CN115286527A - 一类诺卜酸酰胺类化合物的制备方法及其应用 - Google Patents
一类诺卜酸酰胺类化合物的制备方法及其应用 Download PDFInfo
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- CN115286527A CN115286527A CN202210769046.4A CN202210769046A CN115286527A CN 115286527 A CN115286527 A CN 115286527A CN 202210769046 A CN202210769046 A CN 202210769046A CN 115286527 A CN115286527 A CN 115286527A
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- acid amide
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/10—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Environmental Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
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Abstract
Description
技术领域
本发明属于农药合成技术领域,具体涉及到一类诺卜酸酰胺类化合物的制备方法及其应用。
背景技术
农作物的病虫害是影响农业产品及林下资源持续和健康发展的一个重要制约因素之一。而农药作为控制农林作物的病虫害等生物危害的一种特殊商品,在保护农林作物的正常生长、提高农业的生产、促进粮食安全等方面发挥着及其重要的作用。而长期的使用单一的农药品种也会造成植物病菌、害虫及其杂草等产生抗药性。为此开发新的具有靶向作用的农药品种对植物的病害的有效治理至关重要。
琥珀酸脱氢酶抑制剂的主要结构均含有酰胺基团,酰胺键也是许多药物或杀虫剂的关键组成部分,如fluopyram、penflufen、bixafen、fluxapyroxad等。因此,在设计化合物时将酰胺结构引入,寻找具有优良抗真菌活性的药物先导化合物,对于研发新型抗真菌农药、防治农林作物病害具有很好的理论和实际意义。
到目前为止,还未见有诺卜酸酰胺类化合物作为农用杀菌剂使用的报道。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊,而这种简化或省略不能用于限制本发明的范围。
鉴于上述和/或现有技术中存在的问题,提出了本发明。
因此,本发明的目的是,克服现有技术中的不足,提供一类具有抗植物病原真菌活性的诺卜酸酰胺类化合物的制备方法。
为解决上述技术问题,本发明提供了如下技术方案:诺卜酸酰胺类化合物的制备方法,包括,
将诺卜醇经过氧化生成诺卜酸;
诺卜酸与取代苄胺反应合成诺卜酸酰胺类化合物;
其中,诺卜酸酰胺类化合物,结构式为:
其中,
作为本发明所述诺卜酸酰胺类化合物的制备方法的一种优选方案,其中:所述合成诺卜酸,包括,
取诺卜醇于单口瓶中,加入丙酮,冰浴条件下用滴液漏斗缓慢滴入Jones试剂,反应1h,TLC检测,反应完毕,旋转浓缩除去大部分丙酮,加入乙酸乙酯萃取,合并有机层,以饱和食盐水洗涤,无水硫酸钠干燥,旋转浓缩得诺卜酸粗品,用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比40:1~10:1纯化,得油状物诺卜酸;
其中,所述诺卜醇、丙酮、Jones试剂的摩尔比为1:20.6:2.2。
作为本发明所述诺卜酸酰胺类化合物的制备方法的一种优选方案,其中:所述制备诺卜酸酰胺化合物,包括,
将油状物诺卜酸溶于DCM中,后依次加入取代苄胺盐酸盐、DMAP、EDCI,加毕,室温反应,TLC检测原料反应完全,以水、饱和碳酸氢钠、饱和氯化钠依次洗涤,有机相旋转浓缩除去大部分DCM得油状物,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比20:1~5:1,得目标化合物诺卜酸酰胺化合物。
作为本发明所述诺卜酸酰胺类化合物的制备方法的一种优选方案,其中:所述诺卜酸、取代苄胺盐酸盐、DMAP、EDCI的摩尔比为1:1:0.1:1.2,所述诺卜酸与取代苄胺的反应时间为1~3h。
作为本发明所述诺卜酸酰胺类化合物的制备方法的一种优选方案,其中:所述取代苄胺包括苄胺、4-三氟甲基苄胺、2-氟苄胺、3-氟苄胺、4-氟苄胺、2-氯苄胺、3-氯苄胺、2,4-二氟苄胺、2-氯-4-氟苄胺、4-溴苄胺、4-碘苄胺、4-氰基苄胺、4-甲基苄胺、4-异丙基苄胺和4-硝基苄胺。
本发明的再一个目的是,克服现有技术中的不足,提供诺卜酸酰胺类化合物产品。
