A method for preparing a benzoborazole compound

Abstract

The application relates to a preparation method of a benzoboroxine compound. Specifically, the application relates to a preparation method of 5-[6-(trifluoromethyl)-2-quinolyloxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoboroxine. The method has the characteristics of short steps, high atom utilization rate, mild reaction conditions, simple post-treatment, high reaction yield and high product purity, and is suitable for industrial production.

Description

Technical Field

[0001] This application relates to a method for preparing a benzoborazole compound. Specifically, this application relates to a method for preparing 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole. Background Technology

[0002] 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole is a selective PDE-4 inhibitor that is currently in clinical trials in China. Its structural formula is shown below:

[0003]

[0004] CN108148085A and Eur.J.Med.Chem.,213(2021)113171 disclose methods for preparing 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole. The two methods are similar, both involving substitution, Miyaura reaction, reduction, and cyclization reactions to obtain 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole. These methods suffer from low atom utilization, low yield, and high cost; in particular, some steps require additional column chromatography purification, making them completely unsuitable for industrial application.

[0005] To address the aforementioned deficiencies, this application aims to provide a method suitable for the industrial production of benzoborazole compounds, particularly 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole. Summary of the Invention

[0006] On the one hand, the method for preparing the benzoborazole compound of Formula I is characterized by comprising the step of subjecting the compound of Formula II to a borylation reaction and a cyclization reaction to generate the benzoborazole compound of Formula I.

[0007]

[0008] Wherein, R is selected from C1-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C1-C 20 Alkoxy, C2-C 20 Alkenyl groups, C2-C 20 Acryloxy group, C1-C 20 Haloalkyl, C1-C 20 Halogenated alkoxy groups, C3-C14 carbonyl group, C3-C 14 Carbocyclic radical, C6-C 14 Aryl, C6-C 14 aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, 3- to 14-membered heterocyclic, 3- to 14-membered heterocyclic; wherein the C3-C 14 carbonyl group, C3-C 14 Carbocyclic radical, C6-C 14 Aryl, C6-C 14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, 3- to 14-membered heterocyclic, 3- to 14-membered heterocyclic, optionally surrounded by C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, mercapto, cyano, nitro, carboxyl, C1-C6 alkoxycarbonyl, N(R')2, C(O)NH2, sulfonic acid group; R' is independently selected from H or C1-C6 alkyl;

[0009] n is selected from 1, 2, 3, and 4;

[0010] X is selected from chlorine, bromine, iodine, and C1-C. 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group;

[0011] The borylation and cyclization reactions are one-pot reactions.

[0012] In some embodiments, the boryling reagent is selected from pinacol diboronate, isopropanol pinacol boronate, cyclopropyl borate pinacol boronate, isopropenyl borate pinacol boronate, methanol pinacol boronate, tetrahydroxydiboron, or combinations thereof.

[0013] In some embodiments, the boryling reagent is selected from tetrahydroxydiboron.

[0014] In some embodiments, the cyclization reaction is carried out in the presence of a palladium catalyst; wherein the palladium catalyst is selected from:

[0015] Palladium acetate, palladium chloride, Pd2(dba)3 (tris(dibenzylacetone)dipalladium), [Pd(allyl)Cl]2 (allyl palladium(II) chloride dimer), Pd(acac)2 (acetylacetone palladium(II)), PdCl2(PPh3)2 (bis(triphenylphosphine)dichloride palladium), Pd(dppf)Cl2·CH2Cl2 ([1,1′-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane complex), Pd[P(t- Bu)3]2(bis(tri-tert-butylphosphine)palladium), PdCl2(dcypf)(1,1′-bis(di-cyclohexylphosphino)ferrocene dichloride palladium), chloro[tri-tert-butylphosphine-2-(2-aminobiphenyl)]palladium(II), P(Cy)3-Pd-G2chloro[(tricyclohexylphosphine)-2-2-(2′-aminobiphenyl)]palladium(II), methanesulfonyl[tri-tert-butylphosphine-2-(2-aminobiphenyl)palladium(II), XPhos-Pd-G1(chloro(2-di-... Cyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)), SPhos-Pd-G1(chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)), tBuXPhos-Pd-G1(chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl] [2-(2-aminoethyl)phenyl)]palladium(II)), BrettPhos-Pd-G1(chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)), RuPhos-Pd-G1(chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II));

[0016] XPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)), XantPhos-Pd-G2(chloro[(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)), SPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)), RuPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)]palladium(II) Phenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II)), Neopentyl-tBu2P-Pd-G2(chloro(di-tert-butyl-neoptiylphosphino)-2(2-aminobiphenyl)palladium(II)), MorDalphos-Pd-G2(chloro(di-1-adamantylphosphino)morpholinephenyl)(2-(2'-amino-1,1'-biphenyl)palladium(II)), cataCXium-A-Pd-G2(chloro[(n-butyldi(1-adamantyl)phosphino)-2-(2-aminobiphenyl)]palladium(II)), APhos-Pd-G2(chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino(2-amino-1,1'-biphenyl-2-yl)palladium(II));

