CN114605489B - 18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure and preparation method and application thereof - Google Patents

18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure and preparation method and application thereof Download PDF

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CN114605489B
CN114605489B CN202210287294.5A CN202210287294A CN114605489B CN 114605489 B CN114605489 B CN 114605489B CN 202210287294 A CN202210287294 A CN 202210287294A CN 114605489 B CN114605489 B CN 114605489B
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beta
glycyrrhetinic acid
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piperazinyl
isopropanolamine
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CN114605489A (en
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杨松
冯钰梅
周翔
王培义
吴志兵
柳立伟
薛伟
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing within the same carbon skeleton a carboxylic group or a thio analogue, or a derivative thereof, and a carbon atom having only two bonds to hetero atoms with at the most one bond to halogen, e.g. keto-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings

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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dentistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
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  • Environmental Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses an 18 beta-glycyrrhetinic acid amide compound containing an isopropanolamine structure, which takes the 18 beta-glycyrrhetinic acid structure as a lead compound, introduces an amide segment, oxidizes double bonds in the structural segment to obtain an epoxy structure, performs ring opening treatment on the epoxy structure, introduces a series of nitrogen-containing groups into the system, and synthesizes the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure. The invention also discloses a preparation method and application of the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure, and provides an important scientific basis for the research and development and the creation of new pesticides.

Description

18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to an 18 beta-glycyrrhetinic acid amide compound containing an isopropanolamine structure, and a preparation method and application thereof.
Background
The annual outbreak and spread of plant bacterial diseases severely limit the yield and quality of agricultural products and become a serious challenge worldwide. These diseases are mainly formed and transmitted by invasive plant pathogens, causing significant damage to various important commercial crops such as rice, citrus, kiwi, tobacco, and the like. However, the control measures for human beings against these serious diseases have limitations although diversified, the currently commonly adopted measures are agrochemical control methods, but the long-term application of the pathogen resistance and the accumulation of harmful residues in already fragile ecosystems and agricultural products have led to the development of new, efficient and safe bactericides capable of managing the attack of phytopathogenic bacteria.
Natural products are an important source for developing agricultural chemicals because of various kinds, abundant sources, various biological activities, unique actions, easy degradation and/or good environmental compatibility. The development of chemical modifications to natural products has also highly driven the development of new pesticides or pharmaceuticals. Glycyrrhetinic acid exhibits a broad spectrum of biological activities, such as antibacterial, anti-inflammatory, antiviral, anticancer, insecticidal, etc. Wherein, the 18 beta-glycyrrhetinic acid derivative can show good inhibition effect on plant pathogenic bacteria. The study of the biological activity of 18 beta-glycyrrhetinic acid and derivatives thereof has been developed as follows:
huang et al, in "Enhancement of anti-bacterial and anti-tumor activities of pentacyclic triterpenes by introducing exocyclic alpha, beta-unsaturated ketone moiety in ring A [ J ]. Med. Chem. Res.,2014,23,4631-4641," reported the introduction of exocyclic alpha, beta-unsaturated ketone structures in the A ring of 18 beta-glycyrrhetinic acid, and synthesized a series of 18 beta-glycyrrhetinic acid derivatives containing 2-methylene-3-oxo groups. And their antibacterial activity against E.coli (E.coli), staphylococcus aureus (S.aureus) and Bacillus subtilis (B.subtilis) was evaluated. The results show that the compound G2 has better antibacterial activity on staphylococcus aureus and bacillus subtilis, and the Minimum Inhibitory Concentration (MIC) is 45.00 mu M and 35.00 mu M respectively.
de Breej et al, "The licorice pentacyclic triterpenoid component
18 beta-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus [ J ]. Eur.J.Clin.Microbiol.2016,35,555-562 "reported that 18 beta-glycyrrhetinic acid could enhance the antimicrobial activity of the aminoglycoside antibiotics tobramycin, gentamicin, aj Mi Kamei and polymyxin B against two strains of methicillin-resistant Staphylococcus aureus (MRSA) such that the Minimum Inhibitory Concentration (MIC) of these antibiotics was reduced by 32-64 fold.
