Cryptolepine salt derivative, its production method and its application

Abstract

Provided are a cryptolepine salt derivative, and a preparation method therefor and the use thereof. The cryptolepine salt derivative comprises a compound as represented by formula (I). By means of introducing different substituents into the cryptolepine salt derivative, a biological activity of the compound is improved by means of the regulation effects of the substituents on the electrical property and the solubility of the cryptolepine salt derivative, so that the obtained cryptolepine salt derivative has a good prevention and control effect on plant viruses and a bactericidal activity.

Description

Bilobaine salt derivatives and preparation methods and applications thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefits of two Chinese patent applications 202311530160.2 and 202311530564.1 filed on November 16, 2023, the contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the technical field of agricultural protection, and in particular to a cephalaline salt derivative, a preparation method and an application thereof. Background Art

[0004] In 1951, Gellert first isolated cryptolepine, an alkaloid with an indolequinoline structure, from Cryptolepis sanguinolenta. Current research has found that cryptolepine exhibits activity comparable to chloroquine against Plasmodium falciparum. Studies have also demonstrated that cryptolepine derivatives possess certain pharmacological properties. Specifically: 1. Studies have synthesized 11-aniline indolequinoline derivatives and demonstrated potential antitumor activity through in vivo and in vitro experiments. 2. Studies have found that cryptolepine salt derivatives containing an aniline structure exhibit significant inhibitory effects against methicillin-resistant Staphylococcus aureus. Although numerous methods exist for synthesizing cryptolepine structures, they generally suffer from long reaction routes, low yields, and harsh reaction conditions. Furthermore, to date, there is no evidence of the application of cryptolepine salt derivatives in the prevention and treatment of plant viruses and sterilization.

[0005] Summary of the Invention

[0006] The present invention aims to overcome the deficiencies of the prior art. To this end, the present invention provides a cephalaline salt derivative and a preparation method and application thereof. The cephalaline salt derivative has good plant virus control effect and fungicidal activity.

[0007] In order to achieve the above-mentioned object, the present invention provides a leucophylline salt derivative on one hand, wherein the leucophylline salt derivative includes a compound represented by formula (I):

[0008] Formula (I)

[0009] Among them, R 1 At least one selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano;

[0010] R 2 At least one selected from hydrogen and a protecting group;

[0011] R 3 At least one selected from substituted or unsubstituted C1-C6 alkyl groups and C6-C20 aryl groups, wherein the substituent in the substituted C1-C6 alkyl group is selected from at least one C3-C6 cycloalkyl group;

[0012] R 4 At least one selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 fluoroalkyl and C2-C5 ester;

[0013] R 5 At least one selected from hydrogen and -NHR, R is selected from at least one of substituted or unsubstituted C1-C20 alkyl, C3-C6 cycloalkyl, C3-C12 azacycloalkyl and C1-C6 alkyl-substituted C3-C12 azacycloalkyl, wherein the substituent of the substituted C1-C20 alkyl is selected from at least one of C3-C6 cycloalkyl, amino, C1-C12 alkyl-substituted amino, C3-C12 cycloamine, C3-C12 azacycloalkyl and C1-C6 alkyl-substituted C3-C12 azacycloalkyl;

[0014] X - Selected from salt-forming anions.

[0015] The second aspect of the present invention provides a method for preparing the above-mentioned cephalaenoic acid salt derivative, which comprises:

[0016] Method (1): When R 5 When is hydrogen, in the presence of a catalyst and a formylating agent, compound A undergoes an electrophilic substitution reaction to obtain the cephaladine salt derivative;

[0017] Method (2): When R 5 When -NHR is selected, compound B is subjected to a nucleophilic substitution reaction with RNH2 to obtain the cephaladine salt derivative.

[0018] The above compound A is Compound B is

[0019] The third aspect of the present invention provides a use of the above-mentioned cephalaenopsis salt derivative in preventing and controlling plant viruses.

[0020] The fourth aspect of the present invention provides a use of the above-mentioned cephalaenopsis salt derivative in sterilization.

[0021] The leucine salt derivatives of the present invention improve the biological activity of the compounds by introducing different substituents and utilizing the substituents to regulate the electrical properties and solubility of the leucine salt derivatives, so that the obtained leucine salt derivatives have good plant virus prevention and control effects and fungicidal activity. DETAILED DESCRIPTION

[0022] The specific implementation methods of the present invention are further described in detail below in conjunction with the examples. In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components and steps, and does not exclude the presence of other material components or steps.

[0023] In the present invention, The dashed lines in structures with dashed linkages indicate the linkage site and represent the linkage.

[0024] In the present invention, "substituted or unsubstituted C1-C6 alkyl" means that the alkyl group has 1 to 6 carbon atoms, and the H atoms on these carbon atoms may or may not be substituted by substituents; when substituted by substituents, the substituted H atoms may be one or more, and when multiple H atoms are substituted, they may be on the same carbon atom or on different carbon atoms. The same applies to other similar expressions.