本发明的另一个目的是,克服现有技术中的不足,提供所述诺卜酸酰胺类化合物产品在防治农业或林业的植物真菌的应用。
作为本发明所述应用的一种优选方案,其中:所述的植物真菌包括小麦赤霉病菌、油菜菌核病菌和辣椒疫霉病菌。
本发明有益效果:
(1)本发明所述的化合物为一种含有诺卜酸酰胺类衍生物,分子结构新颖,均为新化合物,化学结构特征鲜明,结构式中含有诺卜酸和苄胺基团,其中苄胺与诺卜酸通过酰胺键相连接;本发明所述的化合物的制备方法简便,原料易得,反应条件温和易控。
(2)本发明所述的化合物是一种在农业或林业领域的防治植物真菌的药剂,这种药剂对于防治小麦赤霉病菌、油菜菌核病菌和辣椒疫霉病菌展现出较好的效果。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。其中:
图1为本发明中诺卜酸酰胺类化合物制备方法示意图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合说明书实施例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
其次,此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例,也不是单独的或选择性的与其他实施例互相排斥的实施例。
本发明诺卜酸酰胺类化合物制备方法示意图见图1,包括以下步骤:
(1)将诺卜醇经过氧化合成诺卜酸;
(2)对诺卜酸与各取代苄胺反应合成诺卜酸酰胺。
具体步骤为:
(1)诺卜酸的制备
取诺卜醇(6.6g,39.6mmol)于250ml单口瓶中,加入60ml丙酮溶解,冰浴条件下用滴液漏斗缓慢滴入33ml的Jones试剂,冰浴条件下反应1h,TLC检测,反应完毕,旋转浓缩除去大部分丙酮,加入乙酸乙酯萃取(50ml×3),合并有机层,以饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,旋转浓缩得诺卜酸粗品,用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比40:1~10:1纯化,得油状物诺卜酸2.1g;
(2)诺卜酸酰胺的制备
苄胺,4-三氟甲基苄胺,2-氟苄胺,3-氟苄胺,4-氟苄胺,2-氯苄胺,3-氯苄胺,2,4-二氟苄胺,2-氯-4-氟苄胺,4-溴苄胺,4-碘苄胺,4-氰基苄胺,4-甲基苄胺,4-异丙基苄胺,4-硝基苄胺,(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比20:1~5:1,得目标诺卜酸酰胺化合物。
实施例1
苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mLDCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-1):淡黄色油状物;收率,70.5%。
1H NMR(600MHz,氯仿)δ7.32(tt,J=7.7,1.4Hz,2H),7.28–7.26(m,1H),7.26–7.23(m,2H),5.93(s,1H),5.44(s,1H),4.41(ddd,J=67.8,14.7,5.8Hz,2H),3.07–2.87(m,2H),2.39(dt,J=8.8,5.6Hz,1H),2.32–2.18(m,2H),2.14–2.03(m,2H),1.24(s,3H),1.08(d,J=8.8Hz,1H),0.78(s,3H).13C NMR(150MHz,氯仿)δ170.59,142.54,138.38,128.77,127.88,127.58,122.07,45.39,43.74,40.46,38.04,32.24,31.54,26.16,21.06.
实施例2
制得诺卜酸酰胺衍生物(I-2):
4-三氟甲基苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-2):黄色油状物;收率,72.3%。
1H NMR(600MHz,氯仿)δ7.56(d,J=8.1Hz,2H),7.34(d,J=8.0Hz,2H),6.12(s,1H),5.46(s,1H),4.45(ddd,J=78.2,15.3,6.0Hz,2H),3.07–2.87(m,2H),2.39(dt,J=8.7,5.6Hz,1H),2.33–2.19(m,2H),2.09(d,J=5.5Hz,2H),1.24(s,3H),1.08(d,J=8.7Hz,1H),0.78(s,3H).13C NMR(150MHz,氯仿)δ170.86,142.59,142.43,129.86(q,J=32.3Hz),127.97,125.71(q,J=3.8Hz),124.20(q,J=270.3Hz),122.35,45.78,45.33,40.47,38.09,32.29,31.57,26.16,21.10.
