CN113773288B - 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 - Google Patents

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 Download PDF

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CN113773288B
CN113773288B CN202111157947.XA CN202111157947A CN113773288B CN 113773288 B CN113773288 B CN 113773288B CN 202111157947 A CN202111157947 A CN 202111157947A CN 113773288 B CN113773288 B CN 113773288B
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heterocycle
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dehydroabietylformamide
dehydroabietyl
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CN113773288A (zh
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谷文
杨子辉
刘青松
孙月
王石发
孙雪宝
孙露
陈霖霖
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Nanjing Forestry University
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Nanjing Forestry University
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Abstract

本发明公开了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，该类化合物名称为含杂环的脱氢枞基甲酰胺，结构式为：所述含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用。活性结果表明：本发明化合物对油菜菌核病菌和番茄灰霉病菌有较好的防治效果；对番茄早疫病菌，小麦赤霉病菌和水稻纹枯病显示一定的抑菌活性。

Description

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
技术领域
本发明属于农药合成领域，具体涉及到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。
背景技术
松脂是天然松树中的主要成分，松脂包含两种成分：松香酸和松节油。松香酸有燥湿杀虫、拔毒生肌、止痒止痛功能，是外科常用药。临床常与其他药共研为细末涂搽患处,用来治疗疖、痈、湿疹、脓疱疮及刀伤皮肤出血不止等症状。
松香酸即为脱氢枞酸，脱氢枞胺是脱氢枞酸的衍生物，其即为以氨基替换羧酸基团的重要原料，其还是松香的重要改性产品之一,具有性质稳定，比旋光度较大等其它松香衍生物所不具备的一些独特理化性质。
目前，还未见有含杂环的脱氢枞基甲酰胺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。
本发明有益效果：
(1)本发明所述含杂环的脱氢枞基甲酰胺化合物，分子结构新颖，均为新化合物；化学结构特征鲜明，结构式中含有脱氢枞胺基团，其中脱氢枞胺基团与杂环基团通过酰胺键相连接，对于防治油菜菌核病、番茄灰霉病和番茄早疫病显示出较好的效果，对于水稻纹枯病和小麦赤霉病显示一定的治疗效果。
(2)本发明所述的化合物的制备方法简便，原料易得，反应条件易控。尤其在合成含杂环的脱氢枞基甲酰胺化合物这步反应中，产物经柱层析即可得到。
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为本发明实施例含杂环的脱氢枞基甲酰胺化合物制备方法示意图。
图2为化合物I-11,I-28,I-30的番茄灰霉活体实验示意图。
具体实施方式
本发明含杂环的脱氢枞基甲酰胺化合物制备方法示意图见图1，其中：
取含杂环羧酸和脱氢枞胺于单口瓶中，加入二氯甲烷溶解，搅拌下加入催化剂4-二甲氨基吡啶(DMAP)和缩合剂1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，以饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物。
实施例1
含杂环的脱氢枞基甲酰胺化合物的制备：
取含2-甲基呋喃-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物。
化合物I-1.收率,75％,白色蜡状物.1H NMR(600MHz,CDCl3)δ7.22(d,J＝2.0Hz,1H),7.16(d,J＝8.2Hz,1H),6.99(dd,J1＝8.1Hz,J2＝1.5Hz,1H),6.89(s,1H),6.36(s,1H),5.67(s,1H),3.35-3.27(m,2H),2.94-2.90(m,1H),2.85–2.78(m,2H),2.57(s,3H),2.29(d,J＝12.7Hz,1H),2.04(s,1H),1.97-1.94(m,1H),1.80–1.66(m,3H),1.49-1.45(m,2H),1.40-1.35(m,2H),1.22(d,J＝7.2Hz,9H),0.98(s,3H).13C NMR(150MHz,CDCl3)δ163.82,156.51,146.97,145.50,140.17,134.67,126.84,124.13,123.77,115.60,108.21,49.56,45.64,38.26,37.44,36.32,33.32,30.34,25.34,23.88,18.99,18.60,18.55,13.44.
实施例2
取2-氟吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-2,收率,75％，白色固体；m.p.79-80.5℃.m.p.79-80.5℃；1H NMR(400MHz,CDCl3)δ8.49–8.45(m,1H),8.21(d,J＝4.5Hz,1H),7.26-7.23(m,1H),7.08(d,J＝8.2Hz,1H),6.90(d,J＝8.1Hz,1H),6.85–6.79(m,2H),3.39(dd,J1＝13.6Hz,J2＝6.1Hz,1H),3.29(dd,J1＝13.6Hz,J2＝6.3Hz,1H),2.88-2.69(m,3H),2.22(d,J＝12.8Hz,1H),1.91-1.86(m,1H),1.73–1.60(m,3H),1.43(t,J＝12.6Hz,2H),1.34-1.23(m,2H),1.15-1.12(m,9H),0.93(s,3H)；13C NMR(100MHz,CDCl3)δ161.67(d,J＝7.7Hz),161.05,158.71,150.05(d,J＝4.42Hz),146.86,145.53,143.44,134.55,126.84,124.15,123.84,122.37(d,J＝4.0Hz),116.10(d,J＝27.3Hz),77.00,50.50,45.65,38.21,37.60,37.46,36.28,33.33,30.29,25.34,23.88,23.86,19.07,18.61,18,55；ESI-HRMS:m/zcalcd.for C26H33FN2O[M+H]+:409.2655；found 409.2658.
实施例3
取2-氯吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-3.收率80％,白色固体；m.p.86-87℃.1H NMR(400MHz,CDCl3)δ8.29(d,J＝4.3Hz,1H),7.93(d,J＝7.4Hz,1H),7.18–7.16(m,1H),7.06(d,J＝8.1Hz,1H),6.89(d,J＝8.1Hz,1H),6.79(s,1H),6.58(t,J＝5.4Hz,1H),3.30(d,J＝9.4Hz,2H),2.87–2.68(m,3H),2.21(d,J＝12.8Hz,1H),1.88-1.83(m,1H),1.71–1.60(m,3H),1.46-1.39(m,2H),1.30–1.22(m,2H),1.14–1.11(m,9H),0.93(s,3H).13C NMR(100MHz,CDCl3)δ164.66,150.61,146.86,146.79,145.55,139.75,134.47,131.40,126.79,124.04,123.79,122.66,50.83,45.66,38.24,37.54,37.40,36.30,33.31,30.11,25.19,23.88,23.86,19.01,18.54,18.51.
