CN108659014B - Preparation and application of ethyl chain demethyl cantharidimide dimer - Google Patents
Preparation and application of ethyl chain demethyl cantharidimide dimer Download PDFInfo
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- -1 ethyl chain demethyl cantharidimide dimer Chemical class 0.000 title claims abstract description 17
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- PHOUKBDDOYWEMY-UHFFFAOYSA-N cantharidinimide Natural products O1C2CCC1C1(C)C2(C)C(=O)NC1=O PHOUKBDDOYWEMY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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- Engineering & Computer Science (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a butyl-connected cantharidimide dimer compound which is colorless and transparent microcrystal in appearance, has a melting point of 234.0-238.3 ℃ and a molecular formula C20H24N2O6Molecular weight is 388.41, and its structure is as follows:
Description
The technical field is as follows:
the invention relates to the field of fluorescent materials and pesticide chemistry, in particular to a preparation method of demethyl cantharidimide dimer and application in the field of fluorescent materials and pesticide chemistry.
Background art:
cantharidin is an effective component of the traditional Chinese natural medicament cantharidin, can break primary and secondary DNA structures of cancer cells and further enable the cancer cells to be programmed to die, but the cantharidin is extremely toxic and difficult to synthesize, so that the clinical application of the cantharidin is limited. The demethyl cantharidin imide derivative not only retains the antitumor activity of demethyl cantharidin, but also has the characteristics of changeable structure, easy modification, coordination with metal and the like, and anticancer drug molecules with low toxicity and high activity can be obtained through structural modification; on the other hand, a dimer structure widely existing in natural products is generally recognized to have a better biological activity than a corresponding monomer structure, and drug molecules having the dimer structure have been synthesized in a large amount and used for treating cancer, aids, alzheimer's disease, malaria and various parasitic diseases. However, the type of the cantharidimide-based dimer is very few, and at present, more than ten types are reported in various literatures; the applicant subject group has been engaged in the research of cantharidin derivatives in the field of anticancer drugs for many years, and recently found that such derivatives have special applications in the fields of fluorescent materials and pesticide chemistry.
The organic fluorescent materials are various in types, mostly have conjugated heterocycles and various chromophores, the structures are easy to adjust, and the conjugated length of the organic fluorescent materials is changed by introducing unsaturated groups such as olefinic bonds, benzene rings and the like and various chromophores, so that the photoelectric properties of the compounds are changed. Such as oxadiazole and derivatives thereof, triazole and derivatives thereof, rhodamine and derivatives thereof, coumarin derivatives, 1, 8-naphthalimide derivatives, pyrazoline derivatives, triphenylamine derivatives, porphyrin compounds, carbazole, pyrazine, thiazole derivatives, perylene derivatives and the like. They are widely used in the fields of optical electronic devices, DNA diagnosis, photochemical sensors, organic pigments, dyes, fluorescent whitening agents, photo-oxidants, fluorescent coatings, laser dyes, organic electroluminescent devices (ELD) chemical and biochemical analysis, solar traps, anti-counterfeiting marks, drug tracing, lasers and the like. However, no fluorescent material using demethyl cantharidimide dimer as a skeleton has been reported.
Cantharidin has been rarely studied for pesticides, and in 1974 James e. carrel and Thomas Eisner, written in Science, was at 10-5mol.L-1At very low concentrations, cantharidin has antifeedant effects against a variety of insects. In addition, it also has stomach toxicity, contact killing, and systemic effects. Cantharidin has wide insecticidal spectrum, has strong effect on lepidoptera and homoptera insects, and has obvious inhibition effect on various plant pathogenic fungi. Chenyong et al found that norcantharidin is similar to cantharidin, and has strong stomach toxicity and non-selective antifeedant effect on diamondback moth larvae. However, the toxic activity of norcantharidin is weaker than that of cantharidin, and a good toxic effect can be achieved by increasing the using dosage or adding a synergist. The research of the demethyl cantharidimide dimer used for pesticides is not reported.
