CN111233908A - Benzoxaborol-1-ol compound and preparation method and application thereof - Google Patents
Benzoxaborol-1-ol compound and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
- A01N55/08—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur containing boron
Abstract
The invention belongs to the field of bactericides, and particularly relates to a benzoxaborol-1-alcohol compound and a preparation method and application thereof. The benzoxaborol-1-alcohol compound has good bactericidal activity, can effectively control crop diseases such as tomato early blight, wheat scab, rice sheath blight, strawberry gray mold, apple spot disease, cucumber anthracnose and the like, can obtain excellent antibacterial effect at low concentration, and shows good selectivity. The compound is used as a leucyl-tRNA synthetase inhibitor, utilizes the evolutionary difference of germs and the aminoacyl-tRNA synthetase of eukaryote, has high safety to non-target organisms while killing the germs, and can be used as a bactericide in agriculture.
Description
Technical Field
The invention relates to the field of agricultural bactericides, in particular to a benzoxaborole-1-alcohol compound and a preparation method and application thereof.
Background
aminoacyl-tRNA synthetase is a novel action target of human diseases, widely exists in prokaryotes and eukaryotes, and is an important protein in protein synthesis. The mechanism of action of aminoacyl-tRNA synthetase is divided into two steps: first, an amino acid and ATP are reacted under the catalysis of an aminoacyl-tRNA synthetase to obtain an activated, hydrolyzable aminoacyl-adenylate intermediate. The aminoacyl-tRNA synthetase then catalyzes the transfer of an amino acid molecule to its cognate tRNA, and the resulting aminoacyl-tRNA serves as a substrate for the synthesis of a polypeptide that occurs in a ribosome. Since aminoacyl-tRNA synthetases catalyze the attachment of specific amino acids to the corresponding trnas, which is the first step in protein synthesis and determines the correct translation of the protein, this enzyme plays an extremely important role in cell survival. Moreover, by utilizing the larger evolutionary difference between aminoacyl-tRNA synthetases in prokaryotes and eukaryotes, antibacterial drugs with high selectivity and small side effect can be developed.
The benzo-borole compounds are inhibitors of leucyl-tRNA synthetases, in which the boron atom in the structure forms a spiro adduct with the terminal adenosine of the tRNA from leucine in the editing domain of leucine-tRNA synthetases, and act as noncompetitive inhibitors to inhibit the activity of leucyl-tRNA synthetases. The development of novel aminoacyl-tRNA synthetase inhibitors is very important for the research and development of bactericides with excellent action activity, low drug resistance and high selectivity, at present, the research of benzo-boron ring drugs is concentrated in the fields of antifungal, antitumor and the like, and the active ingredient of the marketed antifungal infection drug Kerydin is a benzo-boron ring compound tavaborole. The chemically synthesized aminoacyl-tRNA synthetase inhibitor mainly comprises benzyl phenyl ether, ethanolamine, quinolinone, biphenyl-substituted pyrazole and benzo boron ring.
However, the application of the boracic ring compound in the field of agricultural disease control is not seen.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide benzoxaborol-1-alcohol compounds, a preparation method of the compounds and application of the compounds in sterilization.
The technical scheme is as follows: in order to achieve the purpose, the technical scheme adopted by the invention is as follows:
on one hand, the invention provides benzoxaborole-1-alcohol compounds, which have the following structural formula:
wherein R is attached to C at position 4,5, 6 or 7 and R is-R1or-L-R3R' is-CH2-or-Y-CH2-；
Wherein R is1Selected from hydrogen, halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8HaloalkynylthiosBase, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldehyde alkynyl, C2-C8Aldehyde halogenated alkynyl, carbon aryl, heterocyclic radical, cyano, nitro and one of other groups;
said other groups are amino, carbonyl, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl, aminothiocarbonyl substituted with 1 or more groups independently selected from the group consisting of: hydrogen, halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, cyano or nitro;
wherein L is a bridged structure selected from O, S, CHR4、NR5COO, thiocarbonyl,Sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl or aminothiocarbonyl, R4、R5Independently selected from hydrogen, halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldeynyl radical or C2-C8Aldehyde-based haloalkynyl;
wherein R is3Is a carbon aryl or heterocyclic radical; further, R3Selected from the group consisting of oxathianes, morpholines, pyridines, pyrimidines, pyridazines, quinolines, pyrazoles, thiazoles, isothiazoles, thiadiazoles, thiophenes, furans, oxazoles, isoxazoles, oxadiazoles, and fluorine-containing, chlorine-containing derivatives of these heterocycles;
wherein Y is linked to a benzene ring selected from O, S, CH2Unsubstituted or substituted with 1 group independently selected from: halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldehyde alkynyl, C2-C8Aldehyde haloalkynyl, carboaryl or heterocyclyl.
In a second aspect, the present invention provides benzoxaborol-1-ol compounds having the structure shown in formula (I):
in a third aspect, the present invention provides benzoxaborol-1-ol compounds having the structure shown in formula (II):
in a fourth aspect, the present invention provides benzoxaborol-1-ol compounds having the structure shown in formula (iii):
in a fifth aspect, the invention also provides when R is-R1R' is-CH2The preparation method of the benzoxaborole-1-alcohol compound comprises the following steps: reacting bromobenzaldehyde or bromobenzoic acid compounds or cyano-substituted bromotoluene compounds with chloromethyl methyl ether to convert the bromobenzaldehyde compounds with hydroxyl protected by methoxy methyl, reacting with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect boron atoms to benzene rings, and finally deprotecting in hydrochloric acid to spontaneously form rings to obtain corresponding benzoxaboro-1-ol compounds;
or when R is-R1R' is-Y-CH2The preparation method of the benzoxaborole-1-alcohol compound comprises the following steps: performing wittig reaction on a bromobenzaldehyde compound, hydrolyzing to obtain a bromophenylacetaldehyde compound, reacting with chloromethyl methyl ether to obtain a bromophenethyl alcohol compound with hydroxyl protected by methoxy methyl, finally reacting with triisopropyl borate in a tetrahydrofuran solvent of n-butyllithium at a low temperature to connect boron atoms to a benzene ring, deprotecting in hydrochloric acid, and spontaneously cyclizing to obtain the corresponding hexabasic benzoxaboro-1-ol compound.