实施例4
取2-三氟甲基吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-4.收率69％,白色固体.m.p.96.5-97.5℃.1H NMR(400MHz,CDCl3)δ:8.67(d,J＝3.0Hz,1H),7.77(d,J＝6.2Hz,1H),7.47-7.44(m,1H),7.16(d,J＝8.1Hz,1H),6.99(d,J＝8.1Hz,1H),6.89(s,1H),6.15(s,1H),3.42-3.23(m,2H),2.96-2.78(m,3H),2.30(d,J＝12.8Hz,1H),1.92–1.63(m,4H),1.49–1.34(m,4H),1.21(d,J＝6.7Hz,9H),0.99(s,3H).13C NMR(100MHz,CDCl3)δ149.76,146.84,145.62,143.69(d,J＝34.2Hz),137.15(d,J＝1.0Hz),134.42,132.12,126.80,126.24,124.05,123.84,121.18(q,J＝273.8Hz),50.91,45.83,38.19,37.27,37.26,35.99,33.33,29.98,25.15,23.89,23.86,18.92,18.43,18.37.
实施例5
取2-溴吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-5.收率54％,白色固体，m.p.87-88.5℃,yield 54％.1H NMR(400MHz,CDCl3)δ8.40-8.37(m,1H),7.89(dd,J1＝7.6Hz,J2＝2.0Hz,1H),7.32(dd,J1＝7.6Hz,J2＝4.7Hz,1H),7.16(d,J＝8.2Hz,1H),6.99(dd,J1＝8.1,J2＝1.3Hz,1H),6.88(s,1H),6.33(s,1H),3.40(d,J＝6.4Hz,2H),2.97–2.78(m,3H),2.31(d,J＝12.8Hz,1H),1.98–1.64(m,1H),1.84-1.66(m,3H),1.57-1.50(m,1H),1.41-1.33(m,2H),1.25–1.17(m,9H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ165.70,150.87,146.91,145.63,138.78,138.11,134.81,134.54,126.83,124.07,123.83,122.84,50.82,45.56,38.28,37.56,37.43,36.32,33.36,30.09,25.18,23.93,23.90,19.02,18.65,18.54.
实施例6
取4-三氟甲基吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物，化合物I-6.收率66％,白色固体,m.p.90.2-91.5℃.1H NMR(400MHz,CDCl3)δ8.67(d,J＝6.3Hz,2H),7.45(d,J＝5.0Hz,1H),7.07(d,J＝8.2Hz,1H),6.89(d,J1＝8.1Hz,1H),6.79(s,1H),5.97(s,1H),3.40-3.35(m,1H),3.23-3.18(m,1H),2.87-2.68(m,3H),2.21(d,J＝12.9Hz,1H),1.85–1.56(m,4H),1.43–1.20(m,4H),1.14–1.11(m,9H),0.92(s,3H).13C NMR(100MHz,CDCl3)δ165.17,151.36,149.30,146.83,145.68,135.06(q,J＝33.3Hz),134.42,130.42,126.83,123.52,122.16(q,J＝272.9Hz),119.81(d,J＝4.39Hz),50.93,45.86,38.26,37.43,37.38,36.09,33.37,29.98,25.16,23.89,18.97,18.47,18.43.
实施例7
取1-甲基-3-二氟甲基吡唑-4-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-7.收率59％,白色固体,m.p.100-101.5℃.1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.16(d,J＝8.2Hz,1H),6.98(dd,J1＝8.1Hz,J2＝1.7Hz,1H),6.78(t,J＝54.2Hz,1H),6.45(s,1H),3.89(s,3H),3.41–3.27(m,2H),2.95–2.75(m,3H),2.28(d,J＝12.7Hz,1H),1.96-1.91(m,1H),1.79–1.68(m,3H),1.52-1.34(m,4H),1.21(d,J＝6.8Hz,9H),0.98(s,3H).13C NMR(100MHz,CDCl3)δ161.19,147.04,145.46,142.25(t,J＝28.7Hz),141.96,135.47,134.75,126.84,124.17,123.77,116.93,112.00(t,J＝231.3Hz),109.68,50.23,45.61,39.39,38.25,37.55,37.51,36.04,33.37,30.28,25.38,23.92,19.07,18.63,18.45.
实施例8
取2-甲氧基吡啶-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-8.收率70％,白色固体,m.p.83.5-84.5℃.1H NMR(400MHz,CDCl3)δ8.53(d,J＝7.4Hz,1H),8.27(d,J＝4.6Hz,1H),8.06(s,1H),7.20(d,J＝8.1Hz,1H),7.08-7.00(m,2H),6.91(s,1H),4.03(s,3H),3.49-3.37(m,2H),2.96-2.82(m,1H),2.91–2.79(m,2H),2.33(d,J＝12.8Hz,1H),2.03-1.98(m,1H),1.85-1.74(m,3H),1.58–1.53(m,2H),1.44-1.37(m,2H),1.27–1.23(m,9H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ163.74,160.40,149.17,147.11,145.55,141.56,134.67,126.79,124.18,123.78,117.77,116.20,54.00,50.16,45.52,38.41,37.55,37.46,36.32,33.35,30.30,25.21,23.90,19.00,18.73,18.67.
