技术领域technical field
本发明属于有机化合物合成技术领域，特别涉及一类双氰基酰胺化合物及其合成方法与应用。The invention belongs to the technical field of organic compound synthesis, and in particular relates to a class of dicyanoamide compounds and a synthesis method and application thereof.
背景技术Background technique
氰基化是有机合成中常见并具有重要实用价值的转变之一，作为一个重要的官能团和生物活性基团，氰基在新农药创制领域受到相当重视。如：杀虫剂锐劲特和溴虫腈，除草剂氰氟草酯，杀菌剂噻唑菌胺、氰菌胺和嘧菌酯等都已在农业领域发挥了重要作用。对新型氰基衍生物的研究，有望获得性能更为优异的具有杀虫、杀螨、杀菌或除草活性的农药先导结构。Cyanolation is one of the common transformations in organic synthesis and has important practical value. As an important functional group and biologically active group, cyano group has received considerable attention in the field of new pesticide creation. For example, the insecticides fipronil and chlorfenapyr, the herbicide cyhalofop-ethyl, and the fungicides ethaboxam, cyanoxanil and azoxystrobin have all played an important role in the agricultural field. The research on new cyano derivatives is expected to obtain lead structures of pesticides with better performance in insecticidal, acaricidal, bactericidal or herbicidal activities.
植物真菌病害约占植物总病害的70-80%，而稻瘟病是目前世界上对水稻产量影响最严重的一种病害，这种病原菌附着胞的黑色素为致病侵染过程中所必需的细胞结构，抑制病原菌黑色素的生物合成是控制该病害的一种有效途径。小柱胞酮脱水酶抑制剂能够通过抑制真菌的黑色素生物合成阻断真菌对作物的侵染，该类农药的代表品种为：三环唑、环丙酰菌胺、氰菌胺等。Plant fungal diseases account for about 70-80% of the total plant diseases, and rice blast is currently the most serious disease affecting rice production in the world. The melanin of the appressorium of this pathogen is a necessary cell for the pathogenic infection process Structure, inhibiting the biosynthesis of melanin in pathogenic bacteria is an effective way to control the disease. Cytoketone dehydratase inhibitors can block fungal infection of crops by inhibiting fungal melanin biosynthesis. Representative varieties of this type of pesticides are: tricyclazole, cyproamid, cyanaprodil, etc.
各类虫害的发生每年都给农业生产造成巨额损失，因此，寻找具有结构新、活性高和选择性好的新型杀虫剂先导结构一直是农药研究领域的重要内容。The occurrence of various insect pests causes huge losses to agricultural production every year. Therefore, searching for new lead structures of insecticides with new structures, high activity and good selectivity has always been an important content in the field of pesticide research.
发明内容Contents of the invention
本发明的目的是提供一类双氰基酰胺化合物。The object of the present invention is to provide a class of dicyanoamide compounds.
本发明的另一个目的是提供一类双氰基酰胺化合物的制备方法。Another object of the present invention is to provide a kind of preparation method of dicyanoamide compound.
本发明还有一个目的是提供一类双氰基酰胺化合物在农业病虫害防治中的应用。Another object of the present invention is to provide the application of a class of dicyanoamide compounds in the control of agricultural diseases and insect pests.
一类双氰基酰胺化合物，其特征在于，所述的化合物具有通式Ⅰ所示的结构：A class of dicyanoamide compounds, characterized in that the compound has a structure shown in general formula I:
其中，in,
R1为烷基、卤代烷基、烷氧基、羟基、氨基、硝基和卤素中的任一种；优选为烷基、烷氧基和卤素中的任一种；Ris any one of alkyl, haloalkyl, alkoxy, hydroxyl, amino, nitro and halogen; preferably any of alkyl, alkoxy and halogen;
R2为H或CH3；R2 is H or CH3 ;
R3-R6为H、F、Cl、Br、I、C1-C3的烷基中的任一种；优选为H；R3 -R6 is any one of H, F, Cl, Br, I, C1 -C3 alkyl; preferably H;
所述的一类双氰基酰胺化合物优选为下述化合物中的任意一种：Described a class of dicyanoamide compounds are preferably any one of the following compounds:
1-氰基-N-(1-氰基-1-(4-氟苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-氯苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-苯基甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-甲氧基苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-甲基苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-叔丁基苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-溴苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(3-氯苯基)甲基)环丙烷甲酰胺、1-氰基-N- (1-氰基-1-(3,4-亚甲基二氧苯基)甲基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-甲基苯基)乙基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-苯基乙基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-甲氧基苯基)乙基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-氯苯基)乙基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(3-氟苯基)乙基)环丙烷甲酰胺、1-氰基-N-(1-氰基-1-(4-溴苯基)乙基)环丙烷甲酰胺。1-cyano-N-(1-cyano-1-(4-fluorophenyl)methyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-chlorobenzene base) methyl) cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-phenylmethyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1- (4-methoxyphenyl)methyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-methylphenyl)methyl)cyclopropanecarboxamide, 1- Cyano-N-(1-cyano-1-(4-tert-butylphenyl)methyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-bromobenzene Base) methyl) cyclopropane carboxamide, 1-cyano-N-(1-cyano-1-(3-chlorophenyl) methyl) cyclopropane carboxamide, 1-cyano-N-(1- Cyano-1-(3,4-methylenedioxyphenyl)methyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-methylphenyl)ethyl base) cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-phenylethyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4- Methoxyphenyl)ethyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-chlorophenyl)ethyl)cyclopropanecarboxamide, 1-cyano-N -(1-cyano-1-(3-fluorophenyl)ethyl)cyclopropanecarboxamide, 1-cyano-N-(1-cyano-1-(4-bromophenyl)ethyl)cyclo propane formamide.
一类双氰基酰胺化合物的制备方法，包括如下步骤：A kind of preparation method of dicyanoamide compound, comprises the steps:
（1）使用氰基乙酸乙酯和通式Ⅱ所示的化合物为原料，在缚酸剂、相转移催化剂存在的条件下，常温反应8~16小时，合环得到通式Ⅲ所示的化合物：(1) Using ethyl cyanoacetate and the compound represented by the general formula II as raw materials, in the presence of an acid-binding agent and a phase transfer catalyst, react at room temperature for 8 to 16 hours, and obtain the compound represented by the general formula III by ring closure :
其中，in,
所述的缚酸剂为：碳酸钾、碳酸钠；Described acid-binding agent is: potassium carbonate, sodium carbonate;
所述的相转移催化剂为：1-丁基-3-甲基咪唑六氟磷酸盐或PEG 400（聚乙二醇400）；The phase transfer catalyst is: 1-butyl-3-methylimidazolium hexafluorophosphate or PEG 400 (polyethylene glycol 400);
（2）在醇的碱溶液中，使通式Ⅲ所示的化合物在0~5℃下水解，得到通式Ⅳ所示的化合物；(2) In an alkaline solution of alcohol, the compound represented by the general formula III is hydrolyzed at 0-5°C to obtain the compound represented by the general formula IV;
所述的碱为：氢氧化钠、氢氧化钾或氢氧化锂；Described alkali is: sodium hydroxide, potassium hydroxide or lithium hydroxide;
（3）使用通式Ⅴ所示的化合物为原料，通过使用TMSCN（三甲基硅氰）和NH3在无水乙腈中进行氰氨基化，得到通式Ⅵ所示的化合物；(3) Using the compound represented by the general formula V as a raw material, the compound represented by the general formula VI is obtained by using TMSCN (trimethylsilyl cyanide) andNH3 in anhydrous acetonitrile to carry out cyanamide;
ⅤⅥⅤⅥ
（4）使用通式Ⅶ所示的化合物为原料，通过与氰化钠在氨的水溶液中反应，得到通式Ⅷ所示的化合物；(4) using the compound shown in the general formula VII as a raw material, and reacting with sodium cyanide in an aqueous ammonia solution to obtain the compound shown in the general formula VIII;
（5）将通式Ⅵ或通式Ⅷ所示的化合物和通式Ⅳ所示的化合物在二氯甲烷、DCC（二环己基碳二亚胺）和DMAP（4-二甲氨基吡啶）存在的条件下进行缩合，得到通式Ⅰ所示的化合物。(5) The compound represented by general formula VI or general formula VIII and the compound represented by general formula IV in the presence of dichloromethane, DCC (dicyclohexylcarbodiimide) and DMAP (4-dimethylaminopyridine) The condensation is carried out under the conditions to obtain the compound represented by the general formula I.