[0025] In the present invention, "C3-C12 azacycloalkyl substituted with C1-C6 alkyl" means that the azacycloalkyl has 3 to 12 carbon atoms, and one or more H atoms on the carbon atoms are replaced by an alkyl group having 1 to 6 carbon atoms. When multiple H atoms are substituted, the substituted H atoms may be on the same carbon atom or on different carbon atoms. The same applies to other similar expressions.

[0026] In the present invention, the alkyl group in expressions such as "C1-C6 alkyl" and "C1-C20 alkyl" may be a straight-chain alkyl group or a branched-chain alkyl group. The same applies to other identical or similar expressions, such as the alkyl portion in "C1-C6 alkoxy", which may be a straight-chain or branched-chain alkyl group.

[0027] In the present invention, The substituent R in the structural formula 1 and R 4There are multiple substitution sites on the benzene ring, and only one site can be substituted or multiple sites can be substituted at the same time. For example, When multiple sites are substituted, each R 1 or R 4 The groups selected are independent and can be the same or different.

[0028] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0029] In addition, in order to better illustrate the present invention, numerous specific details are provided below. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0030] In one aspect, the present invention provides a cephalaline salt derivative, wherein the cephalaline salt derivative includes a compound represented by formula (I):

[0031] Formula (I)

[0032] Among them, R 1 At least one selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano;

[0033] R 2 At least one selected from hydrogen and a protecting group;

[0034] R 3 At least one selected from substituted or unsubstituted C1-C6 alkyl groups and C6-C20 aryl groups, wherein the substituent in the substituted C1-C6 alkyl group is selected from at least one C3-C6 cycloalkyl group;

[0035] R 4 At least one selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 fluoroalkyl and C2-C5 ester;

[0036] R 5At least one selected from hydrogen and -NHR, R is selected from at least one of substituted or unsubstituted C1-C20 alkyl, C3-C6 cycloalkyl, C3-C12 azacycloalkyl and C1-C6 alkyl-substituted C3-C12 azacycloalkyl, wherein the substituent of the substituted C1-C20 alkyl is selected from at least one of C3-C6 cycloalkyl, amino, C1-C12 alkyl-substituted amino, C3-C12 cycloamine, C3-C12 azacycloalkyl and C1-C6 alkyl-substituted C3-C12 azacycloalkyl;

[0037] X - Selected from salt-forming anions.

[0038] In the present invention, R 2 When selected from the protecting groups, the protecting groups refer to the protecting groups suitable for the active hydrogen of the amine in the structure represented by formula (I).

[0039] According to the present invention, in order to obtain a cephalaenopsis alkaloid salt derivative with better plant virus control and bactericidal effects, it is necessary to further select the substituents.

[0040] According to a preferred embodiment of the present invention, wherein:

[0041] R 1 At least one selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen and cyano;

[0042] R 2 At least one selected from hydrogen, p-toluenesulfonyl, benzylsulfonyl, benzyloxycarbonyl, tert-butyloxycarbonyl and benzyl;

[0043] R 3 At least one selected from substituted or unsubstituted C1-C6 alkyl and C6-C12 aryl groups, wherein the substituent in the substituted C1-C6 alkyl group is selected from at least one C3-C6 cycloalkyl group;

[0044] R 4 At least one selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, C1-C3 perfluoroalkyl and C2-C5 ester;

[0045] R 5At least one selected from hydrogen and -NHR, R is selected from at least one of substituted or unsubstituted C1-C12 alkyl, C3-C6 cycloalkyl, C3-C6 azacycloalkyl and C1-C3 alkyl-substituted C3-C6 azacycloalkyl, wherein the substituent of the substituted C1-C12 alkyl is selected from at least one of C3-C6 cycloalkyl, amino, C1-C6 alkyl-substituted amino, C3-C6 cycloamine, C3-C6 azacycloalkyl and C1-C3 alkyl-substituted C3-C6 azacycloalkyl;

[0046] X - Selected from Cl - Br - , I - 、CH3COO - 、NO3 - 、HSO4 - 、H2PO4 - 、BF4 - and SbF6 - At least one of .

[0047] According to the present invention, the above C2-C5 ester group can be represented by -COOR 0 , where R 0 One or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0048] According to a more preferred embodiment of the present invention, wherein:

[0049] Scenario 1: When X - Cl - When , the following structure is satisfied:

[0050] R 1 At least one selected from hydrogen, methyl, methoxy, F, Cl, Br, I and cyano;

[0051] R 2 At least one selected from hydrogen, p-toluenesulfonyl and benzenesulfonyl;

[0052] R 3 At least one selected from the group consisting of methyl, 2,2-dimethylpropyl, cyclopropylmethyl, cyclohexylmethyl and benzyl;

[0053] R 4 At least one selected from hydrogen, methyl, methoxy, F, Cl, Br, I, trifluoromethyl and methyl formate;

[0054] R 5 Selected from hydrogen.