Xiang et al in "Design, synthesis, antibacterial Evaluation, and Induced Apoptotic Behaviors of Epimeric and Chiral 18.beta. -Glycyrrhetinic Acid Ester Derivatives with an Isopropanolamine Bridge against Phytopathogens [ J ]]A series of novel glycyrrhetinic acid ester derivatives are obtained by structural modification of the carboxyl group at the C-30 position of 18 beta-glycyrrhetinic acid by J.Agric.food chem.,2019,67,13212-13220", and biological activity evaluation results show that partial target compounds have an EC50 value range of 3.81-4.82 mu gmL for rice sheath blight (A2, B1-B3 and C1) -1 ) Citrus canker (B1, ec50=3.18 μg mL) -1 ；B2,EC50＝2.76μg mL -1 ) Exhibits excellent inhibitory activity, and has antibacterial activity far superior to that of parent 18 beta-glycyrrhetinic acid (EC 50 values>400μg mL -1 ) Control drug (Rhizoctonia solani resistant EC 50=92.6 μg mL) -1 ) Copper thiabendazole (EC 50=121.8 μg mL against rice bacterial leaf blight bacteria) -1 EC50 = 77.0 μg mL for anti-canker citruses -1 )。
How to continue to use the 18 beta-glycyrrhetinic acid structure as a lead compound and search for an active target compound with high-efficiency antibacterial activity is a problem to be solved urgently at present.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an 18 beta-glycyrrhetinic acid amide compound containing an isopropanolamine structure.
The compound has a structure shown in a general formula (I):
wherein X is selected from: an N atom or S atom; r is R 1 Selected from: hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionallyOne or more of a substituted or unsubstituted alkoxy group, an optionally substituted or unsubstituted cycloalkyl group, an optionally substituted or unsubstituted aryl group, an optionally substituted or unsubstituted heteroaryl group; r is R 2 Selected from: one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl; r is R 3 Selected from: hydroxy or acetoxy.
As a further improvement of the invention, R 1 And R is 2 Each independently selected from: hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl, wherein the substitution refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
As a further improvement of the invention, R 1 And R is 2 Each independently selected from: hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein the substitution refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl.
As a further improvement of the invention, R 1 And R is 2 Each independently selected from: hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzylA group, a 2-bromobenzyl group, a 3-bromobenzyl group, a 4-bromobenzyl group, a 2-aminobenzyl group, a 3-aminobenzyl group, a 4-aminobenzyl group, a 2-hydroxybenzyl group, a 3-hydroxybenzyl group, a 4-hydroxybenzyl group, a 2-nitrobenzyl group, a 3-nitrobenzyl group, a 4-nitrobenzyl group, a 2-trifluoromethylbenzyl group, a 3-trifluoromethylbenzyl group, a 4-trifluoromethylbenzyl group, a morpholinyl group, a piperidinyl group, a 2-methylpiperidinyl group, a 3-methylpiperidinyl group, a 4-methylpiperidinyl group, an R-3-ethylpiperidinecarboxylic acid ethyl ester, an S-3-piperidinecarboxylic acid ethyl ester, a 4-piperidinecarboxylic acid methyl ester, a pyrrolidinyl group, a R-3-hydroxypyrrolidinyl, S-3-hydroxypyrrolidinyl, piperazinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 1-tert-butylpiperazinyl, 1-acetylpiperazinyl, 1-phenylpiperazinyl, 1- (2-methoxyphenyl) piperazinyl, 1- (3-methoxyphenyl) piperazinyl, 1- (4-methoxyphenyl) piperazinyl, 1- (2-methylphenyl) piperazinyl, 