一类双氰基酰胺化合物（通式Ⅰ所示的化合物）在农业病虫害防治中的应用：用于防治稻瘟菌、腐霉菌、粘虫和蚊幼虫。Application of a class of dicyanoamide compounds (compounds represented by general formula I) in the control of agricultural diseases and insect pests: used to control blast fungus, pythium, armyworm and mosquito larvae.
本发明的有益效果为：The beneficial effects of the present invention are:
本发明提出了一类全新结构的双氰基酰胺化合物，经过初步生物活性评价，一些化合物的杀菌活性在抑制稻瘟菌方面超过三环唑，接近多菌灵；在杀虫活性方面，一些化合物能杀死粘虫和蚊幼虫；因此具有较好的杀菌活性和杀虫活性。本发明提供的合成方法合理易行，化合物结构新颖、修饰改造余地大，可做为农药活性先导进行深入研究，而且可能作为农用杀菌剂予以使用，具有很高的生产应用价值。The present invention proposes a class of dicyanoamide compounds with a new structure. After preliminary biological activity evaluation, the bactericidal activity of some compounds exceeds tricyclazole and is close to carbendazim in inhibiting blast fungus; in terms of insecticidal activity, some compounds have It can kill armyworm and mosquito larvae; therefore, it has good bactericidal and insecticidal activity. The synthesis method provided by the invention is reasonable and easy, the compound structure is novel, and there is a large room for modification and transformation. It can be used as a pesticide activity leader for in-depth research, and may be used as an agricultural fungicide, and has high production and application value.
具体实施方式Detailed ways
下面结合具体的实施例对本发明做进一步详细的说明：Below in conjunction with specific embodiment the present invention is described in further detail:
实施例1：1-氰基-N-(1-氰基-1-(4-氟苯基)甲基)环丙烷甲酰胺Example 1: 1-cyano-N-(1-cyano-1-(4-fluorophenyl)methyl)cyclopropanecarboxamide
(1)制备1-氰基环丙烷羧酸乙酯(1) Preparation of ethyl 1-cyanocyclopropanecarboxylate
于500ml三口瓶中，将20g (0.176mol) 氰基乙酸乙酯溶于300mL DMF；然后依次加入60g (0.435mol)无水碳酸钾粉末，滴加36.4g (0.194mol) 1,2-二溴乙烷和5g 1-丁基-3-甲基咪唑六氟磷盐；搅拌条件下于25℃反应11小时；In a 500ml three-necked flask, dissolve 20g (0.176mol) of ethyl cyanoacetate in 300mL of DMF; then add 60g (0.435mol) of anhydrous potassium carbonate powder in sequence, and dropwise add 36.4g (0.194mol) of 1,2-dibromo Ethane and 5g 1-butyl-3-methylimidazolium hexafluorophosphonium salt; reacted at 25°C for 11 hours under stirring conditions;
加入1200mL水充分混合，乙酸乙酯萃取，无水硫酸钠干燥过夜，过滤浓缩，减压蒸馏，0.5mmHg下收集60-77℃的馏分，得1-氰基环丙烷羧酸乙酯无色液体19g，产率77.2%。1H-NMR (CDCl3，ppm)：4.30-4.23 (q, 2H),1.71-1.60 (m, 4H), 1.34(t, 3H)。Add 1200mL of water and mix well, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate, distill under reduced pressure, collect fractions at 60-77°C under 0.5mmHg to obtain ethyl 1-cyanocyclopropanecarboxylate as a colorless liquid 19 g, yield 77.2%.1 H-NMR (CDCl3 , ppm): 4.30-4.23 (q, 2H), 1.71-1.60 (m, 4H), 1.34 (t, 3H).
(2) 制备1-氰基环丙烷羧酸(2) Preparation of 1-cyanocyclopropanecarboxylic acid
将2.62 g的KOH（KOH的有效含量为82%）溶于25mL无水乙醇，0℃下逐滴滴入5g 1-氰基环丙烷羧酸乙酯溶于20mL无水乙醇的溶液，室温下剧烈搅拌反应2小时；减压脱除乙醇，加水20mL溶解，20mL氯仿萃取，除去未反应的1-氰基环丙烷羧酸乙酯，水相用浓盐酸酸化至pH=2，3×60mL氯仿萃取，减压脱溶，得白色固体，产率41.1%。1H-NMR (CDCl3, ppm)：10.64 (s, 1H), 1.82-1.72 (m, 4H)。Dissolve 2.62 g of KOH (the effective content of KOH is 82%) in 25 mL of absolute ethanol, and drop in a solution of 5 g of ethyl 1-cyanocyclopropanecarboxylate dissolved in 20 mL of absolute ethanol at 0°C, and Vigorously stir the reaction for 2 hours; remove ethanol under reduced pressure, add 20 mL of water to dissolve, extract with 20 mL of chloroform, remove unreacted ethyl 1-cyanocyclopropanecarboxylate, acidify the aqueous phase with concentrated hydrochloric acid to pH=2, 3×60 mL of chloroform Extraction and precipitation under reduced pressure gave a white solid with a yield of 41.1%.1 H-NMR (CDCl3 , ppm): 10.64 (s, 1H), 1.82-1.72 (m, 4H).
(3)制备2-氨基-2-(4-氟苯基)乙腈(3) Preparation of 2-amino-2-(4-fluorophenyl)acetonitrile
在100mL厚壁耐压瓶中, 将对氟苯甲醛2.48g (0.02mol)、无水碘化锌0.1g、4A分子筛0.25g溶于25 mL无水乙腈，降温至-15℃以下，通入NH3至饱和，加入2.58g TMSCN后封口，65℃下反应过夜。将反应液过滤、浓缩，以乙醚-石油醚重结晶。In a 100mL thick-walled pressure-resistant bottle, dissolve 2.48g (0.02mol) of p-fluorobenzaldehyde, 0.1g of anhydrous zinc iodide, and 0.25g of 4A molecular sieve in 25 mL of anhydrous acetonitrile, cool to below -15°C, and pass through NH3 to saturation, add 2.58g TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether.
