CN114957113A - 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate and preparation method and application thereof - Google Patents
2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pesticide chemical synthesis, and discloses 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate derivatives with bactericidal activity, a preparation method and application thereof, wherein the general formula is shown as formula I:
wherein R is selected from: one of hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, which is mono-or polysubstituted at the 5-to 8-positions of the quinoline ring. P-fluorobenzoyl chloride and sodium azide are subjected to nucleophilic substitution reaction to generate p-fluorobenzoyl azide, and then the p-fluorobenzoyl azide and 2-chlorine are subjected to nucleophilic substitution reactionQuinoline-3-formaldehyde oxime is subjected to a series reaction and is synthesized by one step. The method has the advantages of easily obtained raw materials, no need of catalysts and additives, simple and convenient operation, mild reaction conditions and high yield.
Description
Technical Field
The invention belongs to the technical field of pesticide chemical synthesis, and particularly relates to 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate and a preparation method and application thereof.
Background
The carbamate and oxime ester structure is an effective active group which is often selected in the creation of new pesticides, and has good biological activities of sterilization, disinsection, weeding, acaricidal activity, detoxification, synergism and the like. In particular, the oxime carbamate structure has the advantages of quick action effect, high selectivity, low toxicity, low residue, easy biodegradation and the like, is widely used as a bactericide, an insecticide and a herbicide in agriculture, and becomes a large class of pesticides. Commercial oxime carbamate pesticides such as methomyl (see structural formula 1) and monocarb (see structural formula 2) have been used for decades and are still a large variety of pesticides in the world.
However, because of single action mechanism and long-term and overuse, germs are easy to generate drug resistance to the pesticides, so that the original high-efficiency medicament loses activity. Meanwhile, the oxime carbamate pesticide has high aggregation toxicity, so that health hazards and environmental pollution are caused. Therefore, researchers have continuously innovated and improved oxime carbamate template structures to develop safer and more effective novel oxime carbamate pesticides (huaxi, wangqiao, bubal, xuhanhong, ouxiaming, patent of invention, CN 101343277; Chuai Youlian, Gao , Qianghao, patent of invention, CN 110156867A). For example, the song baoan topic group reported that an active group 1, 5-bis (2-fluorophenyl) -1, 4-pentadiene-3-one is introduced into an oxime carbamate structure, and the synthesized compound (see structural formula 3) has a certain bactericidal activity, has an inhibition rate of 53.4% for wheat scab pathogen at a concentration of 50mg/L, and is equivalent to the inhibition activity of a control medicament hymexazol, and is expected to develop a novel efficient pesticide (lisosbo, hudength, songbean, poplarn, jinlinhong, schofir, pinus, wangsanjun, chenzhuo, ruping, cancrixia, lingfang e, organic chemistry, 2008,28, 311-; sit et al synthesized 4-fluorobenzaldehyde oxime p-butoxyphenyl carbamate (see structural formula 4) compounds (S.Y.Sit, C.M.conway, K.Xie, R.Bertekap, C.bourin, K.D.Burris, Bioorganic & Medicinal Chemistry Letters,2010,20, 1272-; recently, a preparation method of an aryl ketoxime carbamate ester derivative (shown as a structural formula 5) by using aryl ketoxime, isonitrile and water as raw materials and performing a heating reaction under the conditions of using palladium salt as a catalyst and alkali as an additive has been disclosed (jianghuan peak, huwei, liu ocean, wuwanqing, invention patent CN 106146350 a).
