阅读说明：本技术 一类具有双手性中心的咔唑基异丙醇胺衍生物及其制备方法和应用 (Carbazolyl isopropanolamine derivatives with double chiral centers and preparation method and application thereof ) 是由 王培义 黄星 刘洪武 龙周卿 张玲 朱建军 杨松 柳立伟 于 2021-01-15 设计创作，主要内容包括：本发明涉及一类具有双手性中心的咔唑基异丙醇胺衍生物及其制备方法和应用。该化合物具有如通式(I)所示的结构：本发明以咔唑为基础,合成一系列具有双手性中心的咔唑基异丙醇胺衍生物,该类化合物对植物病原细菌如水稻白叶枯病菌、柑橘溃疡病菌、猕猴桃溃疡病菌等具有优异的抑制效果。(The invention relates to carbazolyl isopropanolamine derivatives with double chiral centers and a preparation method and application thereof. The compound has a structure shown as a general formula (I):)

1. A carbazolyl isopropanolamine derivative having a bimanual center, or a stereoisomer, salt or solvate thereof, wherein: the compound has a structure shown as a general formula (I):

wherein R is₂And R₃The same or different, independently selected from one or more of hydrogen, deuterium, halogen, amino, hydroxyl, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, acetyl, propionyl or butyryl;

R₁one or more selected from the group consisting of optionally substituted or unsubstituted C1-10 alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted C1-10 alkoxy, optionally substituted or unsubstituted C6-10 cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;

denotes the R configuration, S configuration or racemic carbon.

2. The bimanual center carbazolyl isopropanolamine derivative according to claim 1, or a stereoisomer, salt or solvate thereof, wherein:

R₂and R₃The same or different, independently selected from one of hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, acetyl, propionyl or butyrylOr a plurality of;

preferably, R₁One or more selected from the group consisting of C1-5 alkyl, C1-5 alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, or C6-C10 heteroaryl, wherein substituted refers to substitution with one or more of methyl, ethyl, methoxy, ethoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; more preferably, R₁Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, propylamino, dipropylamino, phenyl, benzyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dibromophenyl, difluorophenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, trifluoromethoxybenzyl, chlorobenzyl, bromobenzyl, fluorobenzyl, dichlorobenzyl, dibromobenzyl, difluorobenzyl, pyridine, chloropyridyl, bromopyridinyl, fluoropyridyl, dichloropyridyl, dibromopyridinyl, difluoropyridinyl, naphthyl, biphenyl.

3. Carbazolyl isopropanolamine derivatives or stereoisomers, salts or solvates thereof according to claim 1, characterized in that they are selected from the following compounds:

4. an intermediate compound for preparing carbazolyl isopropanolamine derivatives or stereoisomers, salts or solvates thereof of bimanual centers as claimed in claim 1, characterized by the following:

wherein R is₂And R₃As recited in claim 1;

preferably, it is selected from the following compounds

5. A process for preparing carbazolyl isopropanolamine derivatives or stereoisomers thereof, or salts or solvates thereof at bimanual centers as claimed in any one of claims 1 to 3, comprising the steps of:

preferably, the method further comprises the following steps:

most preferably, further comprising the steps of:

wherein R is₁、R₂、R₃As claimed in claim 1.

6. A composition characterized by comprising a compound of any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

7. Use of a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 6, for controlling an agricultural pest, preferably a bacterial or fungal disease of a plant; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, kiwi canker, grape canker, tomato canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot pathogenic bacteria, wheat scab pathogenic bacteria and potato late blight pathogenic bacteria.

8. A method for controlling agricultural pests is characterized in that: allowing a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 6 to act on the noxious substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, kiwi canker, grape canker, tomato canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot of colza, wheat fusarium graminearum and potato late blight.

9. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of any one of claims 1-3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 6.

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to carbazolyl isopropanolamine derivatives with bimanual centers, and a preparation method and application thereof.

Background

Bacterial diseases of plants are one of the main factors influencing global agricultural production, seriously influence the yield and quality of agricultural products, not only cause great economic loss, but also threaten human health. Such as bacterial leaf blight of rice, citrus canker, kiwifruit canker, tobacco bacterial wilt and the like, can outbreak to different degrees every year, and cause huge economic loss for farmers. The long-term use of traditional bactericides such as thiediazole copper, bismerthiazol, streptomycin sulfate and the like not only increases the drug resistance of plant pathogenic bacteria, but also has harmful effects on the ecological environment and the safety of plants. Therefore, development of novel pesticides having high activity and high selectivity is urgently required.