(4) 制备1-氰基-N-(1-氰基-1-(4-氟苯基)甲基)环丙烷甲酰胺(4) Preparation of 1-cyano-N-(1-cyano-1-(4-fluorophenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.2g (1.8mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.41g (1.98mmol)、4-二甲氨基吡啶(DMAP) 0.24g (1.98mmol)、2-氨基-2-(4-氟苯基)乙腈0.3g (1.98mmol)，搅拌下常温反应5小时。过滤，减压脱溶，残余物加入乙酸乙酯，冰箱中过夜，再次过滤析出固体，滤液浓缩后柱层析(石油醚/乙酸乙酯=5/1)，得白色固体，m.p.134~136℃，产率47.9%；1H-NMR (CDCl3, ppm)：7.52-7.47 (m, 2H), 7.19-7.14 (m, 2H), 7.00 (d, 1H, J=7.9Hz), 6.03 (d, 1H, J=8.0Hz), 1.83-1.76 (m, 2H), 1.65-1.58 (m, 2H)，MS (FAB+): 223.0 (M+Na+)。Dissolve 0.2g (1.8mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.41g (1.98mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.24g (1.98mmol), 2-amino-2-(4-fluorophenyl) acetonitrile 0.3g (1.98mmol), react at room temperature for 5 hours under stirring. Filtrate, desolvate under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter again to precipitate a solid, concentrate the filtrate and perform column chromatography (petroleum ether/ethyl acetate=5/1) to obtain a white solid, mp134~136°C , yield 47.9%;1 H-NMR (CDCl3 , ppm): 7.52-7.47 (m, 2H), 7.19-7.14 (m, 2H), 7.00 (d, 1H, J=7.9Hz), 6.03 (d, 1H, J=8.0Hz), 1.83-1.76 (m , 2H), 1.65-1.58 (m, 2H), MS (FAB+ ): 223.0 (M+Na+ ).
实施例2：1-氰基-N-(1-氰基-1-(4-氯苯基)甲基)环丙烷甲酰胺Example 2: 1-cyano-N-(1-cyano-1-(4-chlorophenyl)methyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯、1-氰基环丙烷羧酸的合成参照实施例1;(1) The synthetic reference example 1 of ethyl 1-cyanocyclopropanecarboxylate, 1-cyanocyclopropanecarboxylate;
(2) 2-氨基-2-(4-氯苯基)乙腈(2) 2-Amino-2-(4-chlorophenyl)acetonitrile
在100 mL厚壁耐压瓶中，将4-氯苯甲醛2.81g (0.02mol)、无水碘化锌0.1g、4A。分子筛0.25g溶于25mL无水乙腈,降温至-15℃，通入NH3至饱和，加入TMSCN 2.58g (0.026mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚重结晶，得2.1g黄褐色固体，熔点51-54℃，产率63.1%。In a 100 mL thick-walled pressure-resistant bottle, add 2.81 g (0.02 mol) of 4-chlorobenzaldehyde, 0.1 g of anhydrous zinc iodide, and 4A. Dissolve 0.25g of molecular sieve in 25mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, add 2.58g (0.026mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from ether to obtain 2.1 g of a tan solid with a melting point of 51-54°C and a yield of 63.1%.
(3) 1-氰基-N-(1-氰基-1-(4-氯苯基)甲基)环丙烷甲酰胺(3) 1-cyano-N-(1-cyano-1-(4-chlorophenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol) 溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶 (DMAP) 0.48 g（3.96mmol）、2-氨基-2-(4-氯苯基)乙腈0.66g (3.96mmol)，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，再次过滤析出固体，滤液浓缩柱层析提纯(石油醚/乙酸乙酯=5/1), 得黄色固体，m.p.138~140℃,产率47.9%；1H-NMR (CDCl3, ppm)：7.44-7.41 (m, 4H), 7.15 (d, 1H, J=8.1 Hz), 6.04 (d, 1H, J=8.1 Hz), 1.82-1.28 (m, 4H); MS(FAB+): 282.5 (M+Na+)。Take 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid and dissolve it in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), 2-amino-2-(4-chlorophenyl) acetonitrile 0.66 g (3.96 mmol), react at room temperature for 5 hours under stirring. Filter, remove the solvent under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter again to precipitate a solid, concentrate the filtrate and purify by column chromatography (petroleum ether/ethyl acetate=5/1), and obtain a yellow solid, mp138~140°C , yield 47.9%;1 H-NMR (CDCl3 , ppm): 7.44-7.41 (m, 4H), 7.15 (d, 1H, J=8.1 Hz), 6.04 (d, 1H, J=8.1 Hz), 1.82-1.28 (m, 4H); MS (FAB+ ): 282.5 (M+Na+ ).
实施例3 ：1-氰基-N-(1-氰基-1-苯基甲基)环丙烷甲酰胺Embodiment 3: 1-cyano-N-(1-cyano-1-phenylmethyl) cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯、1-氰基环丙烷羧酸的合成参照实施例1;(1) The synthetic reference example 1 of ethyl 1-cyanocyclopropanecarboxylate, 1-cyanocyclopropanecarboxylate;
(2) 2-氨基-2-苯基乙腈(2) 2-amino-2-phenylacetonitrile
100 mL厚壁耐压瓶中，将苯甲醛3.18g (0.03mol)、无水碘化锌(ZnI2) 0.15g、 4A。分子筛0.375g溶于38mL无水乙腈, 降温至-15℃，通入NH3至饱和，加入TMSCN 3.86g (0.039mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得2.45g黄色固体，熔点48-50℃，产率61.9%。Add 3.18g (0.03mol) of benzaldehyde, 0.15g of anhydrous zinc iodide (ZnI2 ), and 4A in a 100 mL thick-walled pressure-resistant bottle. Dissolve 0.375g of molecular sieve in 38mL of anhydrous acetonitrile, lower the temperature to -15°C, feed NH3 to saturation, add 3.86g (0.039mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether to obtain 2.45 g of a yellow solid with a melting point of 48-50°C and a yield of 61.9%.
(3) 1-氰基-N-(1-氰基-1-苯基甲基)环丙烷甲酰胺(3) 1-cyano-N-(1-cyano-1-phenylmethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.5g (4.5mmol) 溶于20 mL二氯甲烷，冰浴下加入二环己基碳二亚胺(DCC)1.02g (4.95mmol)、4-二甲氨基吡啶(DMAP) 0.6g (4.95mmol)、2-氨基-2-(苯基)乙腈0.65g (4.95mmol)，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，再次过滤析出物，滤液浓缩柱层析提纯（石油醚：乙酸乙酯=5:1）,得0.5g白色固体，m.p.99~101℃,产率50%；1H-NMR (CDCl3，ppm)：7.46～7.52 (m, 5H), 6.90 (d, 1H, J=8.1Hz), 6.04 (d, 1H, J=8.0Hz), 1.85～1.76 (m, 2H), 1.64～1.59 (m, 2H)；MS (FAB+): 226.1 ( M+ H+)。Dissolve 0.5 g (4.5 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 1.02 g (4.95 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine under ice cooling (DMAP) 0.6g (4.95mmol), 2-amino-2-(phenyl) acetonitrile 0.65g (4.95mmol), react at room temperature for 5 hours under stirring. Filter, remove the solvent under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate again, concentrate the filtrate and purify by column chromatography (petroleum ether: ethyl acetate = 5:1), and obtain 0.5g of white solid, mp99~ 101℃, yield 50%;1 H-NMR (CDCl3 , ppm): 7.46～7.52 (m, 5H), 6.90 (d, 1H, J=8.1Hz), 6.04 (d, 1H, J=8.0Hz ), 1.85～1.76 (m, 2H), 1.64～1.59 (m, 2H); MS (FAB+ ): 226.1 (M+ H+ ).
实施例4： 1-氰基-N-(1-氰基-1-(4-甲氧基苯基)甲基)环丙烷甲酰胺Example 4: 1-cyano-N-(1-cyano-1-(4-methoxyphenyl)methyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-甲氧基苯基)乙腈(3) 2-amino-2-(4-methoxyphenyl)acetonitrile
100 mL厚壁耐压瓶中, 将对甲氧基苯甲醛5.44g (0.04 mol)、无水碘化锌(ZnI2) 0.2 g、4A。分子筛0.5 g溶于50 mL无水乙腈，降温至-15℃，通入NH3至饱和，加入TMSCN 5.15 g (0.052 mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得3.4g灰绿色固体，熔点62-64℃，产率52.5%。In a 100 mL thick-walled pressure-resistant bottle, add 5.44 g (0.04 mol) of p-methoxybenzaldehyde, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A. Dissolve 0.5 g of molecular sieves in 50 mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, add 5.15 g (0.052 mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether to obtain 3.4 g of a gray-green solid with a melting point of 62-64°C and a yield of 52.5%.