On the other hand, nitrogen-containing heterocyclic compounds have become one of the development hotspots of pesticide lead compounds due to the characteristics of diversity of structural forms, good biological activity and selectivity and the like, and occupy a very important position. Among them, quinoline has broad-spectrum biological activity and low toxicity as a very important nitrogen-containing heterocyclic compound, has become a focus for developing new pesticides, and shows good development prospects. Quinoline compounds have been put on the market as a variety of agricultural chemicals, such as quinoline pesticide phenoxyquinoline (see structural formula 6) developed by dao chemical company of the united states, which has a specific effect on the control of powdery mildew, is able to inhibit the growth of attached spores, is harmless to crops, is environmentally safe, and is effective in controlling powdery mildew of cereal crops and vegetable crops (w.r.arnold, m.j.coglan, g.p.jourdan, e.v.krumkalns, and r.g.suhr.1992.quinoline and Cinnoline fungi compounds: US,5240940[ P ]). The quinoline amide (see structural formula 7) pesticide developed by the company has double activities of sterilization and disinsection, can be used as a high-efficiency bactericide, and has 100% control effect on rice blast and grape gray mold (R.E.Hackler, P.L.Johnson, G.P.Jourdan, J.G.Samaritoni, and B.R.Thoreen.1993.N- (4-pyridol or 4-quinolinyl) arylamide pesticides, WO,9304580[ P ]). Therefore, designing and synthesizing quinoline compounds with novel structures and finding high-activity lead compounds from the quinoline compounds to develop novel agricultural fungicides have become an important research direction in the field of pesticide synthesis (Rowei, invention patent CN 109384766A; Huahui, Tangjian, late Wei, Wujian, Liuying, Xulongxiang, Yangxi, Lidong, invention patent CN 111205223A; Tangjian, late Wei, Wujian, Liuying, Lidong, Zhao Mao, invention patent CN 108689928A). In this respect, Nisin, Chenli and the like respectively design and synthesize a class of fluorine-containing quinoline amide or ester compounds (see structural formula 8) according to an active substructure splicing method, and biological activity research shows that the compounds show excellent bactericidal activity on wheat take-all, wheat scab, wheat sharp eyespot, rice blast and the like, and the bactericidal rate reaches more than 90% at a concentration of 50mg/L (Nisin, Schwangming, Diangkun, Kongyan, Shijian, Liuhanhui, Kongjilin, Wenjian, Tanshima, organic chemistry 2015, 35, 2218-doped 2222; Chenli, Chengxian, invented patent, CN 112608277A).
In addition, because fluorine atoms have special properties such as electronic effect, simulation effect and the like, the biological activity of the compound can be multiplied, the physical properties of the compound can be improved, such as membrane permeability increase, hydrophobic function change, oxidation resistance improvement and the like, the fluorine atoms become important research fields of organic fluorine chemistry and pharmaceutical chemistry, and the fluorine atoms are widely applied to the aspects of medicine and pesticide creation.
Based on the research facts and according to the active substructure splicing principle, if quinoline rings and fluorobenzene can be constructed in an oxime carbamate structure to obtain a class of oxime carbamate new compounds, and evaluation of the bactericidal activity of the compounds is significant research work, the specific splicing principle is as follows:
therefore, if a simple and effective synthesis method can be provided to realize the assumption, the wide research and application of the derivatives are undoubtedly promoted, and a research idea is provided for designing and synthesizing similar oxime carbamate derivatives with different heterocyclic structures in the future, so that the method has important reference value. For constructing the oxime carbamate skeleton structure, the existing methods are few, and isocyanate is generally used as a reaction raw material. However, the method has the biggest problems that raw materials are not easy to obtain, and an isocyanate structure has high reactivity, is easy to generate self-polymerization reaction and has poor stability. The methods developed by the Jiangheng et al use aryl ketoxime, isonitrile and water as raw materials, and do not use isocyanate, but use expensive palladium catalysts, and have no practicability. The synthesis method of Sit et al uses carboxylic acid and Diphenylphosphorylazide (DPPA) as reaction raw materials, but the method has low yield, difficult separation and purification of the product, poor atom economy of the reaction, and high cost.
Disclosure of Invention
The invention aims to provide an oxime carbamate derivative with bactericidal activity and a preparation method thereof aiming at the current situation, wherein the method has the advantages of simple synthetic route, cheap and easily obtained required solvent and reagent, no need of any catalyst or additive, simple and convenient experimental operation, mild reaction condition, high yield and potential practical value.