[0017] XPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), SPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), RuPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl ...) 2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)), tBuXPhos-Pd-G3(methanesulfonic acid (2-di-tert-butylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), tert-BuBrettPhos-Pd-G3(methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II)), XantPhos-Pd-G3(methanesulfonic acid-9,9-dimethyl-4,5-bisdiphenylphosphineoxanthracene)(2' -amino-1,1'-biphenyl-2-yl)palladium(II)), RockPhos-Pd-G3([(2-di-tert-butylphosphine-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium methanesulfonate(II)), Neopentyl(t-Bu)2P-Pd-G3([(2-di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium methanesulfonate(II)), Josiphos SL-J009-1-Pd-G3({(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine}[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate), JackiePhos-Pd-G3(methanesulfonic acid [2-bis(3,5-bis(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',4',6'-triisocyanate) Propyl-1,1'-biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), P(Cy3)-Pd-G3(methanesulfonic acid(tricyclohexylphosphine-(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), CPos-Pd-G3([(2-dicyclohexylphosphine-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-Biphenyl)]Palladium(II)methanesulfonate, cataCXium-A-Pd-G3(methanesulfonate[(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]Palladium(II)), (t-Bu)2PMe-Pd-G3(methanesulfonate(di-tert-butyl)methylphosphino(2′-amino-1,1′-biphenyl-2-yl)Palladium(II)), APhos-Pd-G 3(methanesulfonic acid [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2'-amino-1,1'-biphenyl-2-yl)palladium(II)), Ad-BrettPhos-Pd-G3(methanesulfonic acid-2-(di-1-adamantylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (2'-amino-1,1'-biphenyl-2-yl)palladium(II));

[0018] XPhos-Pd-G4((SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium(II)), XantPhos-Pd-G4(methanesulfonic acid(4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino- 1,1'-Biphenyl-2-yl)Palladium(II)), SPhos-Pd-G4(2-Dicyclohexylphosphine-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)Palladium(II)), RuPhos-Pd-G4(2-Dicyclohexyl(2',6'-di-isopropyl-1,1'-biphenyl-2-yl)phosphine)-(2'-methyl Amino-1,1'-biphenyl-2-yl)palladium(II)), P(Cy3)-Pd-G4(methanesulfonic acid (tricyclohexylphosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)), MorDalPhos-Pd-G4(methanesulfonic acid (2-(diadamantylphosphine)morpholinophenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II)), cataCXiu m-Pd-G4((methanesulfonic acid [n-butyldi(adamantane-1-yl)phosphine](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G4(2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl-2-yl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid);

[0019] Or a combination of them.

[0020] In some embodiments, the cyclization reaction is carried out in the presence of a palladium catalyst; wherein the palladium catalyst is selected from:

[0021] Chloro[tri-tert-butylphosphine-2-(2-aminobiphenyl)]palladium(II), XPhos-Pd-G1, XPhos-Pd-G2, XPhos-Pd-G3, XPhos-Pd-G4, P(Cy3)-Pd-G2, or combinations thereof.

[0022] In some embodiments, the cyclization reaction is carried out in the presence of a palladium catalyst; wherein the palladium catalyst is selected from XPhos-Pd-G2.

[0023] In some embodiments, the cyclization reaction is further carried out in the presence of a palladium catalyst ligand; wherein the palladium catalyst ligand is selected from: triphenylphosphine, tri-n-octylphosphine oxide, tricyclohexylphosphine, XPhos, RuPhos, SPhos, DavePhos, QPhos, JohnPhos, BrettPhos, AmPhos, tBuXPhos, tBuMePhos, tBuBrettPhos, tBuDavePhos, AdBrettPhos, AlPhos, PhDave-Phos, Me4tButylXphos, MePhos, Me3(OMe)tBuXPhos, CyJonePhos, Ad2PBu, tBu3P, tBu3P-HBF4, 1,1'-bis(di-tert-butylphosphine)ferrocene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, or combinations thereof.

[0024] In some embodiments, the cyclization reaction is further carried out in the presence of a palladium catalyst ligand; wherein the palladium catalyst ligand is selected from: tricyclohexylphosphine, XPhos, SPhos, QPhos, DavePhos, JohnPhos, BrettPhos, RuPhos, or combinations thereof.

[0025] In some embodiments, the cyclization reaction is further carried out in the presence of a palladium catalyst ligand; wherein the palladium catalyst ligand is selected from XPhos.

[0026] In some embodiments, the borylation and cyclization reactions are carried out under neutral or alkaline conditions.

[0027] In some embodiments, the borylation and cyclization reactions are carried out under alkaline conditions.

[0028] In some embodiments, the base is selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, N,N-dimethylethanolamine, 1,2,2,6,6-pentamethylpiperidine, 1,1,3,3-tetramethylguanidine, ammonium acetate, potassium acetate, sodium acetate, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, cesium carbonate, sodium bicarbonate, calcium bicarbonate, sodium phosphate, potassium phosphate, calcium phosphate, magnesium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium alcohol, sodium alcohol, potassium alcohol, or combinations thereof, wherein the alcohol is a C1-C6 alkyl alcohol.

[0029] In some embodiments, the base is selected from triethylamine, diisopropylethylamine, potassium acetate, or combinations thereof.

[0030] In some embodiments, the base is selected from potassium acetate.

[0031] In some embodiments, the borylation and cyclization reactions are carried out in a suitable organic solvent.

[0032] In some embodiments, the organic solvent is selected from aprotic solvents. In some embodiments, the organic solvent is selected from N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, diethyl ether, toluene, benzene, or combinations thereof.

[0033] In some embodiments, the organic solvent is selected from protic solvents. In some embodiments, the organic solvent is selected from C1-C6 alkyl alcohols, including but not limited to methanol, ethanol, isopropanol, ethylene glycol, etc.