(4) 1-氰基-N-(1-氰基-1-(4-甲氧基苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-methoxyphenyl)methyl)cyclopropanecarboxamide
取0.5 g (4.5 mmol) 1-氰基环丙烷羧酸溶于20 mL二氯甲烷，冰浴下加入二环己基碳二亚胺 (DCC) 1.02 g (4.95 mmol)、4-二甲氨基吡啶(DMAP) 0.6g (4.95 mmol)、2-氨基-2-(4-甲氧基苯基)乙腈0.8 g (4.95mmol)，搅拌下常温反应5小时。过滤，减压脱溶，残余物加入乙酸乙酯，冰箱中过夜，过滤，滤液浓缩柱层析提纯(石油醚/乙酸乙酯=5/1), 得白色固体，m.p.84-86℃,产率61%；1H-NMR(CDCl3，ppm)：7.43 (m, 2H), 6.98 (m, 2H), 6.79 (d, 1H, J=7.3 Hz), 5.95 (d, 1H, J=7.7Hz), 3.85 (s, 3H),1.85～1.75 (m, 2H), 1.66～1.58 (m, 2H)； MS (FAB+):278.0 (M+Na+)。Dissolve 0.5 g (4.5 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 1.02 g (4.95 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) 0.6 g (4.95 mmol), 2-amino-2-(4-methoxyphenyl) acetonitrile 0.8 g (4.95 mmol), reacted at room temperature for 5 hours under stirring. Filter, precipitate under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter, concentrate the filtrate and purify by column chromatography (petroleum ether/ethyl acetate=5/1), and obtain a white solid, mp84-86°C, yield 61%;1 H-NMR (CDCl3 , ppm): 7.43 (m, 2H), 6.98 (m, 2H), 6.79 (d, 1H, J=7.3 Hz), 5.95 (d, 1H, J=7.7Hz ), 3.85 (s, 3H), 1.85～1.75 (m, 2H), 1.66～1.58 (m, 2H); MS (FAB+ ):278.0 (M+Na+ ).
实施例5： 1-氰基-N-(1-氰基-1-(4-甲基苯基)甲基)环丙烷甲酰胺Example 5: 1-cyano-N-(1-cyano-1-(4-methylphenyl)methyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-甲基苯基)乙腈(3) 2-amino-2-(4-methylphenyl)acetonitrile
100 mL厚壁耐压瓶中, 将对甲基苯甲醛4.8 g (0.04 mol)、无水碘化锌 (ZnI2) 0.2g、4A。分子筛0.5 g溶于50 mL无水乙腈，降温至-15℃，通入NH3至饱和，加入TMSCN 5.15 g (0.052mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得2g黄色固体，熔点32-34℃，产率34.2%。In a 100 mL thick-walled pressure-resistant bottle, add 4.8 g (0.04 mol) of p-tolualdehyde, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A. Dissolve 0.5 g of molecular sieves in 50 mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, add 5.15 g (0.052mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether to obtain 2 g of a yellow solid with a melting point of 32-34°C and a yield of 34.2%.
(4) 1-氰基-N-(1-氰基-1-(4-甲基苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-methylphenyl)methyl)cyclopropanecarboxamide
1-氰基环丙烷羧酸0.6 g (5.4 mmol) 溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 1.2 g (5.94 mmol)、4-二甲氨基吡啶(DMAP) 0.72 g (5.94 mmol)、2-氨基-2-(4-甲基苯基)乙腈0.87 g（4.95 mmol），常温反应5小时。过滤，减压脱溶，残余物加乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得白色固体，m.p. 135-137℃, 产率69.8%；1H-NMR (CDCl3，ppm)：7.32 (dd, 4H, J=8.2 Hz), 6.83 (d, 1H, J=7.4 Hz), 5.97 (d, 1H, J=7.9 Hz), 2.40 (s,3H), 1.84～1.75 (m, 2H), 1.66～1.55 (m, 2H)；MS (FAB+): 262.0 (M+Na+)。0.6 g (5.4 mmol) of 1-cyanocyclopropanecarboxylic acid was dissolved in 20 mL of dichloromethane, under ice cooling, 1.2 g (5.94 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine were added (DMAP) 0.72 g (5.94 mmol), 2-amino-2-(4-methylphenyl) acetonitrile 0.87 g (4.95 mmol), react at room temperature for 5 hours. Filtrate, desolvate under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp 135-137℃ , yield 69.8%;1 H-NMR (CDCl3 , ppm): 7.32 (dd, 4H, J=8.2 Hz), 6.83 (d, 1H, J=7.4 Hz), 5.97 (d, 1H, J=7.9 Hz), 2.40 (s,3H), 1.84～1.75 (m, 2H), 1.66～1.55 (m, 2H); MS (FAB+ ): 262.0 (M+Na+ ).
实施例6： 1-氰基-N-(1-氰基-1-(4-叔丁基苯基)甲基)环丙烷甲酰胺Embodiment 6: 1-cyano-N-(1-cyano-1-(4-tert-butylphenyl) methyl) cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-（4-叔丁基苯基）乙腈(3) 2-amino-2-(4-tert-butylphenyl)acetonitrile
100 mL厚壁耐压瓶中,对叔丁基苯甲醛6.48 g (0.04 mol)、无水碘化锌(ZnI2) 0.2 g、4A。分子筛0.5 g溶于50 mL无水乙腈，降温至-15℃，通入NH3至饱和，加入TMSCN 5.15 g (0.052 mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得黄色固体，熔点72-74℃，产率47.6%。In a 100 mL thick-walled pressure-resistant bottle, 6.48 g (0.04 mol) of p-tert-butylbenzaldehyde, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A. Dissolve 0.5 g of molecular sieves in 50 mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, add 5.15 g (0.052 mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from ether-petroleum ether to obtain a yellow solid with a melting point of 72-74°C and a yield of 47.6%.
(4) 1-氰基-N-(1-氰基-1-(4-叔丁基苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-tert-butylphenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.5 g (4.5 mmol)溶于20 mL二氯甲烷，冰浴下加入二环己基碳二亚胺 (DCC) 1.02 g (4.95 mmol)、4-二甲氨基吡啶(DMAP) 0.6 g (4.95 mmol)、2-氨基-2-(4-叔丁基苯基)乙腈1.02 g (5.4 mmol)，常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯（石油醚/乙酸乙酯=5/1）,得白色固体，m.p. 99-102℃, 产率：67.5%；1H-NMR (CDCl3，ppm)：7.50～7.41 (m, 4H) ,6.89(d, 1H,J=7.7 Hz), 5.98 (d, 1H, J=7.8 Hz), 1.84～1.70 (m, 2H), 1.66～1.55 (m, 2H), 1.34 (s, 9H)；MS (FAB+): 304.1 (M+Na+)。Dissolve 0.5 g (4.5 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 1.02 g (4.95 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) 0.6 g (4.95 mmol), 2-amino-2-(4-tert-butylphenyl) acetonitrile 1.02 g (5.4 mmol), react at room temperature for 5 hours. Filtrate, remove the solvent under reduced pressure, add ethyl acetate to the residue, store in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether/ethyl acetate=5/1), and obtain a white solid, mp 99-102°C , Yield: 67.5%;1 H-NMR (CDCl3 , ppm): 7.50～7.41 (m, 4H), 6.89(d, 1H, J=7.7 Hz), 5.98 (d, 1H, J=7.8 Hz) , 1.84～1.70 (m, 2H), 1.66～1.55 (m, 2H), 1.34 (s, 9H); MS (FAB+ ): 304.1 (M+Na+ ).