实施例3
制得诺卜酸酰胺衍生物(I-3):
2-氟苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-3):黄色油状物;收率,74.4%。
1H NMR(600MHz,氯仿)δ7.30(td,J=7.6,1.4Hz,1H),7.27–7.23(m,1H),7.14–6.97(m,2H),5.99(s,1H),5.44(s,1H),4.46(ddd,J=50.9,14.8,6.0Hz,2H),3.13–2.68(m,2H),2.37(dt,J=8.8,5.6Hz,1H),2.32–2.18(m,2H),2.10–2.03(m,2H),1.23(s,3H),1.08(d,J=8.8Hz,1H),0.77(s,3H).13C NMR(150MHz,氯仿)δ170.66,161.14(d,J=244.6Hz),142.47,130.43(d,J=4.3Hz),129.41(d,J=8.0Hz),125.38(d,J=14.7Hz),124.41(d,J=3.6Hz),122.15,115.44(d,J=21.2Hz),45.75,45.34,40.46,38.03,37.67(d,J=3.7Hz),32.19,31.56,26.15.
实施例4
制得诺卜酸酰胺衍生物(I-4):
3-氟苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-4):淡黄色油状物;收率,69.8%。
1H NMR(600MHz,氯仿)δ7.31–7.27(m,1H),7.02(d,J=7.7Hz,1H),6.99–6.90(m,2H),5.96(s,1H),5.47(s,1H),4.42(ddd,J=76.8,15.1,5.9Hz,2H),3.10–2.89(m,2H),2.41(dt,J=8.8,5.6Hz,1H),2.33–2.20(m,2H),2.15–2.07(m,2H),1.25(s,3H),1.08(d,J=8.8Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.75,163.11(d,J=244.9Hz),142.49,141.05(d,J=6.8Hz),130.30(d,J=8.2Hz),123.31(d,J=2.8Hz),122.33,114.65(d,J=21.8Hz),114.50(d,J=21.0Hz),45.78,45.38,43.17,40.48,38.09,32.30,31.58,26.17,21.11.
实施例5
制得诺卜酸酰胺衍生物(I-5):
4-氟苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-5):黄色油状物;收率,73.9%。
1H NMR(600MHz,氯仿)δ7.25–7.18(m,2H),7.04–6.96(m,2H),5.95(s,1H),5.45(s,1H),4.38(ddd,J=69.4,14.7,5.8Hz,2H),2.98(ddd,J=69.6,15.5,1.3Hz,2H),2.38(dt,J=8.7,5.6Hz,1H),2.32–2.19(m,2H),2.09(d,J=5.6Hz,2H),1.24(s,3H),1.05(d,J=8.8Hz,1H),0.78(s,3H).13C NMR(150MHz,氯仿)δ170.70,162.29(d,J=244.2Hz),142.47,134.23,129.57(d,J=7.9Hz),122.23,115.62(d,J=21.3Hz),45.76,45.34,43.02,40.46,38.06,32.27,31.55,26.17,21.09.
实施例6
制得诺卜酸酰胺衍生物(I-6):
2-氯苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-6):白色固体;收率,71.2%,m.p.67.9-69.3℃;1H NMR(600MHz,氯仿)δ7.39–7.31(m,2H),7.24–7.18(m,2H),6.09(s,1H),5.45(s,1H),4.58–4.40(m,2H),3.05–2.86(m,2H),2.37(dt,J=8.8,5.6Hz,1H),2.32–2.16(m,2H),2.08(d,J=5.5Hz,2H),1.23(s,3H),1.09(d,J=8.8Hz,1H),0.76(s,3H).13C NMR(150MHz,氯仿)δ170.63,142.44,135.83,133.74,130.37,129.59,129.04,127.19,122.18,45.80,45.36,41.60,40.45,38.03,32.24,31.57,26.16,21.02.
实施例7
制得诺卜酸酰胺衍生物(I-7):
3-氯苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-7):黄色油状物;收率,75.3%。
1H NMR(600MHz,氯仿)δ7.25–7.18(m,3H),7.14–7.05(m,1H),6.04(s,1H),5.46(s,1H),4.38(ddd,J=89.4,15.1,6.0Hz,2H),3.09–2.86(m,2H),2.41(dt,J=8.8,5.6Hz,1H),2.32–2.20(m,2H),2.14–2.06(m,2H),1.25(s,3H),1.08(d,J=8.8Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.75,142.49,140.55,134.65,130.03,127.82,127.74,125.91,122.32,45.77,45.38,43.07,38.08,32.31,31.58,26.17,21.10.
