CN111233908A - Benzoxaborol-1-ol compound and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of bactericides, and in particular relates to a benzoxaborol-1-alcohol compound and a preparation method and application thereof. Benzoxaborol-1-alcohol compounds have good bactericidal activity and can effectively control crops such as tomato early blight, wheat scab, rice sheath blight, strawberry gray mold, apple spot, cucumber anthracnose, etc. Disease, excellent bacteriostatic effect can be obtained at low concentration, and it shows good selectivity. As leucyl-tRNA synthetase inhibitors, these compounds take advantage of the evolutionary differences between the aminoacyl-tRNA synthetase of pathogens and eukaryotes to kill pathogens and at the same time have high safety to non-target organisms, and are used in agriculture. Can be used as a fungicide.

Description

Benzoxaborol-1-ol compounds, preparation method and application thereof

technical field

The invention relates to the field of agricultural fungicides, in particular to benzoxaborol-1-ol compounds and a preparation method and application thereof.

Background technique

Aminoacyl-tRNA synthetase is a novel target of human diseases, widely exists in prokaryotic and eukaryotic organisms, and is an important protein in protein synthesis. The mechanism of action of aminoacyl-tRNA synthetase is divided into two steps: First, aminoacyl-tRNA synthetase reacts with ATP under the catalysis of aminoacyl-tRNA synthetase to obtain an activated and hydrolyzable aminoacyladenylate intermediate. Then, aminoacyl-tRNA synthetase catalyzes the transfer of amino acid molecules to its cognate tRNA, and the obtained aminoacyl-tRNA serves as a substrate to participate in polypeptide synthesis in the ribosome. Since aminoacyl-tRNA synthetase catalyzes the linking of specific amino acids to the corresponding tRNA, this reaction is the first step in protein synthesis and determines the correct translation of the protein, so the enzyme plays an extremely important role in the survival of cells. Moreover, taking advantage of the large evolutionary differences between aminoacyl-tRNA synthetases in prokaryotic and eukaryotic cells, antibacterial drugs with high selectivity and few side effects can be developed.

Benzoboron compounds are leucyl-tRNA synthetase inhibitors. The boron atom in this structure can form a spiro adduct with adenosine at the tRNA end of leucine in the editing domain of leucine-tRNA synthetase. It acts as a non-competitive inhibitor to inhibit the activity of leucyl-tRNA synthetase. The development of novel aminoacyl-tRNA synthetase inhibitors is very important for the development of fungicides with excellent activity, low drug resistance and high selectivity. The active ingredient of the marketed antifungal infection drug Kerydin is tavaborole, a benzoborane ring compound. Chemically synthesized aminoacyl-tRNA synthetase inhibitors mainly include benzyl phenyl ethers, ethanolamines, quinolinones, biphenyl-substituted pyrazoles and benzoboranes.

However, the application of benzoborane compounds in the field of agricultural disease control has not yet been seen.

SUMMARY OF THE INVENTION

Purpose of the invention: The purpose of the present invention is to provide benzoxaborol-1-ol compounds and their preparation methods and applications in sterilization.

Technical scheme: in order to achieve the above object, the technical scheme adopted in the present invention is as follows:

In one aspect, the present invention provides benzoxaborol-1-alcohol compounds, which have the following structural formula:

Wherein, R is connected to C at 4, 5, 6 or 7, R is -R ₁ or -LR ₃ , and R' is -CH ₂ - or -Y-CH ₂ -;

wherein, R ₁ is selected from hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkyne group, C ₂ -C ₈ haloalkynyl, C ₁ -C ₈ hydroxyalkyl, C ₁ -C ₈ hydroxy haloalkyl, C ₂ -C ₈ hydroxy alkenyl, C ₂ -C ₈ hydroxy haloalkenyl, C ₂ -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ - C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ -mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C _{2 -C 8 mercaptoalkynyl, C 2 -C 8 mercaptohaloalkynyl ,} C ₁ -C ₈ alkylthio, C ₁ -C ₈ Haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldehyde Alkyl alkyl, C ₁ -C ₈ aldohaloalkyl, C ₂ -C ₈ aldoalkenyl, C ₂ -C ₈ aldohaloalkenyl, C ₂ -C ₈ aldoalkynyl, C ₂ -C _8. One of aldehyde haloalkynyl, carboaryl, heterocyclic, cyano, nitro and other groups;

The other groups are amino, carbonyl, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl, amino substituted with one or more groups independently selected from Thiocarbonyl: hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkynyl, C2 _{- C8haloalkynyl} , _{C1 - C8hydroxyalkyl} , _{C1 - C8hydroxyhaloalkyl} , C2- _{C8hydroxyalkenyl} , C2 _{- C8hydroxyhaloalkenyl} , C2 -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ -C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkene Oxy group, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ alkylthio, C ₁ -C ₈ haloalkylthio group, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, cyano or nitro;

Wherein, L refers to a bridge structure, selected from O, S, CHR ₄ , NR ₅ , COO, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl or aminothio substituted carbonyl, R ₄ , R ₅ are independently selected from hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ - _C8alkynyl , C2 _{- C8haloalkynyl} , _{C1 - C8hydroxyalkyl} , _C1 - _{C8hydroxyhaloalkyl} , C2 _{- C8hydroxyalkenyl} , C2- _C8hydroxyl Haloalkenyl, C ₂ -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyl group, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl , C ₂ -C ₈ mercaptoalkenyl, C _{2 -C 8 mercaptohaloalkenyl, C 2 -C 8 mercaptoalkynyl, C 2 -C 8 mercapto alkynyl , C 1} -C ₈ alkylthio, C ₁ -C ₈ haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldol alkyl, C ₁ -C ₈ aldol haloalkyl, C ₂ -C ₈ aldol alkenyl, C ₂ -C ₈ aldol haloalkenyl, C ₂ -C ₈ aldol alkynyl or C ₂ -C ₈ aldehyde haloalkynyl;

wherein, R ₃ is a carboaryl group or a heterocyclic group; further, R ₃ is selected from oxa-thiacycle, morpholine, pyridine, pyrimidine, pyridazine, quinoline, pyrazole, thiazole, isothiazole, thiadiazole, Thiophene, furan, oxazole, isoxazole, oxadiazole, and fluorine- and chlorine-containing derivatives of these heterocycles;

Wherein, Y is connected to the benzene ring, selected from O, S, CH ₂ , unsubstituted or amino substituted by 1 group independently selected from the following groups: halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl , C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ haloalkynyl, C ₁ -C ₈ hydroxyalkyl, C ₁ -C ₈ -hydroxyhaloalkyl, C2 _{- C8hydroxyalkenyl} , C2 _{- C8hydroxyhaloalkenyl} , C2 _{- C8hydroxyalkynyl} , C2- _{C8hydroxyhaloalkynyl} , _{C1 - C8} Alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkyne oxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ -C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ -C ₈ alkylthio, C ₁ -C ₈ haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldol alkyl, C ₁ -C ₈ aldol haloalkyl, C ₂ -C ₈ aldol alkenyl, C ₂ -C8 _{aldohaloalkenyl} , C2 _- C8 _aldoalkynyl , C2 _- C8 _{aldohaloalkynyl} , carboaryl or heterocyclyl.