1- (3-methylphenyl) piperazinyl, 1- (4-methylphenyl) piperazinyl, 1- (2-chlorophenyl) piperazinyl, 1- (3-chlorophenyl) piperazinyl, 1- (4-chlorophenyl) piperazinyl, 1- (2-fluorophenyl) piperazinyl, 1- (3-fluorophenyl) piperazinyl, 1- (4-fluorophenyl) piperazinyl, 1- (2-bromophenyl) piperazinyl, 1- (3-bromophenyl) piperazinyl, 1- (4-bromophenyl) piperazinyl, 1- (2-aminophenyl) piperazinyl, 1- (3-aminophenyl) piperazinyl, 1- (4-aminophenyl) piperazinyl, 1- (2-hydroxyphenyl) piperazinyl, 1- (3-hydroxyphenyl) piperazinyl, 1- (4-hydroxyphenyl) piperazinyl, 1- (2-nitrophenyl) piperazinyl, 1- (3-nitrophenyl) piperazinyl, 1- (4-nitrophenyl) piperazinyl, 1- (2-trifluoromethylphenyl) piperazinyl, 1- (3-trifluoromethylphenyl) piperazinyl, 1- (4-trifluoromethylphenyl) piperazinyl, 1- (2-methoxybenzyl) piperazinyl, 1- (3-methoxybenzyl) piperazinyl, 1- (4-methoxybenzyl) piperazinyl, 1- (2-methylbenzyl) piperazinyl, 1- (3-methylbenzyl) piperazinyl), 1- (2-chlorobenzyl) piperazinyl, 1- (3-chlorobenzyl) piperazinyl, 1- (4-chlorobenzyl) piperazinyl, 1- (2-fluorobenzyl) piperazinyl, 1- (3-fluorobenzyl) piperazinyl, 1- (4-fluorobenzyl) piperazinyl, 1- (2-bromobenzyl) piperazinyl, 1- (3-bromobenzyl) piperazinyl, 1- (4-bromobenzyl) piperazinyl, 1- (2-aminobenzyl) piperazinyl, 1- (3-aminobenzyl) piperazinyl, 1- (4-aminobenzyl) piperazinyl, 1- (2-hydroxybenzyl) piperazinyl, 1- (3-hydroxybenzyl) piperazinyl1- (4-hydroxybenzyl) piperazinyl, 1- (2-nitrobenzyl) piperazinyl, 1- (3-nitrobenzyl) piperazinyl, 1- (4-nitrobenzyl) piperazinyl, 1- (2-trifluoromethylbenzyl) piperazinyl, 1- (3-trifluoromethylbenzyl) piperazinyl, 1- (4-trifluoromethylbenzyl) piperazinyl.
As a further improvement of the present invention, the compound is selected from the following specific compounds:
the invention also provides an intermediate compound for preparing the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure, which comprises the structures shown in chemical formulas II and III:
R 3 selected from: hydroxy or acetoxy.
The invention also provides a method for preparing the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure, which comprises the following steps:
wherein R is 1 、R 2 、R 3 X is as described above.
As a further improvement of the invention, when R 3 When the compound is acetoxyl, the method for preparing the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure comprises the following steps of:
step one, dissolving a mixture of a compound IV, carbodiimide hydrochloride and hydroxybenzotriazole in a solvent, then adding triethylamine, stirring until the mixture is dissolved and clarified, and adding allylamine hydrochloride to participate in a reaction to obtain a compound II;
adding the compound II into an organic solution containing m-chloroperoxybenzoic acid, stirring for reaction, then adjusting the pH value of the mixture solution to 9-10, adding ethyl acetate into the mixture for extraction, washing an organic layer with water, drying, and removing the solvent under vacuum to obtain a compound III;
and thirdly, adding the compound III into an organic solution dissolved with amine, stirring for reaction, adding dichloromethane into the mixed solution for extraction after stopping the reaction, washing with water, drying, removing the solvent, and purifying the remainder by column chromatography to obtain the compound I.
As a further improvement of the invention, the method for preparing the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure comprises the following steps:
wherein R is 1 、R 2 、R 3 X is as described above.