Or when R is L-R3R' is-CH2When L is S, O, (thio) phenol compound III-9 and 2-bromo-4-fluorobenzaldehyde react to obtain (thio) ether compound, sodium borohydride reduces to obtain III-12, III-12 reacts with chloromethyl methyl ether to obtain III-13, and boron reacts with III-13Triisopropyl gallate reacts in tetrahydrofuran solvent of n-butyl lithium at low temperature to enable boron atoms to be connected to benzene rings, deprotection is carried out in hydrochloric acid, and spontaneous cyclization is carried out to obtain corresponding benzoxaborol-1-alcohol compounds III-14. III-14 can also be obtained by hydrolysis reduction of III-15 obtained by reacting III-11 with bis (pinacolato) diboron under the catalysis of palladium, and the synthetic route is as follows:
or when R is L-R3R' is-CH2When L is thiocarbonyl and sulfonyl, the compound III-14 is oxidized by sodium periodate to respectively obtain corresponding benzoxaborol-1-alcohol compounds III-16 and III-17, and the synthetic route is as follows:
or when R is L-R3R' is-CH2When L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 are subjected to Friedel-crafts reaction to obtain a compound III-20, then bromosuccinimide is brominated, the compound III-21 is hydrolyzed with sodium acetate under the alkaline condition, then the compound III-22 is obtained by oxidation, then the compound III-23 is obtained by reaction with ethylene glycol, then the compound III-23 is subjected to low-temperature reaction with triisopropyl borate in a tetrahydrofuran solvent of n-butyllithium to connect boron atoms to benzene rings, deprotection is performed in hydrochloric acid, spontaneous cyclization is performed to obtain a corresponding compound III-25, and finally a Sazaret reagent is used for reaction to obtain a benzoxaboro-1-ol compound III-26, wherein the synthetic route is as follows:
or when R is L-R3R' is-CH2When L is carbonylamino, thiocarbonylamino or sulfonylamino, the compound III-27 is coupled with different acyl chloride, thioacyl chloride and sulfonyl chloride to form the benzoxaborol-1-ol compounds III-28, III-29 and III-30 which are connected by L, and the synthetic route is as follows:
or when R is L-R3R' is-CH2When L is NH, an alcohol compound III-35 is formed by an iodo compound III-31 and a compound III-32 under the protection of tert-butyloxycarbonyl, then a tetrahydropyran protected alcoholic hydroxyl group is formed by the iodo compound III-31 and the compound III-32 in the presence of 3, 4-dihydropyran in the presence of pyridine, and finally deprotection is carried out under acidic conditions to form a benzoxaborol-1-alcohol compound III-39, wherein the synthetic route is as follows:
or when R is L-R3R' is-CH2-, L is CH2In the process, boric acid compound III-40 and 2-methoxy-4-bromobenzaldehyde are subjected to Suzuki coupling reaction to obtain III-42, then are converted into trifluoromethanesulfonic salt III-44 under the action of cerium trichloride and sodium iodide through trifluoromethanesulfonic anhydride, and finally are hydrolyzed under acidic conditions to obtain corresponding benzoxaborol-1-alcohol compound III-46, wherein the synthetic route is as follows:
in a sixth aspect, the invention also provides application of the benzoxaborole-1-alcohol compound in the field of crop disease control.
Wherein the crop diseases are one or more of early blight bacteria, gibberellic disease, rhizoctonia solani, botrytis cinerea, pythium aphanidermatum, alternaria maculata, colletotrichum, late blight bacteria and downy mildew bacteria.
In the definitions of the compounds of the formulae (I) to (III) given above, the terms used are generally defined as follows:
halogen means fluorine, chlorine, bromine or iodine.
By alkyl is meant a straight, branched or cyclic chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl and the like. Haloalkyl refers to a group in which the alkyl group is substituted with one or more halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and the like. By alkenyl is meant straight-chain, branched or cyclic alkenes such as ethenyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1, 2-allenyl, 2, 4-hexadienyl, and the like. The alkynyl group means a straight, branched or cyclic alkynyl group, for example, ethynyl, propynyl, propargyl, and the like.
By alkoxy is meant a straight, branched or cyclic chain alkyl group attached to the structure via an oxygen atom. Haloalkoxy refers to a group in which an alkoxy group is substituted with one or more halogen atoms, for example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, and the like. Alkenyloxy refers to a straight, branched, or cyclic alkenyl group attached to a structure through an oxygen atom. Haloalkenyloxy refers to a group in which an alkenyloxy group is substituted with one or more halogen atoms. Alkynyloxy refers to a straight, branched or cyclic alkynyl group attached to a structure via an oxygen atom. Haloalkynyloxy refers to a group in which the alkynyloxy group is substituted with one or more halogen atoms.
By alkylthio is meant a straight, branched or cyclic chain alkyl radical attached to the structure by a sulfur atom. Haloalkylthio means a group in which an alkylthio group is substituted with one or more halogen atoms, for example, chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio and the like. Alkenylthio means a straight, branched or cyclic alkenyl group attached to a structure via a sulfur atom. Haloalkenylthio means a group in which an alkenyloxy group is substituted by one or more halogen atoms. Alkynylthio refers to a straight, branched or cyclic alkynyl group attached to a structure via a sulfur atom. Haloalkenylthio means a group in which an alkynylthio group is substituted with one or more halogen atoms.
By hydroxyalkyl, mercaptoalkyl and aldehydic alkyl are meant groups in which the alkyl group is substituted with one or more hydroxyl, mercapto and aldehyde groups, respectively. Hydroxyalkenyl, mercaptoalkenyl, and aldenylyl refer to groups in which an alkenyl group is substituted with one or more hydroxyl, mercapto, and aldehyde groups, respectively. Hydroxyalkynyl, mercaptoalkynyl and aldynyl refer to groups in which the alkynyl group is substituted with one or more of a hydroxyl group, a mercapto group and an aldehyde group.
The carbonylamino group means the structure-CO-NH-and the sulfonylamino group means-SO2-NH-structure, sulfinylamino-structure-SO-NH-structure, thiocarbonylamino-structure-CS-NH-structure. Aminocarbonyl means the structure-NH-CO-, aminosulfonyl means-NH-SO2-structure, aminosulfinyl refers to the-NH-SO-structure, aminothiocarbonyl refers to the-NH-CS-structure.
The term "carboaryl" refers to a polyaromatic group composed of carbon atoms unsubstituted or substituted with 1 to 4 groups, for example, 1-methylphenyl, 2-propylnaphthyl and the like. The heterocyclic group means a five-membered or six-membered ring containing 1 or more N, O, S heteroatoms, which is unsubstituted or substituted with 1 to 4 groups. Such as oxathianes, morpholines, pyrans, pyridines, pyrimidines, pyridazines, quinolines, pyrazoles, thiazoles, isothiazoles, thiadiazoles, thiophenes, furans, oxazoles, isoxazoles, oxadiazoles, and halogen-containing (fluorine, chlorine, bromine, iodine) derivatives of these heterocycles.
Some of the compounds of the present invention can be illustrated by the specific compounds listed in tables 1 to 3, and the present invention includes but is not limited to these compounds.
TABLE 1
TABLE 2
TABLE 3
The compound of the general formula (I) can be prepared by reacting bromobenzaldehyde or bromobenzoic acid compound I-1 or cyano-substituted bromobenzyl compound I-2 with chloromethyl methyl ether, converting the reaction product into bromobenzyl alcohol compound I-3 with hydroxyl protected by methoxymethyl, reacting the bromobenzyl alcohol compound I-3 with triisopropyl borate in tetrahydrofuran solvent of n-butyl lithium at low temperature to connect boron atom to benzene ring, finally deprotecting in hydrochloric acid, and spontaneously cyclizing to obtain corresponding benzoxaborol-1-alcohol compound I-4, wherein the synthetic route is as follows:
the invention relates to compounds of general formula (II) when Y is selected from CH2In general, bromobenzaldehyde compound II-5 is subjected to wittig reaction and hydrolysis to obtain bromophenylacetaldehyde compound II-6, and then the bromophenylacetaldehyde compound II-6 is reacted with chloromethyl methyl ether to obtain bromobenzene with hydroxyl protected by methoxy methylEthanol compound II-7, and finally reacting with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect boron atoms to benzene rings, deprotecting in hydrochloric acid, and spontaneously cyclizing to obtain corresponding hexatomic benzoxaborole-1-ol compound II-8, wherein the synthetic route is as follows:
the compound of the general formula (III) of the present invention can be synthesized by the following method when R3 is a substituted phenyl group.