In a second aspect, the present invention provides a benzoxaborol-1-ol compound having the structure shown in formula (I):

In a third aspect, the present invention provides a benzoxaborol-1-ol compound having the structure shown in formula (II):

In a fourth aspect, the present invention provides a benzoxaborol-1-ol compound having a structure represented by formula (III), the compound:

In the fifth aspect, the present invention also provides that when R is -R ₁ and R' is -CH ₂ -, the preparation method of the benzoxaborol-1-alcohol compounds is as follows: bromobenzaldehyde or bromine Substituted benzoic acid compounds or cyano-substituted bromotoluene compounds react with chloromethyl methyl ether to convert into bromobenzyl alcohol compounds whose hydroxyl groups are protected by methoxymethyl, and then react with triisopropyl borate in normal The low temperature reaction in tetrahydrofuran solvent of butyllithium causes the boron atom to be connected to the benzene ring, and finally deprotected in hydrochloric acid to spontaneously form a ring to obtain the corresponding benzoxaborol-1-ol compounds;

Or when R is -R ₁ and R' is -Y-CH ₂ -, the preparation method of the benzoxaborol-1-alcohol compounds is as follows: Wittig reaction occurs from bromobenzaldehyde compounds After hydrolysis, bromophenylacetaldehyde compounds are obtained, which are then reacted with chloromethyl methyl ether to obtain bromophenethyl alcohol compounds whose hydroxyl groups are protected by methoxymethyl groups, and finally reacted with triisopropyl borate in n-butyl group. The low temperature reaction of lithium in tetrahydrofuran solvent causes the boron atom to be attached to the benzene ring, deprotected in hydrochloric acid, and spontaneously forms a ring to obtain the corresponding six-membered benzoxaborol-1-ol compounds.

Or when R is LR ₃ , R' is -CH ₂ -, and L is S, O, the (thio) ether compound is obtained by the reaction of (thio)phenol compound III-9 and 2-bromo-4-fluorobenzaldehyde , and then reduced by sodium borohydride to obtain III-12, then III-12 reacts with chloromethyl methyl ether to obtain III-13, and finally reacts with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to make boron atom Connected to the benzene ring, deprotected in hydrochloric acid, and spontaneously formed a ring to obtain the corresponding benzoxaborol-1-ol compound III-14. III-14 can also be obtained by the hydrolysis and reduction of III-15 by reacting III-11 with double pinacol-based diboron under the catalysis of palladium. The synthetic route is as follows:

Or when R is LR ₃ , R' is -CH ₂ -, and L is thiocarbonyl, sulfonyl, compound III-14 is oxidized by sodium periodate to obtain the corresponding benzoxaborol-1-ols, respectively Ⅲ-16 and Ⅲ-17, the synthetic route is as follows:

Or when R is LR ₃ , R' is -CH ₂ -, and L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 undergo Friedel-Crafts reaction to obtain compound III-20, which is then subjected to bromobutanediol. The imide is brominated, hydrolyzed with sodium acetate under alkaline conditions to obtain compound III-21, and then oxidized to obtain compound III-22, which is then reacted with ethylene glycol to obtain compound III-23, which is then reacted with triisopropyl borate in normal The low temperature reaction of butyllithium in tetrahydrofuran solvent makes the boron atom connect to the benzene ring, deprotection in hydrochloric acid, and spontaneously form a ring to obtain the corresponding compound III-25, which is finally reacted with Sarreth reagent to obtain benzoxaborol-1 -Alcohol compound III-26, the synthetic route is as follows:

Or when R is LR ₃ , R' is -CH ₂ -, and L is carbonylamino, thiocarbonylamino, sulfonylamino, compound III-27 is coupled with different acid chlorides, thioacyl chlorides, and sulfonyl chlorides to form L Connected benzoxaborol-1-alcohol compounds III-28, III-29, III-30, the synthetic route is as follows:

Or when R is LR ₃ , R' is -CH ₂ -, and L is NH, an alcohol compound III-35 is formed from the iodo compound III-31 and compound III-32 under the protection of tert-butoxycarbonyl group, and then With 3,4-dihydropyran in the presence of pyridine, the alcohol hydroxyl group protected by tetrahydropyran is formed, and finally deprotected under acidic conditions to form benzoxaborol-1-ol compounds III-39, synthetic route as follows:

Or when R is LR ₃ , R' is -CH ₂ -, and L is CH ₂ , boronic acid compound III-40 and 2-methoxy-4-bromobenzaldehyde undergo Suzuki coupling reaction to obtain III-42, and then The trifluorosulfonic anhydride was converted into trifluoromethanesulfonate III-44 under the action of cerium trichloride and sodium iodide, and after boranization, the corresponding benzoxaboron- 1-alcohol compound III-46, the synthetic route is as follows:

In a sixth aspect, the present invention also provides the application of benzoxaborol-1-alcohol compounds in the field of preventing and treating crop diseases.

Wherein, the crop disease is one or more of early blight, head blight, sheath blight, botrytis cinerea, pythium, speckle, anthracnose, late blight and downy mildew.

In the definitions of the compounds of the formulae (I) to (III) given by the above formulas, the terms used in the collection are generally defined as follows:

By halogen is meant fluorine, chlorine, bromine or iodine.

By alkyl we mean straight, branched or cyclic chain forms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl group, isopentyl, n-hexyl, cyclopropyl, cyclobutyl and other groups. Haloalkyl refers to groups in which the alkyl group is substituted with one or more halogen atoms, eg, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and the like. By alkenyl is meant straight-chain, branched or cyclic alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1,2-propadienyl, 2,4-hexadienyl, and the like. By alkynyl is meant straight chain, branched or cyclic alkynes, such as ethynyl, propynyl, propargyl and the like.

By alkoxy is meant a straight, branched or cyclic alkyl group attached to the structure via an oxygen atom bond. Haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, for example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, Trifluoromethoxy, chlorofluoromethoxy, etc. Alkenyloxy refers to a straight, branched or cyclic alkenyl group attached to the structure through an oxygen atom bond. 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 bonded to the structure through an oxygen atom bond. Haloalkynyloxy refers to a group in which the alkynyloxy group is substituted with one or more halogen atoms.

The so-called alkylthio group refers to a straight chain, branched chain or cyclic chain alkyl group, which is attached to the structure through a sulfur atom bond. Haloalkylthio refers to a group in which an alkylthio group is substituted with one or more halogen atoms, for example, chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, Trifluoromethylthio, chlorofluoromethylthio, etc. Alkenylthio refers to a straight, branched or cyclic alkenyl group attached to the structure through a sulfur atom bond. Haloalkenylthio refers to a group in which an alkenyloxy group is substituted with one or more halogen atoms. Alkynylthio refers to a straight, branched or cyclic alkynyl group attached to the structure via a sulfur atom bond. A haloalkynylthio group refers to a group in which the alkynylthio group is substituted with one or more halogen atoms.

The so-called hydroxyalkyl, mercaptoalkyl and aldehyde alkyl groups refer to groups in which the alkyl group is substituted with one or more hydroxy, mercapto and aldehyde groups, respectively. Hydroxyalkenyl, mercaptoalkenyl, and aldehyde alkenyl refer to groups in which an alkenyl group is substituted with one or more hydroxy, mercapto, and aldehyde groups, respectively. Hydroxyalkynyl, mercaptoalkynyl, and aldehyde alkynyl refer to groups in which an alkynyl group is substituted with one or more hydroxy, mercapto, and aldehyde groups.

The so-called carbonylamino refers to the -CO-NH- structure, the sulfonylamino refers to the -SO ₂ -NH- structure, the sulfinylamino refers to the -SO-NH- structure, and the thiocarbonylamino refers to the -CS-NH- structure. Aminocarbonyl refers to the -NH-CO- structure, aminosulfonyl refers to the -NH-SO ₂ - structure, aminosulfinyl refers to the -NH-SO- structure, and aminothiocarbonyl refers to the -NH-CS- structure.

The so-called carboaryl group refers to a polyvalent aromatic group composed of unsubstituted or 1-4 groups of carbon atoms, for example, 1-methylphenyl, 2-propylnaphthyl and the like. Heterocyclyl refers to a five-membered or six-membered ring containing one or more N, O, S heteroatoms that is unsubstituted or substituted by 1 to 4 groups. For example, oxthiane, morpholine, pyran, pyridine, pyrimidine, pyridazine, quinoline, pyrazole, thiazole, isothiazole, thiadiazole, thiophene, furan, oxazole, isoxazole, oxadiazole, and These heterocycles contain derivatives of halogens (fluorine, chlorine, bromine, iodine).