实施例8
制得诺卜酸酰胺衍生物(I-8):
2,4-二氟苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-8):淡黄色油状物;收率,73.7%。
1H NMR(600MHz,氯仿)δ7.30(td,J=8.5,6.5Hz,1H),6.86–6.75(m,2H),5.98(s,1H),5.44(s,1H),4.41(ddd,J=54.3,14.9,6.0Hz,2H),3.10–2.81(m,2H),2.37(dt,J=8.8,5.6Hz,1H),2.34–2.17(m,2H),2.14–2.00(m,2H),1.23(s,3H),1.06(d,J=8.8Hz,1H),0.77(s,3H).13C NMR(150MHz,氯仿)δ170.73,162.62(dd,J=214.7,12.0Hz),160.98(dd,J=214.6,11.9Hz),142.42,131.36(dd,J=9.7,6.0Hz),122.22,121.49(dd,J=14.9,3.7Hz),111.47(dd,J=21.0,3.7Hz),103.93(t,J=25.4Hz),45.75,45.31,40.46,38.04,103.93(t,J=3.3Hz),32.20,31.57,26.16,21.02.
实施例9
制得诺卜酸酰胺衍生物(I-9):
2-氯-4-氟苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-9):黄色固体;收率,76.6%,m.p.61.3-62.5℃;1HNMR(600MHz,氯仿)δ7.34(dd,J=8.5,6.1Hz,1H),7.10(dd,J=8.4,2.6Hz,1H),6.94(td,J=8.3,2.6Hz,1H),6.08(s,1H),5.44(s,1H),4.45(ddd,J=53.6,14.9,6.1Hz,2H),3.05–2.84(m,2H),2.37(dt,J=8.8,5.6Hz,1H),2.32–2.17(m,2H),2.13–2.02(m,2H),1.23(s,3H),1.08(d,J=8.8Hz,1H),0.76(s,3H).13C NMR(150MHz,氯仿)δ170.70,161.99(d,J=248.0Hz),142.38,134.32(d,J=10.2Hz),131.93(d,J=3.5Hz),131.55(d,J=8.8Hz),122.24,116.96(d,J=24.7Hz),114.31(d,J=20.8Hz),45.80,45.31,40.96,40.45,38.04,32.24,31.57,26.16,21.03.
实施例10
制得诺卜酸酰胺衍生物(I-10):
4-溴苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-10):黄色油状物;收率,78.0%。
1H NMR(600MHz,氯仿)δ7.47–7.39(m,2H),7.12(d,J=8.3Hz,2H),5.95(s,1H),5.45(s,1H),4.36(ddd,J=78.9,15.0,5.9Hz,2H),3.08–2.87(m,2H),2.39(dt,J=8.7,5.6Hz,1H),2.33–2.18(m,2H),2.09(d,J=5.6Hz,2H),1.25(s,4H),1.07(d,J=8.8Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.69,142.47,137.52,131.85,129.54,122.24,121.45,45.76,45.36,43.04,40.46,38.07,32.29,31.56,26.18,21.11.
实施例11
制得诺卜酸酰胺衍生物(I-11):
4-碘苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-11):淡黄色油状物;收率,71.9%。
1H NMR(600MHz,氯仿)δ7.63(d,J=8.3Hz,2H),6.98(d,J=8.3Hz,2H),5.97(s,1H),5.45(s,1H),4.34(ddd,J=80.0,15.0,5.9Hz,2H),3.10–2.84(m,2H),2.39(dt,J=8.7,5.6Hz,1H),2.25(q,J=18.0Hz,2H),2.09(d,J=4.6Hz,2H),1.25(s,3H),1.07(d,J=8.8Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.71,142.44,138.17,137.80,129.77,122.22,92.92,45.75,45.33,43.12,40.45,38.07,32.28,31.55,26.18,21.10.