When L is S, O, the (thio) phenol compound III-9 and III-10 can be reacted to obtain (thio) ether compound III-11, which is then reduced by sodium borohydride to obtain III-12. And then III-12 reacts with chloromethyl methyl ether to obtain III-13, finally reacts with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect boron atoms to benzene rings, and deprotection is carried out in hydrochloric acid to obtain the corresponding benzoxaborol-1-alcohol compound III-14 through spontaneous cyclization. III-14 can also be obtained by hydrolysis reduction of III-15 obtained by reacting III-11 with bis (pinacolato) diboron under the catalysis of palladium, and the synthetic route is as follows:
the benzoxaborol-1-alcohol compound with L as thiocarbonyl and sulfonyl can be respectively prepared into compounds III-16 and III-17 from corresponding compounds III-14 by sodium periodate oxidation, and the synthetic route is as follows:
when L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 are subjected to Friedel-crafts reaction to obtain a compound III-20, then bromosuccinimide is used for bromination, the compound III-21 is obtained by hydrolysis with sodium acetate under the alkaline condition and is oxidized to obtain a compound III-22, the compound III-23 is reacted with ethylene glycol, the compound III-23 is subjected to low-temperature reaction with triisopropyl borate in a tetrahydrofuran solvent of n-butyl lithium to enable a boron atom to be connected to a benzene ring, deprotection is carried out in hydrochloric acid to obtain a corresponding compound III-25 through spontaneous cyclization, and finally a Saxiet reagent is used for reaction to obtain a benzoxaborol-1-alcohol compound III-26, wherein the synthetic route is as follows:
when L is carbonylamino, thiocarbonylamino and sulfonylamino, the compound III-27 is coupled with different acyl chloride, thioacyl chloride and sulfonyl chloride to form the benzoxaborol-1-alcohol compounds III-28, III-29 and III-30 which are connected by L, and the synthetic route is as follows:
when L is NH, it is usually possible to form alcohol compound III-35 from iodo compound III-31 and compound III-32 under protection of tert-butyloxycarbonyl, then form tetrahydropyran protected alcoholic hydroxyl group with 3, 4-dihydropyran in the presence of pyridine, and finally deprotect under acidic conditions to form III-39, the synthetic route is as follows:
l is CH2In the process, boric acid compound III-40 and 2-methoxy-4-bromobenzaldehyde III-41 are subjected to Suzuki coupling reaction to obtain III-42, then are converted into trifluoromethyl sulfonate III-44 under the action of cerium trichloride and sodium iodide through trifluoro sulfonic anhydride, and finally are hydrolyzed under acidic conditions to obtain corresponding benzoxaborol-1-alcohol compound III-46, wherein the synthetic route is as follows:
the benzoxaborol-1-alcohol compounds with the structures shown in formulas (I) to (III) provided by the invention have a bactericidal effect and have an obvious inhibiting effect on crop pathogenic bacteria such as early blight, gibberellic disease, rhizoctonia solani, botrytis cinerea, spotted blight, anthracnose and the like.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
EXAMPLE 1 preparation of Compound 1
A process for the preparation of compound 1 comprising the steps of:
step A: preparation of 2-bromo-5-fluorobenzyl alcohol
2-bromo-5-fluorobenzaldehyde (62.0g,293mmol) was dissolved in methanol (400mL) and sodium borohydride (5.57g,147mmol) was added portionwise at 0 ℃. Stirring for 1h at room temperature, adding water, distilling under reduced pressure to remove half of the solvent, extracting with ethyl acetate and water extraction system, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, and removing the solvent to obtain 2-bromo-5-fluorobenzyl alcohol.
And B: preparation of 1-bromo-4-fluoro-2- ((methoxymethoxy) methyl) benzene
2-bromo-5-fluorobenzyl alcohol (60.8g,293mmol) and diisopropylethylamine (61mL,0.35mol) were dissolved in dichloromethane, chloromethyl methyl ether (27mL,0.35mol) was added at 0 deg.C, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, the mixture was extracted with chloroform, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by pressure distillation to obtain the 1-bromo-4-fluoro-2- ((methoxyl) methyl) benzene.
And C: preparation of intermediate 2- ((methoxy) methyl) -4-fluorobenzeneboronic acid
1-bromo-4-fluoro-2- ((methoxymethoxy) methyl) benzene (73.2g,293mmol) was dissolved in tetrahydrofuran (400mL) and n-butyllithium (1.6M in hexane, 200mL) was added at-78 ℃ over 45 min. After 5min triisopropyl borate (76.0mL,330mmol) was added over 10min and after 1.5h reaction an intermediate mixture was obtained.
Step D: preparation of Compound 1
To the above intermediate mixture was added water and hydrochloric acid (6M,55mL), and the mixture was distilled under reduced pressure until the solvent was reduced by half. After the mixture was extracted with ethyl acetate and water, the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After desolventizing by distillation under reduced pressure, the residue was treated with isopropyl ether/hexane to give compound 1(26.9g, yield 60%) as a white powder, melting point: 118 ℃ and 120 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.22(s,1H),7.75(dd,J＝8.0,5.9Hz,1H),7.24(dd,J＝9.5,1.8Hz,1H),7.19–7.12(m,1H),4.96(s,2H)。
The compounds 2-12 can be synthesized according to the preparation method of the compound 1 in the example 1, wherein the substituents on the benzene ring of the compounds 2-4 are 6-F, 5-Cl and H respectively.
EXAMPLE 2 preparation of Compound 13
A process for the preparation of compound 13 comprising the steps of:
step A: preparation of 2-bromo-5-fluorobenzaldehyde
2-bromo-5-fluoro-benzaldehyde (4.2g,20.0mmol), methoxymethyltriphenylphosphine chloride (8.5g,24.0mmol) and potassium tert-butoxide (2.8g,24.0mol) were dissolved in N, N-dimethylformamide (50mL) and stirred at room temperature overnight. The reaction was quenched with hydrochloric acid (6M), and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride, and finally dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, tetrahydrofuran (60mL) and hydrochloric acid (6M) were added to the residue, and the mixture was heated under reflux for 8 hours. Water was added to the mixture, the mixture was extracted with diethyl ether, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Finally, decompressing, distilling and desolventizing to obtain the 2-bromo-5-fluorobenzeneacetaldehyde.
And B: preparation of 2- ((methoxy) ethyl) -1-bromo-4-fluorobenzene
2-bromo-5-fluoroacetaldehyde (3.6g,16.6mmol) was dissolved in methanol (40mL), sodium borohydride (640mg,16.6mmol) was added at 0 deg.C and stirred at room temperature for 1 h. Water was added to the mixture, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After desolventizing by distillation under reduced pressure, methylene chloride (50mL), diisopropylethylamine (3.5mL,20mmol) and chloromethyl methyl ether (1.5mL,20mmol) were added to the residue at 0 ℃ and the reaction was stirred at room temperature overnight. Water and chloroform were added to the mixture to extract the mixture, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After reduced pressure distillation and desolventization, the product was chromatographed on silica gel column to obtain 2- ((methoxymethoxy) ethyl) -1-bromo-4-fluorobenzene as colorless oil.
