CN115490647B - Malonate compound containing chiral isoxazole benzenesulfonamide group, preparation method and application - Google Patents
Malonate compound containing chiral isoxazole benzenesulfonamide group, preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a malonate compound containing a chiral isoxazole benzenesulfonamide group, which is characterized in that: the general formula is shown in the following formula (I):
in formula (I): c is a chiral carbon atom, wherein: r is R 1 Is C1-C3 alkyl; r is R 2 Phenyl, substituted phenyl, furyl, cyclohexyl or pentyl. The compound has the effects of resisting cucumber mosaic virus, potato late blight germ, pepper fusarium wilt germ, tobacco bacterial wilt germ, citrus canker germ, rice bacterial leaf blight germ and konjak soft rot germ.
Description
Technical Field
The invention relates to the technical field of chemistry, in particular to a malonate compound containing a chiral isoxazole benzenesulfonamide group, a preparation method of the compound and application of the compound in inhibiting cucumber mosaic virus, potato late blight bacteria, pepper wilt bacteria, tobacco bacterial wilt bacteria, citrus canker bacteria, rice bacterial wilt bacteria and konjak soft rot bacteria.
Background
The plant diseases caused by the trouble of diseases in crop planting can be mainly divided into three types, namely bacterial diseases, fungal diseases and viral diseases. Three diseases have posed a broad threat to plant species. Most crop diseases are complex infection, the symptom is complex, complications are easily caused to harm plant health, the damage is serious, the host direction is wide, and the prevention and the control are difficult. At present, the antiviral agents on the market such as Ningnanmycin, ribavirin and the like have unsatisfactory inhibiting effect on viruses, and copper-based bactericides such as copper thiodiazole and the like bring huge pressure to the environment and continuously improve the drug resistance of bacteria, so that the creation of low-cost, low-toxicity and high-efficiency antiviral agents and bactericides has become the primary task of agriculture.
Chiral drugs occupy a large proportion in currently used drugs, and it is reported that natural or semisynthetic drugs almost have chirality, and more than 700 currently used drugs have half at least one chiral center, so that a great deal of research on environmental behaviors of chiral pollutants and ecological effects considers raceme pollutants as single compounds, and only on the enantiomer form level, the environment problems of chiral pesticides can be accurately evaluated on the risk of human health and ecological systems, and experimental and theoretical basis are provided for the creation and development of efficient, low-toxicity and low-residue pesticides.
In 1999, the Lewis et al (Lewis D L, garrison A W, womack K E, et al Influence of environmental changes on degradation of chiral pollutants in soils [ J ]. Nature,1999, 401 (6756): 898-901.) systems studied the effect of selective degradation of enantiomers of chiral pesticides on environmental conditions, and they performed natural environmental degradation experiments and laboratory simulation experiments on DCPP and organophosphorus pesticides on different lands for hundreds of times, and as a result showed that DCPP and organophosphorus pesticides preferentially degrade different enantiomers in different environments, and that there were also significant differences in ER values, indicating that environmental conditions have an important effect on the selectivity of the environmental behavior of chiral pesticides.
In 2002, zadra et al (Zadra, C.; marucchini, C.; zazzerini, A.Behavior of metalaxyl and its pure R-enantiomer in sunflower plants (Helianthus annus) [ J ]. Journal of agricultural and food chemistry,2002,50 (19): 5373-5377.) studied the selective degradation behavior of the bactericidal metalaxyl enantiomer in sunflower, and the results indicated that the half-life of R-bodies was 24 days, the half-life of S-bodies was 21 days, and that the S-body content was greater than R-bodies in the leaves for the first 25 days, the ER value was between-0.14 and 0.02, and the ER value was gradually increased after 25 days, and that the ER value was 0.065R-body content was significantly greater than S-body content in 85 days.