实施例7： 1-氰基-N-(1-氰基-1-(4-溴苯基)甲基)环丙烷甲酰胺Example 7: 1-cyano-N-(1-cyano-1-(4-bromophenyl)methyl)cyclopropanecarboxamide
(1)1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-溴苯基)乙腈(3) 2-Amino-2-(4-bromophenyl)acetonitrile
100 mL厚壁耐压瓶中, 将对溴苯甲醛7.4 g (0.04 mol)、无水碘化锌(ZnI2) 0.2g、4A。分子筛0.5 g溶于50 mL无水乙腈, 降温至-15℃，通入NH3至饱和，后加入TMSCN 5.15 g (0.052mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得黄色固体，熔点53-55℃，产率73.5%。In a 100 mL thick-walled pressure-resistant bottle, 7.4 g (0.04 mol) of p-bromobenzaldehyde, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A were added. Dissolve 0.5 g of molecular sieve in 50 mL of anhydrous acetonitrile, lower the temperature to -15°C, feed NH3 to saturation, then add 5.15 g (0.052mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from ether-petroleum ether to obtain a yellow solid with a melting point of 53-55°C and a yield of 73.5%.
(4) 1-氰基-N-(1-氰基-1-(4-溴苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-bromophenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.6 g (5.4 mmol) 溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 1.22 g (5.94 mmol)、4-二甲氨基吡啶(DMAP) 0.73 g (5.94mmol)、2-氨基-2-(4-溴苯基)乙腈1.37 g (6.48mmol)，常温反应5小时。过滤，减压脱溶，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1),得白色固体，m.p.124-126℃, 产率29.3%；1H-NMR (CDCl3，ppm)：7.63～7.58 (m, 2H), 7.40～7.35 (m, 2H), 7.07 (d, 1H, J=8.0 Hz), 6.02 (d, 1H, J=8.1 Hz),1.84～1.75 (m, 2H), 1.68～1.57 (m, 2H)；MS (FAB+): 303.8 ( M+ H+)。Dissolve 0.6 g (5.4 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 1.22 g (5.94 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino Pyridine (DMAP) 0.73 g (5.94 mmol), 2-amino-2-(4-bromophenyl) acetonitrile 1.37 g (6.48 mmol), react at room temperature for 5 hours. Filtrate, desolvate under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp124-126°C, Yield 29.3%;1 H-NMR (CDCl3 , ppm): 7.63～7.58 (m, 2H), 7.40～7.35 (m, 2H), 7.07 (d, 1H, J=8.0 Hz), 6.02 (d, 1H, J=8.1 Hz), 1.84～1.75 (m, 2H), 1.68～1.57 (m, 2H); MS (FAB+ ): 303.8 (M+ H+ ).
实施例8： 1-氰基-N-(1-氰基-1-(3-氯苯基)甲基)环丙烷甲酰胺Example 8: 1-cyano-N-(1-cyano-1-(3-chlorophenyl)methyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(3-氯苯基)乙腈(3) 2-Amino-2-(3-chlorophenyl)acetonitrile
100 mL厚壁耐压瓶中, 将间氯苯甲醛5.62 g (0.04 mol)、无水碘化锌 (ZnI2) 0.2g、4A。分子筛0.5 g溶于50 mL无水乙腈，降温至-15℃，通入NH3至饱和，加入TMSCN 5.15 g (0.052 mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得黄色固体，产率45%。In a 100 mL thick-walled pressure-resistant bottle, add 5.62 g (0.04 mol) of m-chlorobenzaldehyde, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A. Dissolve 0.5 g of molecular sieves in 50 mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, add 5.15 g (0.052 mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether to obtain a yellow solid with a yield of 45%.
(4) 1-氰基-N-(1-氰基-1-(3-氯苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(3-chlorophenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.6 g (5.4 mmol) 溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺 (DCC) 1.22 g (5.94 mmol)、4-二甲氨基吡啶 (DMAP) 0.73 g (5.94 mmol)、2-氨基-2-(3-氯苯基)乙腈1.1 g (5.94 mmol)，常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得淡黄色固体，m.p. 91-93℃,产率43.6%；1H-NMR (CDCl3，ppm)：7.48 (m, 1H), 7.44～7.39(m, 3H), 7.13 (d, 1H, J=8 Hz), 6.05 (d, 1H, J=8.2 Hz), 1.83~1.76 (m, 2H), 1.66～1.68 (m, 2H)；MS (FAB+): 258.0 (M-H+)。Dissolve 0.6 g (5.4 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 1.22 g (5.94 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino Pyridine (DMAP) 0.73 g (5.94 mmol), 2-amino-2-(3-chlorophenyl) acetonitrile 1.1 g (5.94 mmol), react at room temperature for 5 hours. Filter, remove the solvent under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), to obtain a light yellow solid, mp 91-93 ℃, yield 43.6%;1 H-NMR (CDCl3 , ppm): 7.48 (m, 1H), 7.44～7.39 (m, 3H), 7.13 (d, 1H, J=8 Hz), 6.05 (d, 1H, J=8.2 Hz), 1.83~1.76 (m, 2H), 1.66~1.68 (m, 2H); MS (FAB+ ): 258.0 (MH+ ).
实施例9： 1-氰基-N- (1-氰基-1-(3,4-亚甲基二氧苯基)甲基)环丙烷甲酰胺Example 9: 1-cyano-N-(1-cyano-1-(3,4-methylenedioxyphenyl)methyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(3,4-亚甲基二氧苯基)乙腈(3) 2-Amino-2-(3,4-methylenedioxyphenyl)acetonitrile
100 mL厚壁耐压瓶中, 在盛有50ml无水乙腈的，将胡椒醛6 g (0.04 mol)、无水碘化锌 (ZnI2) 0.2g、4A。分子筛0.5 g溶于50mL无水乙腈，降温至-15℃，通入NH3至饱和，后加入TMSCN 5.15 g(0.052mol)，封口，65℃反应过夜。反应液过滤、浓缩，乙醚-石油醚重结晶，得黄色固体，产率70.0%。In a 100 mL thick-walled pressure-resistant bottle, add 6 g (0.04 mol) of piperonal, 0.2 g of anhydrous zinc iodide (ZnI2 ), and 4A in 50 ml of anhydrous acetonitrile. Dissolve 0.5 g of molecular sieves in 50 mL of anhydrous acetonitrile, cool down to -15°C, feed NH3 to saturation, then add 5.15 g (0.052 mol) of TMSCN, seal, and react overnight at 65°C. The reaction solution was filtered, concentrated, and recrystallized from diethyl ether-petroleum ether to obtain a yellow solid with a yield of 70.0%.