The invention also provides application of the 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate in preparing a bactericide.
In order to solve the technical problem, the invention is realized as follows:
2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate having the general formula shown in formula I:
wherein R is selected from: one of hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, which is mono-or polysubstituted at the 5-to 8-positions of the quinoline ring.
The preparation method comprises the steps of taking p-fluorobenzoyl chloride as a raw material, carrying out nucleophilic substitution reaction with sodium azide to generate p-fluorobenzoyl azide, carrying out tandem reaction with 2-chloroquinoline-3-formaldoxime, and synthesizing the 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate compound in one step.
The preparation method of the 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate specifically comprises the following steps:
(1) dropwise adding an aqueous solution of sodium azide into an organic solution of p-fluorobenzoyl chloride at the temperature of ice water, and stirring and reacting at the temperature after dropwise adding; after the reaction is finished, extracting, washing, drying and distilling under reduced pressure to remove the solvent to obtain a p-fluorobenzoyl azide intermediate;
(2) dissolving p-fluorobenzoyl azide and 2-chloroquinoline-3-formaldehyde oxime in an organic solvent, and heating for reaction; after the reaction is finished, the target product 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate is obtained by decompressing, evaporating the solvent and separating through column chromatography.
Further, in step (1) of the present invention, the molar ratio of p-fluorobenzoyl chloride to sodium azide is 1: 1.0 to 2.0.
Further, in the step (2), the molar ratio of the p-fluorobenzoyl azide intermediate to the 2-chloroquinoline-3-carbaldehyde oxime is 1.0-2.0: 1.
further, in the step (1), stirring and reacting for 4-8 hours at an ice water temperature of 0-5 ℃; in the step (2), the heating reaction is heating to 80-120 ℃ for 3-10 hours.
Further, in step (1) of the present invention, the organic solution is one of acetone, dioxane, and N, N-dimethylformamide.
Further, in the step (2) of the present invention, the organic solvent is one of acetonitrile, dioxane or N, N-dimethylformamide.
Further, in the step (2) of the present invention, in the column chromatography, the eluent used is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 10-50: 1.
The preparation method is carried out according to the following chemical reaction formula:
the 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate has excellent bactericidal activity and can be applied to preparation of crop bacteria bactericides for preventing and treating wheat powdery mildew, gray mold and the like.
The specific reaction mechanism of the invention is as follows: p-fluorobenzoyl chloride and sodium azide are subjected to nucleophilic substitution reaction at ice water temperature, and the generated p-fluorobenzoyl azide intermediate and 2-chloroquinoline-3-formaldoxime are subjected to continuous Curtius rearrangement and oxime acylation reaction under the heating condition, so that the 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate compound is generated in one step.
Compared with the prior art, the invention has the following advantages:
(1) compared with the prior oxime carbamate compounds, the compound synthesized by the invention has quinoline ring and p-fluorobenzene structures. And the target has excellent bactericidal activity, can be used as a pesticide lead structure for deep research, and has certain reference and application values for pesticide formulation research.
(2) Compared with the traditional preparation method of the oxime carbamate compound, such as an isocyanate method and a noble metal catalysis method, the method for synthesizing the 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate has the advantages of easily obtained raw materials, simple synthesis route, cheap and easily obtained required solvent and reagent, simple and convenient experimental operation, no need of any catalyst or additive, mild reaction conditions, high yield and the like, thereby not only greatly improving the diversity and the synthesis efficiency of an active molecular framework, but also providing a new idea for designing and synthesizing the oxime carbamate compound containing other heterocycles in the future.