[0034] In some embodiments, the organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, or combinations thereof. In some embodiments, the organic solvent is selected from methanol.

[0035] In some embodiments, additives may optionally be used in the borylation and cyclization reactions, including but not limited to ethylene glycol, propylene glycol, butanediol, etc.

[0036] In some embodiments, the temperature range of the borylation reaction and the cyclization reaction is 40–100°C; preferably, the temperature range of the borylation reaction and the cyclization reaction is 50–90°C; more preferably, the temperature range of the borylation reaction and the cyclization reaction is 60–75°C.

[0037] In some embodiments, the compound represented by Formula I is selected from 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole and has the following structure:

[0038]

[0039] The compound represented by Formula II has the following structure:

[0040]

[0041] Wherein, X is selected from chlorine, bromine, iodine, C1-C 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy; more preferably, X is selected from bromine, iodine, or p-toluenesulfonyloxy; even more preferably, X is selected from bromine.

[0042] In some embodiments, the preparation method of the present invention further includes the step of reducing the compound shown in Formula III to the compound shown in Formula II-1.

[0043]

[0044] Wherein, X is selected from chlorine, bromine, iodine, C1-C 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy; more preferably, X is selected from bromine, iodine, or p-toluenesulfonyloxy; even more preferably, X is selected from bromine.

[0045] In some embodiments, the reduction reaction is carried out in the presence of a carbonyl reducing agent; wherein the carbonyl reducing agent includes, but is not limited to, sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborocyanide, hydrogen, diisobutylaluminum hydride, Stryker's reagent, lithium aluminum hydride, red aluminum, stannous chloride, reducing metals (sodium, potassium, lithium, iron, zinc, magnesium, etc.), sulfites, sulfides, metal hydrides (sodium hydride, calcium hydride, etc.), boranes and borane complexes, dicarbonyldicyclopentadienyl titanium, monoisosolzylborane, diisosolzylborane, alkylboranes, or combinations thereof.

[0046] In some embodiments, the reduction reaction is carried out in a suitable organic solvent.

[0047] In some embodiments, the organic solvent is selected from aprotic solvents. In some embodiments, the organic solvent is selected from N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethylene glycol dimethyl ether, sulfolane, hexamethylphosphonic triamine, acetonitrile, propionitrile, butyronitrile, diethyl ether, methyl tert-butyl ether, isopropyl ether, xylene, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, or combinations thereof.

[0048] In some embodiments, the organic solvent is selected from protic solvents. In some embodiments, the organic solvent is selected from water and C1-C6 alkyl alcohols (including but not limited to methanol, ethanol, isopropanol, ethylene glycol, etc.), or combinations thereof.

[0049] In some embodiments, the organic solvent is selected from a combination of tetrahydrofuran and water or a combination of 2-methyltetrahydrofuran and water.

[0050] In some embodiments, the temperature range of the reduction reaction is -20 to 100°C; preferably, the temperature range of the reduction reaction is -10 to 30°C; more preferably, the temperature range of the reduction reaction is 0 to 25°C.

[0051] In some embodiments, the preparation method of the present invention further includes the step of reacting the compound of formula IV with the compound of formula V under alkaline conditions to obtain the compound of formula III.

[0052]

[0053] Wherein, X is selected from chlorine, bromine, iodine, C1-C 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy; more preferably, X is selected from bromine, iodine, or p-toluenesulfonyloxy; even more preferably, X is selected from bromine.

[0054] In some embodiments, the base used in this reaction step is selected from triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, N,N-dimethylethanolamine, 1,2,2,6,6-pentamethylpiperidine, 1,1,3,3-tetramethylguanidine, hydrazine hydrate, potassium fluoride, sodium hydride, ammonium acetate, potassium acetate, sodium acetate, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, cesium carbonate, sodium bicarbonate, calcium bicarbonate, sodium phosphate, potassium phosphate, calcium phosphate, magnesium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium alcohol, sodium alcohol, potassium alcohol, lithium alcohol, sodium alcohol, potassium alcohol, or combinations thereof, wherein the alcohol is a C1-C6 alkyl alcohol. In some embodiments, the base used in this reaction step is selected from triethylamine, diisopropylethylamine, potassium acetate, potassium carbonate, sodium carbonate, cesium carbonate, hydrazine hydrate, potassium fluoride, sodium hydride, or combinations thereof. In some implementations, the base used in this step is selected from potassium carbonate and sodium carbonate.

[0055] In some embodiments, the reaction is carried out in a suitable organic solvent. In some embodiments, the reaction is carried out in an organic solvent selected from the following: aprotic solvents include, but are not limited to, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethylene glycol dimethyl ether, sulfolane, hexamethylphosphonic triamine, acetonitrile, propionitrile, butyronitrile, diethyl ether, methyl tert-butyl ether, isopropyl ether, xylene, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, chloroform, carbon tetrachloride, etc., or combinations thereof; protic solvents include, but are not limited to, C1-C6 alkyl alcohols, such as methanol, ethanol, isopropanol, ethylene glycol, etc., or combinations thereof.

[0056] In some embodiments, the solvent for this reaction step is selected from N,N-dimethylacetamide (DMA) and N,N-dimethylformamide (DMF).

[0057] In some embodiments, the temperature range of this step is 40–160°C; preferably, the temperature range of the reduction reaction is 60–120°C; more preferably, the temperature range of the reduction reaction is 80–100°C.

