A method for synthesizing a benzoborazole compound

Abstract

This invention relates to a method for synthesizing benzoborazole compounds. The method uses o-alkanoylarylboronic acid as a starting material, isopropanol as a hydrogen donor, a protic acid as a catalyst, and hexafluoroisopropanol as a promoter. Under heating conditions, a one-pot reaction simultaneously achieves reduction and cyclization reactions to obtain benzoborazole compounds. The synthetic route of this invention is concise and convenient. The isopropanol used is inexpensive, safe, and insensitive to water and air, effectively avoiding the risk of combustion and explosion caused by the use of metal borohydrides in conventional methods, as well as the purification difficulties caused by residual borate byproducts. Furthermore, the method of this invention has excellent substrate compatibility, enabling the preparation of target products, including the antifungal drug tavaborone and several other highly active benzoborazole compounds, in high yields. The process is stable, reproducible, and suitable for industrial-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and specifically to a method for synthesizing benzoborazole compounds, including tavaborone. Background Technology

[0002] Benzoborazole compounds are a class of five-membered cyclic arylboronic acid half-esters. Since Torssell first synthesized and characterized benzoborazole, these compounds have been widely used in medicinal chemistry, organic synthesis, and supramolecular chemistry. Currently, benzoborazole compounds have been found to possess a variety of biological activities, including antifungal, antibacterial, antiviral, antiparasitic, and anticancer activities. Some of these benzoborazole drugs have already been marketed or entered clinical research stages (Fernandes GFS, Denny WA, Dos Santos JL. Boron in drug design: recent advances in the development of new therapeutic agents[J]. European Journal of Medicinal Chemistry, 2019, 179: 791-804).

[0003]

[0004] Tavaborole, a key representative compound of benzoborazole, is a broad-spectrum antifungal drug developed by Anacor and approved by the US FDA in 2014. It is primarily used to treat onychomycosis (fungal nail infection). It effectively inhibits fungal activity by selectively inhibiting the activity of leucyl-tRNA synthetase, thereby blocking fungal protein synthesis. Besides tavaborole, derivatives with different fluorine positions on the benzene ring have also been reported to have good antibacterial activity (Adamczyk-Woźniak A, Cabaj MK, Dominiak PM, et al. The influence of fluorine position on the properties of fluorobenzoxaboroles[J].Bioorganic Chemistry, 2015, 60: 130-135).

[0005]

[0006] The main synthetic methods for benzoborazole compounds include the following categories: Method 1 uses a 2-bromobenzaldehyde derivative as the starting material, which is reduced with sodium borohydride to obtain the corresponding alcohol. Then, the hydroxyl group is protected with chloromethyl methyl ether, and the target product is obtained by borylation reaction mediated by n-butyllithium. This synthetic route is subject to harsh conditions and must be carried out in an anhydrous and oxygen-free low-temperature environment. In particular, the borylation reaction mediated by n-butyllithium must be completed at a strict low temperature of -78 °C (Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MRK, Sander V, Plattner JJ. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), for the potential treatment of onychomycosis[J]. Journal of Medicinal Chemistry, 2006, 49(15): 4447-4450).

[0007]

[0008] Method 2 uses phenylboronic acid derivatives as raw materials and condenses them with formaldehyde via acid catalysis to construct benzo[borazole]. However, its applicability is limited. This reaction is only compatible with substrates that have electron-donating substituents (such as -OCH3, -CH3) on the benzene ring, and the yield is not ideal in most cases (27%~80%). More importantly, this strategy cannot be effectively extended to substrates that only have electron-withdrawing groups such as fluorine on the benzene ring, such as tavaborole, thus limiting its application (Zhao J, Chen JX, Xu Q, Li H. Synthesis of benzoxaboroles by ortho-oxalkylation of arylboronic acids with aldehydes / ketones in the presence of bronsted acids[J]. Organic Letters,2021, 23(6): 1986-1990).

[0009]

[0010] Method 3 uses o-formylarylboronic acid derivatives as raw materials, and obtains the target product by reduction with sodium borohydride and simultaneous cyclization. The process route is relatively simple. However, this method has some limitations: First, the use of sodium borohydride in industrial scale-up is prone to causing fire and explosion accidents, posing significant safety hazards; second, the reaction byproduct borate is prone to complexing with the product benzoborazole compounds, resulting in residual boron impurities and affecting product purity; third, the yield of this method is only 51% when synthesizing tavaborone, and the yield is only 54%~78% when synthesizing its active derivatives with different fluorination positions on the benzene ring, with overall unsatisfactory yields (Madura ID, Adamczyk-Woźniak A, Jakubczyk M, Sporzyński A. 5-Fluoro-1,3-dihydro-2,1-benzoxaborol-1-ol[J]. Acta Crystallographica Section E: Structure ReportsOnline, 2011, 67(Pt 2): o414-o415; Adamczyk-Woźniak A, Cabaj MK, Dominiak PM, et al. The influence of fluorine position on the properties offluorobenzoxaboroles[J]. Bioorganic Chemistry, 2015, 60: 130-135).