Carbazole derivatives have been reported in the literature to exhibit a broad spectrum of biological activities, such as; antibacterial, antifungal, insecticidal, herbicidal, plant growth regulating, antitumor, and antiinflammatory etc. According to the earlier work of the subject group, the carbazole compounds show better anti-phytopathogen activity.

In order to search for an efficient bactericidal active compound, carbazole is taken as a mother ring, propylene oxide containing a chiral center is connected, ring opening is carried out by chiral amine to obtain a carbazolyl isopropanolamine derivative containing a double-chiral center, and the biological activity of the carbazolyl isopropanolamine derivative is tested, so that an important scientific basis is provided for research, development and creation of new pesticides.

The research on the biological activity of carbazole compounds progresses as follows:

wang et al [ Wang, p.y.; fang, h.s.; shao, w.b.; zhou, j.; chen, z.; song, b.a.; yang, S.Synthesis and biological evaluation of pyridine-functional carboxylic acid derivatives as a formulating organic agents, bioorg.Med.chem.Lett., 2017, 27, 4294-]Synthesize aThe activity of a target compound on Xoo, Xac and ralstonia solanacearum is tested by a turbidity method, and the result shows that the minimum EC of partial compounds on three bacteria₅₀Respectively at 0.4, 0.3 and 0.3 mg/L.

Clausen et al [ Clausen, j.d.; kjellerup, l.; cohrt, k.o.; hansen, j.b.; dalbybrown, w.; winther, A.M.L.Elitation of antimicrobial activity and mechanism of action by n-substitated particle derivatives, bioorg.Med.chem.Lett., 2017, 27, 4564-]Synthesizing a series of compounds with carbazolyl isopropanolamine as parent structure, wherein the compound 5 is H of saccharomycetes and candida albicans⁺Ca in ATPase and mammalian cells²⁺-ATPase、Na⁺，K⁺-ATPase shows a higher inhibitory effect, IC₅₀The values were 2.0, 1.1, 0.3 and 1.0. mu.M, respectively.

2018 Pattanashetty et al [ Pattanashetty, S.H.; hosamani, k.m.; shettar, a.k.; shafeulla, R.M. design, Synthesis and comparative Studies of Novel Carbazole N-phenylacetamide Hybrids as Power antigen, Anti-infilamation, and antibiotic Agents J.Heterococcus chem., 2018, 55, 1765-1774 designed and synthesized a series of N-phenylacetamide substituted Carbazole derivatives, tested against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa in vitro, and showed MIC values of 0.5, 0.25, 1. mu.g/mL respectively, superior to that of ciprofloxacin as a control.

Zhang et al Zhang, y.2018; tangadanchu, v.k.r.; cheng, y.; yang, r.g.; lin, j.m.; a series of carbazole-azole compounds with isopropanolamine as a connecting chain are designed and synthesized by Zhou, C.H.Positive antimicrobial carboxylic acid as minor targeting inhibition of Acetococcus faecalis. ACS Med.chem.Lett., 2018, 9 and 244-249, and the activity of the carbazole-azole compounds on the enterobacter faecalis is tested, and the result shows that the compound 10 has higher activity (MIC is 2 mug/mL).

Disclosure of Invention

An object of the present invention is to provide a carbazolyl isopropanolamine derivative having a chiral center, or a salt or solvate thereof.

Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.

It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.

It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.

Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.

In order to realize the purpose, the invention adopts the following technical scheme:

a carbazolyl isopropanolamine derivative containing a chiral center, or a salt or solvate thereof, the compound having a structure represented by the general formula (I):

wherein R is₂And R₃The same or different, independently selected from one or more of hydrogen, deuterium, halogen, amino, hydroxyl, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, acetyl, propionyl or butyryl;

R₁one or more selected from the group consisting of optionally substituted or unsubstituted C1-10 alkyl, amino, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted C1-10 alkoxy, optionally substituted or unsubstituted C6-10 cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; denotes the R configuration, S configuration or racemic carbon.

Each R₂And R₃The same or different, are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, methyl, ethyl, propyl, isopropyl,One or more of butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, acetyl, propionyl, or butyryl; more preferably, R₂And R₃The same or different, independently selected from one or more of hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, acetyl or propionyl;