实施例9
取1,5-二甲基吡唑-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-9，收率68％,白色固体,m.p.131-133℃.1H NMR(400MHz,CDCl3)δ7.16(d,J＝8.2Hz,1H),6.98(dd,J1＝8.1Hz,J2＝1.5Hz,1H),6.89(d,J＝5.9Hz,2H),6.51(s,1H),3.75(s,3H),3.44-3.39(m,1H),3.22-3.19(m,1H),2.93–2.78(m,3H),2.28-2.25(m,4H),2.00-1.96(m,1H),1.79–1.68(m,3H),1.54-1.47(m,2H),1.42-1.34(m,2H),1.21(d,J＝6.6Hz,9H),0.98(s,3H).13C NMR(100MHz,CDCl3)δ145.44,135.00,126.87,124.25,123.72,106.05,49.24,45.22,38.24,37.70,37.52,36.40,36.20,33.36,30.42,25.45,23.90,18.99,18.81,18.65,11.17.
实施例10
取2-三氟甲基苯甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-10.收率82％；m.p.197-198.5℃；1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.4Hz,1H),7.57-7.49(m,3H),7.23(d,J＝12.1Hz,1H),7.05(d,J＝12.1Hz,1H),6.96(s,1H),6.04(s,1H),3.50-3.45(m,1H),3.34-3.29(m,1H),3.02-2.85(m,3H),2.36(d,J＝19.2Hz,1H),2.00-1.96(m,1H),1.88–1.70(m,3H),1.57-1.35(m,2H),1.28(d,J＝6.9Hz,9H),1.06(s,3H)；13C NMR(100MHz,CDCl3)δ168.00,146.91,145.52,136.06(q,J＝2.2Hz),134.51,131.92,129.58,128.51,127.48(d,J＝17.9Hz),127.07,126.77(d,J＝2.7Hz),126.18(q,J＝5.0Hz),124.85,123.49(t,J＝272.1Hz),124.05,123.77,50.68,45.80,38.21,37.39,37.27,35.95,33.31,31.49,30.04,25.19,23.88,23.84,22.55,18.89,18.46,18.38.
实施例11
取1-甲基-3-三氟甲基吡唑-4-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-11.收率69％,白色蜡状物.1HNMR(600MHz,CDCl3)δ7.92(s,1H),7.16(d,J＝8.2Hz,1H),6.98(dd,J1＝8.1Hz,J2＝1.7Hz,1H),6.88(d,J＝1.3Hz,1H),6.08(s,1H),3.94(s,3H),3.33(d,J＝6.3Hz,2H),2.93-2.89(m,1H),2.83–2.77(m,2H),2.29(d,J＝12.6Hz,1H),1.95-1.91(m,1H),1.79–1.66(m,3H),1.50-1.43(m,2H),1.38–1.27(m,2H),1.22(d,J＝7.1Hz,9H),0.98(s,3H).13C NMR(101MHz,CDCl3)δ160.49,146.93,145.52,137.67(q,J＝55Hz),135.62,134.61,126.83,124.14,123.80,122.38,120.92(q,J＝400Hz),50.38,45.75,39.66,38.23,37.48,37.47(d,J＝1.3Hz),36.07,33.36,30.22,26.86,25.31,23.90,19.06,18.56,18.36.
实施例12
取5-甲基异恶唑4-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-12.收率75％,白色固体,m.p.125-127℃.1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.16(d,J＝8.2Hz,1H),6.99(d,J＝7.8Hz,1H),6.89(s,1H),5.63(s,1H),3.39–3.24(m,2H),2.97-2.91(m,1H),2.85–2.76(m,2H),2.69(s,3H),2.31(d,J＝13.1Hz,1H),1.97-1.91(m,1H),1.82–1.76(m,2H),1.74-1.70(m,1H),1.47–1.40(m,2H),1.38–1.28(m,2H),1.22(d,J＝7.4Hz,8H),0.99(s,3H).13CNMR(150MHz,CDCl3)δ172.17,161.10,147.74,146.91,145.72,134.57,126.91,124.15,123.93,111.88,49.83,45.70,38.27,37.56,37.48,36.44,33.40,30.29,25.34,23.93,19.07,18.64,18.54,12.49.
实施例13
取4-甲基噻唑-5-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-13.收率80％,白色固体,m.p.120-121.5℃.1H NMR(600MHz,CDCl3)δ8.67(s,1H),7.16(d,J＝8.2Hz,1H),7.00–6.98(m,1H),6.89(s,1H),5.81(s,1H),3.41-3.31(m,2H),2.95-2.91(m,1H),2.85–2.78(m,2H),2.71(s,3H),2.31(d,J＝12.7Hz,1H),1.96-1.93(m,1H),1.80-1.71(m,3H),1.50–1.45(m,2H),1.33-1.28(m,2H),1.23–1.21(m,9H),1.00(s,3H).13C NMR(150MHz,CDCl3)δ161.78,155.17,154.91,152.23,146.88,145.68,134.59,126.92,124.19,123.90,50.57,45.89,38.31,37.58,37.53,36.48,33.39,30.36,26.89,25.37,23.93,19.10,18.63,18.58,17.27.
实施例14
取呋喃-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-14.收率81％,白色固体,m.p.129-130℃.1H NMR(600MHz,CDCl3)δ7.40(dd,J＝1.7,0.7Hz,1H),7.16(d,J＝8.2Hz,1H),7.08(dd,J1＝3.5Hz,J2＝0.7Hz,1H),6.99(dd,J1＝8.1Hz,J2＝1.7Hz,1H),6.89(s,1H),6.47(dd,J1＝3.5Hz,J2＝1.8Hz,1H),6.35(s,1H),3.44-3.40(m,1H),3.25-3.21(m,1H),2.94-2.90(m,1H),2.87-2.79(m,2H),2.28(d,J＝12.6Hz,1H),1.98-1.94(m,1H),1.80–1.66(m,3H),1.51–1.47(m,2H),1.41–1.33(m,2H),1.22–1.20(m,9H),0.99(s,3H).13CNMR(150MHz,CDCl3)δ158.42,147.98,147.06,145.62,143.66,134.83,126.94,124.21,123.86,114.12,112.13,49.25,45.27,38.25,37.65,37.52,36.20,33.39,30.34,25.42,23.93,19.01,18.84,18.61.