[0055] Case 2: When X- For I - When , the following structure is satisfied:

[0056] R 1 、R 2 、R 4 is hydrogen, R 3 is methyl, R 5 At least one selected from -NHR, wherein R is selected from at least one of substituted or unsubstituted C1-C12 alkyl, C3-C6 cycloalkyl, C3-C6 azacycloalkyl and C1-C3 alkyl-substituted C3-C6 azacycloalkyl, wherein the substituent of the substituted C1-C12 alkyl is selected from at least one of C3-C6 cycloalkyl, amino, C1-C6 alkyl-substituted amino, C3-C6 cycloamine, C3-C6 azacycloalkyl and C1-C3 alkyl-substituted C3-C6 azacycloalkyl.

[0057] For the second situation, more preferably, when X - For I - When: R 1 、R 2 、R 4 is hydrogen, R 3 is methyl, R 5 is selected from -NHR, and R includes at least one of a C3-C12 straight or branched alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl substituted methyl group, a C3-C6 cycloalkyl substituted propyl group, a substituted or unsubstituted C2-C6 aminoalkyl group, a tetrahydropyrrolyl group, a piperidinyl group, a piperidinylmethyl group, an N-methylpiperidinyl group, and an N-methylpiperidinylmethyl group, wherein the substituents of the substituted C2-C6 aminoalkyl group include methyl, ethyl, and At least one of .

[0058] For the selection of R, more preferably, R is selected from n-propyl, n-pentyl, isopentyl, n-dodecyl, 2-ethylhexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, 2-aminopropyl, 2-methyl-2-aminopropyl, -CH2CH2-NH-CH2CH3, -CH2CH2CH2-NH-CH3, -CH2C(CH3)2-CH2-N(CH3)2, At least one of .

[0059] According to another preferred embodiment of the present invention, when X - Cl -When: R 1 At least one selected from hydrogen, F, Cl, Br and I; R 2 At least one selected from hydrogen, p-toluenesulfonyl and benzenesulfonyl; R 3 At least one selected from the group consisting of methyl, 2,2-dimethylpropyl, cyclopropylmethyl, cyclohexylmethyl and benzyl; R 4 At least one selected from hydrogen, Br, methyl and trifluoromethyl; R 5 Selected from hydrogen.

[0060] According to another preferred embodiment of the present invention, when X - For I - When: R 1 is selected from hydrogen; R 2 is selected from hydrogen; R 3 is selected from methyl; R 4 is selected from hydrogen; R 5 At least one selected from hydrogen and -NHR, wherein R is selected from 2-ethylhexyl, cyclopropylmethyl, aminopropyl, aminobutyl, isopentyl, 2-aminopropyl, At least one of .

[0061] According to a further preferred embodiment of the present invention, the leucoderma salt derivative comprises at least one of the compounds represented by formula (I-1) to formula (I-71):

[0062] According to a particularly preferred embodiment of the present invention, the leucoderma salt derivative comprises at least one of the following compounds:

[0063] According to the present invention, the above-mentioned leucine salt derivatives are improved in their virus prevention and control ability and bactericidal activity by introducing different substituents and utilizing the regulating effect of the substituents on the electrical and solubility properties of the leucine salt derivatives. 5 (When -NHR is selected), a primary amine containing different substituents is specifically introduced at the C-11 position. The primary amine can act as both a hydrogen bond donor and a hydrogen bond acceptor, thereby increasing the hydrogen bond interaction sites between the molecule and the target protein, thereby improving the biological activity of the compound.

[0064] The second aspect of the present invention provides a method for preparing the above-mentioned cephalaenoic acid salt derivative, which comprises:

[0065] Method (1): When R 5 When is hydrogen, in the presence of a catalyst and a formylating agent, compound A undergoes an electrophilic substitution reaction to obtain the cephaladine salt derivative;

[0066] Method (2): When R 5 When -NHR is selected, compound B is subjected to a nucleophilic substitution reaction with RNH2 to obtain the cephaladine salt derivative.

[0067] In the present invention, the compound A is Compound B is

[0068] According to a preferred embodiment of the present invention, the preparation method of the cephalaenopsis alkaloid salt derivative comprises:

[0069] Method (1): When R 5 When is hydrogen, in the presence of a catalyst and a formylating agent, compound A is subjected to an electrophilic substitution reaction with an imine salt to obtain the cephaladine salt derivative;

[0070] Method (2): When R 5 When -NHR is selected, ethyl acetate is used as solvent and compound B is reacted with RNH2 under heating and reflux conditions to undergo a nucleophilic substitution reaction, thereby obtaining the cephalaenoic acid salt derivative.

[0071] According to the present invention, for the above-mentioned method (1), in order to make the reaction proceed better and obtain higher product yield and purity, it is necessary to control the reagents involved in the reaction and the reaction conditions.

[0072] Preferably, the catalyst is selected from at least one of POCl3, SOCl2, ZnCl2 and COCl2, preferably at least one of POCl3 and SOCl2.

[0073] Preferably, the formylating agent is selected from at least one N-substituted formamide, preferably at least one of N,N-dimethylformamide, N-methyl-N-phenylformamide, N,N-dipropylformamide and N-methyl-N-ethylformamide, more preferably at least one of N,N-dimethylformamide and N-methyl-N-phenylformamide.