[0058] In one specific embodiment, the present invention provides a method for preparing 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole, which includes the following steps:

[0059] Step 1: React the compound of formula IV (or its salt) with the compound shown in formula V-1 under alkaline conditions to obtain the compound shown in formula III-1.

[0060]

[0061] Step 2: The compound shown in Formula III-1 (or its salt) is reduced to the compound shown in Formula II-1′.

[0062]

[0063] Step 3: The compound shown in Formula II-1′ (or its salt) is subjected to a borylation reaction and a cyclization reaction to generate the compound shown in Formula I-1 (or its salt).

[0064]

[0065] In step 3, the borylation and cyclization reactions are "one-pot" reactions, and the reaction reagents and reaction conditions in each of the above steps are as described in this article.

[0066] In some embodiments, the method for preparing 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole provided by the present invention further includes purification and refining of the compound of formula I-1 obtained in step 3.

[0067] In some embodiments, the purification of the compound shown in Formula I-1 is carried out under acidic conditions. In one embodiment, the acidic conditions are achieved by adding an acidic reagent, wherein the acidic reagent includes, but is not limited to, solutions of citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, trifluoroacetic acid, formic acid, propionic acid, trichloroacetic acid, chloroacetic acid, cyanoacetic acid, ascorbic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, sulfurous acid, carbonic acid, and various acid salts (including ammonium chloride solution, sodium dihydrogen phosphate solution, etc.), or combinations thereof. In some embodiments, the acidic reagent includes sulfuric acid, hydrochloric acid, hydrobromic acid, or combinations thereof. In one embodiment, the acidic reagent is selected from hydrochloric acid.

[0068] In some embodiments, the purification of the compound shown in Formula I-1 is carried out in a suitable organic solvent. In some embodiments, the solvent for purifying the compound shown in Formula I-1 is selected from acetonitrile, chlorobenzene, chloroform, ethylene oxide, 1,2-dichloroethylene, dichloromethane, 1,2-dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, n-hexane, methanol, 2-methoxyethanol, methylbutanone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, dioxothiophene, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, ethanol, methyl ethyl ketone, etc. Acetone, ethyl acetate, methyl isobutyl ketone, anisole, diethyl ether, 2-methyl-1-propanol, 1-butanol, formic acid, n-propanol, butyl acetate, n-heptane, n-pentanol, methyl tert-butyl ether, isopropyl acetate, isobutyl acetate, methyl acetate, isopropanol, isopropylbenzene, 3-methyl-1-butanol, propyl acetate, dimethyl sulfoxide, tetrahydrofuran, 1,1-diethoxypropane, methyl isopropanone, 1,1-dimethylmethane, 2-methyltetrahydrofuran, 2,2-dimethylpropane, petroleum ether, isooctane, trichloroacetic acid, isopropyl ether, trifluoroacetic acid, water, or combinations thereof. In some embodiments, the solvent for purifying the compound shown in Formula I-1 is selected from ethyl acetate, n-heptane, and / or water, or combinations thereof.

[0069] In some embodiments, the method for preparing 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole provided by the present invention further includes a step of purifying the compound of formula III-1 obtained in step 1. In some embodiments, the purification step includes crystallization after mixing the reaction solution with an aqueous solution. In some embodiments, the aqueous solution comprises water, various aqueous solutions (including but not limited to mixed solutions of other organic solvents and water in different proportions, aqueous solutions of acids, bases or salts of different concentrations, etc.).

[0070] In one specific implementation, the purification step includes mixing the reaction solution with water, followed by crystallization and filtration.

[0071] Beneficial effects: First, the preparation method provided by this invention completes the borylation and cyclization reactions in a "one-pot" process, improving atom utilization and reaction yield. Second, the preparation method of this invention omits the column chromatography purification step, simplifying the process while obtaining high-purity products, making the preparation method suitable for industrial production. Furthermore, the feed rate of the preparation method of this invention reaches the kilogram level, making it suitable for development and industrial production. Detailed Implementation

[0072] definition

[0073] As used in this specification, unless the context indicates otherwise, the following words and phrases are generally intended to have the meanings set forth below.

[0074] As used herein, the term "alkyl" refers to a monovalent group of a straight or branched saturated hydrocarbon chain having 1 to 20 carbon atoms (more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms). The term is exemplified by groups such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, etc.

[0075] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent group of an unsaturated hydrocarbon chain having 2 to 20 carbon atoms (more typically 2 to 10, 2 to 8, or 2 to 6 carbon atoms) and carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The term is exemplified by groups such as vinyl (i.e., -CH=CH2), 1-propenyl (i.e., -CH=CHCH3), 3-propenyl (or allyl, i.e., -CH2CH=CH2), 2-propenyl (i.e., -C(CH3)=CH2), butadienyl (including 1,2-butadienyl and 1,3-butadienyl), etc.

[0076] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent group of an unsaturated hydrocarbon chain having 2 to 20 carbon atoms (more typically 2 to 10, 2 to 8, or 2 to 6 carbon atoms) and carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds). Examples of this term include groups such as ethynyl (i.e., -C≡CH), propynyl (i.e., -CH2C≡CH), propynyl (i.e., -C≡CCH3), etc.

[0077] As used herein, the term "aryl" refers to an aromatic carbocyclic group having 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) of a monocyclic (e.g., phenyl) or polycyclic (e.g., biphenyl) or multiple fused (fused) rings (e.g., naphthyl, fluorenyl, and anthracene). The term is exemplified by groups such as phenyl, fluorenyl, naphthyl, anthracene, 1,2,3,4-tetrahydronaphthalene (if the linking point is through an aryl group), etc.