(3) The synthesized active 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate is used for developing high-efficiency and low-toxicity pesticides, and can be used for preparing bactericides.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the product obtained in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product obtained in example 1;
FIG. 3 is a NMR spectrum of the product obtained in example 2;
FIG. 4 is a NMR chart of the product obtained in example 2;
FIG. 5 is a NMR spectrum of the product obtained in example 3;
FIG. 6 is the NMR spectrum of the product obtained in example 3;
FIG. 7 is a NMR spectrum of the product obtained in example 4;
FIG. 8 is the NMR spectrum of the product obtained in example 4;
FIG. 9 is a NMR chart of the product obtained in example 5;
FIG. 10 is a NMR chart of the product obtained in example 5;
FIG. 11 is a NMR spectrum of the product obtained in example 6;
FIG. 12 is a NMR chart of the product obtained in example 6;
FIG. 13 is a NMR chart of the product obtained in example 7;
FIG. 14 is a NMR spectrum of the product obtained in example 7.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
EXAMPLE 12 Synthesis of chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 50mL acetone to allow complete dissolution. To this solution was added dropwise 15mL of an aqueous solution of sodium azide (0.488g, 7.5mmol) in an ice-water bath at 0 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 5 hours. TLC monitored the progress of the reaction. After the reaction, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give white p-fluorine of high purityBenzoyl azide 0.743g, yield 90%. Then, p-fluorobenzoylazide (0.297g, 1.8mmol) was weighed out and dissolved in acetonitrile (5mL) solvent, and 5mL of acetonitrile solution in which 2-chloroquinoline-3-carbaldehyde oxime (0.31g, 1.5mmol) was dissolved was added. The resulting solution was heated and stirred at 80 ℃ to generate bubbles, and reacted for 10 hours. TLC monitored the progress of the reaction. After the reaction is finished, reducing pressure to evaporate acetonitrile, and performing column chromatography separation and purification on the obtained crude product to obtain a white solid (eluent: petroleum ether: ethyl acetate (v/v) ═ 10:1), wherein the yield is 71.7 percent, and the m.p.139.3-140.2 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H,ArH),8.76(s,1H,HC＝N),8.03(d,J＝8.4Hz,1H,ArH),7.91(d,J＝8.0Hz,1H,ArH),7.82(t,J＝8.0Hz,1H,ArH),7.75(s,1H,NH),7.62(d,J＝7.6Hz,1H,ArH),7.45-7.48(m,2H,ArH),7.05(t,J＝8.0Hz,2H,ArH)； 13 C NMR(100MHz,CDCl 3 )δ160.81,158.39,151.57,150.70,148.80,148.59,137.54,132.58,128.53,128.13,126.52,122.16,121.60,116.04,115.81.
EXAMPLE 22 Synthesis of chloro-6-methylquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 50mL acetone to allow complete dissolution. To this solution was added dropwise 12mL of an aqueous solution of sodium azide (0.325g, 5mmol) in an ice-water bath at 5 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 4 hours. TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 0.702g of a white p-fluorobenzoyl azide having a higher purity in a yield of 85%. Then, p-fluorobenzoylazide (0.297g, 1.8mmol) was weighed out and dissolved in N, N-Dimethylformamide (DMF) (5mL), and 5mL of a solution of 2-chloro-6-methylquinoline-3-carboxaldoxime (0.331g, 1.5mmol) in N, N-Dimethylformamide (DMF) was added. The reaction solution was heated and stirred at 90 ℃ to generate bubbles, and the reaction was carried out for 8 hours. TLC monitored the progress of the reaction. After the reaction is finished, the solvent is evaporated out under reduced pressure, and the obtained crude product is separated and purified by column chromatography to obtain white solid(eluent: petroleum ether: ethyl acetate (v/v) ═ 20:1), yield 74.6%, m.p.155.8-156.3 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H,ArH),8.66(s,1H,HC＝N),7.93(d,J＝8.4Hz,1H,ArH),7.76(s,1H,NH),7.64(d,J＝7.6Hz,2H,ArH),7.45-7.49(m,2H,ArH),7.05(t,J＝8.4Hz,2H,ArH),2.54(s,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 )δ160.83,158.40,151.58,150.86,147.91,138.35,136.81,134.88,132.65,128.17,127.20,126.58,122.02,121.61,121.54,116.01,115.79,21.60.