[0074] Preferably, the molar ratio of compound A to the catalyst is 1:1.2-3, more preferably 1:1.5-2.5, and can be, for example, 1:1.5, 1:1.8, 1:2.2, 1:2.5, and any range therebetween. With respect to the above molar ratio range, when the molar ratio of compound A to the catalyst is greater than 1:3, the yield of the leucine salt derivative is significantly reduced; when the molar ratio of compound A to the catalyst is less than 1:1.2, the yield of the leucine salt derivative is also significantly reduced.

[0075] Preferably, Compound A is provided in the form of a solution when added to the reaction system, wherein the concentration of Compound A is 0.2-1 mmol / mL, preferably 0.4-0.6 mmol / mL, for example, 0.4 mmol / mL, 0.5 mmol / mL, 0.55 mmol / mL, 0.6 mmol / mL, and any range therebetween. The solvent for dissolving Compound A is at least one of the above-mentioned formylating agents.

[0076] Preferably, the temperature of the electrophilic substitution reaction is -20°C to 30°C, preferably -16°C to 25°C, for example, it can be values ​​such as -16°C, -10°C, -5°C, 0°C, 5°C, 10°C, 20°C and 25°C, and any range therebetween; the time is 0.5-4h, preferably 1-2h, for example, it can be values ​​such as 1h, 1.5h, 1.8h and 2h, and any range therebetween.

[0077] According to the present invention, the imide salt is an intermediate obtained by the reaction of the catalyst and the formylating agent. Among them, R x and R y They are respectively two substituents at the N position of N-substituted formamide.

[0078] According to the present invention, for the above-mentioned method (2), in order to make the reaction proceed better and obtain higher product yield and purity, the reaction conditions need to be controlled.

[0079] Preferably, the heating reflux temperature is 90-150°C, preferably 110-130°C, for example, it can be 110°C, 115°C, 122°C and 128°C and the range between any values ​​thereof; the time is 10-24h, preferably 15-17h, for example, it can be 15h, 16h, 16.5h and 17h and the range between any values ​​thereof.

[0080] Preferably, the molar ratio of compound B to RNH2 is 1:1-5, preferably 1:1-3, for example, it can be 1:1, 1:2, 1:2.5 and 1:3 and any range therebetween.

[0081] The third aspect of the present invention provides a use of the above-mentioned cephalaenopsis salt derivative in preventing and controlling plant viruses.

[0082] The fourth aspect of the present invention provides a use of the above-mentioned cephalaenopsis salt derivative in sterilization.

[0083] The leucine salt derivatives provided by the present invention have excellent anti-plant virus activity. The leucine salt derivatives represented by formula (I) exhibit good anti-tobacco mosaic virus activity. Furthermore, the leucine salt derivatives provided by the present invention also have high fungicidal activity, particularly against one or more pathogens that cause cucumber powdery mildew and rice sheath blight.

[0084] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to the following examples. Raw materials in the examples are not particularly described and can be purchased.

[0085] In the following example:

[0086] Examples 1-22 were prepared using the method described above in (1), and Examples 23-47 were prepared using the method described above in (2).

[0087] Compound A was prepared according to the method provided in the literature (Tetrahedron Lett. 1998, 39: 6465-6466).

[0088] Compound B was prepared according to the method provided in the literature (J. Med. Chem. 1998, 41(15): 2754-2764; J. Ethnopharmacol. 2005, 100(1-2): 67-71).

[0089] Preparation Example 1-22

[0090] Preparation Examples 1-22 are used to illustrate the preparation of Compound A.

[0091] 30 mmol of compound a1 (Compound a1 selected in Preparation Examples 1-22 is shown in Table 1) was dissolved in 30 mL of acetonitrile, 40 mmol of sodium hydride was slowly added in batches at 0°C, and after stirring for 10 minutes, the mixture was returned to room temperature, and 33 mmol of R 2 Cl (compound R selected from Preparation Examples 1-22 2 After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The mixture was purified by column chromatography to obtain compound a2 as a white solid.

[0092] Dissolve 11 mmol of compound a2 and 110 mmol of high-purity water in 110 mL of acetone, add 12 mmol of NBS (N-bromosuccinimide) until the reaction is complete, then add 12 mmol of triethylamine and stir for 1 hour to precipitate a large amount of white solid. Filter the solid, wash it several times with acetone, and dry it to obtain compound a3.

[0093] 5 mmol of compound a3, 5.5 mmol (Specific selection of the compound used in Preparation Examples 1-22 is shown in Table 1) and 10 mmol of triethylamine were dissolved in 100 mL of ethyl acetate, heated to reflux for 6 h, and after completion of the reaction, water was added and extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then distilled under reduced pressure and dissolved in ethyl acetate, 25 mmol of boron trifluoride ether solution was added, and the reaction was carried out at 50°C for 3 h. After completion of the reaction, it was cooled to room temperature, saturated sodium bicarbonate solution was slowly added, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The white solid compound A was obtained by column chromatography (Compound A prepared in Preparation Examples 1-22 is shown in Table 1).

[0094] Table 1

[0095] Preparation Example 23

[0096] Preparation Example 23 is used to illustrate the preparation of Compound B.