实施例12
制得诺卜酸酰胺衍生物(I-12):
4-氰基苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-12):黄色油状物;收率,78.1%。
1H NMR(600MHz,氯仿)δ7.60(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H),6.08(s,1H),5.47(s,1H),4.47(ddd,J=80.3,15.6,6.1Hz,2H),3.15–2.82(m,2H),2.40(dt,J=8.7,5.6Hz,1H),2.35–2.16(m,2H),2.10(d,J=5.6Hz,2H),1.25(s,3H),1.07(d,J=8.7Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.93,144.07,142.34,132.55,128.26,122.42,118.79,111.40,45.78,45.28,43.17,40.45,38.10,32.29,31.56,26.18,21.11.
实施例13
制得诺卜酸酰胺衍生物(I-13):
4-甲基苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-13):淡黄色油状物;收率,75.4%;1H NMR(600MHz,氯仿)δ7.13(s,4H),5.88(s,1H),5.44(s,1H),4.37(ddd,J=68.1,14.6,5.6Hz,2H),3.06–2.89(m,2H),2.39(dt,J=8.8,5.6Hz,1H),2.33(s,3H),2.25(q,J=17.2,16.6Hz,2H),2.14–2.07(m,2H),1.25(s,3H),1.08(d,J=8.8Hz,1H),0.79(s,3H).13C NMR(150MHz,氯仿)δ170.69,142.52,137.35,135.23,129.47,127.92,122.17,45.77,45.37,43.61,40.48,38.08,32.29,31.56,26.18,21.24,21.10.
实施例14
制得诺卜酸酰胺衍生物(I-14):
4-异丙基苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-14):淡黄色油状物;收率,78.5%。
1H NMR(600MHz,氯仿)δ7.21–7.15(m,4H),5.86(s,1H),5.44(s,1H),4.38(ddd,J=52.8,14.6,5.7Hz,2H),3.03(d,J=15.4Hz,1H),2.97–2.82(m,2H),2.39(dt,J=8.8,5.6Hz,1H),2.34–2.16(m,2H),2.15–2.04(m,2H),1.24(s,10H),1.23(s,9H),1.09(d,J=8.8Hz,1H),0.78(s,3H).13C NMR(150MHz,氯仿)δ170.57,148.38,142.57,135.69,127.96,126.85,122.03,45.74,45.43,43.56,40.48,38.06,33.95,32.24,31.55,26.17,24.14,24.12,21.06.
实施例15
制得诺卜酸酰胺衍生物(I-15):
4-硝基苄胺(1.11mmol)加入到溶有中间体诺卜酸(1.11mmol)的4mL DCM溶液里,再依次加入DMAP(0.11mmol)、EDCI(1.33mmol)室温反应1h,TLC监测原料反应完全,以水(5ml×3)、饱和碳酸氢钠(5ml)、饱和氯化钠(5ml)依次洗涤,有机相旋转浓缩除去大部分DCM得油状物粗品,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比=20:1~5:1,得目标诺卜酸酰胺衍生物(I-15):淡黄色固体;收率,68.1%,m.p.85.7-87.4℃;1H NMR(600MHz,氯仿)δ8.18(d,J=8.5Hz,2H),7.41(d,J=8.5Hz,2H),6.09(s,1H),5.49(s,1H),4.52(ddd,J=87.8,15.7,6.1Hz,2H),3.12–2.91(m,2H),2.42(dt,J=8.8,5.6Hz,1H),2.28(q,J=17.7Hz,3H),2.12(d,J=5.4Hz,2H),1.26(s,3H),1.09(d,J=8.7Hz,1H),0.81(s,3H).13C NMR(150MHz,氯仿)δ171.01,147.44,146.07,142.35,128.33,124.01,122.55,45.82,45.31,42.96,40.47,38.14,32.35,31.59,26.20,21.15.