And C: preparation of Compound 13
2- ((methoxymethoxy) ethyl) -1-bromo-4-fluorobenzene (7.3g,29.3mmol) was dissolved in tetrahydrofuran (40mL) and n-butyllithium (1.6M in hexane, 20mL) was added at-78 ℃ over 45 min. After 5min, triisopropyl borate (7.60mL,33.0mmol) was added over 10min, and the mixture returned to room temperature after 1.5 h. Water and hydrochloric acid (6M,55mL) were added and the mixture was distilled under reduced pressure until the solvent was reduced by half. After the mixture was extracted with ethyl acetate and water, the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After desolventizing by distillation under reduced pressure, the product was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2:1), dispersed in pentane, and after trituration, filtered to give compound 13(1.0g, yield: 21%) as a white solid product, melting point: 77-82 ℃.1H NMR(300MHz,DMSO-d6)δ(ppm):2.86(t,J＝5.9Hz,2H),4.04(t,J＝5.9Hz,2H),7.0-7.1(m,2H),7.69(dd,J＝8.2,7.2Hz,1H),8.47(s,1H)。
Both compound 14 and compound 15 were synthesized according to the method for the preparation of compound 13 of example 2.
EXAMPLE 3 preparation of Compound 25
A method of preparing compound 25, comprising the steps of:
step A: preparation of 4- ((3, 4-dichlorophenyl) thio) -2-bromobenzaldehyde
2-bromo-4-fluorobenzaldehyde (1.0g,4.92mmol) was dissolved in N, N-dimethylformamide (25mL) and cooled to 0 ℃ in an ice-water bath. Potassium carbonate (2.0g,9.85mmol) and 3, 4-dichlorobenzenethiol (882mg,4.92mmol) were added successively under nitrogen. After stirring the mixture for an additional 2.5h, it was treated with ice water (25 mL). After extraction with ethyl acetate, the organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. And desolventizing the residue by using a rotary evaporator, and purifying the product by using silica gel column chromatography to obtain a pure product of 4- ((3, 4-dichlorophenyl) sulfenyl) -2-bromobenzaldehyde.
And B: preparation of 4- ((3, 4-dichlorophenyl) thio) -2-bromobenzyl alcohol
4- ((3, 4-dichlorophenyl) thio) -2-bromobenzaldehyde (400mg,1.10mmol) was dissolved in methanol (20mL) and cooled to 0 ℃ in an ice-water bath, and sodium borohydride (62mg,1.65mmol) was added to the solution. The reaction was stirred for 0.5h, then saturated sodium bicarbonate was added. After the reaction mixture is desolventized, the reaction mixture is extracted by ethyl acetate, washed by water and saturated sodium chloride respectively, finally dried by anhydrous sodium sulfate and concentrated in vacuum to obtain a viscous oily product, namely 4- ((3, 4-dichlorophenyl) sulfenyl) -2-bromobenzyl methanol.
And C: preparation of (4- (methoxymethoxy) methyl) -3-bromophenyl) (3, 4-dichlorophenyl) sulfide
4- ((3, 4-dichlorophenyl) thio) -2-bromobenzyl methanol (4.3g,11.84mmol) was dissolved in anhydrous dichloromethane (50mL) and N, N-diisopropylethylamine (7.32mL, 41.45mmol) and chloromethyl methyl ether (1.91mL,26.05mmol) were added successively under nitrogen. The mixture was stirred at room temperature overnight and treated with water (15mL), extracted with dichloromethane, and the organic layer was washed with water and saturated sodium chloride and finally dried with anhydrous ammonium sulfate. The residue was desolventized by a rotary evaporator and purified by silica gel column chromatography to give (4- (methoxymethoxy) methyl) -3-bromophenyl) (3, 4-dichlorophenyl) sulfide as a viscous oily product.
Step D: preparation of Compound 25
(4- (methoxymethoxy) methyl) -3-bromophenyl) (3, 4-dichlorophenyl) sulfide (2.4g,5.86mmol) was dissolved in anhydrous tetrahydrofuran (25mL) and cooled to-80 ℃. N-butyllithium (1.6M,4.03mL,6.45mmol) was added dropwise to the solution over 20min under a nitrogen blanket. After the reaction was stirred at-80 ℃ for 20min, triisopropyl borate (1.48mL,6.45mmol) was added dropwise. After the reaction mixture was gradually brought to room temperature and stirred at room temperature overnight, hydrochloric acid (6M,20mL) was added and stirred for 3 h. The mixture was desolventized, extracted with ethyl acetate and finally dried over anhydrous sodium sulfate. The residue was desolventized by a rotary evaporator and then purified by silica gel column chromatography to obtain compound 25(608mg, yield: 33.3%), melting point: 118 ℃ and 119 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.28(s,1H),7.81(s,1H),7.60-7.45(m,4H),7.15(dd,J＝8.4,2.0Hz,1H),5.03(s,2H)。
Both compounds 26 and 27 were synthesized according to the method for preparing compound 25 of example 3.
EXAMPLE 4 preparation of Compound 28
Taking out the compound25(200mg,0.64mmol) in water: methanol (1:10) (15mL), sodium periodate (688mg,3.21mmol) was added, and after stirring at 60 ℃ for 1h, the solvent was evaporated and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The crude product was rotary-distilled and then purified by recrystallization to give compound 28(112.4mg, yield: 53.5%), m.p.: 141 ℃ and 143 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.39(s,1H),8.11(s,1H),7.99(d,J＝2.0Hz,1H),7.88-7.81(m,2H),7.69-7.60(m,2H),5.02(s,2H)。
Both compounds 29 and 30 were synthesized according to the method for preparing compound 28 of example 4.
EXAMPLE 5 preparation of Compound 31
Dissolve compound 25(260mg,0.83mmol) in water: methanol (1:10) (15mL), sodium periodate (894mg,4.17mmol) was added thereto, and after stirring overnight at 60 ℃, the solvent was distilled off and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The crude product was rotary-distilled, and then purified by recrystallization to give compound 31(86mg, yield: 30%), melting point: 154 ℃ and 156 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.49(s,1H),8.35(s,1H),8.20(s,1H),8.12(dd,J＝8.4,2.0Hz,1H),7.90(d,2H),7.68(d,1H),5.06(s,2H)。
Both compounds 32 and 33 were synthesized according to the method for preparing compound 31 in example 5.
EXAMPLE 6 preparation of Compound 34
A method of preparing compound 34, comprising the steps of:
step A: preparation of 4-phenoxy-2-bromobenzaldehyde
Phenol (6.95g,73.88mmol), 2-bromo-4-fluorobenzaldehyde (15g,73.88mmol) and potassium carbonate (18g,0.13mol) were dissolved in DMF (150mL) and heated at 100 ℃ for 16 h. After hot filtration of the mixture, the filter cake was washed with ethyl acetate. The solvent was evaporated at 50 ℃ using a rotary evaporator, the residue was sonicated in n-pentane and filtered to give 4-phenoxy-2-bromobenzaldehyde.
And B: preparation of 4-phenoxy-2-bromobenzyl alcohol
4-phenoxy-2-bromobenzaldehyde (10.5g,37.89mmol) was dissolved in methanol (300mL) and sodium borohydride (7.2g,190.32mmol) was added in portions while cooling in an ice-water bath. The mixture was stirred at room temperature overnight and methanol was evaporated off. The product was dissolved in water and extracted with dichloromethane, dried and the solvent evaporated to give 4-phenoxy-2-bromobenzyl alcohol as an oil.