实施例15
取6-氯哒嗪-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-15.收率80％,白色固体,m.p.126-127℃.1H NMR(600MHz,CDCl3)δ8.26(d,J＝8.8Hz,1H),8.13(s,1H),7.66(d,J＝8.8Hz,1H),7.15(d,J＝8.2Hz,1H),6.97(dd,J1＝8.1Hz,J2＝1.7Hz,1H),6.87(d,J＝1.3Hz,1H),3.53(dd,J1＝13.6Hz,J2＝7.0Hz,1H),3.32(dd,J1＝13.7Hz,J2＝6.6Hz,1H),2.95–2.78(m,3H),2.28(d,J＝12.4Hz,1H),2.01–1.98(m,1H),1.80–1.77(m,2H),1.77–1.69(m,1H),1.51–1.48(m,2H),1.43-1.35(m,2H),1.23–1.20(m,9H),1.02(s,3H).13C NMR(150MHz,CDCl3)δ161.83,159.15,151.86,147.17,145.81,134.87,129.60,128.35,127.11,124.39,124.09,50.41,45.67,38.43,38.15,37.71,36.51,33.61,30.53,25.60,24.15,24.13,19.37,19.00,18.79.
实施例16
取香豆素-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-16.收率61％,白色固体,m.p.206-207℃.1H NMR(600MHz,CDCl3)δ8.98(t,J＝6.0Hz,1H),8.90(s,1H),7.70–7.63(m,2H),7.40-7.35(m,2H),7.16(d,J＝8.2Hz,1H),6.97(dd,J 1＝8.1Hz,J2＝1.7Hz,1H),6.88(s,1H),3.46(dd,J1＝13.6Hz,J2＝6.4Hz,1H),3.34(dd,J 1＝13.6,J2＝6.5Hz,1H),2.94–2.85(m,2H),2.82-2.87(m,1H),1,99-1,96(m,1H),1.82–1.67(m,3H),1.56–1.51(m,2H),1.42-1.36(m,2H),1.29–1.09(m,9H),1.01(s,3H).13C NMR(150MHz,CDCl3)δ161.61,154.38,148.30,147.10,145.49,134.85,133.96,129.75,126.94,125.25,124.30,123.86,118.70,118.57,116.63,50.45,45.65,38.32,37.84,37.59,36.39,33.42,30.47,25.49,23.98,23.95,19.18,18.79,18.71.
实施例17
取1,3-二甲基-5-吡唑甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-17.收率70％,白色固体,m.p.179-180.2℃.1H NMR(600MHz,CDCl3)δ7.17(d,J＝8.2Hz,1H),7.00(dd,J 1＝8.1Hz,J2＝1.5Hz,1H),6.89(s,1H),6.21(s,1H),5.92(s,1H),4.09(s,3H),3.35(dd,J 1＝13.7Hz,J2＝6.5Hz,1H),3.26(dd,J1＝13.7Hz,J2＝6.7Hz,1H),2.93(dd,J1＝17.1Hz,J2＝6.2Hz,1H),2.86–2.75(m,2H),2.31–2.27(m,2H),2.25(s,3H),2.04(s,1H),1.95-1.91(m,1H),1.80–1.73(m,2H),1.70–1.67(m,1H),1.49–1.43(m,2H),1.38–1.35(m,1H),1.23–1.21(m,9H),0.99(s,3H).13C NMR(150MHz,CDCl3)δ160.20,146.98,146.70,145.70,136.02,134.62,126.94,124.23,123.95,105.33,49.75,45.74,38.76,38.32,37.69,36.41,33.43,30.39,25.42,23.98,19.12,18.72,18.61,13.25.
实施例18
取2,2-二氟苯并[d][1,3]二氧代-5-羧酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-18.收率79％,白色固体,m.p.157-158℃.1HNMR(600MHz,CDCl3)δ7.50(d,J＝1.6Hz,3H),7.44(dd,J 1＝8.3Hz,J2＝1.6Hz,1H),7.16(d,J＝8.2Hz,1H),7.07(d,J＝8.3Hz,1H),6.99–6.98(m,1H),6.88(s,1H),6.00(s,3H),3.92(s,1H),3.43(dd,J1＝13.7Hz,J2＝6.4Hz,1H),3.30(d,J1＝13.7Hz,J2＝6.5Hz,1H),2.95-2.90(m,1H),2.83–2.77(m,2H),2.30(d,J＝12.7Hz,3H),2.04-1.94(m,1H),1.81–1.74(m,2H),1.70–1.66(m,1H),1.52–1.45(m,2H),1.41-1.31(m,2H),1.23–1.21(m,9H),1.00(s,3H).13C NMR(150MHz,CDCl3)δ165.94,146.97,145.78(d,J＝17.4Hz),144.00,134.67,131.32,126.98,124.22,123.96,122.62,109.07(d,J＝40.5Hz),108.93,50.49,45.80,38.39,37.71,37.48,36.47(s),33.36,30.38,25.42,23.97,19.13,18.82,18.62.
实施例19
取2-甲基4-三氟甲基噻唑-5-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-19.收率65％,白色蜡状物.1H NMR(600MHz,CDCl3)δ7.16(d,J＝8.2Hz,1H),6.99(d,J＝8.1Hz,1H),6.88(s,1H),6.20(s,1H),3.39-3.29(m,2H),2.94-2.90(m,1H),2.84-2.78(m,2H),2.70(s,3H),2.30(d,J＝12.8Hz,1H),1.91-1.86(m,1H),1.80-1.73(m,2H),1.71–1.67(m,1H),1.51–1.49(m,1H),1.42(s,2H),1.39-1.35(m,2H),1.23-1.21(m,9H),0.99(s,3H).13C NMR(150MHz,CDCl3)δ167.98,158.85,146.75,145.63,140.10,139.15(J＝39Hz),139.62,139.38,136.07,134.47,126.84,124.12,123.88,120.29(J＝270.4Hz),51.22,45.90,38.22,37.35,36.11,33.30,30.15,26.87,25.25,23.90,19.10,19.05,18.51,18.39.
