,其特征在于,所述方法包括以下合成路径:
方法包括以下步骤:
(1)室温条件下,向反应瓶中加入甲醇,称取化合物1和硼氢化钠加入到甲醇中,所述化合物1为三唑酰胺酮;
(2)将所述步骤(1)中的反应体系置于0~60℃下搅拌,反应瓶中即出现大量气泡,反应0.2~1小时;
(3)取所述步骤(2)的反应液TLC监测,反应完毕后,减压蒸馏除去溶剂甲醇,剩余物经硅胶柱进行柱层析分离纯化得到化合物2,即完成三唑酰胺醇类杀菌剂的合成。
4.根据权利要求3的方法,其特征在于:所述步骤1)化合物1与硼氢化钠的投料质量比为2:3。
5.根据权利要求3的方法,其特征在于:所述步骤2)反应温度为40℃,反应时间0.6小时。
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