And C: preparation of 2- ((methoxy) methyl) -5-phenoxybromobenzene
4-phenoxy-2-bromobenzyl alcohol (10.1g,36.18mmol) and N, N-diisopropylethylamine (11mL) were dissolved in dichloromethane (200mL) and chloromethoxymethane (4.1mL) was added dropwise at room temperature. After stirring the mixture at room temperature overnight under nitrogen, washing with sodium bicarbonate, drying and evaporating the solvent to obtain 2- ((methoxymethoxy) methyl) -5-phenoxybromobenzene as a yellow oily product.
Step D: preparation of Compound 34
2- ((methoxymethoxy) methyl) -5-phenoxybromobenzene (11.7g,36.18mmol) and triisopropyl borate (9.6mL,41.60mmol) were dissolved in tetrahydrofuran under nitrogen, the mixture was cooled to-78 deg.C, and n-butyllithium (1.6M in hexane, 26mL) was added dropwise. The ice-water bath was removed and the reaction mixture was stirred for an additional 3 h. Hydrochloric acid (6M,20mL) was added and the solvent was concentrated. The residue was dissolved in methanol and hydrochloric acid (6M) and refluxed for 1.5h, evaporated to remove methanol and extracted with ethyl acetate. After the product is dried and the solvent is removed,purification by column chromatography on silica gel, eluting with hexane: ethyl acetate (2:1) as an eluent gave compound 34 as a white solid (5.1g, yield: 62.4%), melting point: 95-99 ℃.1H NMR(300MHz,DMSO-d6)δ(ppm):9.17(s,1H),7.43-7.35(m,3H),7.28(s,1H),7.19-7.09(m,2H),6.99(d,2H),4.96(s,2H)。
Both compounds 35 and 36 were synthesized according to the method for preparing compound 34 of example 6.
EXAMPLE 7 preparation of Compound 37
A method of preparing compound 37, comprising the steps of:
step A: preparation of 4-benzoyl-2-bromotoluene
Aluminum trichloride (1.5g,11.0mmol) was dissolved in benzene (16mL) and a solution of 4-methyl-3-bromobenzoyl chloride (2.3g,10.0mmol) in benzene (8mL) was added dropwise at room temperature. After the mixture was stirred at 50 ℃ for 2h, it was washed with hydrochloric acid (3M,20mL) and saturated sodium chloride (20mL), and dried over anhydrous sodium sulfate. And removing the solvent from the product by a rotary evaporator, and purifying by silica gel column chromatography to obtain the 4-benzoyl-2-bromotoluene.
And B: preparation of 4-benzoyl-2-bromobenzyl alcohol
4-benzoyl-2-bromotoluene (2.7g,9.8mmol) was taken in carbon tetrachloride (50mL), bromosuccinimide (1.8g,9.8mmol) and benzoyl peroxide (0.1g,0.5mmol) were added, and the mixture was heated and stirred overnight. And evaporating the solvent of the residue by a rotary evaporator and purifying the residue by silica gel column chromatography to obtain an intermediate product 5-benzoyl-2-bromomethylbromobenzene. 5-benzoyl-2-bromomethylbromobenzene (1.7g,4.83mmol) was taken in N, N-dimethylformamide (30mL), sodium acetate (2.0g,24.15mmol) was added, the mixture was stirred at 60 ℃ overnight and ice water (50g) was added. The precipitate was filtered, washed with water and dried under vacuum to give (4-benzoyl-2-bromo) benzyl acetate. Acetic acid (4-benzoyl-2-bromo) benzyl ester (1.6g,4.9mmol) was dissolved in methanol (25mL), sodium hydroxide (15%, 5mL) was added and refluxed for 1 h. After the solvent of the mixture is distilled off, the mixture is extracted by ethyl acetate and dried by anhydrous sodium sulfate, and after the solvent is removed by a rotary evaporator, the mixture is purified by silica gel column chromatography to obtain the 4-benzoyl-2-bromobenzyl alcohol.
Step D: preparation of 4-phenoxy-2-bromobenzaldehyde
4-benzoyl-2-bromobenzyl alcohol (1.5g,5.15mmol) was dissolved in dichloromethane (30mL), pyridinium chlorochromate (2.2g,10.3mmol) and celite (2.5g) were added, and the mixture was stirred at room temperature overnight. After filtration, the product is evaporated by a rotary evaporator to remove the solvent and purified by silica gel column chromatography to obtain the 4-phenoxy-2-bromobenzaldehyde.
Step E: preparation of [2- (4- (1, 3-dioxolan-2-yl) -3-bromophenyl) -2-phenyl ] -1, 3-dioxolan
4-phenoxy-2-bromobenzaldehyde (1.3g,4.57mmol) was dissolved in toluene (50mL), ethylene glycol (2.8g,45.70mmol) and p-toluenesulfonic acid monohydrate (69mg,0.36mmol) were added, and the mixture was refluxed for 96 h. The mixture was washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated to give [2- (4- (1, 3-dioxolan-2-yl) -3-bromophenyl) -2-phenyl ] -1, 3-dioxolane.
Step F: preparation of (2-formyl-5-benzoyl) phenylboronic acid
[2- (4- (1, 3-Dioxolan-2-yl) -3-bromophenyl) -2-phenyl ] -1, 3-dioxolane (0.5g,1.23mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and cooled to-80 ℃. To the mixture was added dropwise n-butyllithium (1.6M in hexane, 0.88mL) over 15min under a nitrogen blanket. The reaction mixture was allowed to return to room temperature and stirred at room temperature overnight. After addition of hydrochloric acid (6M,6mL), stirring was continued for 2h, the solvent was evaporated and extracted with ethyl acetate and dried over anhydrous sodium sulfate. The product is purified by silica gel column chromatography after the solvent is evaporated to obtain (2-formyl-5-benzoyl) phenylboronic acid.
Step G: preparation of [6- (1-phenyl-1-hydroxymethyl) ] -1, 3-dihydro-2, 1-benzoxaboro-1-ol
(2-formyl-5-benzoyl) phenylboronic acid (0.8g,2.95mmol) was dissolved in tetrahydrofuran (8mL) and water (0.5mL), and sodium borohydride (0.2g,5.90mmol) was added with stirring at room temperature. After stirring for 3h, the reaction was quenched by addition of hydrochloric acid (3M,10 mL). The mixture is evaporated, extracted by ethyl acetate and dried by anhydrous sodium sulfate, then the solvent is evaporated, recrystallized and purified to obtain the [6- (1-phenyl-1-hydroxymethyl) ] -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole.
Step H: preparation of Compound 37
Taking [6- (1-phenyl-1-hydroxymethyl)]-1, 3-dihydro-2, 1-benzoxaborol-1-ol (0.2g,0.83mmol) was dissolved in dichloromethane (15mL), pyridinium chlorochromate (0.5g,2.08mmol) and celite (0.5g) were added, and the mixture was stirred at room temperature for 3h before filtration. The product was evaporated in a rotary evaporator to remove the solvent, and then recrystallized to obtain Compound 37(0.15g, yield: 76%). Melting point: 137-139 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.35(s,1H),8.12(s,1H),7.87(dd,J＝8.0,1.6Hz,1H),7.69(m,3H),7.57(m,3H),5.08(s,2H)。
Both compounds 38 and 39 were synthesized according to the method for preparing compound 37 of example 7.