实施例20
取苯并噻吩-2-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-20.收率70％,白色固体,m.p.197-198.8℃.1H NMR(600MHz,CDCl3)δ7.83–7.81(m,2H),7.73(s,1H),7.42-7.37(m,2H),7.17(d,J＝8.2Hz,1H),6.99(dd,J1＝8.1Hz,J2＝1.1Hz,1H),6.89(s,1H),6.10(s,1H),3.44(dd,J1＝13.7Hz,J2＝6.4Hz,1H),3.35(dd,J1＝13.7Hz,J2＝6.6Hz,1H),2.96-2.92(m,1H),2.88–2.79(m,2H),2.31(d,J＝12.8Hz,1H),1.99-1.95(m,1H),1.84–1.74(m,2H),1.72–1.68(m,1H),1.55–1.49(m,2H),1.42-1.35(m,2H),1.24–1.21(m,9H),1.02(s,3H).13CNMR(150MHz,CDCl3)δ162.33,146.95,145.64,140.68,139.06,138.48,134.71,126.95,126.26,124.97,124.90,124.21,123.89,122.65,50.43,45.84,38.31,37.74,37.57,36.40,33.39,30.42,25.42,23.94,23.92,19.10,18.74,18.62.
实施例21
取2-甲基-5-噻唑甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-21.收率83％,白色固体,m.p.145-146℃.1H NMR(600MHz,CDCl3)δ7.95(s,1H),7.16(d,J＝8.2Hz,1H),6.98(d,J＝8.1Hz,1H),6.88(s,1H),6.08(s,1H),3.39(dd,J 1＝13.7Hz,J2＝6.6Hz,1H),3.26(dd,J 1＝13.7Hz,J2＝6.5Hz,1H),2.93-2.89(m,1H),2.84–2.78(m,2H),2.69(s,3H),2.29(d,J＝12.7Hz,1H),1.95-1.91(m,1H),1.77-1.72(m,2H),1.71–1.66(m,1H),1.49–1.44(m,2H),1.39-1.37(m,1H),1.35-1.32(m,1H),1.21(d,J＝7.0Hz,9H),0.98(s,3H).13C NMR(150MHz,CDCl3)δ162.46,159.09,157.61,156.08,146.87,145.49,134.63,126.82,124.13,123.79,118.45,49.89,45.31,38.11,37.78,37.44,36.16,33.28,30.29,26.79,25.37,23.84,19.02,18.77,18.52.
实施例22
取嘧啶-2-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-22，收率66％,白色固体,m.p.198-199.5℃.1H NMR(600MHz,CDCl3)9.19(s,1H),8.93(d,J＝5.0Hz,1H),8.21–8.05(m,2H),7.16(d,J＝8.2Hz,1H),6.98(d,J＝8.1Hz,1H),6.89(s,1H),3.51(dd,J1＝13.6Hz,J2＝7.0Hz,1H),3.28(dd,J1＝13.7Hz,J2＝6.6Hz,1H),2.95-2.91(m,1H),2.87–2.78(m,2H),2.29(d,J＝12.8Hz,1H),2.02–1.98(m,1H),1.81–1.76(m,2H),1.71–1.67(m,1H),1.55-1.50(m,2H),1.43-1.39(m,2H),1.26–1.18(m,9H),1.02(s,3H).13C NMR(150MHz,CDCl3)δ169.94,160.56,146.92,145.65,142.30,134.65,134.28,126.92,124.16,123.88,50.30,45.68,38.26,37.72,37.50,36.38,33.38,30.33,25.37,23.93,23.92,19.50,19.07,18.67,18.56.
实施例23
取5-甲基吲哚-2-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-23.收率52％,白色固体.m.p.258-260.1℃.1H NMR(600MHz,CDCl3)δ9.03(s,1H),7.39(s,1H),7.30(d,J＝8.5Hz,1H),7.16(d,J＝8.2Hz,1H),7.11–7.09(m,1H),6.98(dd,J 1＝8.1Hz,J2＝1.4Hz,1H),6.88(s,1H),6.69(d,J＝1.1Hz,1H),6.12(s,1H),3.42(dd,J1＝13.7Hz,J2＝6.4Hz,1H),3.35(dd,J 1＝13.7Hz,J2＝6.7Hz,1H),2.94-2.91(m,1H),2.87–2.78(m,2H),2.42(s,3H),2.30(d,J＝13.0Hz,1H),1.99-1.96(m,1H),1.81–1.74(m,2H),1.71-1.68(s,1H),1.52-1.49(m,2H),1.42-1.34(m,2H),1.23–1.20(m,9H),1.01(s,3H).13C NMR(150MHz,CDCl3)δ161.76,146.97,145.63,134.65,134.62,130.70,129.92,127.86,126.92,126.35,124.21,123.89,121.13,111.57,101.04,49.99,45.82,38.31,37.76,37.55,36.37,33.40,30.39,25.40,23.94,23.93,21.43,19.13,18.70,18.62.
实施例24
取咔唑-3-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-24.收率67％,白色固体.m.p.221-223℃.1H NMR(600MHz,CDCl3)δ8.41(d,J＝8.2Hz,1H),7.50(d,J＝8.4Hz,1H),7.42(d,J＝9.2Hz,1H),7.30–7.27(m,1H),7.16(dd,J1＝11.4Hz,J2＝7.4Hz,2H),6.98(d,J＝8.1Hz,1H),6.88(s,1H),3.48(dd,J1＝13.7Hz,J2＝6.6Hz,1H),3.37(dd,J1＝13.7Hz,J2＝6.8Hz,1H),2.95–2.78(m,3H),2.28(d,J＝12.7Hz,1H),2.04-2.00(m,1H),1.81–1.74(m,2H),1.71–1.66(m,1H),1.59–1.54(m,2H),1.47–1.37(m,2H),1.24–1.19(m,9H),1.03(s,3H).13C NMR(150MHz,CDCl3)δ162.93,147.14,145.59,141.43,139.24,134.90,127.26,126.95,124.31,123.87,122.77,122.64,121.93,109.94,49.45,45.58,38.32,37.79,37.60,36.33(s),33.42,30.46,25.50,23.98,23.95,19.12,18.84,18.70.