(4) 1-氰基-N- (1-氰基-1-(3,4-亚甲基二氧苯基)甲基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(3,4-methylenedioxyphenyl)methyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.6 g (5.4 mmol) 溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC)1.22 g (5.94 mmol)、4-二甲氨基吡啶 (DMAP) 0.73 g (5.94 mmol)、2-氨基-2-(3,4-亚甲基二氧苯基)乙腈1.14 g (6.48 mmol)，常温反应5小时。过滤，减压脱溶，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯（石油醚\乙酸乙酯=5\1）,得白色固体，m.p. 148-150℃,产率29%； 1H-NMR (CDCl3，ppm)：7.01 (dd, 1H), 6.85～6.92 (m, 3H), 6.04 (s, 2H) , 5.92 (d, 1H, J=7.9 Hz), 1.82～1.75 (m, 2H), 1.64～1.58 (m, 2H) ；MS (FAB+): 292.1 (M+Na+)。Take 0.6 g (5.4 mmol) of 1-cyanocyclopropanecarboxylic acid and dissolve it in 20 mL of dichloromethane, add 1.22 g (5.94 mmol) of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino Pyridine (DMAP) 0.73 g (5.94 mmol), 2-amino-2-(3,4-methylenedioxyphenyl) acetonitrile 1.14 g (6.48 mmol), react at room temperature for 5 hours. Filtrate, precipitate under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp 148-150°C , yield 29%;1 H-NMR (CDCl3 , ppm): 7.01 (dd, 1H), 6.85～6.92 (m, 3H), 6.04 (s, 2H) , 5.92 (d, 1H, J=7.9 Hz ), 1.82～1.75 (m, 2H), 1.64～1.58 (m, 2H); MS (FAB+ ): 292.1 (M+Na+ ).
实施例10： 1-氰基-N-(1-氰基-1-(4-甲基苯基)乙基)环丙烷甲酰胺Example 10: 1-cyano-N-(1-cyano-1-(4-methylphenyl) ethyl) cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-甲基苯基)丙腈(3) 2-Amino-2-(4-methylphenyl)propionitrile
250 mL耐压瓶中， 将氰化钠8.5 g (172 mmol) 、氯化铵 9.2 g (172 mmol)、对甲基苯乙酮20 g (150 mmol)溶于80 mL50% 的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50 mL的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-(4-甲基苯基)丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 20 g (150 mmol) of p-methylacetophenone in 80 mL of 50% aqueous ethanol, and stir 20 mL of concentrated ammonia water was added at low temperature, and the reaction was carried out at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residual The product was dissolved in 150 mL of anhydrous ether, and dry hydrogen chloride gas was introduced at 0°C to produce a large amount of off-white precipitate, which was 2-amino-2-(4-methylphenyl)propionitrile hydrochloride, filtered, and vacuum-dried. Store at low temperature.
取2-氨基-2-(4-甲基苯基)丙腈盐酸盐1.1 g (5.4 mmol) 溶于20mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min, 分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-(4-甲基苯基)丙腈二氯甲烷溶液，备用；Take 1.1 g (5.4 mmol) of 2-amino-2-(4-methylphenyl)propionitrile hydrochloride and dissolve it in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, and separate the liquids without Dry the organic phase with sodium sulfate water for 3 hours, filter to obtain 2-amino-2-(4-methylphenyl)propionitrile dichloromethane solution, and set aside;
（4）1-氰基-N-(1-氰基-1-(4-甲基苯基)乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-methylphenyl)ethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g (3.96 mmol), 滴加2-氨基-2-(4-甲基苯基)丙腈的二氯乙烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得白色固体，m.p. 184-186℃,产率49.5%；1H-NMR (CDCl3，ppm)：7.45～7.23 (m, 4 H),6.78 (s, 1 H), 2.37 (s, 3 H), 2.01 (s, 3 H), 1.75~1.54 (m, 4 H)；MS (FAB+): 276.1 (M+Na+)。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), dichloroethane solution of 2-amino-2-(4-methylphenyl)propionitrile was added dropwise, and stirred at room temperature for 5 hours. Filtrate, remove the solvent under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp 184-186°C , yield 49.5%;1 H-NMR (CDCl3 , ppm): 7.45～7.23 (m, 4 H), 6.78 (s, 1 H), 2.37 (s, 3 H), 2.01 (s, 3 H) , 1.75~1.54 (m, 4 H); MS (FAB+ ): 276.1 (M+Na+ ).
实施例11： 1-氰基-N-(1-氰基-1-苯基乙基)环丙烷甲酰胺Example 11: 1-cyano-N-(1-cyano-1-phenylethyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-苯基丙腈(3) 2-Amino-2-phenylpropionitrile
250 mL耐压瓶中， 将氰化钠8.5 g (172 mmol) 、氯化铵 9.2 g (172 mmol)、对苯乙酮18 g (150 mmol)溶于80 mL 50%的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50 mL 的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-苯基丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 18 g (150 mmol) of p-acetophenone in 80 mL of 50% ethanol aqueous solution, and stir Add 20 mL of concentrated ammonia water and react at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residual The substance was dissolved in 150 mL of anhydrous ether, and dry hydrogen chloride gas was introduced at 0°C to produce a large amount of off-white precipitate, which was 2-amino-2-phenylpropionitrile hydrochloride, which was filtered, vacuum-dried, and stored at low temperature.
取2-氨基-2-苯基丙腈盐酸盐1.0 g (5.4 mmol) 溶于20 mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min, 分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-苯基丙腈二氯甲烷溶液，备用；Take 1.0 g (5.4 mmol) of 2-amino-2-phenylpropionitrile hydrochloride and dissolve it in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, separate the liquids, dry the organic matter with anhydrous sodium sulfate phase for 3 hours, filtered to obtain 2-amino-2-phenylpropionitrile dichloromethane solution, and set aside;
(4) 1-氰基-N-(1-氰基-1-苯基乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-phenylethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g (3.96 mmol), 滴加2-氨基-2-苯基丙腈的二氯乙烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得白色固体， m.p. 112-114℃, 产率58.9%；1H-NMR (CDCl3，ppm)：7.58 ~7.40 (m, 5 H), 6.82 (s,1 H), 2.03 (s, 3H), 1.79~1.55 (m, 4 H)；MS (FAB+):262.0（M+Na+）。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), 2-amino-2-phenylpropionitrile solution in dichloroethane was added dropwise, and stirred at room temperature for 5 hours. Filtrate, remove the solvent under reduced pressure, add the residue to ethyl acetate, store in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp 112-114°C , yield 58.9%;1 H-NMR (CDCl3 , ppm): 7.58 ~7.40 (m, 5 H), 6.82 (s, 1 H), 2.03 (s, 3H), 1.79~1.55 (m, 4 H ); MS (FAB+ ): 262.0 (M+Na+ ).
实施例12： 1-氰基-N-(1-氰基-1-(4-甲氧基苯基)乙基)环丙烷甲酰胺Example 12: 1-cyano-N-(1-cyano-1-(4-methoxyphenyl) ethyl) cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-甲氧基苯基)丙腈(3) 2-amino-2-(4-methoxyphenyl)propionitrile
250 mL耐压瓶中， 将氰化钠8.5 g (172 mmol) 、氯化铵 9.2 g (172 mmol)、对甲氧基苯乙酮22.5 g (150 mmol)溶于80mL 50% 的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50mL 的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-(4-甲氧基苯基)丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 22.5 g (150 mmol) of p-methoxyacetophenone in 80 mL of 50% aqueous ethanol, Add 20 mL of concentrated ammonia water under stirring, and react at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residue Dissolve in 150 mL of anhydrous ether, pass through dry hydrogen chloride gas at 0°C, produce a large amount of off-white precipitate, which is 2-amino-2-(4-methoxyphenyl)propionitrile hydrochloride, filter, vacuum dry, Store at low temperature.