In 2002, zhang et al (Zhang Huiping, jiang Linlin. Research on synthesis and bioactivity of chiral α -cyanoacrylate compounds [ J ]. Chemical and biological engineering, 2012,29 (10): 51-53.) used ethyl cyanoacetate as a starting material to synthesize a-p-trifluoromethylaniline-3- (R/S) -a-methylbenzylamine-2-cyanoacrylate, and structurally characterized intermediates and target compounds; and the biological activity of the a-cyanoacrylate compound is studied. The results show that the compounds have outstanding herbicidal activity, but have certain tobacco mosaic virus resistance and anticancer activity, and have the value of intensive research. The documents show that the compound containing the isoxazole benzenesulfonamide group has better antibacterial activity and the compound containing malonate has wide biological activity.
However, no report on the aspect of higher antibacterial activity of a series of chiral malonate compounds containing isoxazole benzenesulfonamide groups designed and synthesized by introducing isoxazole benzenesulfonamide groups into malonate derivatives with antibacterial activity is yet seen.
Disclosure of Invention
The invention aims to solve the technical problems that: provides a chiral alpha-malonate compound containing isoxazole benzenesulfonamide group and a preparation method thereof.
The invention also aims at preventing and controlling cucumber mosaic virus, potato late blight bacteria, pepper fusarium wilt bacteria, tobacco bacterial wilt bacteria, citrus canker bacteria, rice bacterial leaf blight bacteria and konjak soft rot bacteria.
The technical scheme of the invention is as follows: a malonate compound containing a chiral isoxazole benzenesulfonamide group has the general formula (I):
in formula (I): c is a chiral carbon atom, wherein: r is R 1 Is C1-C3 alkyl; r is R 2 Phenyl, substituted phenyl, furyl, cyclohexyl or pentyl.
The C1-C3 alkyl is methyl, ethyl or isopropyl.
The substituent of the substituted phenyl is halogen, methyl or methoxy.
The preparation method of the malonate compound containing the chiral isoxazole benzenesulfonamide group takes 4-amino-N- (5-chloroisoxazole-3-yl) benzenesulfonamide, substituted aldehyde and malonate as raw materials, takes chiral thiourea catalysts A1 and A2 as chiral catalysts and toluene as a solvent, and synthesizes the malonate compound containing the chiral isoxazole benzenesulfonamide group by a one-pot method, wherein the synthesis method comprises the following steps:
the malonic ester compound containing the chiral isoxazole benzenesulfonamide group is applied to the preparation of medicines and medicaments for preventing and treating crop diseases.
Crop diseases include plant fungal diseases, plant bacterial diseases and plant viral diseases.
The crop diseases comprise cucumber mosaic virus, potato late blight bacteria, pepper fusarium wilt bacteria, tobacco bacterial wilt bacteria, citrus canker bacteria, rice bacterial leaf blight bacteria and konjak soft rot bacteria.
Wherein a part of the compounds have the following structural characteristics:
| I 1 -(R)：R 1 ＝Et；R 2 ＝Ph； | I 1 -(S)：R 1 ＝Et；R 2 ＝Ph； |
| I 2 -(R)：R 1 ＝i-Pr；R 2 ＝4-Cl-Ph； | I 2 -(S)：R 1 ＝i-Pr；R 2 ＝4-Cl-Ph； |
| I 3 -(R)：R 1 ＝Me；R 2 ＝4-Me-Ph； | I 3 -(S)：R 1 ＝Me；R 2 ＝4-Me-Ph； |
| I 4 -(R)：R 1 ＝Et；R 2 ＝4-OMe-Ph； | I 4 -(S)：R 1 ＝Et；R 2 ＝4-OMe-Ph； |
| I 5 -(R)：R 1 ＝Et；R 2 ＝Furyl； | I 5 -(S)：R 1 ＝Et；R 2 ＝Furyl； |
| I 6 -(R)：R 1 ＝Me；R 2 ＝Ch； | I 6 -(S)：R 1 ＝Me；R 2 ＝Ch； |
| I 7 -(R)：R 1 ＝Et；R 2 ＝Pen； | I 7 -(S)：R 1 ＝Et；R 2 ＝Pen； |
the invention has the beneficial effects that: synthesis of isoxazole-containing benzenesulfonamide group-containing hand with cucumber mosaic virus, potato late blight germ, pepper blight germ, tobacco bacterial wilt germ, citrus canker germ, rice bacterial wilt germ, konjak soft rot germ resistanceAn alpha-malonate compound. The invention has the advantages of easily obtained raw materials, simple process, mild reaction conditions and high reaction yield. And in the present invention, compound I 5 In the aspect of preventing and controlling the activity of cucumber mosaic virus, the activity of the cucumber mosaic virus is superior to that of a commercial control medicament Ningnanmycin in treatment, protection and passivation. In addition, the invention also relates to the compound I with optimal biological activity 5 Is subjected to intensive studies and finally determines the activity-optimal compound I in the present invention 5 Is a continuous production and preparation method of the (C).
