A process for the preparation of crizotinib

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of crizanlizumab, which comprises three steps: S1, preparing compound III; S2, preparing compound V; and S3, preparing crizanlizumab. The application not only solves the side reaction, atom waste and yield loss caused by the protecting group, and improves the atom economy and reaction selectivity, but also realizes high-selectivity C-H bond boronation, completely discards the noble metal palladium catalyst, and eliminates heavy metal pollution from the source, conforms to the development trend of green pharmacy, and further solves the bottleneck problems of high cost, high risk and long steps in the industrial production of crizanlizumab, and provides strong safety guarantee for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a method for preparing criborole, a drug used to treat skin diseases. Background Technology

[0002] Crisaborole, chemically named 4-[(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborhexacyclopenten-5-yl)oxy]benzonitrile, is a novel nonsteroidal topical drug belonging to the class of phosphodiesterase-4 (PDE-4) selective inhibitors. It works by targeting and inhibiting PDE-4 enzyme activity, reducing the degradation of the intracellular second messenger cyclic adenosine monophosphate (cAMP), thereby increasing cAMP levels. This mechanism effectively downregulates the expression and release of various pro-inflammatory cytokines (such as IL-4, IL-13, and TNF-α), thus alleviating local inflammation and itching symptoms.

[0003] With the advancement of criborone's clinical application and industrialization, the economic efficiency, safety, and environmental friendliness of its synthesis process have become core bottlenecks for industrial production. Existing publicly available synthetic routes generally suffer from drawbacks such as lengthy steps, harsh reaction conditions, expensive and hazardous reagents, low atom utilization, and large emissions of waste, making it difficult to meet the demands of large-scale green production.

[0004] Route 1: As disclosed in patent document WO2006089067, the original research company has a synthetic route for criborone. This route uses 2-bromo-5-hydroxybenzaldehyde (1) as the starting material. First, its aldehyde group is protected to obtain intermediate 2. Then, intermediate 2 undergoes an aromatic nucleophilic substitution reaction (SNAr) with p-fluorobenzonitrile (3) to generate intermediate 4. Intermediate 4 undergoes a deprotection reaction to obtain intermediate 5. Next, the aldehyde group in intermediate 5 is reduced to a hydroxyl group to obtain intermediate 6. For further functional group transformation, the hydroxyl group of intermediate 6 is protected by THP to obtain intermediate 7. Intermediate 7 is coupled with a borate ester group through Miyaura to obtain intermediate 8. Finally, intermediate 8 undergoes a cyclization reaction under acidic conditions to obtain the target compound criborone. The synthetic route is as follows: ; This synthetic route has significant drawbacks: the steps are lengthy and involve two protection-deprotection operations, resulting in low atom utilization and a decrease in overall yield; the Miyaura coupling requires expensive palladium catalysts and strict anhydrous and oxygen-free conditions, which not only increases production costs but also introduces heavy metal pollution and waste liquid treatment burdens; each purification step (such as column chromatography) consumes a large amount of organic solvents, further reducing efficiency; the introduction and removal efficiency of THP and aldehyde protecting groups is low, which easily leads to side reactions; the borate ester intermediate has poor stability, and subsequent cyclization reactions have selectivity risks such as intramolecular dehydration; the overall economic efficiency and environmental friendliness are poor, making it unsuitable for industrial production.

[0005] Route 2: For example, patent document WO2018216032 discloses a synthetic route for criborone. This route uses 2-bromo-5-hydroxybenzaldehyde (1) as a raw material, which is reduced to obtain intermediate 2, 2 is esterified to obtain intermediate 3, 3 is reacted with p-fluorobenzonitrile (4) via SNAr reaction to obtain intermediate 5, 5 is coupled with Miyaura reaction to obtain intermediate 6, and 6 is cyclized under acidic conditions to obtain criborone. The synthetic route is as follows: ; Although this route reduces the protection-deprotection step compared to Route 1, it still has the following drawbacks: First, the regioselectivity of the acetyl protection step is poor, and the phenolic hydroxyl group is prone to side reactions; second, the subsequent SNAr reaction needs to be carried out under strong base and high temperature conditions, which can easily cause hydrolysis or migration of the protecting group, thereby increasing the generation of impurities, resulting in a decrease in reaction yield and an increase in purification difficulty; in addition, this route still includes the Miyaura coupling reaction, which requires the use of expensive palladium catalyst and excess pinacol diboronic acid ester, resulting in high production costs.