preferably, R₁One or more selected from the group consisting of C1-5 alkyl, C1-5 alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, or C6-C10 heteroaryl, wherein substituted refers to substitution with one or more of methyl, ethyl, methoxy, ethoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; more preferably, R₁Selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, isopropyl, propenyl, allyl, butenyl, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, propylamino, dipropylamino, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, and substituted or unsubstituted naphthyl, wherein the substitution is substituted with one or more of methyl, ethyl, methoxy, ethoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl; most preferably, R₁Selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, isopropyl, propenyl, allyl, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino, chlorophenyl, fluorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, methylphenyl, trifluoromethylphenyl, aminophenyl, hydroxyphenyl, nitrophenyl, dimethylphenyl, di-trifluoromethylphenyl, diaminophenyl, dihydroxyphenyl, dinitrophenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-methylbenzyl, 3-methylbenzyl, isopropyl, amino, methylamino, dimethylamino, amino, chlorophenyl, fluorophenyl, bromophenyl, di-chlorophenyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 2-trifluoromethyl, 4-methylbenzyl, pyridinePyridyl, 3-methylpyridine-2-methylene, 4-methylpyridine-2-methylene, 5-methylpyridine-2-methylene, furan, 2-methylfuran, 3-methylfuran, thiophene, 2-methylthiophene, 3-methylthiophene.

R₂And R₃The same or different, independently selected from one or more of hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, acetyl, propionyl or butyryl;

preferably, R₁One or more selected from the group consisting of C1-5 alkyl, C1-5 alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, or C6-C10 heteroaryl, wherein substituted refers to substitution with one or more of methyl, ethyl, methoxy, ethoxy, amino, hydroxy, halogen, nitro, trifluoromethyl;

more preferably, R₁Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, propylamino, dipropylamino, phenyl, benzyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dibromophenyl, difluorophenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, ethylbenzyl, methoxybenzyl, ethoxybenzyl, trifluoromethoxybenzyl, chlorobenzyl, bromobenzyl, fluorobenzyl, dichlorobenzyl, dibromobenzyl, difluorobenzyl, pyridine, chloropyridyl, bromopyridinyl, fluoropyridyl, dichloropyridyl, dibromopyridinyl, difluoropyridinyl, naphthyl, biphenyl.

More preferably, it is selected from the following compounds:

the present invention also provides an intermediate compound for preparing a compound of the general formula (I) which is represented by the following formula (II):

wherein R is₂And R₃As indicated above; preferably, selected from the following specific compounds:

the invention also provides a preparation method of the carbazolyl isopropanolamine derivative with double chiral centers, or the salt or solvate thereof, which is characterized by comprising the following steps;

most preferably, the following steps are included:

the invention also provides a composition containing the compound or the stereoisomer or the salt or the solvate thereof, and an agriculturally acceptable auxiliary agent or bactericide, pesticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot pathogenic bacteria, wheat scab pathogenic bacteria and potato late blight pathogenic bacteria.

The invention also provides a method for preventing and controlling agricultural pests, which enables the compound or the stereoisomer thereof, the salt thereof or the solvate thereof, or the composition to act on the pests or the living environment thereof; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot of colza, wheat fusarium graminearum and potato late blight.

The present invention also provides a method for protecting a plant from an agricultural pest comprising a method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.

The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C_1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C_1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C_2-6Alkenyl "(or alkenylene) is intended to include C2, C3C4, C5 and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N). When referring to substitution, especially polysubstitution, it is meant that the plurality of substituents are substituted at each position on the indicated group, e.g., dichlorobenzyl refers to 2, 3-dichlorobenzyl, 2, 4-dichlorobenzyl, 2, 5-dichlorobenzyl, 2, 6-dichlorobenzyl, 3, 4-dichlorobenzyl, and 3, 5-dichlorobenzyl.

Combinations of substituents and variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent.

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen may optionally be oxidized and quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.

Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention.

Preferably, C₁-C₁₀Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c₂-C₅Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof.

When reference is made to substituents being alkenyl, alkyl, aryl, benzyl, cycloalkyl, or where these substituents are specifically an alkenyl, alkyl, aryl, benzyl, cycloalkyl group, one to three of the above substituents are meant. For example, chlorobenzyl refers to one to three chloro substituted benzyl groups.

By adopting the technical scheme, the carbazole is used as an initial raw material to synthesize a series of carbazolyl isopropanolamine derivatives with bimanual centers, and the compound is found to have good inhibition effect on pathogenic bacteria of pathogenic plants, has good inhibition effect on pathogenic bacteria [ such as Xanthomonas oryzae pv. oryzae, Xoo, Xanthomonas canker pv. citri, Xanthomonas axonopodis pv. citri) and Actinidia chinensis canker (Pseudomonas syringae pv. actinidiae, Psa) and the like ], and provides an important scientific basis for research and development of new pesticides.

Examples

The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.