EXAMPLE 8 preparation of Compound 40
Taking 6-ammonia1, 3-dihydro-2, 1-benzoxaborol-1-ol (500mg,3.36mmol) was dissolved in acetonitrile (25mL), and sodium bicarbonate (845mg,10.1mmol) and benzoyl chloride (859. mu.L, 7.38mmol) were added. The mixture was stirred at room temperature for 2h, quenched with water and stirred for a further 30 min. The mixture was extracted with ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride, and finally dried over anhydrous sodium sulfate. The precipitated product was concentrated in vacuo, filtered and dried to obtain compound 40(310mg, yield: 36%), melting point: 186 ℃ and 193 ℃.1H NMR(300MHz,CDCl3)δ(ppm):8.82(s,1H),8.0-7.60(m,4H),7.52-7.32(m,3H),7.25(dd,J＝7.8Hz,1H),5.00(s,2H)。
Compounds 41 and 42 were synthesized according to the procedure for the preparation of Compound 40 in example 8.
EXAMPLE 9 preparation of Compound 43
6-amino-1, 3-dihydro-2, 1-benzoxaborol-1-ol (750mg,5.0mmol) was dissolved in acetonitrile (25mL), and potassium carbonate (1.7g,12.6mmol) and benzenesulfonyl chloride (710. mu.L, 5.5mmol) were added. The mixture was stirred at room temperature for 2h, quenched with water and stirred for a further 30 min. The mixture was extracted with ethyl acetate and washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The precipitated product was concentrated in vacuo, filtered and dried to give compound 43(565.0mg, yield: 39%), m.p.: 175 ℃ and 184 ℃.1H NMR(300MHz,CDCl3)δ(ppm):7.68(d,J＝7.8Hz,2H),7.44(d,J＝6.9Hz,1H),7.40-7.17(m,4H),7.13(d,J＝7.8Hz,1H),4.94(s,2H)。
Both compounds 44 and 45 were synthesized according to the method for preparing compound 43 of example 9.
EXAMPLE 10 preparation of Compound 46
A process for the preparation of compound 46 comprising the steps of:
step A: preparation of 4-phenylamino-2-bromotoluene
Benzene iodide (4.4g,21,56mmol), 4-methyl-3-bromoaniline (4.0g,21,56mmol) and dimethyl sulfoxide (50mL) were mixed, and cuprous iodide (0.8g,4.31mmol), L-proline (1.0g,8.61mmol) and sodium tert-butoxide (4.1g,43.13mmol) were added in this order under nitrogen. The reaction was stirred at 50 ℃ for 48h, ice (100.0g) was added and extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The product is purified by rotary evaporation and silica gel column chromatography to obtain the 4-phenylamino-2-bromotoluene.
And B: preparation of tert-butyl N- (4-methyl-3-bromophenyl) -N-phenylcarbamate
4-phenylamino-2-bromotoluene (3.2g,12.44mmol) is dissolved in tetrahydrofuran (60mL), lithium hexamethyldisilazide (27.4mL,27.4mmol) is added dropwise over 30min at-80 ℃, stirring is continued for 30min, di-tert-butyl dicarbonate (6.0g,27.4mmol) is added dropwise over 10min, and reaction is carried out at room temperature for 14 h. The mixture is evaporated to obtain a crude product, and the crude product is subjected to silica gel column chromatography to obtain N- (4-methyl-3-bromophenyl) -N-phenyl carbamic acid tert-butyl ester.
And C: preparation of N- (4-hydroxymethyl-3-bromophenyl) -N-phenylcarbamic acid tert-butyl ester
Tert-butyl N- (4-methyl-3-bromophenyl) -N-phenylcarbamate (4.3g,11.88mmol) was dissolved in tetrachloromethane (300mL), bromosuccinimide (2.5g,14.25mmol) and benzoyl peroxide (0.3g,1.19mmol) were added, and the mixture was refluxed for 20 h. The mixture was cooled to room temperature and filtered, the filtrate was evaporated in vacuo to give a crude product, which was chromatographed on silica gel column to give the intermediate tert-butyl N- (3-bromo-4-bromomethylphenyl) -N-phenylcarbamate. The intermediate (2.65g,6.0mmol) was dissolved in N, N-dimethylformamide (50mL), sodium acetate (2.5g,30mmol) was added and stirred at 70 ℃ for 5 h. Ice (100.0g) was added to the mixture, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain an acetic acid intermediate. The acetic acid intermediate (2.5g,5.95mmol) was dissolved in methanol (50mL), and aqueous sodium hydroxide (8%, 15mL) was added and refluxed for 1 h. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated to give tert-butyl N- (4-hydroxymethyl-3-bromophenyl) -N-phenylcarbamate.
Step D: preparation of tert-butyl N- (4- (tetrahydropyran-2-oxymethyl) -3-bromophenyl) -N-phenylcarbamate
Tert-butyl N- (4-hydroxymethyl-3-bromophenyl) -N-phenylcarbamate (2.1g,5.55mmol) was dissolved in dichloromethane (50mL), and 3, 4-dihydropyran (0.9g,11.11mmol), pyridine (28mg,0.35mmol), and p-toluenesulfonic acid monohydrate (53mg,0.28mmol) were added in this order to react at room temperature for 48 h. The mixture was washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After the solvent of the product is distilled off, the product is purified by silica gel column chromatography to obtain the N- (4- (tetrahydropyran-2-oxymethyl) -3-bromophenyl) -N-phenyl carbamic acid tert-butyl ester.
Step E: preparation of 6- (N-tert-butoxycarbonyl-N-phenylamino) -1, 3-dihydro-2, 1-benzoxaboro-1-ol
Tert-butyl N- (4- (tetrahydropyran-2-oxymethyl) -3-bromophenyl) -N-phenylcarbamate (2.6g,5.54mmol) was dissolved in anhydrous tetrahydrofuran, N-butyllithium (1.6M in hexane, 3.98mL) was added dropwise at-80 ℃ over 20min under nitrogen, stirring was continued for 20min, and triisopropyl borate (1.47mL,6.37mmol) was added over 10 min. After the mixture was gradually returned to room temperature, it was stirred overnight. Hydrochloric acid (6M,10mL) was added and stirred for 1h, tetrahydrofuran was evaporated off, the residue was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and finally purified by silica gel column chromatography to give a boronic acid intermediate, this intermediate (0.6g,1.50mmol) was taken up in ethanol (20mL), pyridine (35.0mg,0.45mmol) and p-toluenesulfonic acid monohydrate (85.0mg,0.45mmol) were added, reacted at 50 ℃ for 4h, the solvent was evaporated off, the residue was dissolved in ethyl acetate (50mL) and washed with water and saturated sodium chloride and finally dried over anhydrous sodium sulfate. Purifying the crude product by silica gel column chromatography to obtain 6- (N-tert-butyloxycarbonyl-N-phenylamino) -1, 3-dihydro-2, 1-benzoxaborol-1-ol.