Detailed Description
Example 1: i 1 - (R): (R) -diethyl 2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (phenyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), benzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) and toluene (40 mL) were added as solvents, the reaction was carried out under ultrasound, TLC was carried out to monitor the progress of the reaction, after 4 hours, the reaction was completed, toluene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 1 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 23 H 24 ClN 3 O 7 S[M+H] + cacld: 522.11012,found:522.10.945.
example 2: i 1 - (S): (S) -diethyl 2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (phenyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), benzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was used to monitor the progress of the reaction, after 4 hours, the reaction was completed, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 1 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 23 H 24 ClN 3 O 7 S[M+H] + cacld: 522.11012,found:522.10.945.
example 3: i 2 - (R): (R) diisopropyl 2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (4-chlorophenyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-chlorobenzaldehyde (0.001 mol), diisopropyl malonate (0.0015 mol) and cinchona alkaloid chiral catalyst A2 (0.0001 mol) were added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasound, TLC was monitored for the progress of the reaction, toluene was recovered under reduced pressure after 4 hours, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 2 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 25 H 27 Cl 2 N 3 O 7 S[M+H] + cacld: 584.09741,found:584.09104.
example 4: i 2 - (S): (S) -2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (4-chlorophenyl) methyl) malonic acid diisopropyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-chlorobenzaldehyde (0.001 mol) and diisopropyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasound, TLC was monitored for progress, after 4 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 2 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 25 H 27 Cl 2 N 3 O 7 S[M+H] + cacld: 584.09741,found:584.09104.
example 5: i 3 - (R): (R) -2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (p-tolyl) methyl) malonic acid dimethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-methylbenzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) and toluene (40 mL) were added as solvents, the reaction was carried out under ultrasound, TLC was monitored for progress of the reaction, after 5 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 3 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 22 H 22 ClN 3 O 7 S[M+H] + cacld: 508.08123,found:508.018.
example 6: i 3 - (S): (S) -2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (p-tolyl) methyl) malonic acid dimethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-methylbenzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasound, TLC was monitored for progress, after 5 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 3 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 22 H 22 ClN 3 O 7 S[M+H] + cacld: 508.08123,found:508.018.
example 7: i 4 -(R)：(R)-2-((((4Diethyl- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (4-methoxyphenyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-methoxybenzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) and toluene (40 mL) were added as a solvent, the reaction was carried out under ultrasound, TLC was completed after 4 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 4 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 24 H 26 ClN 3 O 8 S[M+H] + cacld: 552.11202,found:552.11184.
example 8: i 4 - (S): (S) -diethyl 2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (4-methoxyphenyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), 4-methoxybenzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was terminated after 4 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 4 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 24 H 26 ClN 3 O 8 S[M+H] + cacld: 552.11202,found:552.11184.
example 9: i 5 - (R): (R) -2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) furan-2-yl) methyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), furaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) and toluene (40 mL) were added as solvents, the reaction was carried out under ultrasound, TLC was carried out to monitor the progress of the reaction, after 4 hours, the reaction was completed, toluene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 5 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 21 H 22 ClN 3 O 8 S[M+H] + cacld: 512.08552,found:512.08519.
example 10: i 5 - (S): (S) -2- ((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) furan-2-yl) methyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), furaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was monitored for the progress of the reaction, after 4 hours, the reaction was terminated, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 5 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 21 H 22 ClN 3 O 8 S[M+H] + cacld: 512.08552,found:512.08519.