EXAMPLE synthesis of 32-chloro-6-fluoroquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 30mL dioxane to allow complete dissolution. To this solution was added dropwise 20mL of an aqueous solution of sodium azide (0.651g, 10mmol) in an ice-water bath at 0 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 4 hours. TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 0.760g of white p-fluorobenzoylazide having a higher purity in a yield of 92%. Then, p-fluorobenzoylazide (0.248g, 1.5mmol) was weighed out and dissolved in dioxane (8mL) solvent, and 5mL of dioxane solution dissolved with 2-chloro-6-fluoroquinoline-3-aldoxime (0.337g, 1.5mmol) was added. The reaction solution was heated and stirred at 100 ℃ to generate bubbles, and reacted for 6 hours. TLC monitored the progress of the reaction. After the reaction is finished, the solvent is evaporated under reduced pressure, and the crude product is separated and purified by column chromatography to obtain a light yellow solid (eluent: petroleum ether: ethyl acetate (v/v) ═ 10:1), the yield is 72.7%, and m.p.220.9-221.3 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.90(s,1H,ArH),8.73(s,1H,HC＝N),7.75(d,J＝8.0Hz,2H,ArH),7.67(d,J＝7.6Hz,1H,ArH),7.47-7.53(m,3H,ArH and NH),7.06(t,J＝8.0Hz,2H,ArH)； 13 C NMR(100MHz,CDCl 3 )δ160.83,158.40,151.59,150.96,147.89,147.76,137.69,136.94,132.61,127.85,126.59,126.37,121.76,121.63,121.56,116.03,115.81.
EXAMPLE 42 Synthesis of chloro-6, 8-dimethylquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 30mL of N, N-Dimethylformamide (DMF) to allow complete dissolution. To this solution was added dropwise 12mL of an aqueous solution of sodium azide (0.325g, 5mmol) in an ice-water bath at 3 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 8 hours. TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.693g of white p-fluorobenzoyl azide having a higher purity in a yield of 84%. Then, p-fluorobenzoylazide (0.495g, 3mmol) was weighed out and dissolved in dioxane (10mL) solvent, and 6mL of dioxane solution dissolved with 2-chloro-6, 8-dimethylquinoline-3-aldoxime (0.469g, 2mmol) was added. The reaction solution was heated and stirred at 100 ℃ to cause bubbling, and the reaction was carried out for 4 hours. TLC monitored the progress of the reaction. After the reaction is finished, the solvent is evaporated under reduced pressure, and the crude product is separated and purified by column chromatography to obtain a light yellow solid (eluent: petroleum ether: ethyl acetate (v/v): 40:1), the yield is 68.4%, and m.p.164.9-166.1 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H,ArH),8.61(s,1H,HC＝N),7.80(s,1H,NH),7.45-7.49(m,4H,ArH),7.06(t,J＝8.4Hz,2H,ArH),2.72(s,3H,CH 3 ),2.49(s,3H,CH 3 ). 13 C NMR(100MHz,CDCl 3 )δ160.81,158.38,151.66,151.08,146.89,146.58,144.25,137.92,136.96,136.41,135.01,132.65,126.70,125.10,124.64,121.61,116.02,21.60,17.60.