Disclosure of Invention
1. Structural characterization
The invention relates to a method for preparing ethyl (namely- (CH) by various methods2)2-) is a linked demethylcantharidimide dimer, the structure and related characterization parameters of which are as follows:
the compound is colorless transparent microcrystalline in appearance, has melting point of 261.2-261.5 deg.C, and has molecular formula C18H20N2O6Molecular weight 360.36, chemical name: 2,2' - (ETHANE-1, 2-DIYL) BIS [ HEXAHYDRO-4, 7-OXY-1H-ISOINDOLE-1, 3(2H) -DIONE]The English system is named as: 2,2' - (1,2-ethanediyl) bis [ hexahydro-4, 7-epoxy-1H-isoindolole-1, 3(2H) -dione]The structure is as follows:
elemental analysis showed that the dimer C, H, N was present in 60.12%, 5.65% and 7.79% percent (by formula C)18H20N2O6Calculated theoretical values of 59.99%, 5.59% and 7.77%, respectively); by passing1HNMR and13the structure of the CNMR nuclear magnetic resonance is characterized by the CNMR nuclear magnetic resonance method, and the related spectrograms are respectively shown in figure 1 and figure 2.
2. Synthesis method
The dimer has five synthesis methods: the first method takes unsaturated demethyl cantharidin and ethylenediamine as raw materials and comprises the following steps:
respectively dissolving unsaturated demethylcantharidin and ethylenediamine in a proper organic solvent, mixing according to a certain substance amount ratio, stirring at a certain temperature for reacting for a certain time to obtain a white powdery solid, volatilizing the concentrated solution, filtering, washing the powdery solid with a proper solvent, and then recrystallizing by a proper solvent to obtain a white small blocky crystal A, wherein the component of the white small blocky crystal A is 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -diketone); dissolving the crystal in a proper organic solvent, adding a certain amount of palladium-carbon catalyst, introducing hydrogen, stirring and reacting for a certain time at a certain temperature, filtering, standing and volatilizing, and separating out fine transparent crystal grains which are target product crystals from the solution after several days; in one step of preparing the white small blocky crystal A, the reaction solvent is not needed, the two raw materials are directly mixed according to a certain material quantity ratio, grinding is carried out at normal temperature to obtain paste, and the obtained solid is recrystallized by using a proper solvent to obtain the crystal A.
The second method takes unsaturated demethyl cantharidimide and 1, 2-dibromoethane as raw materials and comprises the following steps:
dissolving unsaturated demethyl cantharidimide and 1, 2-dibromoethane in a proper organic solvent, mixing according to a certain amount of substances, stirring and reacting at a certain temperature for a certain time to obtain a white small blocky solid, volatilizing and concentrating the solution, filtering, washing the powdery solid with a proper solvent, and then recrystallizing by a proper solvent to obtain a white small blocky crystal A, wherein the component of the white small blocky crystal A is 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -diketone); dissolving the crystal in a proper organic solvent, adding a certain amount of palladium-carbon catalyst, introducing hydrogen, stirring and reacting for a certain time at a certain temperature, filtering, standing and volatilizing, and separating out fine transparent crystal grains which are target product crystals from the solution after several days; in one step of preparing the white small blocky crystal A, the reaction solvent is not needed, the two raw materials are directly mixed according to a certain material quantity ratio, grinding is carried out at normal temperature to obtain paste, and the obtained solid is recrystallized by using a proper solvent to obtain the crystal A.
In the third method, furan and 1, 1' - (ethane-1, 2-diyl) -di (1H-pyrrole-2, 5-dione) are used as raw materials, and the steps are as follows:
dissolving 1,1 '- (ethane-1, 2-diyl) -bis (1H-pyrrole-2, 5-dione) in a suitable organic solvent, adding furan according to a certain amount of substance, stirring at a certain temperature for reaction or standing for a certain time to obtain a white powdery solid, volatilizing the concentrated solution, filtering, washing the powdery solid with a suitable solvent, and recrystallizing by using a suitable solvent to obtain a white small blocky crystal A, wherein the component is 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -dione); dissolving the crystal in a proper organic solvent, adding a certain amount of palladium-carbon catalyst, introducing hydrogen, stirring and reacting for a certain time at a certain temperature, filtering, standing and volatilizing, and separating out fine transparent crystal grains which are target product crystals from the solution after several days; in one step of preparing the white small blocky crystal A, the reaction solvent is not needed, the two raw materials are directly mixed according to a certain material quantity ratio, grinding is carried out at normal temperature to obtain paste, and the obtained solid is recrystallized by using a proper solvent to obtain the crystal A.