[0078] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein the alkyl group is as defined herein. The term is illustrative of groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0079] As used herein, the term "alkenoxy" refers to an "alkenyl-O-" group, wherein the alkenyl group is as defined herein. This term is exemplified by groups such as ethyleneoxy, propyleneoxy, butenoxy, isobutenoxy, etc.

[0080] As used herein, the term "alkynyloxy" refers to an "alkynyl-O-" group, wherein the alkynyl group is as defined herein. Examples of this term include groups such as ethynyloxy, propynyloxy, butynyloxy, etc.

[0081] As used herein, the term "aryloxy" refers to an "aryl-O-" group, where the aryl group is as defined herein. The term is illustrative of groups such as phenoxy, fluorenoxy, naphthoxy, anthraceneoxy, 1,2,3,4-tetrahydronaphthoxy (if the linkage is through an aryl group), etc.

[0082] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein the alkyl group is as defined herein. Examples of the term include groups such as trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, etc.

[0083] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, wherein the alkoxy group is as defined herein. The term is exemplified by groups such as trifluoromethoxy, difluoromethoxy, monofluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,-difluoroethoxy, etc.

[0084] As used herein, the term "carbocyclic group" refers to a monocyclic, saturated, or partially unsaturated monocyclic or fused (fused-together) ring, bridged, or spirocyclic group having 3 to 14 carbon atoms as ring atoms. The carbocyclic or carbocyclic group can be saturated or partially unsaturated and can be fused with another saturated, partially unsaturated, or aromatic ring, provided that the ring atom attached to the target molecule is not an aromatic carbon. Examples of carbocyclic or carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, etc.

[0085] As used herein, the term "carbocyclic group" refers to a "carbocyclic-O-" group, wherein the carbocyclic group is as defined herein. This term is exemplified by groups such as cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cyclobutenoxy, cyclopentenoxy, cyclohexenoxy, cycloheptenoxy, cyclopentadienoxy, etc.

[0086] As used herein, the term "heteroaryl" refers to an aromatic cyclic group comprising a monocyclic or multicyclic fused (fused) ring (e.g., comprising two or three rings) containing 5 to 14 ring atoms, wherein, in addition to a carbon atom, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized forms. Multicyclic fused (fused) heteroaryl is formed by fusing a monocyclic heteroaryl as defined above with one or more rings selected from the following to form a multicyclic fused ring system: heteroaryl (to form, for example, naphthidyl, such as 1,8-naphthidyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthidyl, such as 1,2,3,4-tetrahydro-1,8-naphthidyl), carbocyclic (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazole). Such multicyclic fused ring systems may optionally have one or more (e.g., 1, 2, 3, or 4) oxo groups substituted on the carbocyclic or heterocyclic portion of the fused ring. When valence requirements permit, the rings of a multicyclic fused ring system can be interconnected by fusion, spirocyclic, and bridging bonds. It should be understood that the individual rings of a multicyclic fused ring system can be connected relative to each other in any order. It should also be understood that the connection points of a multicyclic fused ring system can be at any location within the system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of a multicyclic fused system. It should also be understood that the connection points of heteroaryl groups can be on any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, inzolyl, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzoimidazolyl, thiaindyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-inzolyl and 3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazolyl.

[0087] As used herein, the term “heteroaryloxy” refers to a “heteroaryl-O-” group, wherein the heteroaryl group is as defined herein. The term is illustrative of groups such as pyridinoxy, pyrrolooxy, pyrazinoxy, pyrimidinoxy, pyridazinoxy, pyrazoloxy, thiophenoxy, indoleoxy, imidazooxy, oxazoloxy, isoxazoloxy, thiazooxy, furanoxy, oxadiazoloxy, thiazooxy, quinolinoxy, isoquinolinoxy, benzothiazooxy, benzooxazoloxy, indazoleoxy, quinoxalolineoxy, quinazolinoxy, 5,6,7,8-tetrahydroisoquinolinoxy, benzofuranoxy, benzimidazoloxy, thiazoindoxy, pyrrolo[2,3-b]pyridinoxy, triazoloxy, 4,5,6,7-tetrahydro-1H-indazoleoxy, and 3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazoloxy, etc.

[0088] As used herein, the term "heterocyclic group" refers to a monocyclic saturated or partially unsaturated group having a 3 to 8-membered monocyclic ring or multiple fused (fused) rings or bridged rings having 3 to 14 ring atoms within the ring, wherein, in addition to carbon atoms, the ring atoms also contain at least one heteroatom selected from oxygen, nitrogen and / or sulfur. Examples of heterocyclic groups include, but are not limited to, azirropropane rings, azirrobutane rings, tetrahydropyrrole rings, piperidine rings, azirroheptane rings, azirrooctane rings, oxacyclopropane rings, oxacyclobutane rings, tetrahydrofuran rings, tetrahydropyran rings, oxacycloheptane rings, oxacyclooctane rings, thiohexacyclopropane rings, thiohexacyclobutane rings, tetrahydrothiophene rings, tetrahydrothioran rings, thiohexacycloheptane rings, thiohexacyclooctane rings, tetrahydroimidazolium rings, tetrahydropyrazole rings, tetrahydrooxazole rings, tetrahydroisooxazole rings, tetrahydrothiazole rings, tetrahydroisothiazole rings, piperazine rings, morpholine rings, dioxane rings, thiooxane rings, dithiazolium rings, dihydropyridyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolium, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, etc.