Part of the compounds of the present invention can be illustrated by the specific compounds listed in Tables 1-3, and the present invention includes but is not limited to these compounds.

Table 1

Table 2

table 3

The compound of general formula (I) of the present invention can usually be reacted with bromobenzaldehyde or bromobenzoic acid compound I-1 or cyano-substituted bromotoluene compound I-2 with chloromethyl methyl ether to convert the hydroxyl group to methyl ether. Oxymethyl-protected bromobenzyl alcohol compound I-3, and then reacted with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect the boron atom to the benzene ring, and finally deprotected in hydrochloric acid, The corresponding benzoxaborol-1-ol compound I-4 is obtained by spontaneous cyclization. The synthetic route is as follows:

In the compound of general formula (II) of the present invention, when Y is selected from CH ₂ , bromobenzaldehyde compounds II-5 can usually be subjected to Wittig reaction and hydrolyzed to obtain bromobenzaldehyde compounds II-6, which are then combined with chlorine Reaction with methyl methyl ether to obtain bromophenethyl alcohol compound II-7 whose hydroxyl group is protected by methoxymethyl group, and finally react with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect the boron atom to the compound II-7. On the benzene ring, deprotection in hydrochloric acid, spontaneous ring formation to obtain the corresponding six-membered benzoxaborol-1-ol compound II-8, the synthetic route is as follows:

The compound of the general formula (III) of the present invention, when R3 is a substituted phenyl group, can be synthesized by the following method.

When L is S, O, (thio) phenolic compounds III-9 and III-10 can usually be reacted to obtain (thio) ether compounds III-11, which are then reduced by sodium borohydride to obtain III-12. Then III-12 was reacted with chloromethyl methyl ether to obtain III-13, and finally it was reacted with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect the boron atom to the benzene ring, and deprotected in hydrochloric acid. Spontaneous ring formation gave the corresponding benzoxaborol-1-ols III-14. III-14 can also be obtained by the hydrolysis and reduction of III-15 by reacting III-11 with double pinacol-based diboron under the catalysis of palladium. The synthetic route is as follows:

The benzoxaborol-1-ol compounds in which L is a thiocarbonyl group and a sulfonyl group can be oxidized by the corresponding compound III-14 with sodium periodate to obtain compounds III-16 and III-17, respectively. The synthetic route is as follows:

When L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 undergo Friedel-Crafts reaction to obtain compound III-20, which is then brominated with bromosuccinimide and hydrolyzed with sodium acetate under alkaline conditions Compound III-21 is oxidized to obtain compound III-22, then compound III-23 reacted with ethylene glycol, and then reacted with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect the boron atom to the benzene ring , deprotected in hydrochloric acid, and spontaneously formed a ring to obtain the corresponding compound III-25. Finally, the benzoxaborol-1-ol compound III-26 was obtained by reacting with Saret reagent. The synthetic route is as follows:

When L is carbonylamino, thiocarbonylamino and sulfonylamino, compound III-27 is coupled with different acid chlorides, thioacyl chlorides and sulfonyl chlorides to form benzoxaborol-1-ol compounds III- 28, Ⅲ-29, Ⅲ-30, the synthetic route is as follows:

When L is NH, the alcohol compound III-35 can be formed by iodine compound III-31 and compound III-32 under the protection of tert-butoxycarbonyl group, and then combined with 3,4-dihydropyran in the presence of pyridine , forming the alcoholic hydroxyl group protected by tetrahydropyran, and finally deprotected under acidic conditions to form III-39. The synthetic route is as follows:

L is _CH It is converted into trifluoromethanesulfonate III-44 under the action of sodium iodide, and finally hydrolyzed under acidic conditions to obtain the corresponding benzoxaborol-1-ol compound III-46 after boranization. The route is as follows:

The benzoxaborol-1-ol compounds with the structures shown in the formulas (I) to (III) provided by the present invention have bactericidal effect, and are effective against crop pathogens such as early blight, scab, sheath blight, Botrytis cinerea, spot bacteria, anthracnose, etc. have obvious inhibitory effects.

Detailed ways

Specific embodiments of the present invention will be described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, but not to limit the present invention.

Preparation of Example 1 Compound 1

The preparation method of compound 1, comprises the following steps:

Step A: Preparation of 2-bromo-5-fluorobenzyl alcohol

2-Bromo-5-fluorobenzaldehyde (62.0 g, 293 mmol) was dissolved in methanol (400 mL), and sodium borohydride (5.57 g, 147 mmol) was added in portions at 0°C. After stirring at room temperature for 1 h, water was added, half of the solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and water extraction system, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 2-bromo -5-Fluorobenzyl alcohol.

Step B: Preparation of 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene

Dissolve 2-bromo-5-fluorobenzyl alcohol (60.8g, 293mmol) and diisopropylethylamine (61mL, 0.35mol) in dichloromethane, add chloromethyl methyl ether (27mL, 0.35mol) at 0°C ) and stirred at room temperature overnight. Water was added, the mixture was extracted with chloroform, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Pressurized distillation to remove the solvent to obtain 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene.

Step C: Preparation of Intermediate 2-((methoxymethoxy)methyl)-4-fluorophenylboronic acid

1-Bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene (73.2 g, 293 mmol) was dissolved in tetrahydrofuran (400 mL), and n-butyl was added at -78°C within 45 min Lithium (1.6M in hexanes, 200 mL). After 5 min, triisopropyl borate (76.0 mL, 330 mmol) was added in 10 min, and the intermediate mixture was obtained after 1.5 h of reaction.

Step D: Preparation of Compound 1

Water and hydrochloric acid (6M, 55 mL) were added to the above intermediate mixture and 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 precipitation by distillation under reduced pressure, the residue was treated with isopropyl ether/hexane to obtain compound 1 (26.9 g, yield 60%) as white powder, melting point: 118-120°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.22 (s, 1H), 7.75 (dd, J=8.0, 5.9 Hz, 1H), 7.24 (dd, J=9.5, 1.8 Hz, 1H) , 7.19–7.12 (m, 1H), 4.96 (s, 2H).

The synthesis of compounds 2-12 can be obtained by referring to the preparation method of compound 1 in Example 1, wherein the substituents on the benzene ring of compounds 2-4 are 6-F, 5-Cl and H, respectively.

Preparation of Example 2 Compound 13

The preparation method of compound 13, comprises the following steps:

Step A: Preparation of 2-bromo-5-fluorophenylacetaldehyde

Take 2-bromo-5-fluoro-benzaldehyde (4.2g, 20.0mmol), methoxymethyltriphenylphosphine chloride (8.5g, 24.0mmol) and potassium tert-butylate (2.8g, 24.0mol) Dissolve in N,N-dimethylformamide (50 mL) and stir 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 evaporated under reduced pressure, tetrahydrofuran (60 mL) and hydrochloric acid (6 M) were added to the residue, and the mixture was heated under reflux for 8 h. Water and ether were added to the mixture for extraction, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Finally, 2-bromo-5-fluorophenylacetaldehyde is obtained by desolvation by distillation under reduced pressure.

Step B: Preparation of 2-((methoxymethoxy)ethyl)-1-bromo-4-fluorobenzene

2-Bromo-5-fluorophenylacetaldehyde (3.6 g, 16.6 mmol) was dissolved in methanol (40 mL), sodium borohydride (640 mg, 16.6 mmol) was added at 0° C. and stirred at room temperature for 1 h. Water was added to the mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After desolvation by distillation under reduced pressure, dichloromethane (50 mL), diisopropylethylamine (3.5 mL, 20 mmol) and chloromethyl methyl ether (1.5 mL, 20 mmol) were added to the residue at 0°C, and the reaction system was Stir overnight at room temperature. Water was added to the mixture, followed by extraction with chloroform, and the organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After desolvation by distillation under reduced pressure, the product was subjected to silica gel column chromatography to obtain 2-((methoxymethoxy)ethyl)-1-bromo-4-fluorobenzene as a colorless oil.