[0097] Dissolve 20 mmol of compound b1 in a mixture of 8 mL of N,N-dimethylformamide and 8 mL of 1,4-dioxane. Slowly add 24 mmol of bromoacetyl bromide dropwise at 0°C and stir overnight at room temperature. After the reaction is complete, pour the reaction solution into an appropriate amount of ice water to precipitate a large amount of white solid. Filter, wash with copious amounts of water five times, and air-dry to obtain compound b2.

[0098] Dissolve 19.4 mmol of compound b2 in 10 mL of N,N-dimethylformamide, add 69.4 mmol of aniline, and heat under reflux at 120°C for 18 h. After the reaction is completed, cool to room temperature, slowly add 5% potassium hydroxide solution to adjust the pH to 11, and extract with dichloromethane several times. Collect the aqueous phase, adjust the pH to 2-3 with 5% hydrobromic acid solution, and let it stand at room temperature overnight to precipitate a large amount of white solid. Filter and dry to obtain compound b3.

[0099] Add 150 g of PPA (polyphosphoric acid) to 15.8 mmol of compound b3, heat at 130°C for 2 h, cool to room temperature after completion of the reaction, pour the reaction solution into an appropriate amount of ice water, adjust the pH to neutral with saturated potassium hydroxide solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and evaporate under reduced pressure. Purify by column chromatography to obtain compound b4.

[0100] 33 mL of POCl3 (phosphorus oxychloride) was slowly added dropwise to 13 mmol of compound b4, and the mixture was heated under reflux at 120°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and slowly poured into an appropriate amount of ice water. The pH was adjusted to neutral with saturated potassium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The mixture was purified by column chromatography to obtain compound b5.

[0101] Dissolve 0.5 mmol of compound b5 in 2 mL of N,N-dimethylformamide, add 1.5 mmol of iodomethane and heat at 100°C for 8 h. After the reaction is completed, cool to room temperature and add ethyl acetate. A large amount of solid will precipitate. Filter it, wash it several times with ethyl acetate and dry it to obtain compound B.

[0102] Examples 1-22

[0103] Examples 1-22 are used to illustrate the synthesis of cephalaenopsis quinidine salt derivatives represented by formula (I-1) to formula (I-22).

[0104] At -16°C, 2 mmol of POCl3 (phosphorus oxychloride) was slowly added dropwise to 1 mL of N,N-dimethylformamide and stirred for 0.5 h. A solution of 1 mmol of the corresponding compound A (wherein, Examples 1-22 respectively used the compound A obtained in Preparation Examples 1-22 above) dissolved in 2 mL of N,N-dimethylformamide was then added dropwise at 0°C and allowed to react at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into ice water and stirred to precipitate a solid. 10% sodium hydroxide solution was added to adjust the pH to approximately 10. The mixture was allowed to stand for 1 h and then filtered to obtain the leucine salt derivatives represented by Formulas (I-1) to (I-22), respectively (the calculated yields, melting points, and observed states of the products are shown in Table 3).

[0105] Examples 23-47

[0106] Examples 23-47 are used to illustrate the synthesis of cephalaenopsis quinacridoides salt derivatives represented by formula (I-44) to formula (I-68).

[0107] 0.5 mmol of compound B was weighed and dissolved in 20 mL of ethyl acetate, 1 mmol of the corresponding RNH2 was added (the group R of the compound RNH2 selected in Examples 23-47 is shown in Table 2) and heated to reflux for 16 hours. After the reaction was completed, it was cooled to room temperature. Solids precipitated, filtered, washed several times with ethyl acetate, and dried to obtain the leucoderma salt derivatives represented by formula (I-44) to formula (I-68) respectively (the calculated yield of the products, the measured melting point and the observed state are shown in Table 3).

[0108] Table 2

[0109] Table 3

[0110] Comparative Example 1

[0111] Synthesis of 5-methyl-7-bromo-5H-indolo[3,2-b]quinoline (whose structure is shown in Formula II below).

[0112] Formula II

[0113] 2mmol POCl3 (phosphorus oxychloride) was added dropwise to 1mL N,N-dimethylformamide at -16℃ and stirred for 0.5h. The mixture was stirred at room temperature for 1 h, and then a saturated sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was rinsed with a saturated sodium bicarbonate solution. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a solid residue, which was purified by column chromatography using dichloromethane / methanol as eluent to obtain a yellow solid product.

[0114] 0.1 mol of dimethylamine hydrochloride was dissolved in 1 mL of N,N-dimethylformamide, and then 0.05 mol of the yellow solid product obtained in the previous step was added to the reaction system and heated under reflux for 1.5 h. After the reaction was completed, the mixture was cooled and 5 mL of 5% sodium carbonate solution was added. The mixture was stirred at room temperature for 10 min, extracted with ethyl acetate three times, and then rinsed with saturated sodium carbonate. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a solid residue. The residue was purified by column chromatography using dichloromethane / methanol as eluent to obtain a purple solid product in a yield of 35%.