[0089] As used herein, the term “heterocyclic group” refers to a “heterocyclic-O-” group, wherein the heterocyclic group is as defined herein. The term is illustrative of groups such as azircyclopropaneoxy, azircyclobutaneoxy, tetrahydropyrroloxy, piperidinoxy, azircycloheptaneoxy, azircyclooctaneoxy, oxacyclopropaneoxy, oxacyclobutaneoxy, tetrahydrofuranoxy, tetrahydropyranoxy, oxacycloheptaneoxy, oxacyclooctaneoxy, thiocyclopropaneoxy, thiocyclobutaneoxy, tetrahydrothiophenoxy, tetrahydrothioranoxy, thiocycloheptaneoxy, thiocyclooctaneoxy, tetrahydroimidazooxy, tetrahydropyrazoleoxy, tetrahydrooxazoloxy, tetrahydroisoxazoloxy, tetrahydrothiazooxy, tetrahydroisothiazooxy, piperazineoxy, morpholinoxy, dioxaneoxy, thiazooxy, dithiazooxy, dithiazooxy, dihydropyridinoxy, 4,5,6,7-tetrahydro-1H-benzo[d]imidazooxy, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridinoxy, etc.

[0090] As used herein, the term "one-pot reaction" refers to a reaction in which multiple steps required for the synthesis of a target molecule are completed in the same reaction vessel without the separation or purification of intermediate products.

[0091] Example

[0092] The following embodiments provide a further non-limiting detailed description of the technical solution of this application. They should not be considered as limiting the scope of this application, but only as exemplary illustrations and typical representatives. The solvents, reagents, and raw materials used in this application are all commercially available chemically pure or analytically pure products.

[0093]

[0094] Example 1

[0095] Step 1: Preparation of 2-bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzaldehyde (III-1)

[0096]

[0097] 2-Chloro-6-(trifluoromethyl)quinoline (Ⅳ, 9.658 kg), 2-bromo-5-hydroxybenzaldehyde (Ⅴ-1, 8.390 kg), K₂CO₃ (11.534 kg), and DMF (22.92 kg) were added to a reaction vessel. Under nitrogen protection, the mixture was stirred and heated to approximately 90°C and the reaction was maintained at this temperature for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (approximately 96 kg) was added dropwise to the reaction solution during this period. The reaction solution was filtered, and the filter cake was washed with water to obtain a wet product. This wet product was dried under vacuum to obtain 2-bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzaldehyde (Ⅲ-1, 15.862 kg, 96.3%).

[0098] 1 H NMR (400MHz, DMSO-d6) δ10.22 (s, 1H), 8.65 (d, J = 8.8Hz, 1H), 8.48 (s, 1H), 7. 87~7.93(m,2H),7.75-7.81(m,2H),7.61~7.64(m,1H),7.50(d,J=8.8Hz,1H).

[0099] ESI-MS (m / z): 395.9837 [M+H] + .

[0100] Step 2: Preparation of 2-bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzyl alcohol (II-1′)

[0101]

[0102] 2-Bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzaldehyde (III-1, 15.862 kg) and 2-methyltetrahydrofuran (82.138 kg) were added to a reaction vessel and stirred until cooled to approximately 0°C. Sodium borohydride (0.62 kg) was dissolved in water (3.056 kg) and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction was maintained at this temperature for 0.5 h. After the reaction was completed, water (approximately 40 kg) was added to the reaction solution sequentially. The pH of the aqueous phase of the reaction solution was then adjusted to 2–3 with dilute hydrochloric acid. The solution was allowed to stand and separated, and the organic phase was separated and concentrated. An isopropanol / n-heptane (volume ratio approximately 1:5) mixture was added to the concentrated residue, and the mixture was heated under reflux for 1 h, followed by cooling to approximately 5°C. The filter cake was filtered, washed with a mixture of isopropanol and n-heptane, and then dried under vacuum to obtain 2-bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzyl alcohol (II-1′, 13.958 kg, 87.9%).

[0103] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=8.8Hz,1H),8.49(s,1H),7.90(d,J=9.2Hz,1H),7.82(d,J=8.8Hz,1H),7.67(d,J=8.4Hz, 1H),7.47(d,J=8.8Hz,1H),7.40(d,J=2.8Hz,1H),7.17(dd,J=8.4,2.8Hz,1H),5.54(t,J=5.6Hz,1H),4.54(d,J=6.0Hz,2H).

[0104] ESI-MS (m / z): 397.9997 [M+H] + .

[0105] Step 3: Preparation of 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (Ⅰ-1)

[0106]

[0107] 2-Bromo-5-(6-(trifluoromethyl)-2-quinolinoxy)benzyl alcohol (II-1′, 13.958 kg), methanol (110.56 kg), potassium acetate (10.472 kg), ethylene glycol (6.564 kg), Xphos (83.78 g), Xphos-Pd-G2 (69.11 g), and tetrahydroxydiboron (4.720 kg) were added to a reaction flask and heated to reflux for 1.5 h under nitrogen protection. After the reaction was complete, the reaction solution was filtered. The resulting filter cake was added to water and ethyl acetate (approximately 1:1 by volume), stirred, allowed to stand, and separated to obtain the organic phase. The organic phase was filtered through a microporous membrane (0.45 μm), and the filtrate was collected. After concentrating the filtrate, methanol (110.5 kg) was added to the residue, and the mixture was heated to reflux. Then, the temperature was lowered to 0-5℃, filtered, and the filter cake was dried under vacuum to obtain crude 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (Ⅰ-1) 1 (10.29 kg, 85.8%).