[0011]

[0012] To address the problems of lengthy synthetic routes, use of expensive and dangerous stoichiometric reducing agents, poor functional group tolerance, low yield, difficulty in separating by-product borates, and sensitivity of the reaction system to water in existing technologies, this invention provides a method for synthesizing benzoborazole compounds that features a short route, safe and inexpensive reducing agents, no metal catalysts, insensitivity to water and air, good functional group tolerance, and high yield. Summary of the Invention

[0013] The technical solution and content of this invention relate to a method for synthesizing benzoborazole compounds (I), characterized in that, using o-alkanoylarylboronic acid (II) as a raw material, isopropanol as a hydrogen donor, a protic acid as a catalyst, and hexafluoroisopropanol (HFIP) as a promoter, the reaction is carried out under heating conditions to obtain benzoborazole compounds (I):

[0014] Among them, R 1Selected from hydrogen, alkyl, alkoxy, aryloxy, halogen, trifluoromethyl, hydroxyl, nitro, amino, cyano, ester, aryl; R 2 Selected from hydrogen, alkyl, and aryl groups.

[0015] Preferred, R 1 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, or trifluoromethyl; The R 2 Selected from hydrogen or methyl.

[0016] In the preparation method described in this invention, the protic acid is p-toluenesulfonic acid, p-bromobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, L-proline, camphorsulfonic acid, acetic acid, hydrochloric acid, or phosphoric acid.

[0017] In the preparation method described in this invention, the reaction temperature is 100-160℃.

[0018] Compared with existing technologies, this invention has the following significant advantages: First, this invention uses o-alkanoylarylboronic acid as a raw material, and can simultaneously achieve reduction and cyclization reactions to construct benzoborazole rings in a one-pot reaction, resulting in a short and convenient synthetic route. Second, the reaction uses isopropanol as the hydrogen source for reduction, which is inexpensive, safe, and insensitive to water and air, avoiding the risk of combustion and explosion caused by the use of metal borohydrides in conventional methods, as well as the purification difficulties caused by residual borate byproducts. Finally, the method of this invention has excellent substrate compatibility, and can prepare target products, including the antifungal drug tavaborone and several other highly active benzoborazole compounds, in high yields. The process is stable, reproducible, and suitable for industrial-scale production. Attached Figure Description

[0019] Figure 1 It is the antifungal drug tavaroboron I-3. 1 H NMR spectrum.

[0020] Figure 2 It is the antifungal drug tavaroboron I-3. 13 C10 NMR spectrum. Implementation

[0021] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings and specific examples. It should be noted that these embodiments are merely examples, intended to aid in understanding the technical solutions of the present invention and to provide implementation guidance for those skilled in the art. It should be understood that these descriptions do not constitute any limitation on the scope of protection of the present invention.

[0022] Unless otherwise expressly stated, the production processes, experiments, tests or analysis methods involved in the embodiments of the present invention are all considered to be conventional methods known to those skilled in the art, and can be performed in accordance with conventional conditions or relevant product instructions. The steps and names involved are also generally clear and unambiguous in the art.

[0023] The instruments, equipment, raw materials, reagents, or samples used in the embodiments have no special requirements in terms of source. They are all conventional products obtained through regular commercial channels or prepared according to known methods, and their source does not have a substantial impact on the implementation results of the present invention.

[0024] Unless otherwise expressly defined, the scientific and technical terms used in this invention have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions in this specification shall prevail.

[0025] The terms "preferred," "better," and "exemplary" used in this invention are only used to describe a specific solution or effect, and are not intended to be necessary limitations on the solution or restrictions on the scope of protection.

[0026] The descriptions of numerical parameters (such as quantity, concentration, temperature, time, etc.) in this invention should be understood as having reasonable deviations caused by factors such as measuring instruments, operational errors, and statistical fluctuations. The range of such deviations should be within the range that can be accepted by those skilled in the art based on common sense. Example 1

[0027]

[0028] Add 2-formylphenylboronic acid (150.0 mg, 1.0 mmol, 1.0 equiv) and p-toluenesulfonic acid sequentially to the sealing tube. p -TsOH, 34.4 mg, 0.2 mmol, 0.2 equiv), isopropanol (1 mL) and the promoters shown in Table 3 were added, sealed, and reacted at 120 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product benzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-1 (yields are shown in Table 1).