[0006] Route 3: For example, patent document CN108864160 discloses a synthetic route for criborone. This route uses 2-bromo-5-hydroxybenzaldehyde (1) as a raw material, which is reduced to obtain intermediate 2. Intermediate 2 is obtained by a protecting group substitution reaction to obtain intermediate 3. Intermediate 3 is introduced into boric acid by a substitution reaction under n-butyllithium conditions to obtain intermediate 5. Intermediate 5 is reacted with p-fluorobenzonitrile (6) via an SNAr reaction to obtain criborone. The synthetic route is as follows: ; While this route simplifies the process, it still suffers from several serious drawbacks: First, it uses n-butyllithium as a key reagent, which is extremely sensitive to air and must be operated under strictly anhydrous and oxygen-free conditions, posing significant safety hazards. Furthermore, the reaction must be carried out at an ultra-low temperature of -78°C, imposing stringent requirements on the reaction equipment and greatly increasing the difficulty of process control, severely hindering industrial production. Second, the SNAr reaction exhibits poor regioselectivity, and the boron hydroxyl group is prone to side reactions that generate impurities, resulting in low reaction yields and directly affecting the quality of the active pharmaceutical ingredient.

[0007] Route 4: As disclosed in patent document CN101914109B, a synthetic route for criborone is obtained. This route uses 2-bromo-5-hydroxybenzaldehyde (1) as a raw material, reacts with p-fluorobenzonitrile (2) via an SNAr reaction to obtain intermediate 3, 3 is reduced to obtain intermediate 4, 4 is protected with a THP group to obtain intermediate 5, 5 is introduced with a borate ester under n-butyllithium conditions to obtain intermediate 6, and 6 is cyclized under acidic conditions to obtain criborone. The synthetic route is as follows: ; This route, like route three, requires the use of n-butyllithium, resulting in stringent reaction conditions, demanding operational requirements, and significant safety hazards. When a THP protecting group is introduced, the resulting product exhibits poor stability, readily deprotecting and regenerating intermediate 4, leading to low yields. Furthermore, reactions involving n-butyllithium show poor selectivity, numerous byproducts, and difficulty in effective post-processing, resulting in significant product loss and high production costs, severely limiting its industrial application.

[0008] Route 5: As reported in Organic Process Research & Development, 2025, 29, 5, 1317-1327, a synthetic route for criborone is described. This route uses m-cresol (1) as a raw material, which is brominated to obtain intermediate 2. 2 forms a eutectic with DABCO 3. 3 is reacted with p-fluorobenzonitrile (4) via SNAr reaction to obtain intermediate 5. 5 is brominated to obtain intermediates 6 and 7. Under alkaline conditions, they are completely converted to intermediate 6. 6 is esterified to obtain intermediate 8. Without treatment, it is coupled via Miyaura reaction to obtain intermediate 9. 9 is reduced and cyclized under acidic conditions to obtain criborone. The synthetic route is as follows: ; Although the starting materials for this route are inexpensive and readily available, it has several significant drawbacks: m-cresol is highly toxic, requiring strict adherence to operational safety and environmental regulations; the overall reaction steps are lengthy and cumbersome, leading to a significant extension of the production cycle; the eutectic formation process of the key intermediate with DABCO requires harsh conditions and is difficult to scale up; in addition, the route still includes the Miyaura coupling reaction, resulting in a large amount of waste generated by the overall process, a low green chemistry score, and is not conducive to industrial-scale production.

[0009] Route 6: As reported in Organic Process Research & Development, 2025, 29, 12, 3179-3188, a synthetic route for criborone is described. This route uses 2-bromo-5-hydroxybenzaldehyde (1) as a starting material, reacts with p-fluorobenzonitrile (2) via an SNAr reaction to obtain intermediate 3. Intermediate 3 is then coupled with bis-pinacol boronic acid ester (B2Pin2) via a Miyaura coupling reaction to obtain intermediate 4. Intermediate 4 is then reduced to obtain intermediate 5. Intermediate 5 is cyclized under acidic conditions to obtain the final product criborone. The synthetic route is as follows: ; Although this synthetic route is significantly shorter in terms of steps compared to other processes, its production cost is high due to the palladium-catalyzed Miyaura coupling reaction. Therefore, this route is expensive to scale up, limiting its industrial application.