Step C: Preparation of Compound 13

2-((methoxymethoxy)ethyl)-1-bromo-4-fluorobenzene (7.3 g, 29.3 mmol) was dissolved in tetrahydrofuran (40 mL), and n-butyl was added at -78°C within 45 min Lithium (1.6M in hexanes, 20 mL). After 5 min, triisopropyl borate (7.60 mL, 33.0 mmol) was added in 10 min, and the mixture returned to room temperature after 1.5 h. Water and hydrochloric acid (6M, 55 mL) were added and 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 desolvation by distillation under reduced pressure, the product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), the crude product was dispersed in pentane, and after stirring, a white solid product Compound 13 (1.0 g, Yield: 21%), melting point: 77-82°C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 2.86 (t, J=5.9 Hz, 2H), 4.04 (t, J=5.9 Hz, 2H), 7.0-7.1 (m, 2H), 7.69 (dd, J=8.2, 7.2 Hz, 1H), 8.47 (s, 1H).

The synthesis of compound 14 and compound 15 can be obtained by referring to the preparation method of compound 13 in Example 2.

Example 3 Preparation of Compound 25

The preparation method of compound 25, comprises the following steps:

Step A: Preparation of 4-((3,4-Dichlorophenyl)thio)-2-bromobenzaldehyde

2-Bromo-4-fluorobenzaldehyde (1.0 g, 4.92 mmol) was dissolved in N,N-dimethylformamide (25 mL), and cooled to 0 °C with an ice-water bath. Under nitrogen protection, potassium carbonate (2.0 g, 9.85 mmol) and 3,4-dichlorobenzenethiol (882 mg, 4.92 mmol) were added sequentially. After stirring the mixture for a further 2.5 h, 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. The residue was removed by rotary evaporator, and the product was purified by silica gel column chromatography to obtain pure 4-((3,4-dichlorophenyl)sulfanyl)-2-bromobenzaldehyde.

Step B: Preparation of 4-((3,4-Dichlorophenyl)thio)-2-bromobenzyl alcohol

Dissolve 4-((3,4-dichlorophenyl)sulfanyl)-2-bromobenzaldehyde (400 mg, 1.10 mmol) in methanol (20 mL) and cool it to 0°C with an ice-water bath, add sodium borohydride to the solution (62 mg, 1.65 mmol). The reaction was stirred for 0.5 h, then saturated sodium bicarbonate was added. After the reaction mixture was desolubilized, extracted with ethyl acetate, washed with water and saturated sodium chloride respectively, finally dried with anhydrous sodium sulfate, and concentrated in vacuo to obtain 4-((3,4-dichlorophenyl)sulfur as a viscous oily product base)-2-bromobenzyl alcohol.

Step C: Preparation of (4-(methoxymethoxy)methyl)-3-bromophenyl)(3,4-dichlorophenyl)sulfide

Dissolve 4-((3,4-dichlorophenyl)sulfanyl)-2-bromobenzyl alcohol (4.3 g, 11.84 mmol) in anhydrous dichloromethane (50 mL), under nitrogen protection, add N successively , N-diisopropylethylamine (7.32 mL, 41.45 mmol) and chloromethyl methyl ether (1.91 mL, 26.05 mmol). The mixture was stirred at room temperature overnight and treated with water (15 mL), and after extraction with dichloromethane, the organic layer was washed with water and saturated sodium chloride, and finally dried over anhydrous ammonium sulfate. The residue was desolubilized by rotary evaporator and purified by silica gel column chromatography to obtain (4-(methoxymethoxy)methyl)-3-bromophenyl)(3,4-dichlorobenzene) as a viscous oily product. base) thioether.

Step D: Preparation of Compound 25

Dissolve (4-(methoxymethoxy)methyl)-3-bromophenyl)(3,4-dichlorophenyl)sulfide (2.4 g, 5.86 mmol) in dry tetrahydrofuran (25 mL) and Cool to -80°C. Under nitrogen protection, n-butyllithium (1.6 M, 4.03 mL, 6.45 mmol) was added dropwise to the solution over 20 min. After the reaction was stirred at -80°C for 20 min, triisopropyl borate (1.48 mL, 6.45 mmol) was added dropwise. After the reaction mixture was gradually returned to room temperature and stirred at room temperature overnight, hydrochloric acid (6M, 20 mL) was added and stirred for 3 h. The mixture was desolubilized, extracted with ethyl acetate, and finally dried over anhydrous sodium sulfate. The residue was desolubilized by a rotary evaporator, and then purified by silica gel column chromatography to obtain compound 25 (608 mg, yield: 33.3%), melting point: 118-119°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.28 (s, 1H), 7.81 (s, 1H), 7.60-7.45 (m, 4H), 7.15 (dd, J=8.4, 2.0 Hz, 1H), 5.03 (s, 2H).

The synthesis of compounds 26 and 27 can be obtained by referring to the preparation method of compound 25 in Example 3.

Example 4 Preparation of Compound 28

Dissolve compound 25 (200 mg, 0.64 mmol) in water: methanol (1:10) (15 mL), add sodium periodate (688 mg, 3.21 mmol), stir at 60 °C for 1 h, evaporate the solvent and extract with ethyl acetate . The organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the crude product was rotary evaporated, recrystallized and purified to obtain compound 28 (112.4 mg, yield: 53.5%), melting point: 141-143°C. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

The synthesis of compounds 29 and 30 can be obtained by referring to the preparation method of compound 28 in Example 4.

Example 5 Preparation of Compound 31

Dissolve compound 25 (260 mg, 0.83 mmol) in water: methanol (1:10) (15 mL), add sodium periodate (894 mg, 4.17 mmol), stir at 60 °C overnight, evaporate the solvent, and extract with ethyl acetate . The organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the crude product was rotary evaporated, recrystallized and purified to obtain compound 31 (86 mg, yield: 30%), melting point: 154-156°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.49 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 8.12 (dd, J=8.4, 2.0 Hz, 1H) , 7.90(d, 2H), 7.68(d, 1H), 5.06(s, 2H).

The synthesis of compounds 32 and 33 can be obtained by referring to the preparation method of compound 31 in Example 5.

Example 6 Preparation of Compound 34

The preparation method of compound 34, comprises the following steps:

Step A: Preparation of 4-phenoxy-2-bromobenzaldehyde

Phenol (6.95 g, 73.88 mmol), 2-bromo-4-fluorobenzaldehyde (15 g, 73.88 mmol) and potassium carbonate (18 g, 0.13 mol) were dissolved in DMF (150 mL) and heated at 100° C. for 16 h. After the mixture was filtered hot, the filter cake was washed with ethyl acetate. The solvent was evaporated with a rotary evaporator at 50°C, and the residue was placed in n-pentane and sonicated and filtered to obtain 4-phenoxy-2-bromobenzaldehyde.

Step B: Preparation of 4-phenoxy-2-bromobenzyl alcohol

4-phenoxy-2-bromobenzaldehyde (10.5 g, 37.89 mmol) was dissolved in methanol (300 mL), and sodium borohydride (7.2 g, 190.32 mmol) was added in portions under ice-water cooling. The mixture was stirred overnight at room temperature and the methanol was evaporated. The product was dissolved in water and extracted with dichloromethane, dried and evaporated to give 4-phenoxy-2-bromobenzyl alcohol as an oil.