[0108] 10.290 kg of crude 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (I-1) was stirred in dilute hydrochloric acid for 3 h and filtered to obtain a filter cake. The filter cake was washed with water and dried under vacuum to obtain crude 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (I-1) (9.244 kg, 90.4%).

[0109] Crude 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (Ⅰ-1) 2 (9.244 kg) was dissolved in ethyl acetate by stirring. The solution was filtered through a microporous membrane (0.45 μm), and the filtrate was concentrated. Ethyl acetate / n-heptane (v / v ratio approximately 1:2) was added to the concentrated residue, and the mixture was heated to reflux and then cooled to crystallize. The filter cake was washed with a mixed solution of ethyl acetate / n-heptane (v / v ratio approximately 1:2) and dried under vacuum to obtain 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole (Ⅰ-1, 8.32 kg, 90.6%).

[0110] 1H NMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 8.63 (d, J = 9.2Hz, 1H), 8.48 (s, 1H), 7.89 ~ 7.92 (m, 1H), 7. 80~7.84(m,2H),7.46(d,J=8.8Hz,1H),7.34(d,J=1.2Hz,1H),7.24~7.26(m,1H),5.03(s,2H).

[0111] APCI-MS (m / z): 346.0871 [M+H] + .

[0112] Although the invention has been described in some detail by way of illustration and examples, those skilled in the art will readily understand, based on the teachings of the invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. A method for preparing a benzoborazole compound of Formula I, characterized in that, This includes reacting the compound shown in Formula II with a borylation reaction and a cyclization reaction to generate the benzoborazole compound shown in Formula I. Wherein, R is selected from C1-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C1-C 20 Alkoxy, C2-C 20 Alkenyl groups, C2-C 20 Acryloxy group, C1-C 20 Haloalkyl, C1-C 20 Halogenated alkoxy groups, C3-C 14 carbonyl group, C3-C 14 Carbocyclic radical, C6-C 14 Aryl, C6-C 14 aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, 3- to 14-membered heterocyclic, 3- to 14-membered heterocyclic; wherein the C3-C 14 carbonyl group, C3-C 14 Carbocyclic radical, C6-C 14 Aryl, C6-C 14 Aryloxy, 5- to 14-membered heteroaryl, 5- to 14-membered heteroaryloxy, 3- to 14-membered heterocyclic, 3- to 14-membered heterocyclic, optionally surrounded by C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, mercapto, cyano, nitro, carboxyl, C1-C6 alkoxycarbonyl, N(R')2, C(O)NH2, sulfonic acid group; R' is independently selected from H or C1-C6 alkyl; n is selected from 1, 2, 3, and 4; X is selected from chlorine, bromine, iodine, and C1-C. 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; The borylation and cyclization reactions are one-pot reactions.

2. The preparation method according to claim 1, characterized in that, The boronizing reagent is selected from pinacol diboronate, isopropanol pinacol boronate, cyclopropyl borate pinacol boronate, isopropenyl borate pinacol boronate, methanol pinacol boronate, tetrahydroxydiboron, or combinations thereof.