example 11: i 6 - (R): (R) -2- (((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (cyclohexyl) methyl) malonic acid dimethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), cyclohexylformaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was terminated after 6 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 6 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 21 H 26 ClN 3 O 7 S[M+H] + cacld: 500.12118,found:500.12087.
example 12: i 6 - (S): (S) -2- (((((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) (cyclohexyl) methyl) malonic acid dimethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), cyclohexylformaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, a cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, toluene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was terminated after 6 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 6 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 21 H 26 ClN 3 O 7 S[M+H] + cacld: 500.12118,found:500.12087.
example 13: i 7 - (R): (R) -2- (1- ((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) hexyl) malonic acid diethyl ester; in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), valeraldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A2 (0.0001 mol) was added, benzene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was used to monitor the progress of the reaction, after 5 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 7 Physicochemical properties of- (R): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 22 H 30 ClN 3 O 7 S[M+H] + cacld: 516.15510,found:516.15483.
example 14: i 7 - (S): (S) -2- (1- ((4- (N- (5-chloroisoxazol-3-yl) sulfamoyl) phenyl) amino) hexyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (5-chloroisoxazol-3-yl) benzenesulfonamide (0.001 mol), valeraldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, cinchona alkaloid chiral catalyst A1 (0.0001 mol) was added, benzene (40 mL) was used as a solvent, the reaction was carried out under ultrasonic conditions, TLC was used to monitor the progress of the reaction, after 5 hours, toluene was recovered under reduced pressure, and the objective product was obtained by column chromatography (petroleum ether: ethyl acetate=6:1V/V).
I 7 Physicochemical properties of- (S): yellow oil, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR (100MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 22 H 30 ClN 3 O 7 S[M+H] + cacld: 516.15510,found:516.15483.
example 15: therapeutic, inactivating and protective activities of target compounds against cucumber mosaic virus
(1) Test method
A. Virus purification
Adopting a method of Chen (Chen, J.; et al 2017), selecting and inoculating for more than 3 weeks, infecting upper leaves of a host Nicotiana tabacum.L plant by a CMV system, homogenizing in a phosphate buffer, filtering by double-layer gauze, centrifuging at 8000g, treating by polyethylene glycol for 2 times, centrifuging again, and suspending the precipitate by the phosphate buffer to obtain the CMV refined extract. The whole experiment was performed at 4℃and the absorbance at 260nm was measured with an ultraviolet spectrophotometer, and the virus concentration was calculated according to the formula.
Virus concentration (mg/mL) = (A260×dilution)/E0.1% 1cm 260nm
Wherein E represents the extinction coefficient, i.e.the value of the light absorption (optical density) at an optical path length of l cm, of a suspension having a concentration of 0.1% (1 mg/mL) at a wavelength of 260 nm. E0.1% of CMV 1cm 260nm is 5.0.
B. Active therapeutic effects of agents on CMV infection: selecting purslane in 5-6 leaf period with growing vigor, topping, spreading silicon carbide uniformly on whole leaves, dipping virus juice (6×10-3 mg/mL) on whole leaves with a gang pen, inoculating virus, naturally airing, and washing with clear water. After the leaves are dried, the left half She Qing is lightly coated with a writing brush Shi Yaoji, the right half She Tushi is used as a control, the number of dead spots is recorded after 6-7 days, and the inhibition rate is calculated according to the following formula.