Step F: preparation of Compound 46
6- (N-tert-Butoxycarbonyl-N-phenylamino) -1, 3-dihydro-2, 1-benzoxaboron-1-ol (150.0mg,0.46mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (0.4mL,5.38mmol) was added dropwise at 0 ℃ under nitrogen, and the reaction was neutralized by adding saturated sodium bicarbonate after the mixture was slowly brought to room temperature and stirred for 3 h. The organic layer was separated, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated and purified by silica gel column chromatography and recrystallization to give compound 46(13.2mg, yield: 13%), melting point: 108-110 ℃.1H NMR(300MHz,DMSO-d6)δ(ppm):9.07(s,1H),8.12(s,1H),7.50(s,1H),7.22(m,4H),7.05(d,J＝8.1Hz,2H),6.80(d,J＝7.2Hz,1H),4.91(s,2H)。
Compounds 47 and 48 were synthesized according to the method for preparing Compound 46 in example 10.
EXAMPLE 11 preparation of Compound 49
A method for preparing compound 49, comprising the steps of:
step A: preparation of 4-benzyl-2-methoxybenzaldehyde
Benzylboronic acid (2.15g,10mmol), 2-methoxy-4-bromobenzaldehyde (2.44g,18mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (1.46g,2mmol), caesium fluoride (3.02g,20mmol) and potassium carbonate (4.14g,30mmol) were dissolved in dioxane (30mL), air was removed for 10min and heated at 80 ℃ for 16h, after cooling to room temperature, diluted with ethyl acetate and finally concentrated by filtration over celite. And (4) carrying out silica gel column chromatography on the crude product to obtain 4-benzyl-2-methoxybenzaldehyde.
And B: preparation of 4-benzyl-2-hydroxybenzaldehyde
4-benzyl-2-methoxybenzaldehyde (1.14g,5mmol), cerium trichloride (1.85g,7.5mmol) and sodium iodide (1.13g,7.5mmol) were dissolved in methyl cyanide (20mL), refluxed for 18h, diluted with ethyl acetate and washed with anhydrous sodium thiosulfate, dried and concentrated to give 4-benzyl-2-hydroxybenzaldehyde.
And C: preparation of 4-benzyl-2-trifluoromethanesulfonic benzaldehyde
4-benzyl-2-hydroxybenzaldehyde (0.44g,2.08mmol) was dissolved in dichloromethane (10mL), the solution cooled to-78 deg.C and triethylamine (0.68mL,6.24mmol) and trifluoromethanesulfonic anhydride (0.40mL,3.12mmol) were added. The mixture was stirred at-78 ℃ for 30min, quenched with water (2mL), diluted with dichloromethane (50mL) and washed with hydrochloric acid (1M,20mL), dried and concentrated to give 4-benzyl-2-trifluoromethanesulfonic benzaldehyde.
Step D: preparation of 4-benzyl-2- (4,4,5, 5-tetramethyl- [1,3,2] dioxoborolan-2-ylbenzaldehyde
4-benzyl-2-trifluoromethanesulfonic acid benzaldehyde (0.68g,2.08mmol), bis (pinacolato) diboron (0.80g,3.12mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.31g,0.42mmol) and potassium acetate (0.61g,6.24mmol) are dissolved in dioxane (15mL) and reacted at 80 ℃ for 16h, then cooled to room temperature, diluted with ethyl acetate, filtered and concentrated by taking kieselguhr as a medium, and the crude product is purified by column chromatography to obtain 4-benzyl-2- (4,4,5, 5-tetramethyl- [1,3,2] dioxoborolan-2-benzaldehyde.
Step E: preparation of Compound 49
Taking 4-benzyl-2- (4,4,5, 5-tetramethyl- [1,3, 2)]Dioxoborolan-2-benzaldehyde (0.61g,1.89mmol) was dissolved in methanol (10mL) and tetrahydrofuran (10mL) and sodium borohydride (0.16g,4.17mmol) was added in portions. The mixture was stirred at 0 ℃ for 30min, quenched with hydrochloric acid (6M,0.5mL) and diluted with water (20mL), and stirred at room temperature for an additional 1 h. The solid product was collected and washed with water (10mL), and dried under vacuum to give compound 49(290mg, yield: 68%), m.p.: 173 ℃ and 175 ℃.1H NMR(300MHz,CDCl3)δ(ppm):7.56(s,1H),7.35-7.22(m,4H),7.22-7.13(m,3H),5.06(s,2H),4.01(s,2H)。
Compounds 50 and 51 were synthesized according to the procedure for the preparation of Compound 49 of example 11.
Experimental example: examples of biological Activity tests
The bactericidal activity of the compounds of the invention was tested as follows:
the growth rate method is adopted to carry out primary antibacterial activity determination on 6 common agricultural fungi of botrytis cinerea, early blight of tomato, gibberellic disease of wheat, rhizoctonia solani of rice, colletotrichum of cucumber and alternaria mali, and EC is carried out on compounds with high partial inhibition rate50And (4) determining the toxicity.
The specific operation is as follows: the 6 fungi tested were activated once on PDA medium before bacteriostatic testing and cultured at 25 deg.C for 2-8 days, and the hyphal edge was perforated with a 5mm diameter hole punch for further use. The benzoxaborole-1-alcohol compound is weighed and N, N-dimethylformamide is used as a solvent to prepare a test solution with corresponding concentration, wherein the general concentration is in ppm level. Taking prepared test solution and streptomycin sulfate from the culture medium, taking the N, N-dimethylformamide solution without the test solution as a reference substance, respectively inoculating 6 fungi into the corresponding sterilized culture medium, and then placing the culture medium in an incubator at 25 ℃. The growth of the fungus was observed during the cultivation and was determined in the presence of different test samples.
The names and abbreviations of 6 fungi used in the bioactivity test are shown in Table 4
TABLE 4
| Common name | Latin name | Abbreviation for here |
| Botrytis cinerea (Fr.) Franch | Botrytis cinrea | Bacterium A |
| Early blight of tomato | Alternaria solani | Bacterium C |
| Wheat scab germ | Gibberella zeae | Bacterium D |
| Rhizoctonia solani of rice | Rhizoctonia solani | Bacterium E |
| Colletotrichum cucumerinum | Cucumber anthrax | G bacterium |
| Apple spot pathogen | Alternaria Leaf Spot | Bacterium H |
Results of preliminary screening test of some of the compounds in the examples and EC50Virulence determination results are shown in tables 5 and 6 (fungal names are represented by short names, osthole, boscalid and carbendazim in Table 6 are marketed fungicide controls)
TABLE 5
TABLE 6
From the results shown in tables 5 and 6, it can be seen that the above compounds all exhibit excellent fungicidal effects, and exhibit inhibitory activity against crop fungi at low concentrations. For some fungi, the compounds have better bacteriostatic effect than even osthole, boscalid and carbendazim and have broad bactericidal spectrum.
In conclusion, the benzoxaborol-1-ol compound has the effect of killing crop germs, is used as a leucyl-tRNA synthetase inhibitor, utilizes the evolutionary difference of prokaryotes and eukaryotes, has higher selectivity and safety, and is a potential broad-spectrum, safe and efficient bactericidal substance.