As a further improvement of the invention, the method for preparing the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure comprises the following steps:
the invention also provides a composition which contains the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure and an agriculturally usable auxiliary agent or bactericide, pesticide or herbicide; the formulation of the composition is selected from: emulsifiable Concentrates (EC), powders (DP), wettable Powders (WP), granules (GR), aqueous Solutions (AS), suspensions (SC), ultra low volume sprays (ULV), soluble Powders (SP), microcapsules (MC), smoke agents (FU), aqueous Emulsions (EW) or water dispersible granules (WG).
The invention also provides application of the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure, wherein the application is that the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure is used for preventing and controlling agricultural diseases and insect pests, and the agricultural diseases and insect pests are selected from the following: plant bacterial diseases or plant fungal diseases.
As a further improvement of the present invention, the agricultural pest is selected from the group consisting of: plant leaf blight or plant canker.
As a further improvement of the present invention, the agricultural pest is selected from the group consisting of: bacterial leaf blight of rice, bacterial leaf blight of cucumber, bacterial leaf blight of konjak, citrus canker, grape canker, tomato canker, kiwi fruit canker, apple canker, cucumber gray mold, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat red mold, potato late blight or blueberry root rot.
The invention also provides a method for preventing and controlling agricultural diseases and insect pests by using the 18 beta-glycyrrhetinic acid amide compound containing an isopropanolamine structure, wherein the method is that the 18 beta-glycyrrhetinic acid amide compound containing the isopropanolamine structure acts on harmful substances or living environments thereof, and the agricultural diseases and insect pests are selected from the following groups: bacterial or fungal plant diseases.
The present invention also provides a method of protecting plants from agricultural pests, comprising the step of contacting the plants with an 18 β -glycyrrhetinic acid amide compound having an isopropanolamine structure as described above.
Compared with the prior art, the invention has the beneficial effects that:
the compound provided by the invention has good inhibition effect on pathogenic bacteria, has good inhibition effect on pathogenic bacteria (such as rice bacterial blight bacteria (Xanthomonas oryzae pv. Oryzae, xoo), citrus canker bacteria (Xanthomonas axonopodis pv. Citri, xac) and the like), and provides an important scientific basis for the research and development and creation of new pesticides.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. For example "C 1-10 Alkyl "(or alkylene) is intended to mean C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, e.g. "C 1-6 Alkyl "means 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 is replaced by 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 that includes both straight or branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. For example "C 2-6 Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 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.
"alkynyl" is a hydrocarbon that includes both straight or branched chain structures and has one or more carbon-carbon triple bonds that occur at any stable point in the chain. For example "C 2-6 Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
The term "substituted" as used herein refers to any one or more hydrogen atoms on a specified atom or group being replaced with a selected specified group, provided that the specified atom's general valency is not exceeded. Substituents are named to the central structure, unless otherwise indicated. For example, it is understood that when (cycloalkyl) alkyl is the possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a ring 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, particularly polysubstituted, it is meant that a plurality of substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl refers to 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. The stable compound or stable structure implies that the compound is sufficiently stable when isolated from the reaction mixture in useful purity, and is formulated to form an effective therapeutic agent. Preferably, the compounds at present do not comprise N-halogen, S (O) 2 H or S (O) H group.
The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even though the halo in the haloalkyl is explicitly fluoro, chloro, bromo, iodo, it also refers to substituted alkyl groups having one or more fluoro, chloro, bromo, iodo substituents.
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. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and/or from 1 to 4 nitrogen atoms provided that the total number of heteroatoms in each ring is 4 or less and that each ring has at least one carbon atom. The fused ring completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one wholly aromatic ring and the nitrogen other fused rings may be aromatic or non-aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring. When the valency permits, if the other ring is cycloalkyl or heterocycle, it is additionally optionally substituted with =o (oxygen).
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarin, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the present 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 inorganic and/or organic acids and bases. In addition, the term "salt" may include zwitterionic (inner salts), such as when the compounds of formula I contain basic moieties such as amine or pyridine or imidazole rings, and acidic moieties such as carboxylic acids. 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 bioactivity of the salt. However, other salts may be useful, such as by employing isolation or purification steps in the preparation process, and are therefore also included within the scope of the present invention.