实施例25
取喹喔啉-2-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-25.收率82％,白色固体.m.p.123-125℃.1H NMR(600MHz,CDCl3)δ9.67(s,1H),8.19–8.17(m,1H),8.11–8.08(m,2H),7.87-7.81(m,2H),7.16(d,J＝8.2Hz,1H),6.97(d,J＝8.1Hz,1H),6.89(s,1H),3.56(dd,J1＝13.7Hz,J2＝7.0Hz,1H),3.37(dd,J1＝13.7Hz,J2＝6.7Hz,1H),2.98-2.94(m,1H),2.92–2.85(m,1H),2.82-2.78(m,1H),2.30(d,J＝12.8Hz,1H),2.08-2.04(m,1H),1.86–1.77(m,2H),1.74–1.71(m,1H),1.61–1.55(m,2H),1.49-1.37(m,2H),1.25(s,3H),1.20(d,J＝6.9Hz,6H),1.06(s,3H).13C NMR(150MHz,CDCl3)δ168.16,156.86,146.96,145.49,134.58,129.67,126.81,124.17,123.72,122.00,114.39,77.00,67.10,49.07,44.89,38.08,37.47,37.29,36.05,33.40,30.23,25.26,23.97,23.96,23.95,18.92,18.64,18.47.
实施例26
取苯并噻唑-2-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-26.收率93％,白色固体,m.p.185-186℃.1H NMR(600MHz,CDCl3)δ8.06(d,J＝8.1Hz,1H),7.95(d,J＝7.8Hz,1H),7.55–7.46(m,3H),7.17(d,J＝8.2Hz,1H),7.03–6.97(m,1H),6.89(s,1H),3.51(dd,J1＝13.7Hz,J2＝7.0Hz,1H),3.32(dd,J1＝13.7Hz,J2＝6.7Hz,1H),2.96–2.78(m,3H),2.30(d,J＝12.6Hz,1H),2.02-1.98(m,1H),1.82-1.75(m,2H),1.73–1.69(m,1H),1.59–1.54(m,2H),1.47-1.39(m,2H),1.24–1.20(m,9H),1.04(s,3H).13C NMR(150MHz,CDCl3)δ163.98,160.01,152.81,146.98,145.62,137.15,134.78,126.93,126.71,126.59,124.29,124.23,123.87,122.34,50.31,45.51,38.22,37.90,37.57,36.30,33.39,30.37,25.45,23.93,23.91,19.12,18.79,18.61.
实施例27
取4-[5-(三氟甲基)-1,2,4-噁二唑-3-基]苯甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-27.收率90％,白色固体,m.p.183-184.5℃.1HNMR(600MHz,CDCl3)δ8.17(d,J＝8.5Hz,2H),7.87(d,J＝8.5Hz,2H),7.17(d,J＝8.2Hz,1H),6.99(d,J＝8.1Hz,1H),6.89(s,1H),6.17(s,1H),3.47(dd,J 1＝13.7Hz,J2＝6.4Hz,1H),3.37(dd,J 1＝13.7Hz,J2＝6.5Hz,1H),2.97-2.92(m,1H),2.86–2.79(m,2H),2.32(d,J＝14.7Hz,1H),2.00-1.97(m,1H),1.83–1.75(m,2H),1.73-1.69(m,1H),1.58-1.55(m,1H),1.53-1.49(m,1H),1.43-1.35(m,2H),1.25–1.21(m,9H),1.03(s,3H).13C NMR(150MHz,CDCl3)δ168.48,166.55,146.97,145.74,141.04,138.25,134.68,128.02,127.56(t,J＝32.3Hz),127.34,127.01(d,J＝8.6Hz),125.82,124.98,124.23,123.97,123.07,120.85(q,J＝233.5Hz),50.58,45.85,38.35,37.76,36.49,33.42,30.41,25.39,19.14,18.84,18.63.
实施例28
取2-苯基-4-噻唑甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-28.收率32.7％,白色蜡状物.1H NMR(600MHz,CDCl3)δ8.05(s,1H),7.92–7.90(m,2H),7.57(t,J＝6.6Hz,1H),7.45–7.43(m,3H),7.16(d,J＝8.2Hz,1H),6.97(dd,J1＝8.1Hz,J2＝1.5Hz,1H),6.89(s,1H),3.46(dd,J1＝13.6Hz,J2＝6.9Hz,1H),3.32(dd,J1＝13.7Hz,J2＝6.8Hz,1H),2.97–2.86(m,2H),2.83-2.78(m,1H),2.28(d,J＝12.6Hz,1H),2.05-2.02(m,1H),1.81-1.74(m,2H),1.72–1.69(m,1H),1.57–1.55(m,2H),1.44–1.41(m,2H),1.24(s,3H),1.20(d,J＝6.9Hz,6H),1.02(s,3H).13C NMR(150MHz,CDCl3)δ167.99(s),161.14(s),150.88,147.08,145.50,134.82,132.80,130.52,128.96,126.88,126.60,124.24,123.80,122.72,49.87,45.58,38.29,37.84,37.53,36.32,33.37,30.49,26.87,25.42,23.92,19.12,18.69,18.66.