取2-氨基-2-(4-甲氧基苯基)丙腈盐酸盐1.3 g (5.4 mmol) 溶于20 mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min,分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-(4-甲氧基苯基)丙腈二氯甲烷溶液，备用；Dissolve 1.3 g (5.4 mmol) of 2-amino-2-(4-methoxyphenyl)propionitrile hydrochloride in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, and separate , dry the organic phase over anhydrous sodium sulfate for 3 hours, filter to obtain 2-amino-2-(4-methoxyphenyl)propionitrile dichloromethane solution, and set aside;
(4) 1-氰基-N-(1-氰基-1-(4-甲氧基苯基)乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-methoxyphenyl)ethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g(3.96 mmol), 滴加2-氨基-2-(4-甲氧基苯基)丙腈二氯乙烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得白色固体，m.p. 122-124℃,产率43%；1H-NMR (CDCl3，ppm)：7.50~6.94 (m, 4 H), 6.74 (s, 1 H), 3.83 (s, 3H), 2.02 (s, 3 H), 1.76~1.71 (m, 2 H), 1.57~1.54 (m, 2H)；MS (FAB+) : 268.0(M-H+)。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), was added dropwise with 2-amino-2-(4-methoxyphenyl)propionitrile dichloroethane solution, and reacted at room temperature for 5 hours under stirring. Filtrate, remove the solvent under reduced pressure, add the residue to ethyl acetate, keep in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp 122-124°C , yield 43%;1 H-NMR (CDCl3 , ppm): 7.50~6.94 (m, 4 H), 6.74 (s, 1 H), 3.83 (s, 3H), 2.02 (s, 3 H), 1.76~1.71 (m, 2 H), 1.57~1.54 (m, 2H); MS (FAB+ ): 268.0 (MH+ ).
实施例13：1-氰基-N-(1-氰基-1-(4-氯苯基)乙基)环丙烷甲酰胺Example 13: 1-cyano-N-(1-cyano-1-(4-chlorophenyl)ethyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2)1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-氯苯基)丙腈(3) 2-Amino-2-(4-chlorophenyl)propionitrile
250 mL耐压瓶中， 将氰化钠8.5 g (172 mmol) 、氯化铵 9.2 g (172 mmol)、对氯苯乙酮23 g (150 mmol)溶于80 mL 50% 的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50 mL的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-(4-氯苯基)丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 23 g (150 mmol) of p-chloroacetophenone in 80 mL of 50% aqueous ethanol, and stir 20 mL of concentrated ammonia water was added at low temperature, and the reaction was carried out at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residual The substance was dissolved in 150 mL of anhydrous ether, and dry hydrogen chloride gas was introduced at 0°C to produce a large amount of off-white precipitate, which was 2-amino-2-(4-chlorophenyl)propionitrile hydrochloride, filtered, vacuum-dried, and low-temperature save.
取2-氨基-2-(4-氯苯基)丙腈盐酸盐1.4 g (5.4 mmol) 溶于20mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min, 分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-(4-氯苯基)丙腈二氯甲烷溶液，备用；Take 1.4 g (5.4 mmol) of 2-amino-2-(4-chlorophenyl)propionitrile hydrochloride and dissolve it in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, separate liquids, anhydrous Dry the organic phase with sodium sulfate for 3 hours, filter to obtain 2-amino-2-(4-chlorophenyl)propionitrile dichloromethane solution, and set aside;
(4) 1-氰基-N-(1-氰基-1-(4-氯苯基)乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-chlorophenyl)ethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g (3.96 mmol), 滴加2-氨基-2-(4-氯苯基)丙腈二氯甲烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得黄色固体，m.p. 136-138℃, 产率54.5%；1H-NMR (CDCl3，ppm)：7.50~7.39 (m, 4 H), 6.91(s,1 H), 1.99 (s,3 H), 1.79~1.55 (m, 4 H)；MS (FAB+): 271.9 (M- H+)。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), 2-amino-2-(4-chlorophenyl)propionitrile dichloromethane solution was added dropwise, and reacted at room temperature for 5 hours under stirring. Filtrate, remove the solvent under reduced pressure, add the residue to ethyl acetate, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a yellow solid, mp 136-138°C , yield 54.5%;1 H-NMR (CDCl3 , ppm): 7.50~7.39 (m, 4 H), 6.91(s,1 H), 1.99 (s,3 H), 1.79~1.55 (m, 4 H); MS (FAB+ ): 271.9 (M-H+ ).
实施例14： 1-氰基-N-(1-氰基-1-(3-溴苯基)乙基)环丙烷甲酰胺Example 14: 1-cyano-N-(1-cyano-1-(3-bromophenyl)ethyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(3-溴苯基)丙腈(3) 2-Amino-2-(3-bromophenyl)propionitrile
250 mL耐压瓶中， 将氰化钠8.5 g (172 mmol) 、氯化铵 9.2 g (172 mmol)、间溴苯乙酮30 g (150 mmol)溶于80 mL 50% 的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50 mL的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-(3-溴苯基)丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 30 g (150 mmol) of m-bromoacetophenone in 80 mL of 50% aqueous ethanol, and stir 20 mL of concentrated ammonia water was added at low temperature, and the reaction was carried out at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residual The substance was dissolved in 150 mL of anhydrous ether, and dry hydrogen chloride gas was introduced at 0°C to produce a large amount of off-white precipitate, which was 2-amino-2-(3-bromophenyl)propionitrile hydrochloride, filtered, vacuum-dried, and low-temperature save.
取2-氨基-2-(3-溴苯基)丙腈盐酸盐1.41 g (5.4 mmol) 溶于20mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min, 分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-(3-溴苯基)丙腈二氯甲烷溶液，备用；Take 1.41 g (5.4 mmol) of 2-amino-2-(3-bromophenyl)propionitrile hydrochloride and dissolve it in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, separate liquids, anhydrous Dry the organic phase with sodium sulfate for 3 hours, filter to obtain a solution of 2-amino-2-(3-bromophenyl)propionitrile in dichloromethane, and set aside;
（4）1-氰基-N-(1-氰基-1-(3-溴苯基)乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(3-bromophenyl)ethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g (3.96 mmol), 滴加2-氨基-2-(3-溴苯基)丙腈二氯甲烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得白色固体，m.p.116-118℃, 产率46 %；1H-NMR (CDCl3，ppm)：7.66~7.47 (m,4 H), 7.34~7.26(m, 1 H), 6.91 (s, 1 H), 1.99 (s, 3 H), 1.79~1.57 (m, 4 H)；MS (FAB+)：340.0 (M+Na+)。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), 2-amino-2-(3-bromophenyl)propionitrile dichloromethane solution was added dropwise, and stirred at room temperature for 5 hours. Filter, remove the solvent under reduced pressure, add ethyl acetate to the residue, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a white solid, mp116-118°C, Yield 46 %;1 H-NMR (CDCl3 , ppm): 7.66~7.47 (m, 4 H), 7.34~7.26 (m, 1 H), 6.91 (s, 1 H), 1.99 (s, 3 H ), 1.79~1.57 (m, 4 H); MS (FAB+ ): 340.0 (M+Na+ ).