实施例16
杀菌活性(离体)实验
本实验中所有试验菌株购买于中国农业微生物菌种保藏管理中心(ACCC)及中国林业菌种保藏管理中心(CFCC),为小麦赤霉病菌(ACCC 31060)、水稻纹枯病菌(ACCC38870)、辣椒疫霉病菌(ACCC 36279)、番茄灰霉病菌(ACCC 36027)、油菜菌核病菌(ACCC30096)、辣椒炭疽病菌(ACCC 37623)和马铃薯晚疫病菌( MYA-1113TM)。采用的培养基为马铃薯琼脂葡萄糖培养基(简称PDA)。PDA培养基配方:马铃薯(去皮)200g,葡萄糖20g,琼脂15g,蒸馏水1000mL,配制方法:将马铃薯洗净去皮,称200g切成小块,加水煮烂(煮沸20-30分钟,能被玻璃棒戳破即可),用八层纱布过滤于烧杯中,根据实验需要加15-20g琼脂,加入20g葡萄糖,搅拌均匀,充分溶解后稍冷却,补足水至1000mL,分装后121℃灭菌15分钟,冷却后备用。
实验方法:采用生长速率法。
(1)先将7种植物真菌在PDA平板上25℃培养3-6d左右待用;
(2)将PDA培养基加热溶化,冷却至45-50℃,加入50mg/L浓度的待测化合物制成含50mg/L药液的培养基,并分别倒入培养皿中冷却,联苯吡菌胺(bixafen)作为阳性对照;
(3)以无菌操作手续,用打孔器在培养6d的各菌株菌丝边缘(生长状况尽量一致)打取圆形菌饼(直径0.50cm),再用接种针挑至含药平板中央,然后将培养皿倒置于培养箱(28℃)中培养;
(4)于处理后不同时间观察测定菌丝的生长情况,并采用十字交叉法测得直径并处理数据,计算抑制率;
抑制率(%)=(对照菌丝直径-处理菌丝直径)/(对照菌丝直径-0.5)×100;
每个处理重复3次。
表1诺卜酸酰胺类化合物对六种农业致病真菌的抑制活性试验结果
注:试验中每个处理设三次重复,表中数据为三次重复的平均值。
实验组I-1~I-15以及对照药剂联苯吡菌胺的杀菌活性测定结果见表1。
由表1和表2可见,50mg/L浓度时,化合物I-1~I-15对6种植物真菌显示出不同程度的抑菌活性,部分化合物对马铃薯晚疫病菌显示比较好的抑菌活性,对小麦赤霉病菌和油菜菌核病菌显示中等的抑制活性。部分化合物对马铃薯晚疫病菌抑制率高于对照药剂联苯吡菌胺。说明这些化合物对该菌的抑制活性与阳性对照药联苯吡菌胺相当,具有开发抗真菌剂的潜力。
实施例17
琥珀酸脱氢酶(SDH)抑制活性筛选:
筛选菌株:试验菌株小麦赤霉病菌(ACCC 31060)购买于中国农业微生物菌种保藏管理中心(ACCC)官网。
试验方法:进一步进行了部分化合物的琥珀酸脱氢酶(SDH)抑制活性。
具体方法如下:
酶的提取:小麦赤霉病菌接种量为0.05OD 600nm,在摇床(180rpm,28℃)上培养5天,在PDB培养基中培养。收集菌丝,并用研钵和杵在液氮中破坏。所得粉末在线粒体提取缓冲液中重悬至10%w/v。(线粒体提取缓冲液:10mM KH2PO4,pH 7.2,10mM KCl,10mM MgCl2,0.5M蔗糖,0.2mM EDTA,2mM PMSF)提取物离心澄清(5000g,4℃,10min,2次),将完整线粒体在4℃下以10000g离心20分钟,并在相同的缓冲液中重悬。将线粒体悬浮液浓缩为浓度10mg/mL的溶液中,在-80℃保存至使用。SDH活性在几个月内保持稳定。
酶抑制活性的检测:Ubiquinone/DCPIP.线粒体悬液用提取缓冲液稀释1/5,在10mM琥珀酸存在下30℃预活化30min。ubiquinone/DCPIP活性抑制测定:在200μL的含140μM二氯苯酚(DCPIP)和1mM2,3-二甲氧基-5-甲基-1,4-苯醌(Q)的检测缓冲液中添加10μL的预激活线粒体进行。
检测缓冲液(50mM phosphate-sodium,pH 7.2,250mM蔗糖,10mM琥珀酸)。药剂浓度范围为1.886~40.010μM,2×稀释倍数步长法(5种药剂浓度+DMSO对照)。在96孔板中,在反应温度(30℃)下预平衡10min,加入10μL预活化的提取的线粒体悬液进行反应。DCPIP抑制在30℃下595nm处监测。半抑制浓度(IC50)用数据处理系统(IBM SPSS Statistics23)计算吸光度斜率(OD/min)。部分化合物对SDH酶活性抑制结果见表2。