3. The preparation method according to claim 1, characterized in that, The cyclization reaction is carried out in the presence of a palladium catalyst; wherein the palladium catalyst is selected from: Palladium acetate, palladium chloride, Pd2(dba)3 (tris(dibenzylacetone)dipalladium), [Pd(allyl)Cl]2 (allyl palladium(II) chloride dimer), Pd(acac)2 (acetylacetone palladium(II)), PdCl2(PPh3)2 (bis(triphenylphosphine)dichloride palladium), Pd(dppf)Cl2·CH2Cl2 ([1,1′-bis(diphenylphosphine)ferrocene]palladium(II)dichloromethane complex), Pd[P(t- Bu)3]2(bis(tri-tert-butylphosphine)palladium), PdCl2(dcypf)(1,1′-bis(di-cyclohexylphosphino)ferrocene dichloride palladium), chloro[tri-tert-butylphosphine-2-(2-aminobiphenyl)]palladium(II), P(Cy3)-Pd-G2chloro[(tricyclohexylphosphine)-2-2-(2′-aminobiphenyl)]palladium(II), methanesulfonyl[tri-tert-butylphosphine-2-(2-aminobiphenyl)palladium(II), XPhos-Pd-G1(chloro(2-di-... Cyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)), SPhos-Pd-G1(chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)), tBuXPhos-Pd-G1(chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl] [2-(2-aminoethyl)phenyl)]palladium(II)), BrettPhos-Pd-G1(chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II)), RuPhos-Pd-G1(chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)); XPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)), XantPhos-Pd-G2(chloro[(4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)), SPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)), RuPhos-Pd-G2(chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)]palladium(II)), 1'-Biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)), Neopentyl-tBu2P-Pd-G2(chloro(di-tert-butyl-neoptiylphosphino)-2(2'-aminobiphenyl)palladium(II)), MorDalphos-Pd-G2(chloro(di-1-adamantylphosphino)morpholinophenyl)(2(2-aminobiphenyl)palladium(II)), cataCXium-A-Pd-G2(chloro[(n-butyldi(1-adamantyl)phosphino)-2-(2-aminobiphenyl)]palladium(II)), APhos-Pd-G2(chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino(2-amino-1,1'-biphenyl-2-yl)palladium(II)); XPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), SPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), RuPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl ...) -2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)), tBuXPhos-Pd-G3(methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G3(methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-2',4',6'-biphenyl) propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), tert-BuBrettPhos-Pd-G3(methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II)), XantPhos-Pd-G3(methanesulfonic acid-9,9-dimethyl-4,5-bisdiphenylphosphineoxanthracene)(2'- (amino-1,1'-biphenyl-2-yl)palladium(II)), RockPhos-Pd-G3([(2-di-tert-butylphosphine-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II)methanesulfonate), Neopentyl(t-Bu)2P-Pd-G3([(2-di-tert-butylneoptiophine)-2-(2'-aminobiphenyl)]palladium(II)methanesulfonate), Josiphos SL-J009-1-Pd-G3({(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine}[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate), JackiePhos-Pd-G3(methanesulfonic acid [2-bis(3,5-bis(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',4',6'-tri... Isopropyl-1,1'-biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II)), P(Cy3)-Pd-G3(tricyclohexylphosphine-(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid), CPos-Pd-G3([(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1′-Biphenyl)]Palladium(II)methanesulfonate, cataCXium-A-Pd-G3([(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]Palladium(II)), (t-Bu)2PMe-Pd-G3((di-tert-butyl)methylphosphino(2′-amino-1,1′-biphenyl-2-yl)Palladium(II)), APhos-Pd- G3(methanesulfonic acid [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II)), Ad-BrettPhos-Pd-G3(methanesulfonic acid-2-(di-1-adamantylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II)); XPhos-Pd-G4((SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium(II)), XantPhos-Pd-G4(methanesulfonic acid(4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene)(2'-methylamino-1 ,1'-biphenyl-2-yl)palladium(II)), SPhos-Pd-G4(methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)), RuPhos-Pd-G4(methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropyl-1,1'-biphenyl-2-yl)phosphino)-(2'-methylamino) -1,1'-biphenyl-2-yl)palladium(II)), P(Cy3)-Pd-G4(methanesulfonic acid (tricyclohexylphosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)), MorDalPhos-Pd-G4(methanesulfonate (2-(diadamantylphosphine)morpholinophenyl)[2-(2′-methylamino-1,1′-biphenyl-2-yl)]palladium(II)), cataCX ium-Pd-G4((methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)), BrettPhos-Pd-G4(2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl-2-yl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid); Or a combination of them.

4. The preparation method according to claim 3, characterized in that, The cyclization reaction is further carried out in the presence of a palladium catalyst ligand, wherein the palladium catalyst ligand is selected from: triphenylphosphine, tri-n-octylphosphine oxide, tricyclohexylphosphine, XPhos, RuPhos, SPhos, DavePhos, QPhos, JohnPhos, BrettPhos, AmPhos, tBuXPhos, tBuMePhos, tBuBrettPhos, tBuDavePhos, AdBrettPhos, AlPhos, PhDave-Phos, Me4tButylXphos, MePhos, Me3(OMe)tBuXPhos, CyJonePhos, Ad2PBu, tBu3P, tBu3P-HBF4, 1,1'-bis(di-tert-butylphosphine)ferrocene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, or combinations thereof.

5. The preparation method according to claim 1, characterized in that, The borylation and cyclization reactions are carried out under neutral or alkaline conditions.

6. The preparation method according to any one of claims 1-5, characterized in that, The compound represented by Formula I is selected from 5-[6-(trifluoromethyl)-2-quinolinoxy]-1,3-dihydro-1-hydroxy-[2,1]-benzoborazole and has the following structure: The compound represented by Formula II has the following structure:

7. The preparation method according to claim 6, characterized in that, The method further includes the step of reducing the compound shown in Formula III to the compound shown in Formula II-1. Wherein, X is selected from chlorine, bromine, iodine, C1-C 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy.

8. The preparation method according to claim 7, characterized in that, The reduction reaction is carried out in the presence of a carbonyl reducing agent; wherein the carbonyl reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium triacetoxyborohydride, sodium cyanoborocyanide, hydrogen, diisobutylaluminum hydride, Stryker reagent, lithium aluminum hydride, red aluminum, stannous chloride, reducing metals (sodium, potassium, lithium, iron, zinc, magnesium, etc.), sulfites, sulfides, metal hydrides (sodium hydride, calcium hydride, etc.), boranes and borane complexes, dicarbonyldicyclopentadienyl titanium, monoisosolzylborane, diisosolzylborane, alkylboranes, or combinations thereof.

9. The preparation method according to claim 7 or 8, characterized in that, The method further includes the step of reacting the compound of formula IV with the compound of formula V under alkaline conditions to obtain the compound of formula III. Wherein, X is selected from chlorine, bromine, iodine, C1-C 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy.

10. The compound shown in Formula II-1 or a salt thereof, in, X is selected from chlorine, bromine, iodine, and C1-C. 20 alkylsulfonyloxy, or C6-C 14 arylsulfonyloxy, wherein the C1-C 20 Alkylsulfonyloxy, C6-C 14 The arylsulfonyloxy group is optionally substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen group, a cyano group, and / or a nitro group; preferably, X is selected from chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or benzenesulfonyloxy.

11. The compound according to claim 10, wherein the compound is selected from: Or its salt.

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