[0010] In addition, patent document CN116925117A also discloses a method for preparing a criborone intermediate, which constructs an intermediate through aromatic nucleophilic substitution and Miyaura borylation reaction, and then obtains criborone through reductive cyclization. The synthetic route is as follows: ; Although this route avoids the use of protecting groups and highly reactive hazardous reagents, it still uses palladium catalysts (such as bis(triphenylphosphine)palladium dichloride) and pinacol diboronate for the Miyaura borylation reaction, failing to fundamentally solve the problems of heavy metal residues, high production costs, and significant environmental pressure.

[0011] In summary, existing publicly available methods for synthesizing criborone generally suffer from technical drawbacks such as long steps, poor regioselectivity, low yield, low atom utilization, and complex purification procedures. The introduction of the boron fragment requires the use of organometallic lithium reagents or precious metal palladium catalysts. The former involves stringent reaction conditions, produces numerous byproducts, and poses high production safety risks; the latter has high production costs and leaves significant heavy metal residues that pollute the environment, making it difficult to meet the demands of high efficiency and economy for industrial production. Therefore, a new technical solution is needed to address these technical problems. Summary of the Invention

[0012] The purpose of this invention is to provide a method for preparing criborone, in order to solve the problems mentioned in the background art. The current methods for synthesizing criborone are difficult to meet the requirements of high efficiency and economy for industrial production, and generally suffer from technical defects such as long steps, poor regioselectivity, low yield, low atom utilization, and complex purification operations.

[0013] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing creborol, comprising the following specific steps: S1. Starting from 3-hydroxybenzaldehyde and p-fluorobenzonitrile, an aromatic nucleophilic substitution reaction is carried out in solvent A at 90-110°C for 3-6 hours in the presence of acid-binding agent A to obtain compound III. The molar ratio of 3-hydroxybenzaldehyde, p-fluorobenzonitrile, and acid-binding agent A is 1:2-4:1-3. Acid-binding agent A is selected from one or more of Li2CO3, Na2CO3, K2CO3, and Cs2CO3. Solvent A is selected from one or more of toluene, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone. S2. Compound III obtained in S1 and tert-butylamine are added to solvent B and subjected to a condensation reaction at 70–90 °C in the presence of a dehydrating agent for 4–6 h. After the reaction is complete, the mixture is cooled to room temperature, and acid-binding agent B is added. Then, boron tribromide is slowly added dropwise at 20–40 °C for 4–6 h to obtain intermediate III-1. After the raw materials are completely converted, the insoluble matter is removed by filtration. Water and alkali are added to the filtrate at 0–20 °C for 0.5–3 h to hydrolyze the mixture to obtain compound V. The mass ratio of compound III to the dehydrating agent is 1:1–4. The mass ratio of compound III to acid-binding agent B is... The molar ratio is 1:1 to 4, the molar ratio of compound III to the base is 1:2 to 5, the dehydrating agent is selected from one or more of tris(2,2,2-trifluoroethyl)borate, tetraethyl titanate, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous copper sulfate, 3Å molecular sieve and 4Å molecular sieve, the acid-binding agent B is 2,6-dimethylpyridine, the base is selected from one or more of LiOH, NaOH and KOH, and the solvent B is selected from one or more of toluene, acetonitrile, dichloromethane, dichloroethane, isopropanol and tetrahydrofuran. S3. Dissolve compound V obtained in S2 in solvent C, and carry out aldehyde reduction cyclization at 0-20℃ for 0.5-3 hours under the action of reducing agent and acid, and separate to obtain creborol. The molar ratio of compound V to reducing agent and acid is 1:0.2-1.0:0.5-2.5. The reducing agent is selected from potassium borohydride, lithium borohydride and sodium borohydride. The acid is selected from hydrochloric acid, sulfuric acid, citric acid and glacial acetic acid. Solvent C is selected from one or more mixed solvents composed of methanol, ethanol, isopropanol and water. Its synthetic route is as follows: .

[0014] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention uses 3-hydroxybenzaldehyde and p-fluorobenzonitrile as starting materials, and obtains criborone through only three core reactions: aromatic nucleophilic substitution, one-pot condensation boronization, and reductive cyclization. Compared with the original research and existing public routes, this invention shortens the reaction steps and simplifies the process, completely eliminating redundant steps such as aldehyde protection and hydroxyl protection-deprotection, effectively avoiding side reactions, atom waste, and yield loss caused by protecting groups, and significantly improving atom economy and reaction selectivity. The imine transient-directed boronization is used to achieve highly selective CH bond boronization, completely eliminating the need for precious metal palladium catalysts. Furthermore, the readily available and inexpensive boron tribromide is used as the boron source, eliminating heavy metal pollution at the source, significantly reducing raw material procurement costs and environmental costs for waste liquid treatment, which is in line with the development trend of green pharmaceuticals. This invention further solves the bottleneck problems of high cost, high risk, and long steps in the industrial production of criborone, and provides a strong safety guarantee for industrial production.