C 1 -C 10 Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decyloxy and isomers thereof; c (C) 2 -C 5 Alkenyl refers to ethenyl, propenyl, allylA group, a butenyl group, a pentenyl group and isomers thereof.
When referring to substituents as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when referring to such substituents as in particular to a particular alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, one to three of the above substituents are meant. For example methylphenyl refers to one to three methyl-substituted phenyl groups.
Example 1: preparation of intermediate 3 beta-acetoxy-18 beta-glycyrrhetinic acid
18 beta-glycyrrhetinic acid (21.25 mmol) was added to 20mL of anhydrous pyridine solution in which DMAP (2.55 mmol) and acetic anhydride (84.98 mmol) were dissolved, and reacted at room temperature for 5 hours. After the reaction, most of the solvent is removed by rotating under reduced pressure, 60mL of water is added for stirring and dissolution, then the pH is regulated to 2-3 by dilute hydrochloric acid, a precipitate is formed, and a white solid is obtained by suction filtration. The yield was 95.93%; its nuclear magnetic data is 1 H NMR(500MHz,CDCl 3 )δ5.71(s,1H,12-CH＝C),4.52(dd,J＝11.7,4.7Hz,1H,3-CHOOCCH 3 ),2.79(dt,J＝13.7,3.5Hz,1H,1a-H),2.37(s,1H,9-H),2.18(dd,J＝13.0,4.1Hz,1H,18-H),2.05(s,3H,32-CH 3 ),2.09–1.97(m,2H,16a-H+19a-H),1.96–1.90(m,1H,21a-H),1.83(td,J＝13.9,5.2Hz,1H,15a-H),1.75–1.52(m,5H,6a-H+2-H+7a-H+21b-H),1.51–1.30(m,5H,6b-H+7b-H+19b-H+22-H),1.37(s,3H,27-CH 3 ),1.26–0.99(m,3H,15b-H+16b-H+1b-H),1.22(s,3H,29-CH 3 ),1.16(s,3H,25-CH 3 ),1.13(s,3H,26-CH 3 ),0.87(s,6H,23-CH 3 +24-CH 3 ),0.83(s,3H,28-CH 3 ),0.84–0.77(m,1H,5-H). 13 C NMR(101MHz,CDCl 3 )δ200.4,181.4,171.1,169.5,128.5,80.7,61.7,55.0,48.3,45.5,43.81,43.2,40.9,38.8,38.1,37.7,37.0,32.7,31.9,30.9,28.6,28.5,28.1,26.4,23.6,23.4,21.33,18.7,17.4,16.7,16.4.
Example 2: preparation of intermediate 31- (vinyl-2-ylmethyl) -1- (3β -acetoxy-18β -glycyrrhetinic acid) -amide
A mixture of 3β -acetoxy-18β -glycyrrhetinic acid (19.50 mmol), EDCI (25.35 mmol) and HOBt (19.50 mmol) was dissolved in 100mL anhydrous dichloromethane. Then 5.41mL of triethylamine was added dropwise, and the mixture was stirred at room temperature until the mixture was dissolved and clear, and allylamine hydrochloride (23.40 mmol) was added to participate in the reaction. After the reaction, vacuum desolventizing, extracting with ethyl acetate, washing with water, drying with sodium sulfate, and vacuum desolventizing. Finally, dichloromethane and methanol (120:1-100:1) are used as eluent, and the white solid is obtained after column chromatography purification, and the yield is 98.22%; the nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 )δ5.90(t,J＝5.7Hz,1H,30-CONH),5.80(ddt,J＝17.1,10.3,5.6Hz,1H,2′-CH＝CH 2 ),5.62(s,1H,12-CH＝C),5.12(ddd,J＝13.7,11.6,1.4Hz,2H,3′-CH＝ 2 CH),4.48(dd,J＝11.6,4.8Hz,1H,3-CHOOCCH 3 ),3.99–3.73(m,2H,1′-NH 2 CH),2.75(dt,J＝13.5,3.4Hz,1H,1a-H),2.32(s,1H,9-H),2.15(dd,J＝13.2,3.8Hz,1H,18-H),2.02(s,3H,32-CH 3 ),2.07–1.93(m,2H,16a-H+19a-H),1.82(dd,J＝13.9,4.3Hz,1H,21a-H),1.77(dd,J＝3.8,2.1Hz,1H,15a-H),1.75–1.51(m,5H,6a-H+2-H+7a-H+21b-H),1.48–1.30(m,5H,6b-H+7b-H+19b-H+22-H),1.33(s,3H,27-CH 3 ),1.16–1.01(m,3H,15b-H+16b-H+1b-H),1.12(s,6H,29-CH 3 +25-CH 3 ),1.09(s,3H,26-CH 3 ),0.85(s,6H,23-CH 3 +24-CH 3 ),0.79(s,3H,28-CH 3 ),0.77(d,J＝11.5Hz,1H,5-H). 