Step C: Preparation of 2-((methoxymethoxy)methyl)-5-phenoxybromobenzene

4-phenoxy-2-bromobenzyl alcohol (10.1g, 36.18mmol) and N,N-diisopropylethylamine (11mL) were dissolved in dichloromethane (200mL), and chloromethoxy was added dropwise at room temperature base methane (4.1 mL). The mixture was stirred overnight at room temperature under nitrogen, washed with sodium bicarbonate, dried and evaporated to give the product 2-((methoxymethoxy)methyl)-5-phenoxybromobenzene as a yellow oil.

Step D: Preparation of Compound 34

2-((Methoxymethoxy)methyl)-5-phenoxybromobenzene (11.7 g, 36.18 mmol) and triisopropyl borate (9.6 mL, 41.60 mmol) were dissolved in tetrahydrofuran under nitrogen protection , the mixture was cooled to -78°C, and n-butyllithium (1.6M in hexane, 26mL) was added dropwise. The ice-water bath was removed and the reaction mixture was continued to stir for 3 h. Hydrochloric acid (6M, 20 mL) was added and the solvent was concentrated. The residue was dissolved in methanol and hydrochloric acid (6M) and refluxed for 1.5 h, the methanol was evaporated and extracted with ethyl acetate. After the product was dried and evaporated to remove the solvent, it was purified by silica gel column chromatography, eluted with hexane:ethyl acetate (2:1) as the eluent, to obtain compound 34 (5.1 g, yield: 62.4%) as a white solid. , Melting point: 95-99 ℃. ¹ H NMR (300MHz, DMSO-d ₆ )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).

The synthesis of compounds 35 and 36 can be obtained by referring to the preparation method of compound 34 in Example 6.

Example 7 Preparation of Compound 37

The preparation method of compound 37, comprises the following steps:

Step A: Preparation of 4-benzoyl-2-bromotoluene

Aluminum trichloride (1.5 g, 11.0 mmol) was dissolved in benzene (16 mL), and a solution of 4-methyl-3-bromobenzoyl chloride (2.3 g, 10.0 mmol) in benzene (8 mL) was added dropwise at room temperature. After the mixture was stirred at 50°C for 2 h, it was washed with hydrochloric acid (3M, 20 mL) and saturated sodium chloride (20 mL), and dried over anhydrous sodium sulfate. After removing the solvent by rotary evaporator, the product was purified by silica gel column chromatography to obtain 4-benzoyl-2-bromotoluene.

Step B: Preparation of 4-benzoyl-2-bromobenzyl alcohol

Take 4-benzoyl-2-bromotoluene (2.7g, 9.8mmol) in carbon tetrachloride (50mL), add bromosuccinimide (1.8g, 9.8mmol) and benzoyl peroxide ( 0.1 g, 0.5 mmol), heated and stirred overnight. The residue was evaporated by rotary evaporator to remove solvent and purified by silica gel column chromatography to obtain the intermediate product 5-benzoyl-2-bromomethylbromobenzene. Then take 5-benzoyl-2-bromomethyl bromobenzene (1.7g, 4.83mmol) in N,N-dimethylformamide (30mL), add sodium acetate (2.0g, 24.15mmol), the mixture is heated at 60 Stir overnight at °C and add ice water (50 g). The precipitate was filtered, washed with water, and dried under vacuum to give (4-benzoyl-2-bromo)benzyl acetate. Dissolve (4-benzoyl-2-bromo)benzyl acetate (1.6 g, 4.9 mmol) in methanol (25 mL), add sodium hydroxide (15%, 5 mL) and reflux for 1 h. After the mixture was evaporated to remove the solvent, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the solvent was removed by a rotary evaporator, it was purified by silica gel column chromatography to obtain 4-benzoyl-2-bromobenzyl alcohol.

Step D: Preparation of 4-phenoxy-2-bromobenzaldehyde

Dissolve 4-benzoyl-2-bromobenzyl alcohol (1.5g, 5.15mmol) in dichloromethane (30mL), add pyridinium chlorochromate (2.2g, 10.3mmol) and diatomaceous earth (2.5g), Stir overnight at room temperature. After filtration, the product was evaporated by rotary evaporator to remove solvent and purified by silica gel column chromatography to obtain 4-phenoxy-2-bromobenzaldehyde.

Step E: Preparation of [2-(4-(1,3-dioxolan-2-yl)-3-bromophenyl)-2-phenyl]-1,3-dioxolane

Dissolve 4-phenoxy-2-bromobenzaldehyde (1.3g, 4.57mmol) in toluene (50mL), add ethylene glycol (2.8g, 45.70mmol) and p-toluenesulfonic acid monohydrate (69mg, 0.36mmol) , refluxed for 96h. The mixture was washed with saturated sodium bicarbonate, water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain [2-(4-(1,3-dioxolan-2-yl)-3 -bromophenyl)-2-phenyl]-1,3-dioxolane.

Step F: Preparation of (2-formyl-5-benzoyl)phenylboronic acid

Take [2-(4-(1,3-dioxolan-2-yl)-3-bromophenyl)-2-phenyl]-1,3-dioxolane (0.5g, 1.23mmol) Dissolve in dry tetrahydrofuran (10 mL) and cool to -80°C. Under nitrogen protection, n-butyllithium (1.6 M in hexane, 0.88 mL) was added dropwise to the mixture over 15 min. The reaction mixture was returned to room temperature and stirred at room temperature overnight. After adding hydrochloric acid (6M, 6 mL), stirring was continued for 2 h, the solvent was evaporated, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After evaporating the solvent, the product was purified by silica gel column chromatography to obtain (2-formyl-5-benzoyl)phenylboronic acid.

Step G: Preparation of [6-(1-phenyl-1-hydroxymethyl)]-1,3-dihydro-2,1-benzoxaborol-1-ol

Dissolve (2-formyl-5-benzoyl)phenylboronic acid (0.8 g, 2.95 mmol) in tetrahydrofuran (8 mL) and water (0.5 mL), add sodium borohydride (0.2 g, 5.90 mmol) with stirring at room temperature ). After stirring for 3 h, hydrochloric acid (3M, 10 mL) was added to quench the reaction. After the mixture was evaporated, extracted with ethyl acetate and dried over anhydrous sodium sulfate, the solvent was evaporated and purified by recrystallization to obtain [6-(1-phenyl-1-hydroxymethyl)]-1,3-dihydro-1-hydroxyl -2,1-Benzoxaboron.

Step H: Preparation of Compound 37

Dissolve [6-(1-phenyl-1-hydroxymethyl)]-1,3-dihydro-2,1-benzoxaborol-1-ol (0.2g, 0.83mmol) in dichloromethane (15 mL), pyridinium chlorochromate (0.5 g, 2.08 mmol) and diatomaceous earth (0.5 g) were added and the mixture was stirred at room temperature for 3 h before filtration. The product was evaporated to remove the solvent by a rotary evaporator, and then recrystallized to obtain compound 37 (0.15 g, yield: 76%). Melting point: 137-139°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.35 (s, 1H), 8.12 (s, 1H), 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (m, 3H) , 7.57 (m, 3H), 5.08 (s, 2H).

The synthesis of compounds 38 and 39 can be obtained by referring to the preparation method of compound 37 in Example 7.

Example 8 Preparation of Compound 40

Dissolve 6-amino-1,3-dihydro-2,1-benzoxaborol-1-ol (500mg, 3.36mmol) in acetonitrile (25mL), add sodium bicarbonate (845mg, 10.1mmol) and benzene Formyl chloride (859 μL, 7.38 mmol). The mixture was stirred at room temperature for 2 h, then quenched with water, and stirring was continued for 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 under vacuum, filtered and dried to give compound 40 (310 mg, yield: 36%), m.p.: 186-193°C. ¹ H NMR (300 MHz, CDCl ₃ ) 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).

The synthesis of compounds 41 and 42 can be obtained by referring to the preparation method of compound 40 in Example 8.