[0015] 2. By controlling the reaction temperature of each step between 0 and 110°C and operating at normal pressure, this invention eliminates the safety hazards of ultra-low temperature energy consumption and flammability and explosion, effectively reduces equipment requirements and operating difficulty, significantly improves the stability and repeatability of the process, and is more suitable for large-scale industrial production.

[0016] 3. This invention utilizes tert-butylamine to generate an imine from an aldehyde group, followed by in-situ directed boron tribromide CH boration, and then hydrolysis to obtain boric acid intermediate V. This completely avoids the use of heavy metal palladium and high-risk organolithium reagents, eliminating metal residues and the risk of combustion and explosion at the source, meeting the requirements of green chemistry. It also significantly reduces raw material costs and post-processing difficulties. Based on this, the three reactions of condensation, boration, and hydrolysis are completed directly and continuously in the same reactor without separating intermediates. The entire process only requires three steps to obtain the final product, significantly simplifying the production process, shortening the production cycle, reducing solvent consumption and waste emissions, and improving atom economy and overall yield.

[0017] 4. This invention achieves highly selective conversion and effectively suppresses byproduct formation by precisely controlling reaction conditions and optimizing material types, ratios, and process parameters. The yield of each reaction step can reach over 90%, significantly improving production efficiency and economic benefits. Furthermore, the materials and reagents used are inexpensive and readily available, with controllable costs. Post-processing only requires simple operations such as filtration and recrystallization to obtain the high-quality target product criborole with a purity of over 99.9%, eliminating the need for complex separation and purification equipment and processes. This greatly simplifies the production process, reduces production costs and operational complexity, further enhancing the economic feasibility of the process and demonstrating significant potential for industrial application, providing efficiency assurance for large-scale production.

[0018] 5. The criborone synthesis route of the present invention is characterized by "high efficiency, economy, safety and environmental protection". It successfully solves the industrialization bottleneck in the existing criborone synthesis process, which not only ensures the high yield and high purity of the product, but also significantly reduces the production and environmental protection costs. It has strong practical application value and market competitiveness, and provides reliable technical support for the large-scale and low-cost production of criborone. Attached Figure Description

[0019] Figure 1 This is the mass spectrum of creborol in Example 3 of the present invention; Figure 2 The criborone in Example 3 of the present invention 1 H-NMR spectrum; Figure 3 The criborone in Example 3 of the present invention 13 C-NMR spectrum; Figure 4 This is the UPLC detection spectrum of criborone in Example 3 of the present invention.

[0020] Wherein: KLP is an abbreviation for criborone; KLP-A, KLP-B, and KLP-F are known impurities of criborone. Detailed Implementation

[0021] The following examples are used to further illustrate the content of the present invention and do not limit the application of the present invention.

[0022] Example 1: Preparation of compound III (4-(3-formylphenoxy)benzonitrile), the synthetic route is as follows: .

[0023] Under a nitrogen atmosphere, 3-hydroxybenzaldehyde (I) (200.0 g, 1.64 mol), p-fluorobenzonitrile (II) (595.8 g, 4.92 mol), and potassium carbonate (K2CO3) (453.3 g, 3.28 mol) were sequentially added to a reactor. N,N-dimethylacetamide (DMF) (1 L) was then introduced into the reactor under negative pressure. Stirring was started, and the temperature was raised to 100°C and maintained for 4 hours. After the reaction was complete, heating was stopped, and the temperature was lowered to 30°C. Drinking water (5 L) and ethyl acetate (EA) (3.3 L) were added to the reactor. After stirring for 0.5 hours, the mixture was allowed to stand and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in a 45°C water bath until no more liquid dripped out. Add EA (0.8 L), cool to 0℃ and stir to precipitate crystals for 1 h. Stop stirring, release the reaction liquid from the bottom of the vessel, centrifuge to dry the material, and place the filter cake at 50℃ under vacuum to dry for 2 h to obtain 349.5 g of off-white solid (structural formula III, i.e. compound III), yield: 95.6%, Purity: 99.53%.