The compounds to which the present invention relates and the uses thereof are described above in detail. However, the present invention is not limited to the specific details of the above-described embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (7)
1. Benzoxaborole-1-ol compounds, characterized in that the compounds have the following structural formula:
wherein R is attached to C at position 4,5, 6 or 7 and R is-R1or-L-R3R' is-CH2-or-Y-CH2-；
Wherein R is1Selected from hydrogen, halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldehyde alkynyl, C2-C8Aldehyde halogenated alkynyl, carbon aryl, heterocyclic radical, cyano, nitro and one of other groups;
said other group is amino, carbonyl, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl or aminothiocarbonyl substituted with 1 or more groups independently selected from the group consisting of: hydrogen, halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, cyano and nitro;
wherein L is selected from-O-, -S-, -CHR4-、-NR5-, -COO-, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl or aminothiocarbonyl, R4、R5Are respectively and independently selected from hydrogen, halogen and C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldeynyl radical or C2-C8Aldehyde-based haloalkynyl;
wherein R is3Is a carbon aryl or heterocyclic radical;
wherein Y is linked to the benzene ring and is selected from-O-, -S-, -CH2-amino unsubstituted or substituted with 1 group independently selected from: halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldehyde alkynyl, C2-C8Aldehyde haloalkynyl, carboaryl or heterocyclyl.
2. The benzoxaborol-1-ol compound according to claim 1, wherein the structural formula of said benzoxaborol-1-ol compound is as shown in any one of formulas (I) to (III):
3. benzoxaborol-1-ol compounds according to claim 1, characterized in that: the R is3Selected from carbon aryl or heterocyclic radical which is unsubstituted or substituted by 1-4 groups independently selected from the following groups: halogen, C1-C8Alkyl radical, C1-C8Haloalkyl, C2-C8Alkenyl radical, C2-C8Haloalkenyl, C2-C8Alkynyl, C2-C8Halogenated alkynyl, C1-C8Hydroxyalkyl radical, C1-C8Hydroxy haloalkyl, C2-C8Hydroxyalkenyl, C2-C8Hydroxyhaloalkenyl, C2-C8Hydroxyalkynyl group, C2-C8Hydroxy haloalkynyl, C1-C8Alkoxy radical, C1-C8Haloalkoxy, C2-C8Alkenyloxy radical, C2-C8Haloalkenyloxy, C2-C8Alkynyloxy, C2-C8Haloalkynyloxy, C1-C8Mercaptoalkyl radical, C1-C8Mercapto haloalkyl, C2-C8Mercaptoalkenyl radical, C2-C8Mercapto haloalkenyl, C2-C8Mercaptoalkynyl, C2-C8Mercapto haloalkynyl, C1-C8Alkylthio radical, C1-C8Haloalkylthio, C2-C8Alkenylthio radical, C2-C8Haloalkenylthio group, C2-C8Alkynylthio, C2-C8Haloalkylthio, C1-C8Aldehydic alkyl radical, C1-C8Aldehydic haloalkyl, C2-C8Aldenyl radical, C2-C8Aldehyde haloalkenyl, C2-C8Aldehyde alkynyl, C2-C8Aldehyde-based haloalkynyl;
wherein the heterocyclic group is selected from oxygen sulfur heterocyclic ring, morpholine, pyran, pyridine, pyrimidine, pyridazine, quinoline, pyrazole, thiazole, isothiazole, thiadiazole, thiophene, furan, oxazole, isoxazole, oxadiazole or derivatives containing halogen in the heterocyclic ring.
4. A process for producing benzoxaborol-1-ol compounds according to any one of claims 1 to 3, wherein R is-R1R' is-CH2The preparation method of the benzoxaborole-1-alcohol compound comprises the following steps: reacting bromobenzaldehyde or bromobenzoic acid compounds or cyano-substituted bromotoluene compounds with chloromethyl methyl ether to convert the bromobenzaldehyde compounds with hydroxyl protected by methoxy methyl, reacting with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect boron atoms to benzene rings, and finally deprotecting in hydrochloric acid to spontaneously form rings to obtain corresponding benzoxaboro-1-ol compounds;
or when R is-R1R' is-Y-CH2The preparation method of the benzoxaborole-1-alcohol compound comprises the following steps: performing wittig reaction on a bromobenzaldehyde compound, hydrolyzing to obtain a bromophenylacetaldehyde compound, reacting with chloromethyl methyl ether to obtain a bromophenethyl alcohol compound with hydroxyl protected by methoxy methyl, finally reacting with triisopropyl borate in a tetrahydrofuran solvent of n-butyllithium at low temperature to connect a boron atom to a benzene ring, deprotecting in hydrochloric acid, and spontaneously cyclizing to obtain a corresponding hexa-membered benzoxaboro-1-ol compound.
5. A process for producing benzoxaborol-1-ol compounds according to any one of claims 1 to 3, wherein R is L-R3R' is-CH2When L is S or O, reacting (sulfur) phenolic compounds with 2-bromo-4-fluorobenzaldehyde to obtain (sulfur) ether compounds, reducing with sodium borohydride to obtain III-12, reacting the III-12 with chloromethyl methyl ether to obtain III-13, reacting with triisopropyl borate in tetrahydrofuran solvent of n-butyl lithium at low temperature to connect boron atoms to benzene rings, deprotecting in hydrochloric acid, and spontaneously cyclizing to obtain corresponding benzoxaborol-1-ol compounds III-14;
or when R is L-R3R' is-CH2When L is thiocarbonyl or sulfonyl, the compound III-14 is oxidized by sodium periodate to respectively obtain corresponding benzoxaborol-1-ol compounds III-16 and III-17;
or when R is L-R3R' is-CH2When L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 undergo Friedel-crafts reaction to obtain a compound III-20, then bromosuccinimide is used for bromination, the compound III-21 is obtained by hydrolysis with sodium acetate under the alkaline condition and is oxidized to obtain a compound III-22, then the compound III-22 reacts with ethylene glycol to obtain a compound III-23, the compound III-23 reacts with triisopropyl borate in a tetrahydrofuran solvent of n-butyl lithium at a low temperature to enable boron atoms to be connected to benzene rings, deprotection is carried out in hydrochloric acid, spontaneous cyclization is carried out to obtain a corresponding compound III-25, and finally a Sazaret reagent is used for reaction to obtain a benzoxaboron-1-ol compound III-26;
or when R is L-R3R' is-CH2When L is carbonylamino, thiocarbonylamino or sulfonylamino, the compound III-27 is coupled with different acyl chloride, thioacyl chloride and sulfonyl chloride to form the benzoxaborol-1-ol compounds III-28, III-29 and III-30 connected by L;
or when R is L-R3R' is-CH2-, when L is NH, forming alcohol compound III-35 from iodo compound III-31 and compound III-32 under protection of tert-butyloxycarbonyl group, then forming alcohol hydroxyl protected by tetrahydropyran with 3, 4-dihydropyran in presence of pyridine, and finally reactingDeprotecting under acidic condition to form benzoxaborol-1-ol compound III-39;
or when R is L-R3R' is-CH2-, L is CH2During the preparation, boric acid compound III-40 and 2-methoxy-4-bromobenzaldehyde are subjected to Suzuki coupling reaction to obtain III-42, then trifluoro sulfonic anhydride is converted into trifluoro methylsulfonate III-44 under the action of cerous chloride and sodium iodide, and finally, after boration, the corresponding benzoxaborol-1-alcohol compound III-46 is obtained through hydrolysis under acidic conditions.
6. Use of the benzoxaborol-1-ol compound according to any one of claims 1 to 3 in the field of controlling crop diseases.
7. The use according to claim 6, wherein the crop disease is one or more of early blight, gibberellic disease, rhizoctonia solani, botrytis cinerea, pythium, alternaria, anthracnose, late blight and downy mildew.
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