EXAMPLE 52 Synthesis of chloro-6-ethylquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793 g)5mmol) and 50mL of acetone were dissolved completely. To this solution was added dropwise 15mL of an aqueous solution of sodium azide (0.488g, 7.5mmol) in an ice-water bath at 4 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 5 hours. TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.743g of white p-fluorobenzoylazide of higher purity in a yield of 90%. Then, p-fluorobenzoylazide (0.495g, 3mmol) was weighed out and dissolved in N, N-Dimethylformamide (DMF) (8mL), and 6mL of a solution of 2-chloro-6-ethylquinoline-3-aldoxime (0.352g, 1.5mmol) in DMF was added. The reaction solution was heated and stirred at 120 ℃ to generate bubbles, and reacted for 3 hours. TLC monitored the progress of the reaction. After the reaction is finished, the solvent is evaporated under reduced pressure, and the crude product is separated and purified by column chromatography to obtain a white solid (eluent: petroleum ether: ethyl acetate (v/v) ═ 20:1), the yield is 82.5%, and the m.p.153.2-154.4 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H,ArH),8.69(s,1H,HC＝N),7.95(d,J＝8.4Hz,1H,ArH),7.83(s,1H,NH),7.69(d,J＝8.4Hz,2H,ArH),7.46-7.49(m,2H,ArH),7.05(t,J＝8.0Hz,2H,ArH),2.84(q,J＝7.6Hz,2H,CH 2 CH 3 ),1.33(t,J＝7.2Hz,3H,CH 2 CH 3 )； 13 C NMR(100MHz,CDCl 3 )δ160.79,158.36,151.62,150.80,147.92,144.46,136.99,133.94,132.67,128.25,126.63,125.90,121.93,121.58,121.52,116.01,115.78,28.79,15.09.
EXAMPLE 62 Synthesis of chloro-6-methoxyquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 50mL acetone to allow complete dissolution. To this solution was added dropwise 20mL of an aqueous solution of sodium azide (0.65g, 10mmol) in an ice-water bath at 0 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 5 hours. TLC monitored the progress of the reaction. After the reaction, the reaction solution was extracted with ethyl acetate(25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 0.776g of a white p-fluorobenzoylazide of higher purity in 94% yield. Then, p-fluorobenzoylazide (0.297g, 1.8mmol) was weighed out and dissolved in N, N-Dimethylformamide (DMF) (6mL), and 6mL of a solution of 2-chloro-6-methoxyquinoline-3-carboxaldoxime (0.355g, 1.5mmol) in DMF was added. The reaction solution was heated and stirred at 120 ℃ to generate bubbles, and reacted for 3 hours. TLC monitored the progress of the reaction. After the reaction is finished, the solvent is evaporated under reduced pressure, and the crude product is separated and purified by column chromatography to obtain a white solid (eluent: petroleum ether: ethyl acetate (v/v) ═ 30:1), the yield is 81.6%, and the m.p.149.5-152.1 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H,ArH),8.67(s,1H,HC＝N),7.92(d,J＝8.0Hz,1H,ArH),7.71(s,1H,NH),7.46-7.54(m,3H,ArH),7.15(s,1H,ArH),7.07(t,J＝8.0Hz,2H,ArH),3.94(s,3H,OCH 3 )； 13 C NMR(100MHz,CDCl 3 )δ158.79,150.88,146.27,144.84,143.13,136.00,130.92,130.23,129.91,128.81,127.75,126.73,125.52,116.05,115.83,105.45,105.07,55.73.
EXAMPLE 72 Synthesis of chloro-6-tert-butylquinoline-3-aldoxime-O- (N-p-fluorophenyl) carbamate
To a 150mL round bottom flask was added p-fluorobenzoyl chloride (0.793g, 5mmol) and 50mL acetone to allow complete dissolution. To this solution was added dropwise 15mL of an aqueous solution of sodium azide (0.488g, 7.5mmol) in an ice-water bath at 0 ℃. At the end of the dropwise addition, stirring was continued at this temperature for 5 hours. TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (25 mL. times.3), the organic phase was washed twice with water (25 mL. times.2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 0.743g of white p-fluorobenzoylazide having a higher purity in a yield of 90%. Then, p-fluorobenzoylazide (0.198g, 1.2mmol) was weighed out and dissolved in dioxane (8mL) solvent, and 5mL of dioxane solution dissolved with 2-chloro-6-tert-butylquinoline-3-aldoxime (0.263g, 1.0mmol) was added. The obtained reaction solution is heated and stirred at the temperature of 100 ℃, bubbles are generated, and the reaction 6And (4) hours. TLC monitored the progress of the reaction. After the reaction is finished, reducing pressure to evaporate acetonitrile, and performing column chromatography separation and purification on the obtained crude product to obtain a white solid (eluent: petroleum ether: ethyl acetate (v/v): 50:1), wherein the yield is 71.2%; m.p.164.9-166.1 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H,ArH),8.74(s,1H,HC＝N),7.98(d,J＝8.8Hz,1H,ArH),7.93(d,J＝8.8Hz,1H,ArH),7.83(s,1H,ArH),7.78(s,1H,NH),7.50(d,J＝8.8Hz,1H,ArH),7.47(d,J＝8.4Hz,1H,ArH),7.06(t,J＝8.4Hz,2H,ArH),1.41(s,9H,t-Bu)； 13 C NMR(100MHz,CDCl 3 )δ160.81,151.58,151.29,150.81,148.16,147.26,137.47,132.65,131.73,128.03,126.34,123.45,121.89,121.62,121.55,116.02,115.80,35.12,31.01.