[0024] Example 2: Preparation of compound V (4-(4-cyanophenoxy)-2-formylphenylboronic acid), the synthetic route is as follows: .

[0025] Under a nitrogen atmosphere, 4-(3-formylphenoxy)benzonitrile (III) (200.0 g, 0.90 mol), tert-butylamine (IV) (80.7 g, 1.10 mol), magnesium sulfate (MgSO4) (600.0 g), and 4Å molecular sieve (200.0 g) were sequentially added to a reactor. Dichloroethane (1 L) was then introduced into the reactor under negative pressure. Stirring was started, and the temperature was raised to 80 °C and maintained for 5 h. After the reaction was completed, heating was stopped and the temperature was lowered to 25°C. 2,6-Dimethylpyridine (192.3 g, 1.80 mol) was added to the reactor. After the addition was complete, boron tribromide (BBr3) (450.9 g, 1.80 mol) was slowly added dropwise. The reaction was kept at this temperature for 5 hours. Stirring was stopped, and the reaction solution was discharged from the bottom of the reactor. The material was then centrifuged to dry. The resulting filtrate was a dichloroethane solution of 4-{3-[(tert-butylimino)methyl]-4-(dibromoboryl)phenoxy}benzonitrile (Ⅲ-1).

[0026] Under a nitrogen atmosphere, 108.0 g (2.70 mol) of NaOH (sodium hydroxide) was added to a reactor. The reactor was then subjected to negative pressure, and a dichloroethane solution of III-1 and 0.5 L of water were sequentially introduced. Stirring was started, and the temperature was lowered to 15°C for 1 hour. After the reaction was complete, 1.4 L of 2 N hydrochloric acid solution was added to the reactor to adjust the pH to 3. Stirring was stopped, and the reaction solution was discharged from the bottom of the reactor. The material was centrifuged to dry, and the filter cake was vacuum dried at 50°C for 2 hours to obtain 215.8 g of a white solid (structural formula V, i.e., compound V). Yield: 90.2%, Purity: 98.92%.

[0027] Example 3: Preparation of compound VI (4-[(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboranecyclopenten-5-yl)oxy]benzonitrile), the synthetic route is as follows: .

[0028] Under a nitrogen atmosphere, 200.0 g (0.75 mol) of 4-(4-cyanophenoxy)-2-formylphenylboronic acid (V) was added to a reactor. Isopropanol (1.5 L) and water (0.5 L) were then introduced into the reactor under negative pressure. Stirring was started, and the temperature was lowered to 10°C. Potassium borohydride (20.5 g (0.38 mol)) was added in batches, controlling the feeding rate to ensure the internal temperature did not exceed 25°C. The exhaust gas was buffered in an empty reactor to prevent material overflow. After the addition was complete, the reaction was carried out at 10°C for 1.5 h until compound V was completely reacted. After the reaction was complete, 190 mL of 4N hydrochloric acid aqueous solution was added, followed by dropwise addition of purified water (3 L). The mixture was kept at this temperature and stirred for 1 h. Stirring was stopped, the reaction liquid was drained from the bottom of the reactor, centrifuged to remove excess water, and the filter cake was vacuum dried at 50°C for 2 h to obtain 182.8 g of crude criborone (structural formula VI, i.e., compound VI), yield: 97.2%.

[0029] Under a nitrogen atmosphere, crude criborone (VI) (100.0 g, 0.40 mol) was added to a reaction vessel. Glacial acetic acid (400 mL) and purified aqueous solution (200 mL) were then introduced into the reaction vessel under negative pressure. Stirring was started, and the temperature was raised to 80°C. After dissolving and clarifying the solution, the temperature was slowly lowered to 70°C, seed crystals were added, and the mixture was stirred at 70°C for 1.5 h. The temperature was then lowered to 25°C, and crystallization was carried out for 6 h. Stirring was stopped, the reaction solution was drained from the bottom of the vessel, centrifuged to dryness, and the filter cake was vacuum dried at 50°C for 2 h to obtain 182.8 g of criborone product (structural formula VI), yield: 99.8%. Purity: 99.99%.

[0030] The following are the 1H NMR spectra of the finished product, creborol: 1H NMR (600 MHz, DMSO-d6) δ: 9.23 (s,1H), 7.88–7.85 (m, 2H), 7.81 (d,J = 12.0 Hz, 1H), 7.18–7.14 (m, 3H), 7.10 (dd, J = 6.0, 18 Hz, 1H), 4.98 (s,2H).