Example 9 Preparation of Compound 43

Dissolve 6-amino-1,3-dihydro-2,1-benzoxaborol-1-ol (750mg, 5.0mmol) in acetonitrile (25mL), add potassium carbonate (1.7g, 12.6mmol) and Benzenesulfonyl chloride (710 μL, 5.5 mmol). The mixture was stirred at room temperature for 2 h, then quenched with water, and stirring was continued for 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 under vacuum, filtered and dried to give compound 43 (565.0 mg, yield: 39%) as a tan solid, melting point: 175-184°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.68 (d, J=7.8 Hz, 2H), 7.44 (d, J=6.9 Hz, 1 H), 7.40-7.17 (m, 4H), 7.13 (d , J=7.8Hz, 1H), 4.94 (s, 2H).

The synthesis of compounds 44 and 45 can be obtained by referring to the preparation method of compound 43 in Example 9.

Example 10 Preparation of Compound 46

The preparation method of compound 46, comprises the following steps:

Step A: Preparation of 4-phenylamino-2-bromotoluene

Mix benzene iodide (4.4g, 21,56mmol), 4-methyl-3-bromoaniline (4.0g, 21,56mmol) and dimethyl sulfoxide (50mL), and add cuprous iodide successively under nitrogen protection (0.8 g, 4.31 mmol), L-proline (1.0 g, 8.61 mmol) and sodium tert-butoxide (4.1 g, 43.13 mmol). The reaction system was stirred at 50° C. for 48 h, ice (100.0 g) was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The product was purified by rotary evaporation and silica gel column chromatography to obtain 4-phenylamino-2-bromotoluene.

Step B: Preparation of tert-butyl N-(4-methyl-3-bromophenyl)-N-phenylcarbamate

Dissolve 4-phenylamino-2-bromotoluene (3.2 g, 12.44 mmol) in tetrahydrofuran (60 mL), and add lithium hexamethyldisilazide (27.4 mL, 27.4 mmol) dropwise at -80°C within 30 min, Stirring was continued for 30 min, and di-tert-butyl dicarbonate (6.0 g, 27.4 mmol) was added dropwise within 10 min, and the reaction was carried out at room temperature for 14 h. The mixture was evaporated to give a crude product which was subjected to silica gel column chromatography to give tert-butyl N-(4-methyl-3-bromophenyl)-N-phenylcarbamate.

Step C: Preparation of tert-butyl N-(4-hydroxymethyl-3-bromophenyl)-N-phenylcarbamate

Dissolve tert-butyl N-(4-methyl-3-bromophenyl)-N-phenylcarbamate (4.3 g, 11.88 mmol) in tetrachloromethane (300 mL), add bromosuccinimide ( 2.5 g, 14.25 mmol) and benzoyl peroxide (0.3 g, 1.19 mmol), refluxed for 20 h. The mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum to obtain the crude product, which was then subjected to silica gel column chromatography to obtain the intermediate product N-(3-bromo-4-bromomethylphenyl)-N-phenylcarbamate tert-butyl ester . The intermediate product (2.65 g, 6.0 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium acetate (2.5 g, 30 mmol) was added, and the mixture was stirred at 70° C. for 5 h. Ice (100.0 g) was added to the mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain an acetic acid intermediate. The acetic acid intermediate (2.5 g, 5.95 mmol) was dissolved in methanol (50 mL), sodium hydroxide aqueous solution (8%, 15 ml) was added, and the mixture was 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 obtain tertiary N-(4-hydroxymethyl-3-bromophenyl)-N-phenylcarbamate Butyl ester.

Step D: Preparation of tert-butyl N-(4-(tetrahydropyran-2-oxymethyl)-3-bromophenyl)-N-phenylcarbamate

Dissolve N-(4-hydroxymethyl-3-bromophenyl)-N-phenylcarbamate tert-butyl ester (2.1 g, 5.55 mmol) in dichloromethane (50 mL), add 3,4-dihydrogen Pyran (0.9 g, 11.11 mmol), pyridine (28 mg, 0.35 mmol) and p-toluenesulfonic acid monohydrate (53 mg, 0.28 mmol) were reacted at room temperature for 48 h. The mixture was washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. After the product was evaporated to remove the solvent, it was purified by silica gel column chromatography to obtain tert-butyl N-(4-(tetrahydropyran-2-oxymethyl)-3-bromophenyl)-N-phenylcarbamate.

Step E: Preparation of 6-(N-tert-butoxycarbonyl-N-phenylamino)-1,3-dihydro-2,1-benzoxaborol-1-ol

Dissolve N-(4-(tetrahydropyran-2-oxymethyl)-3-bromophenyl)-N-phenylcarbamate tert-butyl ester (2.6 g, 5.54 mmol) in anhydrous tetrahydrofuran, Under nitrogen protection, n-butyllithium (1.6M in hexane, 3.98 mL) was added dropwise at -80°C within 20 min, stirring was continued for 20 min, and triisopropyl borate (1.47 mL, 6.37 mmol) was added within 10 min. After the mixture gradually returned to room temperature, it was stirred overnight. Hydrochloric acid (6M, 10 mL) was added and stirred for 1 h, tetrahydrofuran was evaporated, 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 obtain the intermediate product of boric acid , take the intermediate product (0.6 g, 1.50 mmol) and dissolve it in ethanol (20 mL), add pyridine (35.0 mg, 0.45 mmol) and p-toluenesulfonic acid monohydrate (85.0 mg, 0.45 mmol), and react at 50 ° C for 4 h , the solvent was evaporated, the residue was dissolved in ethyl acetate (50 mL) and washed with water and saturated sodium chloride, and finally dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography to obtain 6-(N-tert-butoxycarbonyl-N-phenylamino)-1,3-dihydro-2,1-benzoxaborol-1-ol.

Step F: Preparation of Compound 46

Dissolve 6-(N-tert-butoxycarbonyl-N-phenylamino)-1,3-dihydro-2,1-benzoxaborol-1-ol (150.0 mg, 0.46 mmol) in dichloromethane (10 mL), trifluoroacetic acid (0.4 mL, 5.38 mmol) was added dropwise at 0°C under nitrogen protection, the mixture was slowly returned to room temperature and stirred for 3 h, saturated sodium bicarbonate was added to neutralize the reaction system. The organic layer was separated, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by silica gel column chromatography and recrystallization to obtain compound 46 (13.2 mg, yield: 13%), melting point: 108-110°C . ¹ H NMR (300MHz, DMSO-d ₆ )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).

The synthesis of compounds 47 and 48 can be obtained by referring to the preparation method of compound 46 in Example 10.

Example 11 Preparation of Compound 49

The preparation method of compound 49, comprises the following steps:

Step A: Preparation of 4-benzyl-2-methoxybenzaldehyde

Take benzylboronic acid (2.15g, 10mmol), 2-methoxy-4-bromobenzaldehyde (2.44g, 18mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (1.46g, 2mmol), cesium fluoride (3.02g, 20mmol) and potassium carbonate (4.14g, 30mmol) were dissolved in dioxane (30mL), the air was removed for 10min and heated at 80°C for 16h, cooled to room temperature , diluted with ethyl acetate, and finally concentrated by filtration through celite. The crude product was subjected to silica gel column chromatography to obtain 4-benzyl-2-methoxybenzaldehyde.

Step B: Preparation of 4-benzyl-2-hydroxybenzaldehyde

Dissolve 4-benzyl-2-methoxybenzaldehyde (1.14g, 5mmol), cerium trichloride (1.85g, 7.5mmol) and sodium iodide (1.13g, 7.5mmol) in cyanide methane (20mL) , refluxed for 18h, diluted with ethyl acetate and washed with anhydrous sodium thiosulfate, dried and concentrated to obtain 4-benzyl-2-hydroxybenzaldehyde.