13 C NMR(101MHz,CDCl 3 )δ200.0,175.6,171.0,169.9,134.5,128.4,116.4,80.6,61.7,55.0,48.2,45.4,43.6,43.2,41.9,41.8,38.8,38.0,37.7,36.9,32.7,31.9,31.5,29.6,28.5,28.0,26.4,23.5,23.3,21.3,18.7,17.4,16.7,16.4.
example 3: preparation of intermediate 31- (ethylene oxide-2-ylmethyl) -1- (3 beta-acetoxy-18 beta-glycyrrhetinic acid) -amide
Intermediate 31- (vinyl-2-ylmethyl) -1- (3. Beta. -acetoxy-18. Beta. -glycyrrhetinic acid) -amide (0.91 mmol) was added to a solution of 6 ml of m-chloroperoxybenzoic acid (3.64 mmol) in tetrahydrofuran, reacted at 0℃for 4 hours, followed by 4mol L -1 The pH value is adjusted to 9-10 by sodium hydroxide solution. Finally, 30mL of ethyl acetate was added to the mixture for extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate, then the solvent was removed under vacuum to give a white solid.
Example 4: preparation of 1-piperazine-3- (3 beta-acetoxy-18 beta-glycyrrhetinic acid-30-amido) -2-hydroxy propanol
31- (ethylene oxide-2-methyl) -1- (3 beta-acetoxy-18 beta-glycyrrhetinic acid) -amide (0.88 mmol) is added into 5mL isopropyl alcohol solution dissolved with piperazine (1.06 mmol), the reaction is stopped after 8h reaction at 60 ℃, 30mL methylene chloride is added into the mixed solution for extraction, water washing is carried out for three times, drying and desolventizing are carried out, and column chromatography purification is carried out, thus obtaining pale yellow solid with the yield of 39.82%.
Example 5: preparation of 1-piperazine-3- (18 beta-glycyrrhetinic acid-30-amide) -2-hydroxy propanol
The compound 1-piperazine-3- (3 beta-acetoxy-18 beta-glycyrrhetinic acid-30-amido) -2-hydroxy propanol (0.44 mmol), 4mol L -1 Sodium hydroxide solution (3.52 mmol) and mixed solvent (5 mL, methanol/tetrahydrofuran=1/1.5, V/V) were added to a 25mL round bottom flask and reacted at room temperature for 5 hours. After that, 30mL of methylene chloride was added to the system for extraction, and the mixture was washed with water three times. Separating the organic layer, drying, and vacuum-treatingThe solvent was removed under conditions. Finally, column chromatography purification using dichloromethane and methanol (20:1-10:1) as eluent gave a pale yellow solid in 73.72% yield.
Other target compounds are synthesized by adopting corresponding raw materials or substituents and referring to the implementation steps. The structure and nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized 18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure are shown in table 1, and the physicochemical properties are shown in table 2.
Nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the compounds of Table 1
TABLE 2 physicochemical Properties of the target Compounds
Pharmacological example 1:
EC 50 (median effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to a compound, and is also an important parameter for setting the concentration of the compound when researching the action mechanism of the target compound. In the concentration gradient experiment, proper 5 concentrations are set by adopting a double dilution method, and finally the inhibition rate of the medicament to plant pathogenic bacteria and the medicament concentration are converted into logarithmic values, and the virulence curve is obtained by SPSS software regression analysis, so that EC is calculated 50 。
Testing the effective medium concentration EC of the target compound to plant pathogenic bacteria by using turbidity method 50 The test subjects were rice bacterial leaf blight bacteria (Xoo) and citrus canker bacteria (Xac). DMSO was dissolved in the medium as a blank. Putting rice bacterial leaf blight bacteria (rice bacterial leaf blight pathogenic bacteria are in an M210 solid culture medium) into an NB culture medium, and carrying out shake culture in a constant-temperature shaking table at 28 ℃ and 180rpm until the bacterial leaf blight bacteria are in a logarithmic growth phase for later use; the citrus canker fungus (on M210 solid medium) is placed in NB medium and shake-cultured in a thermostatic shaker at 28℃and 180rpm until logarithmic growth phase is ready for use. 5mL of toxic NB liquid culture medium with different concentrations (for example, 100,50,25,12.5,6.25 mug/mL) of the medicament (compound) is prepared, and is added into a test tube, 40 mu L of NB liquid culture medium containing phytopathogenic bacteria is respectively added, and the mixture is oscillated in a constant temperature shaking table at 28-30 ℃ and 180rpm, so that bacterial leaf blight of rice is cultivated for 36h and citrus canker is cultivated for 48h. Measuring OD of bacterial solutions with various concentrations on a spectrophotometer 595 Values, and additionally determining the OD of corresponding concentrations of toxic sterile NB liquid medium 595 Values.
Corrected OD = bacteria-containing medium OD-sterile medium OD
Inhibition ratio = [ (corrected control medium bacterial liquid OD value-corrected toxic medium OD value)/(d value)
After correction, the OD value of the control culture medium bacterial liquid is multiplied by 100
The present invention is described with the aid of examples, but the contents of examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
TABLE 3 EC of 18 beta-glycyrrhetinic acid-30-amides containing Isopropanolamide Structure against phytopathogenic bacteria 50
As can be seen from Table 3, the target compounds exhibited excellent inhibitory activity against plant pathogenic bacteria (such as Rhizoctonia solani and Rhizoctonia cerealis) in an in vitro test. Compounds 2-3, 10-12, 14-15 and 24-25 showed excellent inhibitory activity against rice bacterial blight fungus (Xanthomonas oryzae pv. Oryzae, xoo), EC thereof 50 3.64-18.34 μg/mL; compounds 2-4, 13-14, 17 and 24-25 show good inhibitory activity against Leuconostoc citruses (Xanthomonas axonopodis pv. Citri, xac), the EC thereof 50 4.16-18.44 mug/mL; can be used for preparing pesticides against plant pathogenic bacteria.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (2)

1. A method for preparing an 18 beta-glycyrrhetinic acid amide compound containing an isopropanolamine structure, which is characterized by comprising the following steps:
wherein,,
the compound is selected from the following compounds:
2. the process according to claim 1, wherein when R 3 In the case of acetoxy, the preparation method comprises the following steps:
step one, dissolving a mixture of a compound IV, carbodiimide hydrochloride and hydroxybenzotriazole in a solvent, then adding triethylamine, stirring until the mixture is dissolved and clarified, and adding allylamine hydrochloride to participate in a reaction to obtain a compound II;
adding the compound II into an organic solution containing m-chloroperoxybenzoic acid, stirring for reaction, then adjusting the pH value of the mixture solution to 9-10, adding ethyl acetate into the mixture for extraction, washing an organic layer with water, drying, and removing the solvent under vacuum to obtain a compound III;
and thirdly, adding the compound III into an organic solution dissolved with amine, stirring for reaction, adding dichloromethane into the mixed solution for extraction after stopping the reaction, washing with water, drying, removing the solvent, and purifying the remainder by column chromatography to obtain the compound I.
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