Method one, method two and method three are all two-step reactions which differ in the reactants, but the molar ratios of the reactants are all between 4:1 and 1: 2.
The method IV takes demethyl cantharidin and ethylenediamine as raw materials and comprises the following steps:
respectively dissolving demethylcantharidin and ethylenediamine in a proper organic solvent, mixing according to a certain substance amount ratio, stirring at a certain temperature for reacting for a certain time to obtain a white powdery solid, volatilizing the concentrated solution, filtering, washing the powdery solid with a proper solvent, and then recrystallizing with a proper solvent to obtain a target product; or directly mixing the two raw materials according to a certain mass ratio without using a reaction solvent, grinding at normal temperature to obtain a paste, and recrystallizing the obtained solid by using a proper solvent to obtain the target product.
The method V takes demethyl cantharidimide and 1, 2-dibromoethane as raw materials and comprises the following steps:
dissolving demethyl cantharidimide and 1, 2-dibromoethane in a proper organic solvent, mixing according to a certain substance quantity ratio, stirring and reacting for a certain time at a certain temperature to obtain white powdery solid, volatilizing the concentrated solution, filtering, washing the powdery solid with a proper solvent, and then recrystallizing through a proper solvent to obtain a target product; or directly mixing the two raw materials according to a certain mass ratio without using a reaction solvent to obtain a paste, grinding at normal temperature, and recrystallizing the obtained solid with a proper solvent to obtain the target product.
Method four and method five are single step reactions which differ in the reactants but the molar ratios of the reactants are between 4:1 and 1: 2.
The organic solvent (including solvent for reaction, washing and recrystallization) in the above five methods is selected from: methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, toluene, acetone, N-Dimethylformamide (DMF), and the like; no solvent is used in the solid phase reaction.
Preferably, the reaction temperature and the recrystallization temperature are normal temperature or heating, the reaction method is stirring or standing, and the recrystallization method is natural volatilization in a standing state.
Preferably, the reaction time and recrystallization time are selected from: 2 hours to 3 days.
The invention has the beneficial effects that: can synthesize complex fluorescent materials and pesticide raw materials by simple steps and reactants.
3. Ultraviolet and fluorescent properties.
At 10-5The ultraviolet spectrum of the compound is tested in a mol/L ethanol solution, and the compound is found to have an ultraviolet absorption peak near 233nm (shown in figure 3).
Is also at 10-5In mol/L ethanol solution, ultraviolet light with the wavelengths of 253nm, 273nm and 293nm is respectively used for excitation, the fluorescence property of the compound is tested, strong fluorescence emission is found between 325 nm and 525nm, fluorescence generated by excitation of the ultraviolet light with the wavelength of 293nm is especially strong, even can be seen by naked eyes, and the fluorescence spectrum is shown in figure 4.
4. And (4) insecticidal experiments.
The method comprises the steps of taking diamondback moth larvae as an experimental object for insecticidal experiments, testing by using a 75% ethanol solution, measuring the comprehensive toxicity of the compound to the diamondback moth larvae by using an insect soaking method, predicting the lowest full lethal concentration and the highest full survival concentration of the diamondback moth larvae according to a preliminary experiment, setting 5-7 gradient concentrations within the range, soaking 3-year-old diamondback moth larvae into the liquid medicine with each concentration for 5 seconds, then placing the larvae on absorbent paper to absorb the redundant liquid medicine on the larvae, placing the larvae into a cylindrical bottle (the diameter is 3.5cm, and the height is 7.5cm) paved with moisturizing filter paper, soaking cabbage leaves (the size is about 2cm × cm) in the liquid medicine for 2-3 seconds, absorbing the redundant liquid medicine, placing the larvae into the cylindrical bottle for feeding, treating 10 larvae each time, repeating each concentration gradient for three times, treating with clear water as a control, placing each treatment into a climatic incubator, controlling the humidity to be about 25 ℃, controlling the relative humidity to be 75% in a photoperiod 14/10(L/D), examining the death condition after 24 hours, and counting the death condition according to obtain the toxicity value of the compound, and calculating the LC concentration of the LC 35 mg/125 mg of the larvae.