[0029] As shown in Table 1, the yield of this reaction catalyzed by p-toluenesulfonic acid was 48% without the addition of a accelerator. With the addition of HFIP as a accelerator, the yield increased significantly to 71%. However, the reaction was not good with the addition of DMF and EtOH.

[0030] 1 H NMR (400 MHz, CDCl3) d 7.78 (d, J= 7.2 Hz, 1H), 7.50 (t, J= 7.6 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 6.12 (s, 1H), 5.15 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 153.74, 131.46, 131.22, 130.72, 127.37, 121.23, 71.42; HRMS (ESI)calcd for C7H6BO2 [M - H] - 134.0461, found 133.0450. Example 2

[0031]

[0032] 2-Formylphenylboronic acid (150.0 mg, 1.0 mmol, 1.0 equiv), a certain amount of catalyst as shown in Table 2, hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 120 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product benzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-1 (yields are shown in Table 2). Example 3

[0033]

[0034] 2-Formylphenylboronic acid (150.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted with stirring at the temperatures shown in Table 3 for 24 h. Volatile components were removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product benzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-1 (yields are shown in Table 3). Example 4

[0035]

[0036] 3-Fluoro-2-formylphenylboronic acid (168.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 4-fluorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-2 is a white solid (115.1 mg, y = 75%).

[0037] 1 H NMR (400 MHz, CDCl3) d : 7.53 (d, J= 7.2 Hz, 1H), 7.38 (tt, J= 7.6, 4.6Hz, 1H), 7.16 (dt, J= 14.8, 8.8 Hz, 1H), 5.52 (s, 1H), 5.18 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 158.52, 156.04, 139.48, 129.93, 126.38, 117.54, 68.43;HRMS (ESI) calcd for C7H5BFO2 [M - H] - 151.0367, found 151.0357. Example 5

[0038]

[0039] 4-Fluoro-2-formylphenylboronic acid (168.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 5-fluorobenzo[ c [1,2]oxaborane-1(3H )-ol I-3, namely tavaboronol, is a white solid (124.4 mg, y = 82%).

[0040] 1 H NMR (400 MHz, CDCl3) d 7.73 (dd, J= 8.0, 5.6 Hz, 1H), 7.11 – 6.95 (m,2H), 5.64 (s, 1H), 5.09 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 166.66, 164.17,156.46, 132.70, 115.23, 108.36, 70.92; HRMS (ESI) calcd for C7H5BFO2[M - H] - 151.0367, found 151.0357. Example 6

[0041]

[0042] 5-Fluoro-2-formylphenylboronic acid (168.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 6-fluorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-4 is a white solid (124.4 mg, y = 83%).

[0043] 1 H NMR (400 MHz, CDCl3) d 7.40 (dd, J= 8.0, 2.3 Hz, 1H), 7.31 (dd, J= 8.4, 4.5 Hz, 1H), 7.19 (td, J= 8.8, 2.4 Hz, 1H), 5.92 (s, 1H), 5.10 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 163.85, 161.41, 148.99, 122.82, 119.02, 116.63, 71.08;HRMS (ESI) calcd for C7H5BFO2 - [M - H] - 151.0367, found 151.0357. Example 7

[0044]

[0045] 6-Fluoro-2-formylphenylboronic acid (168.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 7-fluorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-5 is a white solid (118.4 mg, y = 79%).

[0046] 1 H NMR (400 MHz, CDCl3) d 7.48 (td, J= 7.6, 5.5 Hz, 1H), 7.14 (d, J= 7.6Hz, 1H), 6.97 (t, J= 8.0 Hz, 1H), 5.44 (s, 1H), 5.11 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 165.82, 163.33, 156.60, 134.10, 117.55, 113.78, 71.22; HRMS (ESI)calcd for C7H5BFO2[M - H] - 151.0367, found 151.0357. Example 8

[0047]

[0048] 3,4-Difluoro-2-formylphenylboronic acid (186.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 4,5-difluorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-6 is a white solid (132.6 mg, y = 78%).

[0049] 1 H NMR (400 MHz, CDCl3) d 7.46 (dd, J= 8.4, 4.3 Hz, 1H), 7.25 – 7.09 (m,1H), 5.28 (s, 1H), 5.16 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 153.70, 151.20,143.87, 141.80, 127.09, 118.05, 68.00; HRMS (ESI) calcd for C7H4BF2O2[M - H] - 169.0273, found 169.0263. Example 9

[0050]

[0051] 4-Chloro-2-formylphenylboronic acid (184.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 5-chlorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-7 is a white solid (150.4 mg, y = 90%).