实施例15： 1-氰基-N-(1-氰基-1-(4-溴苯基)乙基)环丙烷甲酰胺Example 15: 1-cyano-N-(1-cyano-1-(4-bromophenyl)ethyl)cyclopropanecarboxamide
(1) 1-氰基环丙烷羧酸乙酯；(2) 1-氰基环丙烷羧酸的合成参照实施例1;(1) ethyl 1-cyanocyclopropanecarboxylate; (2) synthetic reference example 1 of 1-cyanocyclopropanecarboxylate;
(3) 2-氨基-2-(4-溴苯基)丙腈(3) 2-Amino-2-(4-bromophenyl)propionitrile
250 mL耐压瓶中，将氰化钠8.5 g (172 mmol) 、氯化铵 9.2g (172 mmol)、对溴苯乙酮30 g (150 mmol)溶于80 mL 50%的乙醇水溶液，搅拌下加入浓氨水20 mL，65℃下反应8小时。反应完毕，降温，将反应混合物倾入300 mL冰水混合物，3×50 mL 的二氯乙烷提取，4×50 mL的水洗涤有机相，无水硫酸镁干燥，过滤，脱溶，将残余物溶于150 mL无水乙醚, 0℃下通入干燥的氯化氢气体，产生大量灰白色沉淀，为2-氨基-2-(4-溴苯基)丙腈盐酸盐，过滤，真空干燥，低温保存。In a 250 mL pressure-resistant bottle, dissolve 8.5 g (172 mmol) of sodium cyanide, 9.2 g (172 mmol) of ammonium chloride, and 30 g (150 mmol) of p-bromoacetophenone in 80 mL of 50% aqueous ethanol, and stir 20 mL of concentrated ammonia water was added at low temperature, and the reaction was carried out at 65°C for 8 hours. After the reaction was completed, the temperature was lowered, the reaction mixture was poured into 300 mL of ice-water mixture, extracted with 3×50 mL of dichloroethane, the organic phase was washed with 4×50 mL of water, dried over anhydrous magnesium sulfate, filtered, desolvated, and the residual The product was dissolved in 150 mL of anhydrous ether, and dry hydrogen chloride gas was introduced at 0°C to produce a large amount of off-white precipitate, which was 2-amino-2-(4-bromophenyl)propionitrile hydrochloride, filtered, vacuum-dried, and low-temperature save.
取2-氨基-2-(4-溴苯基)丙腈盐酸盐1.41 g (5.4 mmol) 溶于20mL 二氯甲烷，加入10 mL 10%的NaOH水溶液，搅拌10 min, 分液，无水硫酸钠干燥有机相3小时，过滤，得2-氨基-2-(4-溴苯基)丙腈二氯甲烷溶液，备用；Take 1.41 g (5.4 mmol) of 2-amino-2-(4-bromophenyl)propionitrile hydrochloride and dissolve it in 20 mL of dichloromethane, add 10 mL of 10% NaOH aqueous solution, stir for 10 min, separate liquid, anhydrous Dry the organic phase with sodium sulfate for 3 hours, filter to obtain a solution of 2-amino-2-(4-bromophenyl)propionitrile in dichloromethane, and set aside;
(4) 1-氰基-N-(1-氰基-1-(4-溴苯基)乙基)环丙烷甲酰胺(4) 1-cyano-N-(1-cyano-1-(4-bromophenyl)ethyl)cyclopropanecarboxamide
取1-氰基环丙烷羧酸0.4 g (3.6 mmol)溶于20 mL二氯甲烷，冰浴下，加入二环己基碳二亚胺(DCC) 0.82 g (3.96 mmol)、4-二甲氨基吡啶(DMAP) 0.48 g (3.96 mmol), 滴加2-氨基-2-(4-溴苯基)丙腈二氯甲烷溶液，搅拌下常温反应5小时。过滤，减压除去溶剂，残余物加入乙酸乙酯，冰箱中过夜，过滤析出物，滤液浓缩柱层析提纯(石油醚\乙酸乙酯=5\1), 得黄色固体，m.p. 150-152℃, 产率50.3%；1H-NMR (CDCl3，ppm)：7.58~7.40 (m, 4 H), 6.86(s, 1 H), 1.99 (s, 3 H), 1.78~1.54 (m, 4H); MS (FAB+)：340.2 (M+Na+)。Dissolve 0.4 g (3.6 mmol) of 1-cyanocyclopropanecarboxylic acid in 20 mL of dichloromethane, add 0.82 g (3.96 mmol) of dicyclohexylcarbodiimide (DCC), 4-dimethylamino Pyridine (DMAP) 0.48 g (3.96 mmol), 2-amino-2-(4-bromophenyl)propionitrile dichloromethane solution was added dropwise, and stirred at room temperature for 5 hours. Filtrate, remove the solvent under reduced pressure, add the residue to ethyl acetate, put it in the refrigerator overnight, filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether\ethyl acetate=5\1), and obtain a yellow solid, mp 150-152°C , yield 50.3%;1 H-NMR (CDCl3 , ppm): 7.58~7.40 (m, 4 H), 6.86(s, 1 H), 1.99 (s, 3 H), 1.78~1.54 (m, 4H ); MS (FAB+ ): 340.2 (M+Na+ ).
实施例16 ：化合物的杀菌活性Embodiment 16: the bactericidal activity of compound
杀菌生物活性测试以百菌清和多菌灵为对照药剂，测定了目标化合物对多种植物病原菌菌丝生长速率的抑制活性。按照中华人民共和国农业行业标准（NY/T 1156.2-2006），采用菌丝生长速率法进行测定。Bactericidal biological activity test Using chlorothalonil and carbendazim as control agents, the inhibitory activity of the target compound on the mycelial growth rate of various plant pathogens was determined. According to the agricultural industry standard of the People's Republic of China (NY/T 1156.2-2006), the mycelium growth rate method was used for determination.
表-1：化合物杀菌活性初筛数据 (一)Table-1: Preliminary screening data of compound bactericidal activity (1)
表-2：化合物杀菌活性初筛数据 (二)Table-2: Preliminary screening data of compound bactericidal activity (2)
由实施例16之数据，可知本发明中的双氰基环酰胺类化合物对腐霉菌和稻瘟菌具有较好的抑制活性，其中实施例6化合物的活性与对照药剂百菌清相当，高于对照药剂多菌灵和三环唑，另外这些化合物中的实施例10、11、12、13、14、15还对油菜菌核病、黄瓜灰霉病、苹果轮纹病、小麦赤霉病等显示出一定的抑制活性，有望作为杀菌剂先导化合物进行研究及应用。From the data of Example 16, it can be seen that the dicyanocyclic amide compounds in the present invention have better inhibitory activity to Pythium and Magnaporthe oryzae, wherein the activity of the compound of Example 6 is equivalent to that of the contrast agent chlorothalonil, which is higher than The contrast agents carbendazim and tricyclazole, in addition the embodiments 10, 11, 12, 13, 14, 15 in these compounds are also effective against rape sclerotinia, cucumber gray mold, apple ring spot, wheat scab etc. It shows a certain inhibitory activity and is expected to be used as a fungicide lead compound for research and application.
实施例17 ：化合物的杀虫活性Embodiment 17: the insecticidal activity of compound
选取粘虫和蚊子幼虫为测试对象，对目标化合物进行了活性初筛对照，测试方法为以目标化合物稀释溶液来处理所选试虫：对粘虫处理浓度为600μg/mL，对蚊幼虫处理浓度为5μg/mL, 测试方法依照国标方法进行测试。在600μg/mL浓度下处理粘虫，在5μg/mL浓度下处理蚊幼虫，活性如表-3：Armyworms and mosquito larvae were selected as test objects, and the target compound was tested for activity screening. The test method was to treat the selected test insects with a diluted solution of the target compound: the treatment concentration for armyworms was 600 μg/mL, and the treatment concentration for mosquito larvae was 600 μg/mL. The test method is 5 μg/mL, and the test method is tested according to the national standard method. Treat armyworms at a concentration of 600 μg/mL and mosquito larvae at a concentration of 5 μg/mL, the activity is shown in Table-3:
表-3化合物的杀虫初筛活数据The insecticidal primary screening activity data of the compound of table-3
由实施例17之数据，可知化合物中的一些显示一定的杀虫活性，如：实施例9和10对粘虫幼虫具有一定的杀灭作用，而实施例4、7、8、10、13则对蚊幼虫具有一定的杀灭作用，故这类化合物有望作为杀虫剂先导进行研究。By the data of embodiment 17, some show certain insecticidal activity in known compound, as: embodiment 9 and 10 have certain killing effect to armyworm larvae, and embodiment 4,7,8,10,13 then It has a certain killing effect on mosquito larvae, so this kind of compound is expected to be studied as a lead insecticide.
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