表2
通过进一步进行化合物I-1的SDH抑制活性测试,从表2可以看出化合物I-2的IC50值为54.137μM,虽低于阳性对照联苯吡菌胺(IC50=18.573μM),但对SDH也有一定的抑制作用,有进一步开发抗真菌剂的潜力。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (8)
2.如权利要求1所述诺卜酸酰胺类化合物的制备方法,其特征在于:所述合成诺卜酸,包括,
取诺卜醇于单口瓶中,加入丙酮,冰浴条件下用滴液漏斗缓慢滴入Jones试剂,反应1h,TLC检测,反应完毕,旋转浓缩除去大部分丙酮,加入乙酸乙酯萃取,合并有机层,以饱和食盐水洗涤,无水硫酸钠干燥,旋转浓缩得诺卜酸粗品,用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比40:1~10:1纯化,得油状物诺卜酸;
其中,所述诺卜醇、丙酮、Jones试剂的摩尔比为1:20.6:2.2。
3.如权利要求1所述诺卜酸酰胺类化合物的制备方法,其特征在于:所述合成诺卜酸酰胺,包括,
将油状物诺卜酸溶于DCM中,后依次加入取代苄胺、DMAP、EDCI,加毕,室温反应,TLC检测原料反应完全,以水、饱和碳酸氢钠、饱和氯化钠依次洗涤,有机相旋转浓缩除去大部分DCM得油状物,最后粗品用200-300目硅胶柱层析分离纯化,石油醚/乙酸乙酯体积比20:1~5:1,得目标化合物诺卜酸酰胺。
4.如权利要求1所述诺卜酸酰胺类化合物的制备方法,其特征在于:所述诺卜酸、取代苄胺、DMAP、EDC的摩尔比为1:1:0.1:1.2,所述诺卜酸与取代苄胺的反应时间为1~3h。
5.如权利要求1~4中任一所述诺卜酸酰胺类化合物的制备方法,其特征在于:所述取代苄胺包括苄胺、4-三氟甲基苄胺、2-氟苄胺、3-氟苄胺、4-氟苄胺、2-氯苄胺、3-氯苄胺、2,4-二氟苄胺、2-氯-4-氟苄胺、4-溴苄胺、4-碘苄胺、4-氰基苄胺、4-甲基苄胺、4-异丙基苄胺和4-硝基苄胺。
6.权利要求1~5中任一所述诺卜酸酰胺类化合物制备方法制得的产品。
7.如权利要求6所述产品在防治农业或林业的植物真菌中的应用。
8.如权利要求7所述的应用,其特征在于:所述的植物真菌包括所述的植物真菌包括小麦赤霉病菌、油菜菌核病菌和辣椒疫霉病菌。
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CN108084022A (zh) * | 2018-01-17 | 2018-05-29 | 江西农业大学 | 乙二醇单氢化诺卜基醚及其羧酸酯的合成方法及其应用 |
CN113773288A (zh) * | 2021-09-30 | 2021-12-10 | 南京林业大学 | 一类含杂环的脱氢枞基甲酰胺类化合物及其制备方法和应用 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108084022A (zh) * | 2018-01-17 | 2018-05-29 | 江西农业大学 | 乙二醇单氢化诺卜基醚及其羧酸酯的合成方法及其应用 |
CN113773288A (zh) * | 2021-09-30 | 2021-12-10 | 南京林业大学 | 一类含杂环的脱氢枞基甲酰胺类化合物及其制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
AURÉLIE DOS SANTOS等: "《Reductive Passerini/Tsuji–Trost Strategy towards β, γ-Unsaturated Amides》", 《SYNLETT》, vol. 25, no. 13, pages 1901 - 1903 * |
王秀等: "《含天然蒎烯结构的4-酰基-3-氨基-1, 2, 4-三唑-硫醚衍生物的合成、抑菌活性、三维定量构效关系及分子对接研究》", 《CHINESE JOURNAL OF ORGANIC CHEMISTRY》, vol. 42, no. 3, pages 871 - 883 * |
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