example 8 bactericidal Activity assay
1. Test bacterium
Pyricularia oryzae (Pyricularia oryzae), Botrytis cinerea (Botrytis cinerea), Pseudoperonospora cubensis (Pseudoperonospora cubensis), Blumeria graminis (Blumeia graminis), Puccinia sorghi (Puccinia sorghi), Cucumis sativus (Cucumis sativus L., variety Kyoto, New Zephysa 4), Triticum aestivum L., variety Zhoumai No. 12), Zea mays (Zea mays L., variety white sticky);
2. measurement method
1) Spore germination test method
The spore germination test method measures the bactericidal activity of a target compound on rice blast (rice blast) and gray mold (gray mold), and measures the spore germination activity of a sample for inhibiting rice pyricularia oryzae (rice blast) and gray botrytis (vegetable gray mold) by adding a test sample into a culture solution. The concentration of the test samples is 8.33 mg/L; the concentrations of the control medicaments isoprothiolane and fluazinam are both 8.33 mg/L.
2) Potted seedling testing method
The bactericidal activity of the target compound on cucumber downy mildew (cucumber downy mildew), wheat powdery mildew (wheat powdery mildew), wheat rust (wheat rust) and cucumber anthracnose (cucumber anthracnose) is determined by a pot seedling test method.
Host plant culture
Cucumber, wheat and corn seedlings are cultivated in a greenhouse and grow to the 2-leaf stage for later use.
② preparing liquid medicine
Accurately weighing sample of the preparation, adding solvent and 0.05% Tween-20 tap water, and preparing into liquid medicines each 20ml of 50mg/L for research on bactericidal activity of live vaccine. The concentrations of the contrast agents of cyazofamid, kresoxim-methyl, tebuconazole and prochloraz are all 25 mg/L.
(iii) spray treatment
The sprayer is a crop sprayer, the spraying pressure is 1.5kg/cm2, and the liquid spraying amount is about 1000L/hm 2 . After the test material is treated, the test material is naturally air-dried and inoculated with pathogenic bacteria after 24 hours.
Fourthly, inoculation of pathogenic bacteria
The inoculator sprays a cucumber downy mildew sporangium suspension (5X 105 spores/ml), a cucumber colletotrichum spore suspension (5X 105 spores/ml) and a maize rust spore suspension (5X 106 spores/ml) onto the host crop, respectively, and then moves into a climatic chamber for cultivation (24 ℃, RH >90, no light). After 24h, the test materials are moved to a greenhouse for normal management, and the bactericidal activity of the test samples is investigated after 4-7 d; the spores of Erysiphe graminis were shaken on wheat and cultured in a greenhouse, and the bactericidal activity of the compounds was investigated after 5-7 days.