5. And (5) a fungus inhibition experiment.
The activity test of two plant pathogenic bacteria (rice blast and tomato wilt) is carried out by adopting a bacterium block method, and a culture medium is a potato agar culture medium (PDA): peeled potato 200g, cane sugar 15g, agar 17g and distilled water 1000 ml; after the hyphae grow well, a sterilized block maker with the diameter of 0.8cm is used for making the hyphae into a fungus block, then the fungus block is clamped by a sterilized forceps and placed in the center of a culture dish containing 100mg/L compound solution (the solvent is 25% ethanol solution), one cell in each dish and one group in three dishes are placed at 27 ℃ for culturing for 72 hours, the diameter of the bacterial plaque is measured, and compared with a blank experiment, the hyphae growth inhibition rate is calculated by the following formula:
inhibition ratio (average colony diameter of control group-average colony diameter of treated group) ÷ average colony diameter of control group × 100%
Test results show that the inhibition rates of the compound on rice blast bacteria and tomato fusarium wilt bacteria are 89% and 91% respectively.
6. Detailed description of the preferred embodiments
In order to better understand the present invention, the following five specific examples further illustrate the technical solution of the present invention.
Example 1.
Weighing 3.32g of unsaturated norcantharidin (0.02mol) and dissolving in 50mL of toluene, stirring vigorously, adding 0.81mL (0.01mol) of 1, 2-ethylenediamine, stirring at normal temperature for 24H to obtain a white suspension, volatilizing the solvent to obtain about 10mL, filtering, washing the precipitate with dichloromethane, and recrystallizing with methanol to obtain a white small-blocky crystal called crystal A, wherein the component is 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -dione); weighing 0.50g of crystal A0, adding 40mL of methanol, carrying out ultrasonic oscillation for 10min, adding 0.05g of palladium-carbon catalyst, introducing hydrogen, reacting for 8h at 40 ℃, filtering after the reaction is finished, standing for volatilization, and precipitating fine transparent crystal grains in the solution after three days to obtain the target product.
Example 2.
Dissolving 0.33g of unsaturated demethylcantharidimide in 30ml of acetone, adding 0.19g of 1, 2-dibromoethane according to the mass ratio of 2:1, stirring at normal temperature for 24H to obtain a white suspension, volatilizing the solvent to obtain about 10ml of the residual solvent, filtering, washing the precipitate with dichloromethane, and then recrystallizing with methanol to obtain a white small blocky crystal called crystal A, wherein the component is 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -diketone); weighing 0.50g of crystal A0, adding 40mL of methanol, carrying out ultrasonic oscillation for 10min, adding 0.05g of palladium-carbon catalyst, introducing hydrogen, reacting for 8h at 40 ℃, filtering after the reaction is finished, standing for volatilization, and precipitating fine transparent crystal grains in the solution after three days to obtain the target product.
Example 3.
0.22g of 1,1 '- (ethane-1, 2-diyl) -bis (1H-pyrrole-2, 5-dione) was dissolved in 50ml of toluene, 0.20g of furan was added in an amount of 1:2 based on the amount of the substance, the solution was concentrated to 20ml after refluxing for 10 hours, filtered, and the precipitate was washed with dichloromethane and then recrystallized from methanol to give a white small lump of crystal A, which was 2,2' - (ethane-1, 2-diyl) bis (3a,4,7,7 a-tetrahydro-4, 7-epoxy-1H-isoindole-1,3(2H) -dione); weighing 0.50g of crystal A0, adding 40mL of methanol, carrying out ultrasonic oscillation for 10min, adding 0.05g of palladium-carbon catalyst, introducing hydrogen, reacting for 8h at 40 ℃, filtering after the reaction is finished, standing for volatilization, and precipitating fine transparent crystal grains in the solution after three days to obtain the target product.