C. In vivo protection of CMV infection by agents
In vivo protection of CMV infection by agents: selecting purslane in 5-6 leaf period with consistent growth vigor, lightly coating Shi Yaoji on the left half She Qing by using a writing brush, using solvent with corresponding concentration on the right half She Tushi as a control, scattering silicon carbide evenly on the whole leaves after 24 hours, dipping virus juice (6X 10-3 mg/mL) of the whole leaf inoculated virus by using a gang pen, flushing by using clear water, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
D. In vivo inactivation of CMV infection by agents
The in-vivo deactivation of CMV infection by the agent comprises topping purslane in 5-6 leaf period with consistent growth vigour, sprinkling carborundum on whole leaves, and adding phosphoric acid buffer solution to the CMV; diluting the virus to 6X 10-3mg/mL, mixing the compound with an equal volume of virus juice, inactivating for 30 minutes, manually rubbing and inoculating the compound to the left half of Portulaca oleracea with silicon carbide scattered, mixing a solvent with the virus juice at a corresponding dosage, inoculating the compound to the right half of Portulaca oleracea with silicon carbide scattered, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
X％＝(CK－T)/CK×100
X is the relative inhibition rate (%),
CK average number of dead spots of half leaves without applied agent
T average number of dead spots of half leaf coated with Shi Yaoji
Wherein CK and T are the average of three replicates of each group
(2) Biological test results
TABLE 1 treatment, protection and inactivation Activity of target Compounds against cucumber mosaic Virus
The CMV activity of the target compound is tested by adopting a half-leaf spot-drying method with the concentration of 500mg/L and Ningnanmycin as a control medicament, and the biological activity measurement result of the table 1 shows that the malonate compound containing the chiral isoxazole benzenesulfonamide group has medium to excellent inhibitory activity on CMV, wherein I 5 (R) is superior to the control medicament Ningnanmycin in treatment, protection and passivation.
In order to further study the CMV resistance of malonate compounds containing chiral isoxazole benzenesulfonamide groups, we determined I in the compounds 5 (R) treatment of EC 50 Values, results are shown in Table 2.
TABLE 2 part of the therapeutic Activity of target Compounds against CMV EC 50 Value of
As can be seen from the results, I 5 (R) EC for CMV protective Activity 50 185.1 mug/mL, which is better than 236.0 mug/mL of control medicament Ningnanmycin
Example 16: inhibition activity of target compound on potato late blight bacteria and pepper fusarium wilt bacteria
(1) Test method
The bacteriostatic activity of the compounds was determined using the ex vivo growth rate method (Tarun, k.c.; et al, 2006). Potato dextrose agar medium (PDA medium: potato 200g, agar 20g, glucose 20g, distilled water 1000 mL) is heated to a molten state (40-60 ℃), 10mL of the liquid medicine (10 times of the final concentration of the liquid medicine) is poured into 90mL of PDA medium, fully and uniformly shaken, uniformly poured into a culture dish with the diameter of 9cm, horizontally placed, and cooled and solidified. The 4mm diameter bacterial dish is picked up by a puncher at the edge of the fresh pathogenic bacteria colony which has been cultivated for 4d, the bacterial dish is placed in the center of a reagent-containing PDA flat plate in an inverted mode, then the bacterial dish is placed in a 27 ℃ constant temperature and humidity incubator for inverted cultivation, observation is started when a blank control colony grows to be close to two thirds of the flat plate, the colony diameter is measured by a crisscross method, and the average value is obtained (Song Suqin, et al, 2004). The blank was not dosed, but contained the same concentration of solvent and 0.5% tween 20, and each treatment was repeated three times. The inhibition of hyphal growth by the agent was calculated by the following formula:
I(％)＝(C-T)/(C-0.4)×100％
where I is inhibition, C is blank diameter (cm), and T is treatment diameter (cm).
(2) Biological test results
TABLE 3 inhibition Activity of target Compounds against potato late blight pathogen, capsicum blight pathogen
As can be seen from the biological activity test results in Table 3, most of the compounds show higher inhibition activities on potato late blight bacteria and pepper fusarium wilt bacteria. Wherein I in the compound 5 (R)、I 7 The inhibition rate of (R) on potato late blight and pepper fusarium wilt is equivalent to the inhibition activity of the commercial control drug hymexazol on potato late blight and pepper fusarium wilt.