Evaluation of Fungicide Activity
The spore germination test adopts an HTS evaluation method, and the pot culture test adopts an eye observation method to investigate the bactericidal activity of a test sample according to the morbidity degree of a control. Results were shown in 100-0 with reference to the American society for Plant Diseases, with results on four grades, a "100" grade representing no disease or no germination of spores, a "80" grade representing a small amount of germination or germination but growth of sterile silk, a "50" grade representing about 50% germination of spores and a shorter hyphae after germination, and a "0" grade representing the most severe degree of disease or similar to the blank control. The preliminary biological activity test result (shown in table 1) shows that the designed 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate new compound has excellent bactericidal activity on Wheat Powdery Mildew (WPM) and Gray Mold (GM), and the bactericidal rate is up to more than 80%; the bactericidal composition has moderate inhibitory activity on Cucumber Downy Mildew (CDM) and Wheat Rust (WR), and the bactericidal rate is 40-70%; the bactericidal activity to Cucumber Anthracnose (CA) and Rice Blast (RB) is lower and is below 40 percent.
TABLE 1 fungicidal Activity data for the target Compounds
Note: CDM: cucumber downy mildew; WPM: wheat powdery mildew; WR: wheat rust; CA: anthracnose of cucumber; RB: rice blast; GM: gray mold.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
- 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate, characterized by the general formula shown in formula I:
wherein R is selected from: one of hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, which is mono-or polysubstituted at the 5-to 8-positions of the quinoline ring. - 2. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate according to claim 1, comprising the steps of:(1) dropwise adding a sodium azide aqueous solution into an organic solution of p-fluorobenzoyl chloride at an ice water temperature, and stirring for reaction after dropwise addition is finished; after the reaction is finished, extracting, washing, drying and decompressing and distilling off the solvent to obtain a p-fluorobenzoyl azide intermediate;(2) dissolving the obtained p-fluorobenzoyl azide intermediate and 2-chloroquinoline-3-formaldehyde oxime in an organic solvent, and heating for reaction; after the reaction is finished, the solvent is evaporated out by decompression and separated by column chromatography to obtain the target product 2-chloroquinoline-3-formaldehyde oxime-O- (N-p-fluorophenyl) carbamate.
- 3. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate as claimed in claim 2, wherein: in the step (1), the molar ratio of the p-fluorobenzoyl chloride to the sodium azide is 1: 1.0 to 2.0.
- 4. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate as claimed in claim 3, wherein: in the step (2), the molar ratio of the p-fluorobenzoyl azide to the 2-chloroquinoline-3-carbaldehyde oxime is 1.0-2.0: 1.
- 5. the method for preparing 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate according to claim 4, wherein: in the step (1), the temperature of ice water is 0-5 ℃, and the reaction is carried out for 4-8 hours; in the step (2), the heating reaction is heating to 80-120 ℃ and reacting for 3-10 hours.
- 6. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate as claimed in claim 5, wherein: in the step (1), the organic solution is one of acetone, dioxane or N, N-dimethylformamide.
- 7. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate as claimed in claim 6, wherein: in the step (2), the organic solvent is one of acetonitrile, dioxane or N, N-dimethylformamide.
- 8. The process for the preparation of 2-chloroquinoline-3-carbaldehyde oxime-O- (N-p-fluorophenyl) carbamate as claimed in claim 7, wherein: in the step (2), in the column chromatography, the eluent is a mixed solvent of petroleum ether and ethyl acetate; the volume ratio of the petroleum ether to the ethyl acetate is 10-50: 1.
- 9. An application of the 2-chloroquinoline-3-formaldoxime-O- (N-p-fluorophenyl) carbamate as defined in any one of claims 1 to 8 in preparation of a bactericide.
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| CN101691354A (en) * | 2009-09-29 | 2010-04-07 | 浙江工业大学 | Method for chemically synthesizing 2-heteroaryl substituted quinoline derivatives |
| CN109422680A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of N- acetylquinoline -2- amide and its derivative |
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| CN101691354A (en) * | 2009-09-29 | 2010-04-07 | 浙江工业大学 | Method for chemically synthesizing 2-heteroaryl substituted quinoline derivatives |
| CN109422680A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of N- acetylquinoline -2- amide and its derivative |
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