[0052] 1 H NMR (400 MHz, CDCl3) d 7.66 (d, J= 8.4 Hz, 1H), 7.48 – 7.30 (m, 2H), 5.18 (s, 1H), 5.07 (s, 2H); 13 C NMR (100 MHz, DMSO) d : 156.06, 143.21, 135.65,132.09, 127.07, 121.62, 69.49; HRMS (ESI) calcd for C7H5BClO2[M - H] - 167.0077, found 167.0062. Example 10

[0053]

[0054] 5-Chloro-2-formylphenylboronic acid (184.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 6-chlorobenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-8 is a white solid (144.4 mg, y = 86%).

[0055] 1 H NMR (400 MHz, CDCl3) d 7.71 (s, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.31 (dd, J= 22.4, 8.3 Hz, 1H), 5.36 (s, 1H), 5.09 (s, 2H); 13 C NMR (100 MHz, DMSO) d :152.39, 141.25, 131.83, 130.38, 129.85, 123.43, 69.67; HRMS (ESI) calcd forC7H5BClO2[M - H] -167.0072, found 167.0063. Example 11

[0056]

[0057] 2-Formyl-4-trifluoromethylphenylboronic acid (218.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 5-trifluoromethylbenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-9 is a white solid (155.7 mg, y = 77%).

[0058] 1 H NMR (400 MHz, CDCl3) d 7.88 (d, J= 7.6 Hz, 1H), 7.73 – 7.56 (m, 2H), 5.54 (s, 1H), 5.17 (s, 2H); 13 C NMR (100 MHz, CDCl3) d : 154.03, 131.34, 125.60,124.42, 122.89, 118.26, 118.22, 71.27; HRMS (ESI) calcd for C8H5BF3O2 [M - H] - 201.0335, found 201.0328. Example 12

[0059]

[0060] 2-Formyl-5-trifluoromethylphenylboronic acid (218.1 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 6-trifluoromethylbenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-10 is a white solid (163.6 mg, y = 81%).

[0061] 1 H NMR (400 MHz, CDCl3) d : 8.04 (s, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 5.45 (s, 1H), 5.17 (s, 2H).; 13 C NMR (100 MHz, CDCl3) d :157.17, 130.26, 128.13, 127.83, 125.82, 123.11, 121.76, 71.31; HRMS (ESI)calcd for C8H5BF3O2[M - H] - 201.0335, found 201.0328. Example 13

[0062]

[0063] 2-Formyl-5-methylphenylboronic acid (164.1 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 6-methylbenzo[ c [1,2]oxaborane-1(3 H)-Alcohol I-11 is a white solid (112.5 mg, y = 76%).

[0064] 1 H NMR (400 MHz, CDCl3) d : 7.48 (s, 1H), 7.23 – 7.14 (m, 2H), 5.41 (s,1H), 5.01 (s, 2H), 2.33 (s, 3H); 13 C NMR (100 MHz, CDCl3) d : 151.18, 136.91,136.88, 132.30, 130.90, 121.00, 71.32, 21.41; HRMS (ESI) calcd for C8H8BO2 [M- H] - 147.0617, found 147.0608. Example 14

[0065]

[0066] 2-Formyl-3-methoxyphenylboronic acid (180.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 4-methoxybenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-12 is a white solid (92.0 mg, y = 56%).

[0067] 1 H NMR (400 MHz, CDCl3) d 7.66 (d, J= 8.0 Hz, 1H), 6.92 (dt, J= 10.8, 5.4Hz, 1H), 6.85 (s, 1H), 5.42 (s, 1H), 5.06 (s, 2H), 3.85 (s, 3H); 13 C NMR (100MHz, CDCl3) d: 162.68, 156.51, 131.87, 119.47, 114.67, 105.85, 71.08, 55.48;HRMS (ESI) calcd for C8H 10 BO3[M + H] + 165.0718, found 165.0717. Example 15

[0068]

[0069] 2-Acetylphenylboronic acid (164.0 mg, 1.0 mmol, 1.0 equiv), p-toluenesulfonic acid (34.4 mg, 0.2 mmol, 0.2 equiv), hexafluoroisopropanol (HFIP, 1 mL), and isopropanol (i-PrOH, 1 mL) were added sequentially to a sealed tube. The tube was sealed and reacted at 140 °C with stirring for 24 h. Volatile components were removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give the target product 3-methylbenzo[ c [1,2]oxaborane-1(3 H )-Alcohol I-13 is a white solid (103.7 mg, y = 70%).