[0115] The structural characterization results are:

[0116] 1 HNMR(400MHz,DMSO-d6)δ9.05(s,1H),8.70(s,1H),8.58(d,J=9.0Hz,1H),8.44(d,J= 8.3Hz,1H),8.02-7.87(m,1H),7.74(t,J=7.5Hz,1H),7.69-7.60(m,2H),4.92(s,3H).

[0117] Comparative Example 2

[0118] Synthesis of 11-(4'-(2-aminoethyl)piperazinyl)-substituted iodine salt (whose structure is shown in the following formula III).

[0119] Formula III

[0120] Mix 0.1 mol of 7-chloro-11-iodo-methylindolo[3,2-b]quinoline and 60 mL of ethylene glycol ether, add 0.15 mol of 4-(2-aminoethyl)piperazine, and stir at 120°C for 0.5 h. Cool to precipitate a solid, collect the reddish-brown solid by filtration, and recrystallize from an ether-ethanol mixture to obtain a yellow solid with a yield of 80%.

[0121] The structural characterization results are:

[0122] 1 HNMR(400Hz,DMSO-d6)δ8.60(d,J=8.4Hz,1H),8.44(s,1H),8.27(d,J=8.8Hz,1H),7.92(dd,J=8.4,7.2Hz,1H) ,7.72(d,J=8.8Hz,1H),7.80(t,J=7.6Hz,1H),7.48(d,J=8.4Hz,1H,),4.55(s,3H),2.85(m,8H),2.65(m,4H).

[0123] Test Example 1

[0124] The assay procedure for anti-tobacco mosaic virus (TMV) activity is as follows:

[0125] 1. Virus purification and concentration determination:

[0126] The crude virus extract was treated with polyethylene glycol twice by centrifugation and then refrigerated at 4°C until use. The absorbance at a wavelength of 260 nm was measured using a UV spectrophotometer, and the virus concentration was calculated according to the formula.

[0127] Virus concentration (mg / ml) = (A 260 × dilution factor) / E 0.1％ 1cm 260nm .

[0128] Wherein E represents the extinction coefficient, i.e. the light absorption (optical density) value of a suspension with a concentration of 0.1% (1 mg / ml) at a wavelength of 260 nm and an optical path of 1 cm.

[0129] TMV's E 0.1％ 1cm 260nm It is 3.1.

[0130] 2. Preparation of cephalaenopsis alkaloid solution:

[0131] After weighing, the leucophylline salt compound, Ningnanmycin and ribavirin original drug were added to DMF to dissolve and prepare 1×10 5 The stock solution was prepared by adding 1‰ Tween 80 aqueous solution to the required concentration.

[0132] 3. In vivo protection:

[0133] Select uniformly growing Sanxi tobacco plants at the 3-5 leaf stage and spray the entire plant with the pesticide, with three replicates per treatment. A 1‰ Tween 80 aqueous solution was also used as a control. After 24 hours, emery (500 mesh) was sprinkled on the leaves. A brush dipped in the virus solution was gently rubbed twice along the entire leaf surface along the veins, supporting the underside of the leaf with the palm of your hand. The virus concentration was 10 μg / mL. After inoculation, the leaves were rinsed with running water. Three days later, the number of lesions was recorded and the efficacy was calculated.

[0134] 4. In vivo therapeutic effect:

[0135] Select uniformly growing Sansi tobacco plants at the 3-5 leaf stage. Use a brush to inoculate the entire leaf with the virus at a concentration of 10 μg / mL. Rinse with running water after inoculation. After the leaves have dried, spray the entire plant with the pesticide. Repeat three times for each treatment, using a 1‰ Tween 80 aqueous solution as a control. After three days, record the number of lesions and calculate the efficacy.

[0136] 5. In vivo passivation activity test:

[0137] Select uniformly growing Sansi tobacco trees at the 3-5 leaf stage. Mix the agent with an equal volume of virus sap and inactivate it for 30 minutes. Then, inoculate by friction at a virus concentration of 20 μg / mL. Immediately rinse with running water after inoculation. Repeat three times. Use a 1‰ Tween 80 aqueous solution as a control. Count the number of lesions after three days and calculate the results.

[0138] Relative inhibition rate (%) = [(number of control necrosis spots + number of treated necrosis spots) / number of control necrosis spots] × 100%.

[0139] All compounds were tested for their inactivation activity against tobacco mosaic virus at a treatment dose of 500 μg / mL. The positive control was a commercial anti-plant virus agent, ribavirin.

[0140] The anti-tobacco mosaic virus (TMV) activity test results of the cephalosporin salt derivatives having structures represented by formula (I1) to formula (I22) and formula (I44) to formula (I68), ningnanmycin and ribavirin are shown in Table 4 below:

[0141] Table 4

[0142] As can be seen from the data in Table 1, at a dose of 500 μg / mL, the anti-TMV activity exhibited by most of the leucine salt derivatives in the examples is better than that of comparative examples 1 and 2. Among them, the anti-TMV activity of the leucine salt derivatives with structures represented by formula (I-5), formula (I-6), formula (I-13), formula (I-20), formula (I-48), formula (I-54) and formula (I-55) is comparable to that of commercial ningnanmycin, while the leucine salt derivatives with structures represented by formula (I-5), formula (I-6), formula (I-7), formula (I-13), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-47), formula (I-48), formula (I-54), formula (I-55), formula (I-56), formula (I-61), formula (I-62) and formula (I-67) have better anti-TMV activity than ribavirin.