Example 17: inhibition activity of target compound on bacterial wilt, citrus canker, rice bacterial blight and konjak soft rot
(1) Test method
The bactericidal activity of the compounds was determined using nephelometry (Yang l.; et al, 2017). The test compound was prepared at a concentration of 100. Mu.g/mL. NB culture medium (3.0 g beef extract, 5.0g peptone, 1.0g yeast powder, 10.0g glucose, 1000mL distilled water, pH 7.0-7.2) is prepared, a small piece of culture medium containing tobacco bacterial wilt, citrus canker, rice bacterial blight and konjak soft rot is respectively inoculated by inoculation and circular cutting, the two NB culture mediums are placed, plugs are plugged, and the culture medium is subjected to shaking culture at a constant temperature of 180rpm until a growth log phase (OD=0.6-0.8) is reserved. mu.L of the bacterial liquid, 4mL of water-Tween (1% Tween 20) and 1mL of the prepared compound solution were taken, and the test tube was incubated at 28.+ -. 1 ℃ and continuously shaken at 180rpm for 1-3 days. Bacterial growth was monitored by measuring optical density at 595nm (OD 595), but with the same concentration of solvent and 0.1% Tween 20 as a blank, copper thiabendazole as a control agent, and each treatment was repeated three times. The inhibition of bacteria by the agent was calculated by the following formula:
I＝(Ctur-Ttur)/Ctur×100％
where I is the inhibition rate, ctur represents the corrected turbidity value of bacterial growth in the non-drug treated tube (blank), ttur represents the corrected turbidity value of bacterial growth in the compound treated tube.
(2) Biological test results
Table 4 inhibition Activity of target Compounds against Rhizoctonia solani, ulmaria tangutica, rhizoctonia solani, amorphophallus konjac soft rot
As can be seen from the biological activity test results in Table 4, at the concentration of 100 mug/mL, most of the compounds show higher inhibition activities on bacterial wilt, citrus canker, rice bacterial wilt and konjak soft rot. Wherein I in the compound 3 (R)、I 5 (R) and I 7 The inhibition rate of (R) on bacterial wilt bacteria, citrus canker bacteria, rice bacterial blight bacteria and konjak soft rot bacteria is higher than 90%, which is equivalent to commercial control medicine hymexazol.
The embodiment of the invention is assisted with the technical scheme of the invention. The invention has the advantages of simple synthetic route and higher yield, and obtains a novel and efficient novel medicament with inhibition effect on cucumber mosaic virus, potato late blight bacteria, pepper fusarium wilt bacteria, tobacco bacterial wilt bacteria, citrus canker bacteria, rice bacterial blight bacteria and konjak soft rot bacteria.
Claims (6)
1. A malonate compound containing a chiral isoxazole benzenesulfonamide group is characterized in that: the general formula is shown in the following formula (I):
in formula (I): c is a chiral carbon atom, wherein: r is R 1 Is C1-C3 alkyl; r is R 2 Phenyl, substituted phenyl, furyl, cyclohexyl or pentyl; the substituent of the substituted phenyl is halogen, methyl or methoxy.
2. The malonic ester compound containing a chiral isoxazole benzenesulfonamide group according to claim 1, which is characterized in that: the C1-C3 alkyl is methyl, ethyl or isopropyl.
3. The method for preparing the malonate compound containing the chiral isoxazole benzenesulfonamide group according to claim 1, which is characterized in that: the synthesis method of the malonate compound containing the chiral isoxazole benzene sulfonamide group by using 4-amino-N- (5-chloroisoxazole-3-yl) benzene sulfonamide, substituted aldehyde and malonate as raw materials, chiral thiourea catalysts A1 and A2 as chiral catalysts and toluene as a solvent through a one-pot method comprises the following synthesis routes:
4. the use of a malonate compound containing a chiral isoxazole benzenesulfonamide group according to any one of claims 1-2 for the preparation of a medicament for the control of crop diseases.
5. The use according to claim 4, characterized in that: the crop diseases are plant fungal diseases, plant bacterial diseases and plant virus diseases.
6. The use according to claim 4, characterized in that: the crop diseases are cucumber mosaic virus, potato late blight bacteria, pepper fusarium wilt bacteria, tobacco bacterial wilt bacteria, citrus canker bacteria, rice bacterial leaf blight bacteria and konjak soft rot bacteria.
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| US5514691A (en) * | 1993-05-20 | 1996-05-07 | Immunopharmaceutics, Inc. | N-(4-halo-isoxazolyl)-sulfonamides and derivatives thereof that modulate the activity of endothelin |
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