Step C: Preparation of 4-benzyl-2-trifluoromethanesulfonylbenzaldehyde

Dissolve 4-benzyl-2-hydroxybenzaldehyde (0.44g, 2.08mmol) in dichloromethane (10mL), cool the solution to -78°C, add triethylamine (0.68mL, 6.24mmol) and trifluoromethanesulfonic acid Anhydride (0.40 mL, 3.12 mmol). The mixture was stirred at -78°C for 30 min, quenched with water (2 mL), diluted with dichloromethane (50 mL) and washed with hydrochloric acid (1 M, 20 mL), dried and concentrated to give 4-benzyl-2-trifluoromethanesulfonic acid benzene formaldehyde.

Step D: Preparation of 4-benzyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxoboropentan-2-ylbenzaldehyde

Take 4-benzyl-2-trifluoromethanesulfonic acid benzaldehyde (0.68g, 2.08mmol), double pinacol diboron (0.80g, 3.12mmol), [1,1'-bis(diphenylene) (0.31 g, 0.42 mmol) and potassium acetate (0.61 g, 6.24 mmol) were dissolved in dioxane (15 mL), reacted at 80 °C for 16 h and cooled to room temperature, Diluted with ethyl acetate, filtered and concentrated with celite as medium, the crude product was purified by column chromatography to obtain 4-benzyl-2-(4,4,5,5-tetramethyl-[1,3, 2] Dioxaboropent-2-ylbenzaldehyde.

Step E: Preparation of Compound 49

Dissolve 4-benzyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxoboropentan-2-ylbenzaldehyde (0.61g, 1.89mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), sodium borohydride (0.16 g, 4.17 mmol) was added in portions. The mixture was stirred at 0 °C for 30 min, quenched with hydrochloric acid (6 M, 0.5 mL) and diluted with water (20 mL), continued It was stirred at room temperature for 1 h. The solid product was collected and washed with water (10 mL) and dried under vacuum to give compound 49 (290 mg, yield: 68%), melting point: 173-175°C. ¹ H NMR (300 MHz, CDCl ₃ ) 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).

The synthesis of compounds 50 and 51 can be obtained by referring to the preparation method of compound 49 in Example 11.

Experimental example: biological activity test example

The bactericidal activity test method of the compound of the present invention is as follows:

The growth rate method was used to determine the preliminary antibacterial activities of 6 common agricultural fungi, Strawberry Botrytis cinerea, Tomato early phytophthora, Wheat scab, Rhizoctonia oryzae, Cucumber Anthracnose, and Apple Spot. Some compounds with higher inhibition rates were subjected to EC ₅₀ virulence assays.

The specific operations are as follows: the 6 kinds of fungi used in the test need to be activated once on the PDA medium before the antibacterial test, and cultured at 25°C for 2-8 days. Weigh the benzoxaborol-1-alcohol compounds and use N,N-dimethylformamide as the solvent to prepare the test solution of the corresponding concentration, the general concentration is ppm level. Take the prepared test solution and streptomycin sulfate from the culture medium, and use the N,N-dimethylformamide solution without the test substance as the reference substance, inoculate the 6 kinds of fungi into the corresponding sterilized medium, and then placed in a 25°C incubator. The growth of fungi was observed during the culture period, and the growth of fungi in the presence of different test substances was determined.

The names and abbreviations of the 6 fungi used in the biological activity test are shown in Table 4

Table 4

common name Latin name this article for short Strawberry Botrytis cinerea Botrytis cinrea A bacteria tomato early blight Alternaria solani C bacteria Fusarium head blight Gibberella zeae D bacteria Rice sheath blight Rhizoctonia solani E bacteria Cucumber anthracnose Cucumber anthrax G bacteria Apple Spot Alternaria Leaf Spot H bacteria

In the embodiment, the preliminary screening test results of some compounds and the EC ₅₀ toxicity assay results are shown in Table 5 and Table 6 (the fungal name is represented by abbreviation, and the osthole, boscalid and carbendazim in table 6 are listed sterilizations. agent control)

table 5

Table 6

From the results shown in Table 5 and Table 6, it can be seen that the above compounds all exhibit good bactericidal effects, and can exhibit inhibitory activity against crop fungi at low concentrations. For some fungi, these compounds are even better than osthole, boscalid and carbendazim, and have broad-spectrum bactericidal properties.

To sum up, the benzoxaborol-1-ol compound of the present invention has the effect of killing crop pathogens, and as a leucyl-tRNA synthetase inhibitor, it utilizes the evolution of prokaryotic and eukaryotic organisms. This kind of substance has high selectivity and safety, and is a kind of potential broad-spectrum, safe and efficient bactericidal substance.

The compounds involved in the present invention and their uses are described in detail above. However, the present invention is not limited to the specific details of the above-mentioned embodiments, and within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all belong to the protection scope of the present invention.

In addition, it should be noted that the specific technical features described in the above-mentioned specific embodiments can be combined in any suitable manner under the condition of no contradiction. In order to avoid unnecessary repetition, the present invention has The combination method will not be specified otherwise.

In addition, the various embodiments of the present invention can also be combined arbitrarily, as long as they do not violate the spirit of the present invention, they should also be regarded as the contents disclosed in the present invention.

Claims (7)

1. benzoxaboron-1-alcohol compounds, characterized in that, the compounds have the following structural formula:

Wherein, R is connected to C at 4, 5, 6 or 7, R is -R ₁ or -LR ₃ , and R' is -CH ₂ - or -Y-CH ₂ -; wherein, R ₁ is selected from hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkyne group, C ₂ -C ₈ haloalkynyl, C ₁ -C ₈ hydroxyalkyl, C ₁ -C ₈ hydroxy haloalkyl, C ₂ -C ₈ hydroxy alkenyl, C ₂ -C ₈ hydroxy haloalkenyl, C ₂ -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ - C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ -mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C _{2 -C 8 mercaptoalkynyl, C 2 -C 8 mercaptohaloalkynyl ,} C ₁ -C ₈ alkylthio, C ₁ -C ₈ Haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldehyde Alkyl alkyl, C ₁ -C ₈ aldohaloalkyl, C ₂ -C ₈ aldoalkenyl, C ₂ -C ₈ aldohaloalkenyl, C ₂ -C ₈ aldoalkynyl, C ₂ -C _8. One of aldehyde haloalkynyl, carboaryl, heterocyclic, cyano, nitro and other groups; The other groups are amino, carbonyl, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, aminosulfonyl, or amino substituted with one or more groups independently selected from Thiocarbonyl: hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkynyl, C2 _{- C8haloalkynyl} , _{C1 - C8hydroxyalkyl} , _{C1 - C8hydroxyhaloalkyl} , C2- _{C8hydroxyalkenyl} , C2 _{- C8hydroxyhaloalkenyl} , C2 -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ -C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkene Oxy group, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ alkylthio, C ₁ -C ₈ haloalkylthio base, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, cyano and nitro; Wherein, L is selected from -O-, -S-, -CHR ₄ -, -NR ₅ -, -COO-, thiocarbonyl, sulfonyl, carbonylamino, sulfonylamino, thiocarbonylamino, aminocarbonyl, amino Sulfonyl or aminothiocarbonyl, R ₄ and R ₅ are independently selected from hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ Haloalkenyl, C2- _C8alkynyl , C2 _{- C8haloalkynyl} , _{C1 - C8hydroxyalkyl} , _{C1 - C8hydroxyhaloalkyl} , C2- _{C8hydroxyalkenyl} , C ₂ -C ₈ hydroxyhaloalkenyl, C _{2 -C 8 hydroxyalkynyl, C 2 -C 8 hydroxyhaloalkynyl ,} C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ -C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ - C ₈ alkylthio, C ₁ -C ₈ haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ halogen Alkynylthio, C ₁ -C ₈ aldehyde alkyl, C ₁ -C ₈ aldehyde haloalkyl, C ₂ -C ₈ aldehyde alkenyl, C ₂ -C ₈ aldehyde haloalkenyl, C ₂ - C ₈ aldehyde alkynyl or C ₂ -C ₈ aldehyde haloalkynyl; Wherein, R ₃ is carboaryl or heterocyclyl; Wherein, Y is connected to the benzene ring, selected from -O-, -S-, -CH ₂ -, unsubstituted or amino substituted by 1 group independently selected from the following groups: halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ haloalkynyl, C ₁ -C ₈ hydroxyalkane group, C ₁ -C ₈ hydroxyhaloalkyl, C ₂ -C ₈ hydroxy alkenyl, C ₂ -C ₈ hydroxy haloalkenyl, C ₂ -C ₈ hydroxy alkynyl, C ₂ -C ₈ hydroxy haloalkynyl , C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercaptoalkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ - C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ -C ₈ alkylthio, C ₁ -C ₈ haloalkylthio, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ halogen Alkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldehyde alkyl, C ₁ -C ₈ aldehyde haloalkyl, C ₂ -C ₈ Aldoalkenyl, C2 _{- C8aldohaloalkenyl} , C2 _{- C8aldoalkynyl} , C2 _{- C8aldohaloalkynyl} , carboaryl or heterocyclyl. 2 . The benzoxaborol-1-alcohol compound according to claim 1 , wherein the structural formula of the benzoxaborol-1-alcohol compound is as formula (I) to (III) The structure shown in either:

3. The benzoxaborol-1-alcohol compound according to claim 1, characterized in that: the R ₃ is selected from unsubstituted or substituted by 1-4 groups independently selected from the following groups of carbon aromatics radical or heterocyclyl: halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ haloalkenyl, C ₂ -C ₈ alkynyl, C2 _{- C8haloalkynyl} , _{C1 - C8hydroxyalkyl} , _{C1 - C8hydroxyhaloalkyl} , C2- _{C8hydroxyalkenyl} , C2 _{- C8hydroxyhaloalkenyl} , C2 -C ₈ hydroxyalkynyl, C ₂ -C ₈ hydroxyhaloalkynyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ haloalkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ Haloalkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C ₈ haloalkynyloxy, C ₁ -C ₈ mercaptoalkyl, C ₁ -C ₈ mercaptohaloalkyl, C ₂ -C ₈ mercapto Alkenyl, C ₂ -C ₈ mercaptohaloalkenyl, C ₂ -C ₈ mercaptoalkynyl, C ₂ -C ₈ mercaptohaloalkynyl, C ₁ -C ₈ alkylthio, C ₁ -C ₈ halogenated alkylthio base, C ₂ -C ₈ alkenylthio, C ₂ -C ₈ haloalkenylthio, C ₂ -C ₈ alkynylthio, C ₂ -C ₈ haloalkynylthio, C ₁ -C ₈ aldol alkyl alkenyl, C ₁ -C ₈ aldol haloalkyl, C ₂ -C ₈ aldoalkenyl, C ₂ -C ₈ aldol haloalkenyl, C ₂ -C ₈ aldol alkynyl, C ₂ -C ₈ aldehyde haloalkynyl; Wherein, the heterocyclic group is selected from the group consisting of oxthiane, morpholine, pyran, pyridine, pyrimidine, pyridazine, quinoline, pyrazole, thiazole, isothiazole, thiadiazole, thiophene, furan, oxazole, isoxazole , oxadiazoles, or these heterocyclic halogen-containing derivatives. 4. The preparation method of benzoxaborol-1-alcohol compounds according to any one of claims 1 to 3, wherein when R is -R ₁ and R' is -CH ₂ -, the The preparation method of the benzoxaborol-1-alcohol compounds is as follows: bromobenzaldehyde or bromobenzoic acid compounds or cyano-substituted bromotoluene compounds react with chloromethyl methyl ether to convert into hydroxyl groups The bromobenzyl alcohol compound protected by methoxymethyl group is then reacted with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature to connect the boron atom to the benzene ring, and finally deprotected in hydrochloric acid, spontaneously Ring into the corresponding benzoxaborol-1-ol compounds; Or when R is -R ₁ and R' is -Y-CH ₂ -, the preparation method of the benzoxaborol-1-alcohol compounds is as follows: Wittig reaction occurs from bromobenzaldehyde compounds After hydrolysis, bromophenylacetaldehyde compounds are obtained, which are then reacted with chloromethyl methyl ether to obtain bromophenethyl alcohol compounds whose hydroxyl groups are protected by methoxymethyl groups. Finally, they are reacted with triisopropyl borate in n-butyllithium. The low temperature reaction in tetrahydrofuran solvent made the boron atom connected to the benzene ring, deprotected in hydrochloric acid, and spontaneously formed a ring to obtain the corresponding six-membered benzoxaborol-1-ol compounds. 5. The preparation method of benzoxaborol-1-alcohol compounds according to any one of claims 1 to 3, wherein when R is LR ₃ , R' is -CH ₂ -, and L is S or O, by (thio) phenolic compound and 2-bromo-4-fluorobenzaldehyde reaction to obtain (thio) ether compound, then by sodium borohydride reduction to obtain III-12, then III-12 and chloromethyl methyl The ether reacts to obtain III-13, and finally reacts with triisopropyl borate in tetrahydrofuran solvent of n-butyllithium at low temperature so that the boron atom is connected to the benzene ring, deprotected in hydrochloric acid, and spontaneously forms a ring to obtain the corresponding benzoxy Boron-1-ol compounds III-14; Or when R is LR ₃ , R' is -CH ₂ -, and L is thiocarbonyl or sulfonyl, compound III-14 is oxidized by sodium periodate to obtain the corresponding benzoxaborol-1-ols, respectively III-16 and III-17; Or when R is LR ₃ , R' is -CH ₂ -, and L is carbonyl, substituted benzene or heterocyclic compounds III-18 and III-19 undergo Friedel-Crafts reaction to obtain compound III-20, and then pass through bromobutanedi The imide is brominated, hydrolyzed with sodium acetate under alkaline conditions to obtain compound III-21 and oxidized to obtain compound III-22, then reacted with ethylene glycol to obtain compound III-23, and then reacted with triisopropyl borate in n-butyl The low temperature reaction of lithium in tetrahydrofuran solvent makes the boron atom connected to the benzene ring, deprotected in hydrochloric acid, and spontaneously formed into a ring to obtain the corresponding compound III-25, and finally reacted with Sarreth reagent to obtain benzoxaborol-1-ol Class compound III-26; Or when R is LR ₃ , R' is -CH ₂ -, and L is carbonylamino, thiocarbonylamino or sulfonylamino, compound III-27 is coupled with different acid chlorides, thioacyl chlorides, and sulfonyl chlorides to form L Linked benzoxaborol-1-ols III-28, III-29, III-30; Or when R is LR ₃ , R' is -CH ₂ -, and L is NH, an alcohol compound III-35 is formed from the iodo compound III-31 and compound III-32 under the protection of tert-butoxycarbonyl, and then With 3,4-dihydropyran in the presence of pyridine, the alcohol hydroxyl group protected by tetrahydropyran is formed, and finally deprotected under acidic conditions to form benzoxaborol-1-ol compound III-39; Or when R is LR ₃ , R' is -CH ₂ -, and L is CH ₂ , boronic acid compound III-40 and 2-methoxy-4-bromobenzaldehyde undergo Suzuki coupling reaction to obtain III-42, and then The trifluorosulfonic anhydride was converted into trifluoromethanesulfonate III-44 under the action of cerium trichloride and sodium iodide, and after boraneation, the corresponding benzoxaboron- 1-Alcohols III-46. 6. Application of the benzoxaborol-1-alcohol compound according to any one of claims 1 to 3 in the field of preventing and treating crop diseases. 7. application according to claim 6, is characterized in that, described crop disease is early blight, scab, sheath blight, botrytis cinerea, Pythium, speckle, anthracnose, late blight and one or more of downy mildew.