[0143] Test Example 2

[0144] Bactericidal activity test, the determination procedure is as follows:

[0145] Potted test for rice sheath blight activity: Select uniformly growing rice seedlings and spray them with the specified concentration on their leaves. A blank control, sprayed with water, was also established. Each treatment was replicated twice. Twenty-four hours after treatment, the plants were inoculated with the rice sheath blight pathogen. After inoculation, the plants were placed in a greenhouse (25±4°C) and maintained as normal. Six days after inoculation, the efficacy was visually assessed.

[0146] The in vivo bactericidal activity test results of the cephalosporin salt derivatives having structures represented by Formula (I 1) to Formula (I 22) and Formula (I 44) to Formula (I 68) and thiofuranamide are shown in Table 5 below:

[0147] Table 5

[0148] As can be seen from the data in Table 2, in the in vivo pot experiment, the leucophylline salt derivatives exhibited certain in vivo fungicidal activity against rice sheath blight, while Comparative Examples 1 and 2 were inactive. Among them, the leucophylline salt derivatives represented by the structures represented by Formula (I-1) and Formula (I-16) exhibited more than 95% in vivo fungicidal activity against rice sheath blight. Meanwhile, the leucophylline salt derivatives represented by the structures represented by Formula (I-4), Formula (I-5), Formula (I-9), Formula (I-14), Formula (I-18), Formula (I-20), Formula (I-22), Formula (I-49), Formula (I-65), and Formula (I-68) exhibited more than 50% in vivo fungicidal activity against rice sheath blight.

[0149] The products obtained in Examples 1-47 were characterized to verify the correct structure. The results are shown in Table 6:

[0150] Table 6

[0151] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A derivative of cryptolepine salt having a chemical structure represented by formula (I): Where R 1 selected from at least one group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano; R 2 selected from at least one group consisting of hydrogen and a protecting group; R 3 selected from at least one group consisting of substituted or unsubstituted C1-C6 alkyl and C6-C20 aromatic group; wherein the substituent of the substituted C1-C6 alkyl is selected from at least one group consisting of C3-C6 cycloalkyl; R 4 selected from at least one group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 fluoroalkyl and C2-C5 ester group; R 5selected from at least one group consisting of hydrogen and -NHR; wherein R is selected from at least one group consisting of substituted or unsubstituted C1-C20 alkyl, C3-C6 cycloalkyl, C3-C12 azacyclic alkyl, and C3-C12 azacyclic alkyl substituted with C1-C6 alkyl; wherein the substituent of the substituted C1-C20 alkyl is selected from at least one group consisting of C3-C6 cycloalkyl, an amino group, an amino group substituted with C1-C12 alkyl, C3-C12 cyclic amino group, C3-C12 azacyclic alkyl, and C3-C12 azacyclic alkyl substituted with C1-C6 alkyl; X - selected from the salt-forming anion.

2. A derivative of cryptolepine salt according to claim 1, where R 1 selected from at least one group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen and cyano; R 2selected from at least one group consisting of hydrogen, para-toluenesulfonyl, benzenesulfonyl, benzyloxycarbonyl, tert-butoxycarbonyl and benzyl; R 3 selected from at least one group consisting of substituted or unsubstituted C1-C6 alkyl and C6-C12 aromatic group; wherein the substituent of the substituted C1-C6 alkyl is selected from at least one group consisting of C3-C6 cycloalkyl; R 4 selected from at least one group consisting of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, C1-C3 perfluoroalkyl and C2-C5 ester group; R 5selected from at least one group consisting of hydrogen and -NHR; wherein R is selected from at least one group consisting of substituted or unsubstituted C1-C12 alkyl, C3-C6 cycloalkyl, C3-C6 azacyclic alkyl, and C3-C6 azacyclic alkyl substituted with C1-C3 alkyl; wherein the substituent of the substituted C1-C12 alkyl is selected from at least one group consisting of C3-C6 cycloalkyl, an amino group, an amino group substituted with C1-C6 alkyl, a C3-C6 cyclic amino group, C3-C6 azacyclic alkyl, and C3-C6 azacyclic alkyl substituted with C1-C3 alkyl; X - selected from at least one group consisting of Cl - , Br - , I - , CH3COO - , NO3 - , HCO4 - , H2PO4 - , BF4 - and SbF6 - .