实施例29
取5-苯基-3-异噁唑甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-29.收率90％,白色固体,m.p.240-242.5℃.1H NMR(600MHz,CDCl3)δ7.79–7.77(m,2H),7.49–7.45(m,3H),7.16(d,J＝8.2Hz,1H),6.98(dd,J1＝8.2Hz,J2＝1.5Hz,1H),6.94(s,1H),6.88-6.86(m,2H),3.45(dd,J1＝13.7Hz,J2＝6.8Hz,1H),3.30(dd,J1＝13.7Hz,J2＝6.7Hz,1H),2.95-2.91(m,1H),2.88–2.78(m,2H),2.29(d,J＝12.7Hz,1H),1.99-1.95(m,1H),1.82–1.74(m,2H),1.72-1.68(m,1H),1.54–1.50(m,2H),1.42-1.35(m,2H),1.26–1.17(m,9H),1.01(s,3H).13C NMR(150MHz,CDCl3)δ171.62,159.11(d,J＝10.1Hz),146.99,145.64,134.72,130.68,129.12,126.88(d,J＝14.2Hz),125.93(s),124.24,123.90,99.23,49.92,45.58,38.27,37.79,37.56,36.29,33.36,30.36,25.42,23.96,19.15,18.73,18.61.
实施例30
取4-(1-H-吡唑基)苯甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-30.收率85％,白色固体,m.p.233-235℃,1H NMR(600MHz,CDCl3)δ7.97(d,J＝2.4Hz,1H),7.85–7.83(m,2H),7.78–7.75(m,3H),7.17(d,J＝8.2Hz,1H),6.99(dd,J1＝8.1Hz,J2＝1.7Hz,1H),6.89(s,1H),6.50(dd,J1＝2.4Hz,J2＝1.9Hz,1H),6.12(s,1H),3.46–3.43(m,1H),3.37(dd,J1＝13.7Hz,J2＝6.6Hz,1H),2.96-2.92(m,1H),2.87-2.79(m,2H),2.31(d,J＝12.7Hz,1H),2.01-1.97(m,1H),1.82-1.76(m,2H),1.74–1.69(m,1H),1.53–1.50(m,2H),1.42–1.35(m,2H),1.24–1.20(m,8H),1.03(s,3H).13C NMR(150MHz,CDCl3)δ166.66,146.99,145.65,142.21,141.71,134.70,132.42,128.30,126.94,126.78(s),124.20,123.89,118.63,108.26,50.40,45.85,38.33,37.69,37.55,36.43,33.38,30.40,25.41,23.93,23.91,19.09,18.77,18.62.
实施例31
取3-苯基吡唑-5-甲酸(1.20mmol)和脱氢枞胺(1.0mmol)于单口瓶中，加入二氯甲烷(10mL)溶解，搅拌下加入催化剂4-二甲氨基吡啶(0.20mmol)和缩合剂EDCI(1.20mmol)，加毕，25℃反应6～10h，TLC检测，反应完毕，饱和碳酸氢钠溶液洗涤有机层，以水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化(洗脱剂二氯甲烷)并干燥得目标化合物I-31.收率89％,白色固体m.p.180-181.5℃,1H NMR(600MHz,CDCl3)δ7.61(d,J＝7.9Hz,2H),7.44-7.41(m,2H),7.38-7.36(m,1H),7.16(d,J＝8.2Hz,1H),7.04(s,1H),6.97(d,J＝8.1Hz,2H),6.87(s,1H),3.44(dd,J1＝13.7Hz,J2＝6.7Hz,1H),3.30(dd,J1＝13.7Hz,J2＝6.6Hz,1H),2.92–2.78(m,3H),2.27(d,J＝12.8Hz,1H),1.99-1.96(m,1H),1.78-1.70(m,2H),1.67-1.65(m,1H),1.53–1.50(m,2H),1.41–1.37(m,2H),1.22–1.19(m,9H),1.00(s,3H).13C NMR(150MHz,CDCl3)δ161.83,147.07,145.54,134.82,129.08,128.84,126.90,125.62,124.22,123.80,103.20,77.00,49.73,45.55,38.24,37.74,37.52,36.24,33.38,30.37,25.42,23.93,23.92,19.06,18.69,18.62.
实施例32
对目标化合物的合成反应条件，即催化剂和缩合剂种类进行了探讨，以I-10的合成为例，取原料2-三氟甲基苯甲酸和脱氢枞胺于单口瓶中，加入二氯甲烷溶解，搅拌下加入催化剂和缩合剂，加毕，25℃反应，TLC检测。
表1缩合反应条件探讨
探讨了三种反应条件，EDCI/DMAP作为实验条件，反应情况最好，收率较高；其余两种反应情况一般，且有新杂质生成。
实施例33
杀菌活性(离体)实验
本实验中所用的植物真菌为实验室4℃保存的菌种，为水稻纹枯病菌(ACCC38870)、番茄灰霉病菌(ACCC 36027)、黄瓜枯萎病菌(ACCC 37985)、油菜菌核病菌(ACCC30096)、番茄早疫病菌(ACCC 36110)和小麦赤霉病菌(ACCC31060)，菌种均从中国农业微生物菌种保藏管理中心(ACCC)购买。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30分钟，冷却后备用。
实验方法：采用生长速率法。
(1)先将6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250μL的10g/L浓度的待测化合物I制成含50mg/L药液的培养基，并分别倒入培养皿中冷却，啶酰菌胺(boscalid)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；
(5)抑制率(％)＝(对照菌丝直径-处理菌丝直径)/(对照菌丝直径-0.5)×100；
(6)每个处理重复3次。
表2含杂环的脱氢枞基甲酰胺化合物对六种农业致病真菌的抑制活性试验结果
a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
表3部分化合物的EC50值(mg/L)
实验组I-1-I-31以及对照药剂啶酰菌胺的杀菌活性测定结果见表2和表3。由表2和表3的结果可见，50mg/L浓度时，化合物I-1-I-31对6种植物真菌显示出不同程度的抑菌活性，部分化合物对油菜菌核病菌和番茄灰霉病菌有较好的防治效果，个别化合物对番茄早疫病菌，小麦赤霉病菌和水稻纹枯病显示一定的抑菌活性。
鉴于部分目标化合物对几种植物真菌具有较好的抑制活性，测试了部分抑制率较高的化合物的EC50值。从表3可以看出，化合物I-11对番茄灰霉病菌的EC50值优于啶酰菌胺的EC50值；部分化合物如I-28和I-30对油菜菌核病菌的EC50介于0.05-0.5mg/L之间，与啶酰菌胺的EC50值相当。此外，化合物I-28和I-11对番茄早疫病菌的EC50低于啶酰菌胺，该系列化合物具有开发抗真菌剂的潜力。