[0070] 1 H NMR (400 MHz, CDCl3) d 7.72 (d, J= 7.2 Hz, 1H), 7.49 (td, J= 7.6, 1.3Hz, 1H), 7.37 (t, J= 7.2 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 5.34 (q, J= 6.8Hz, 1H),5.20 (s, 1H), 1.53 (d, J= 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) d : 158.49, 131.09,130.47, 130.43, 127.31, 120.98, 78.26, 22.27; HRMS (ESI) calcd for C8H8BO2[M -H] - 147.0617, found 147.0608. Example 16

[0071] Controlled test: This invention designed a series of controlled experiments to explore the possible mechanism of this reduction / cyclization reaction (Equation 1). First, at 140... o In equation C, the reaction proceeds with only isopropanol as solvent, without a catalyst or HFIP, but the yield is only 9% (Equation 1, A). This may be because the borate group in the substrate has some catalytic effect on the reaction, but the effect is not significant. Adding 0.2 equivalents of p-TsOH to the system increases the yield to 54% (Equation 1, B), indicating that the protic acid has catalytic activity for this reaction. Adding HFIP in the absence of a protic acid and with only isopropanol results in a 19% yield (Equation 1, C), indicating that HFIP promotes the reaction. Furthermore, adding HFIP in the presence of a protic acid further increases the yield to 90% (Equation 1, D), indicating that HFIP can promote the catalytic effect of the protic acid on this reaction. In addition, when the system contains no isopropanol and only HFIP is used as solvent, the target product is not detected (Equation 1, E), indicating that HFIP cannot act as a hydrogen donor under these conditions. We also tried using formylphenylboronic acid pinacol ester (i.e., the borate hydroxyl group is protected) as a substrate. Although the reaction could proceed, the yield was only 61% (Equation 1, F), suggesting that the hydrogen in the borate hydroxyl group may be involved in the formation of the transition state.

[0072]

[0073] Based on this, the possible catalytic cycle mechanism is deduced as follows (Equation 2): First, p-TsOH and HFIP synergistically activate the aldehyde and borate groups in o-formylphenylboronic acid II through hydrogen bonding, generating transition state A. Subsequently, under the activation of p-TsOH, the aldehyde group forms a six-membered ring transition state B with the hydrogen donor isopropanol, while the aldehyde oxygen complexes with the boron center. In B, isopropanol is oxidized to acetone via hydrogen transfer, releasing the target benzoborazole product I, and regenerating p-TsOH and HFIP, completing the catalytic cycle.

[0074] Example 17

[0075] Benzoborazole compound I-3 is the marketed antifungal drug tavaborole, while compounds I-2, I-4, I-5, and I-9 have been reported in the literature to have good antifungal activity (Adamczyk-Woźniak A, Cabaj MK, Dominiak PM, et al. The influence of fluorine position on the properties of fluorobenzoxaboroles[J]. Bioorganic Chemistry, 2015, 60: 130-135; Adamczyk-Woźniak, A, Tarkowska, M, Lazar, Z, et al. Synthesis, structure, properties and antimicrobial activity of para trifluoromethyl phenylboronic derivatives). Bioorg. Chem. 2022, 119 (105560). The method described in this invention can be applied to the synthesis of benzoborazole compounds, including the above-mentioned active compounds.

Claims

1. A method for synthesizing a benzoborazole compound (I), characterized in that, Using o-alkanoylarylboronic acid (II) as a starting material, isopropanol as a hydrogen donor, a protic acid as a catalyst, and hexafluoroisopropanol (HFIP) as a promoter, the reaction was carried out under heating conditions to obtain benzoborazole compound (I). The synthetic route is as follows: Among them, R 1 Selected from hydrogen, alkyl, alkoxy, aryloxy, halogen, trifluoromethyl, hydroxyl, nitro, amino, cyano, ester, aryl; R 2 Selected from hydrogen, alkyl, and aryl groups.

2. The synthesis method according to claim 1, characterized in that, The R 1 Selected from hydrogen, methyl, methoxy, fluorine, chlorine, or trifluoromethyl; The R 2 Selected from hydrogen or methyl.

3. The synthesis method according to claim 1, characterized in that, The protic acid is p-toluenesulfonic acid, p-bromobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, L-proline, camphorsulfonic acid, acetic acid, hydrochloric acid, or phosphoric acid.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature is 100-160℃.

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