3. A derivative of a cryptolepine salt according to claim 2, in which: situation 1: if X - is Cl - , That R 1selected from at least one group consisting of hydrogen, methyl, methoxy, F, Cl, Br, I and cyano; R 2 selected from at least one group consisting of hydrogen, p-toluenesulfonyl and benzenesulfonyl; R 3 selected from at least one group consisting of methyl, 2,2-dimethylpropyl, cyclopropylmethyl, cyclohexylmethyl and benzyl; R 4 selected from at least one group consisting of hydrogen, methyl, methoxy, F, Cl, Br, I, trifluoromethyl and methyl formate group; R 5 is hydrogen; situation 2: if X - represents I - , That R 1 , R 2 , R 4 represent hydrogen, R 3 is methyl, R 5selected from at least one of -NHR, where R is selected from at least one group consisting of substituted or unsubstituted C1-C12 alkyl, C3-C6 cycloalkyl, C3-C6 azacyclic alkyl, and C3-C6 azacyclic alkyl substituted with C1-C3 alkyl; where the substituent of the substituted C1-C12 alkyl is selected from at least one group consisting of C3-C6 cycloalkyl, an amino group, an amino group substituted with C1-C6 alkyl, a C3-C6 cyclic amino group, C3-C6 azacyclic alkyl, and C3-C6 azacyclic alkyl substituted with C1-C3 alkyl; preferably, in situation 2, if X - represents I - , then R 1 , R 2 , R 4 represent hydrogen, R 3 is methyl, R 5selected from -NHR, where R comprises at least one group consisting of linear or branched C3-C12 alkyl, C3-C6 cycloalkyl, methyl substituted with C3-C6 cycloalkyl, propyl substituted with C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 alkylamino group, tetrahydropyrrole group, piperidyl, piperidylmethyl, N-methylpiperidyl and N-methylpiperidinemethyl; where the substituent of the substituted C2-C6 alkylamino group is selected from at least one group consisting of methyl, ethyl and 4. A derivative of a cryptolepine salt according to any one of claims 1-3, where R is selected from at least one group consisting of n-propyl, n-amyl, isoamyl, n-dodecyl, 2-ethylhexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cycloamylmethyl, cyclohexylmethyl, cyclopropylethyl, cycloamylethyl, cyclohexylethyl, cyclopropylpropyl, cycloamylpropyl, cyclohexylpropyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, 2-aminopropyl, 2-methyl-2-aminopropyl, -CH2CH2-NH-CH2CH3, -CH2CH2CH2-NH-CH3, -CH2C(CH3)2-CH2-N(CH3)2, And 5. A derivative of a cryptolepine salt according to any one of paragraphs 1-4, characterized in that the derivative of a cryptolepine salt includes at least one of the compounds represented by formula (I-1) to formula (I-71):

6. A derivative of a cryptolepine salt according to claim 5, characterized in that the derivative of a cryptolepine salt includes at least one of the following compounds:

7. A method for producing a derivative of cryptolepine salt according to any one of paragraphs 1-6, wherein the method comprises: method (1): if R 5 represents hydrogen, carrying out the reaction of electrophilic substitution of compound A in the presence of a catalyst and a formylating reagent to obtain a derivative of cryptolepine salt; method (2): if R 5 selected from -NHR, carrying out the nucleophilic substitution reaction of compound B using RNH2 to obtain a derivative of cryptolepine salt.

8. The method of obtaining according to paragraph 7, including: method (1): if R 5 represents hydrogen, carrying out the reaction of electrophilic substitution of compound A imide salt in the presence of a catalyst and a formylating reagent to obtain a cryptolepine salt derivative; method (2): if R 5 selected from -NHR, carrying out the nucleophilic substitution reaction of compound B with RNH2 under reflux and using ethyl acetate as solvent to give the cryptolepine salt derivative.

9. The production method according to claim 7 or 8, wherein in the method (1) the catalyst is selected from at least one of POCl3, SOCl2, ZnCl2 and COCl2, preferably selected from at least one of POCl3 and SOCl2; preferably the formylating reagent is selected from at least one of N-substituted formamides, preferably selected from at least one of N,N-dimethylformamide, N-methyl-N-phenylformamide, N,N-dipropylformamide and N-ethyl-N-methylformamide, more preferably selected from at least one of N,N-dimethylformamide and N-methyl-N-phenylformamide; preferably, the molar ratio of compound A to the catalyst is 1:1.2-3, preferably 1:1.5-2.5; preferably, when added to the reaction system, compound A is in a solution wherein the concentration of compound A is from 0.2 to 1 mmol / ml, preferably from 0.4 to 0.6 mmol / ml; preferably, the temperature for carrying out the electrophilic substitution reaction is from -20°C to 30°C, preferably from -16°C to 25°C; the duration of the electrophilic substitution reaction is from 0.5 to 4 hours, preferably from 1 to 2 hours; preferably the imide salt is an intermediate compound obtained by the reaction of a catalyst and a formylating reagent, where R x and R y represent two substituents at the N atom in N-substituted formamide, respectively.

10. The production method according to claim 7 or 8, wherein in the method (2), the reflux heating temperature is from 90 to 150°C, preferably from 110 to 130°C, and the reflux heating duration is from 10 to 24 hours, preferably from 15 to 17 hours; preferably, the molar ratio of compound B to RNH2 is 1:1-5, preferably 1:1-3.

11. The use of a derivative of cryptolepin salt according to any one of claims 1-6 for the prevention and prophylaxis of plant virus.

12. Use of a derivative of cryptolepine salt according to any one of claims 1-6 for sterilization.

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