Example 4.
Weighing 3.36g of norcantharidin, putting into a mortar, adding 0.6g of ethylenediamine, grinding at normal temperature for 4h to obtain paste, adding 80ml of methanol to dissolve, filtering, standing for volatilization, and after three days, precipitating fine transparent grains in the solution to obtain the target product.
Example 5.
Weighing 3.34g of demethyl cantharidimide, putting the demethyl cantharidimide into a mortar, adding 1.88g of 1, 2-dibromoethane, grinding for 4 hours at normal temperature to obtain paste, adding 80ml of methanol to dissolve, filtering, standing and volatilizing, and precipitating fine transparent grains in the solution after three days to obtain the target product.
7. Description of the drawings
FIG. 1 is a drawing of a target compound1HNMR spectrogram.
FIG. 2 is a drawing of a target compound13CNMR spectrogram.
FIG. 3 is a UV-Vis spectrum of the target compound.
FIG. 4 is a fluorescence spectrum of a target compound.
Claims (3)
1. An ethyl-linked cantharidimide dimer compound with colorless transparent microcrystalline appearance, melting point of 261.2-261.5 deg.C, and molecular formula C18H20N2O6Molecular weight is 360.36, and its structure is as follows:
2. the process for preparing a cantharidimide dimer compound as claimed in claim 1, which comprises: two reactants are taken as raw materials, one-step or two-step reaction is carried out in a proper organic solvent, or the reaction can be directly finished by the two raw materials without the solvent, and the two-step reaction steps are as follows:
1) respectively dissolving the raw materials 1 and 2 in a proper organic solvent, mixing according to the mass ratio of 4:1 to 1:2, stirring and reacting for 2 hours to 3 days at normal temperature or under heating to obtain a white powdery solid which is an intermediate product, or directly mixing and reacting the two raw materials without using the organic solvent to obtain the intermediate product;
2) dissolving the intermediate product in a proper organic solvent, adding a certain amount of palladium-carbon catalyst, introducing hydrogen, stirring and reacting at normal temperature or under heating for 2 hours to 3 days, filtering, standing and volatilizing, and separating out fine transparent crystal grains in the solution after three days to obtain a target product;
the one-step reaction steps are as follows:
respectively dissolving the raw materials 1 and 2 in a proper organic solvent, mixing according to the mass ratio of 4:1 to 1:2, stirring and reacting for 2 hours to 3 days at normal temperature or under heating to obtain a white powdery solid, volatilizing the concentrated solution, filtering, washing the powdery solid with a proper solvent, and then recrystallizing by a proper solvent to obtain a target product; or directly mixing the two raw materials according to the mass ratio of 4:1 to 1:2 without using a reaction solvent, grinding and reacting for 2 hours to 3 days at normal temperature to obtain paste, and recrystallizing the obtained solid by using a proper solvent to obtain a target product;
in the above two-step reaction, the two reactant feedstocks may be selected from: unsaturated demethylcantharidin and ethylenediamine, or unsaturated demethylcantharidinimide and 1, 2-dibromoethane, or furan and 1, 1' - (ethane-1, 2-diyl) -bis (1H-pyrrole-2, 5-dione); in one-step reaction, the two reactants can be selected from demethylcantharidin and ethylenediamine, or demethylcantharidinimide and 1, 2-dibromoethane;
in the above two-step or one-step reaction, the reaction solvent and recrystallization solvent are selected from: methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, toluene, acetone, and N, N-dimethylformamide, and if a solid phase reaction is adopted, the reaction solvent is omitted.
3. The use of a compound according to claim 1 and its agriculturally pharmaceutically acceptable salts for the preparation of pesticides for the control of diamondback moth larvae or rice blast or tomato blight.
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