实施例34
琥珀酸脱氢酶活性测试
油菜菌核菌(ACCC 30096)是从中国农业科学院微生物菌种保藏管理中心购买，其SDH酶的提取：培养物接种量为0.05OD 600nm，在摇床(180rpm,25℃)上培养7天。通过真空过滤收取细胞，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,0.2mMEDTA二乙胺四乙酸,2mM PMSF苯甲基磺酰氟)提取物离心:提取物离心澄清(5000g,4℃,10min,2次),取上清液.上清液10000g离心20分钟，弃上清液，沉淀即为线粒体颗粒.重新悬浮在相同的缓冲液中.线粒体悬浮液的浓度为10mg/mL，储存在-80℃保存至使用。
ubiquinone/DCPIP活性抑制测定为，在200μL的含140μM二氯苯酚(DCPIP)和1mM2,3-二甲氧基-5-甲基-1,4-苯醌(Q0)的检测缓冲液(100ml)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,3mM NaN3,10mM succinate琥珀酸),先加入苯琨和二氯苯酚(DCPIP)，然后于96孔板上先加入药液，后加入缓冲液，药剂浓度范围为4.4uM-150uM,5×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(酶)进行反应。DCPIP抑制在30℃下595nm处监测。半抑制浓度(IC 50)用数据处理系统(IBM SPSS 25.0)计算吸光度斜率(OD/h)。
表4部分化合物的琥珀酸脱氢酶活性
化合物I-28和I-30对琥珀酸脱氢酶有一定抑制活性，化合物作用于此靶点。
实施例35
杀菌活体实验
于市面购买质地和大小均匀，光滑的西红柿果实，以灭菌水洗涤后，再以75％乙醇洗涤，室温阴干。称取适量化合物I-11，I-28,I-30和boscalid，以0.2％Tween-80水溶液溶解配置成200mg/L，100mg/L两个浓度。然后对每个西红柿果实表面进行喷雾(喷雾量为5mL，1个浓度),喷雾均匀，后自然阴干。待果实表面无液体后，以接种针刺穿果皮，接番茄灰霉菌饼(0.5cm直径)，每个果实接种三个菌饼，阳性对照为啶酰菌胺，空白对照为DMSO。设置组内平行和组外平行。两个平行组置于(25±2℃和95％相对湿度)培养4天。测量病斑直径并计算抑制率。保护活性抑制率(％)的计算公式：(空白对照病斑直径-测试化合物的病斑直径)/空白对照病斑直径-0.5)×100。
表5化合物I-11,I-28,I-30对番茄灰霉活体生物活性
a注:试验中每个处理设九次重复
在200mg/L浓度下，化合物I-11对番茄灰霉菌的抑制率为85.76％，接近啶酰菌胺对番茄灰霉菌的抑制率(85.20％)；进一步降低浓度为100mg/L时，化合物对番茄灰霉的抑制率为66.35％，高于啶酰菌胺；I-28对番茄灰霉菌的抑制率为88.38％，略高于啶酰菌胺；I-30在两种浓度下对番茄灰霉菌的抑制率一般。
本发明所述含杂环的脱氢枞基甲酰胺类化合物，相比以往酰胺类杀菌剂，胺部分为天然产物脱氢枞胺基，结构区别明显，化学结构特征鲜明，对于防治番茄灰霉病和油菜菌核病显示出较好的效果，对于番茄早疫病，水稻纹枯病和小麦赤霉病显示一定的治疗效果。
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 (15)

1.一类含杂环的脱氢枞基甲酰胺类化合物，其特征在于：该类化合物名称为含杂环的脱氢枞基甲酰胺，结构式为：
其中，Het基团为
中的一种。
2.如权利要求1所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：包括，
将脱氢枞胺与含杂环羧酸在催化剂、缩合剂和有机溶剂条件下，一步反应合成含杂环的脱氢枞基甲酰胺。
3.如权利要求2所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：所述催化剂为4-二甲氨基吡啶。
4.如权利要求2所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：所述缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐。
5.如权利要求2所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：所述有机溶剂为二氯甲烷。
6.如权利要求2所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：脱氢枞胺、催化剂和缩合剂的摩尔比为1:0.2:1.2。
7.如权利要求2所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：所述一步反应合成含杂环的脱氢枞基甲酰胺，其中，反应温度为室温，反应时间为6～10h。
8.如权利要求5所述含杂环的脱氢枞基甲酰胺类化合物的制备方法，其特征在于：还包括，
反应6～10h后TLC检测反应完毕，饱和碳酸氢钠溶液洗涤有机层三次，水洗涤三次，饱和食盐水洗涤三次，无水硫酸钠干燥，抽滤，减压浓缩除去二氯甲烷得粗品，硅胶柱色谱法纯化并干燥得目标化合物。
9.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的番茄早疫病菌的应用，其特征在于：所述含杂环的脱氢枞基甲酰胺化合物为如下所示结构式中的一种：
10.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为水稻纹枯病菌、油菜菌核病菌、小麦赤霉病菌和番茄早疫病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
11.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为水稻纹枯病菌、番茄灰霉病菌、油菜菌核病菌、小麦赤霉病菌和番茄早疫病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
12.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为番茄灰霉病菌、油菜菌核病菌、小麦赤霉病菌和番茄早疫病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
13.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为番茄灰霉病菌和番茄早疫病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
14.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为番茄灰霉病菌和小麦赤霉病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
15.含杂环的脱氢枞基甲酰胺化合物在防治农业或林业的植物真菌的应用，其特征在于：所述植物真菌为油菜菌核病菌、番茄早疫病菌和小麦赤霉病菌；
所述含杂环的脱氢枞基甲酰胺化合物结构式如下所示：
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