Example 1: preparation of intermediate (R) -9- (oxiranemethyl-2-ylmethyl) -9H-carbazole

Carbazole (6.0mmol), KOH (9.0mmol) and 10mL dmdff were added to a 25mL round bottom flask, stirred for 30min under ice bath conditions, then epichlorohydrin containing the R configuration (6.0mmol) was slowly added, and the mixture was stirred for 10 min. The reaction was finished after 5h in ice bath. Extracting with ethyl acetate, washing with saturated ammonium chloride solution, collecting organic phase, drying with anhydrous sodium sulfate, desolventizing, and performing column chromatography (PE: EA, V: V is 30: 1) to obtain white solid with yield of 45.6%. The nuclear magnetic data are:¹H NMR(400MHz，DMSO-d₆，ppm)δ8.15(d，J＝7.7Hz，2H，carbazol-H)，7.66(d，J＝8.3Hz，2H，carbazol-H)，7.4-7.41(m，2H，carbazol-H)，7.26-7.17(m，2H，carbazol-H)，4.79(dd，J＝15.7，3.2Hz，1H，N- ₂CH)，4.43(dd，J＝15.7，5.7Hz，1H，N- ₂CH)，3.32(qd，J＝5.8，3.2Hz，1H，O- ₂CH)，2.76(dd，J＝5.0，4.1Hz，1H，O-CH)，2.58(dd，J＝5.1，2.6Hz，1H，O- ₂CH)；¹³C NMR(101MHz，DMSO-d₆，ppm)δ140.8，126.2，122.6，120.7，119.5，110.1，50.7，45.2，44.7.

meanwhile, the other chiral intermediates are the same as those in example 1 except that the epoxy bromopropane is replaced by the levo/dextro epichlorohydrin.

Example 2: (R) -1- (9H-carbazol-9-yl) -3- ((((R) -1-phenylethyl) amino) propan-2-ol

(R) -9- (Oxiran-2-ylmethyl) -9H-carbazole (0.90mmol), (R) -1-phenyleth-1-amine (1.8mmol) and K₂CO₃(0.90mmol) and 5mL of anhydrous isopropanol were put in a 15mL reaction flask, reacted at 60 ℃ for 6 hours, and subjected to column Chromatography (CH)₂Cl₂∶CH₃OH (200: 1, V/V)) to give a white solid in 79.0% yield.

Other target compounds were synthesized by following the procedures of the above examples using the corresponding starting materials or substituents.

The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized carbazolyl isopropanolamine derivative with double chiral centers are shown in table 1, and the physicochemical properties are shown in table 2.

Nuclear magnetic resonance hydrogen and carbon spectra data for the compounds of table 1

Table 2 physicochemical properties of the compounds of the present application

Pharmacological example 1:

EC₅₀(mean effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated₅₀。

Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting turbidity method₅₀The test subjects were rice bacterial blight (Xoo), citrus canker (Xac) and kiwi fruitUlcer bacteria (Psa). DMSO was dissolved in the medium as a blank control. Placing rice bacterial leaf blight bacteria (in M210 solid culture medium) in NB culture medium, and shake culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; the citrus canker pathogen (on M210 solid medium) was placed in NB medium and shake-cultured in a constant temperature shaker at 28 ℃ and 180rpm until logarithmic phase for use. 5mL of toxic NB liquid culture medium prepared by the medicament (compound) into different concentrations (for example: 100, 50, 25, 12.5, 6.25 μ g/mL) is added into a test tube, 40 μ L of NB liquid culture medium containing plant disease bacteria is respectively added, shaking is carried out in a constant temperature shaking table at 28 ℃ and 180rpm, the bacterial blight pathogenic bacteria of rice are cultured for 36h, the citrus canker pathogenic bacteria are cultured for 48h, and the kiwifruit canker pathogenic bacteria are cultured for 36 h. The OD was measured on a spectrophotometer using the bacterial solutions of the respective concentrations₅₉₅Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium₅₉₅The value is obtained.

Corrected OD value-bacteria-containing medium OD value-sterile medium OD value

Percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100

The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.

TABLE 3 EC of the Compounds of the present application against phytopathogenic bacteria₅₀

As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria (e.g., bacterial blight of rice, canker citrus and kiwifruit canker) in the in vitro test. Especially compound 2 on bacterial blight of riceThe bacteria have extremely excellent activity, EC₅₀1.00 mu g/mL; the compound 6 has excellent activity on water citrus canker pathogen, EC₅₀2.41 mu g/mL; meanwhile, the compound 9 also shows excellent inhibitory activity to the kiwifruit canker pathogen, EC₅₀It was 4.25. mu.g/mL. Therefore, the compounds have great research prospects and can be used for preparing pesticides for resisting plant pathogenic bacteria.