[0031] The following are the carbon NMR spectra of the finished product, creborol: 13C NMR (150 MHz, DMSO-d6) δ: 160.6, 157.1, 156.7, 134.7,132.6,126.8, 119.0, 118.7, 112.7, 105.5, 69.7.

[0032] Example 4: Preparation of Compound III (4-(3-formylphenoxy)benzonitrile) Under a nitrogen atmosphere, 3-hydroxybenzaldehyde (Ⅰ) (200.0 g, 1.64 mol), p-fluorobenzonitrile (Ⅱ) (595.8 g, 4.92 mol), and Na2CO3 (sodium carbonate) (347.6 g, 3.28 mol) were sequentially added to a reactor. DMF (1 L) was then introduced into the reactor under negative pressure. Stirring was started, and the temperature was raised to 100°C and maintained for 5 hours. After the reaction was complete, heating was stopped, and the temperature was lowered to 30°C. Drinking water (5 L) and EA (3.3 L) were added to the reactor. After stirring for 0.5 hours, the mixture was allowed to stand and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in a 45°C water bath until no more liquid dripped out. Add EA (0.8 L), cool to 0℃ and stir to precipitate crystals for 1 h. Stop stirring, release the reaction liquid from the bottom of the vessel, centrifuge to dry the material, and place the filter cake at 50℃ under vacuum to dry for 2 h to obtain 273.4 g of off-white solid (structural formula III), yield: 74.7%, Purity: 95.67%.

[0033] Example 4 differs from Example 1 in that the acid-binding agent is replaced with Na2CO3. Experimental results show that Na2CO3 is less basic than K2CO3, and the yield of the aromatic nucleophilic substitution reaction is lower.

[0034] Example 5: Preparation of Compound III (4-(3-formylphenoxy)benzonitrile) The difference between Example 5 and Example 1 is that the acid-binding agent was replaced with Cs₂CO₃ (cesium carbonate). The yield of this step was 93.2%. Experimental results show that the reaction results and yield of Cs₂CO₃ are comparable to those of K₂CO₃, but its cost is higher, and the amount of materials and solvents used is significantly increased. Therefore, K₂CO₃ is preferred.

[0035] Example 6: Preparation of Compound III (4-(3-formylphenoxy)benzonitrile) The difference between Example 6 and Example 1 is that the acid-binding agent was replaced with NaOH. The yield of this step was 40.8%. Experimental results show that excessively strong basicity of NaOH can easily lead to an increase in side reactions during nucleophilic substitution.

[0036] Example 7: Preparation of compound V (4-(4-cyanophenoxy)-2-formylphenylboronic acid) Under a nitrogen atmosphere, 4-(3-formylphenoxy)benzonitrile (III) (200.0 g, 0.90 mol), tert-butylamine (IV) (80.7 g, 1.10 mol), MgSO4 (600.0 g, 4.98 mol), and 4Å molecular sieve (200.0 g) were sequentially added to a reactor. Dichloroethane (1 L) was evacuated into the reactor under negative pressure. Stirring was started, and the temperature was raised to 80 °C and maintained for 5 h. After the reaction was complete, heating was stopped, and the temperature was lowered to 25 °C. Triethylamine (182.1 g, 1.80 mol) was added to the reactor. After the addition was complete, BBr3 (450.9 g, 1.80 mol) was slowly added dropwise, and the reaction was maintained for 3 h. Monitoring showed no further reaction, and the reaction time was extended to 10 h, but no product was formed.

[0037] The difference between Example 7 and Example 2 is that the acid-binding agent was replaced with triethylamine. Experimental results show that triethylamine is less effective than 2,6-dimethylpyridine. The latter not only effectively inhibits the occurrence of side reactions but also protects the sensitive substrate from attack during the acid-binding process and has better reaction compatibility.

[0038] Example 8: Preparation of compound V (4-(4-cyanophenoxy)-2-formylphenylboronic acid) The difference between Example 8 and Example 2 is that the acid-binding agent was replaced with pyridine. The yield of this step was 79.5%. Experimental results show that pyridine is less effective than 2,6-dimethylpyridine. The presence of the two methyl groups in 2,6-dimethylpyridine increases steric hindrance, which can more effectively suppress side reactions, protect sensitive substrates, and improve reaction selectivity and yield, thus making it superior to ordinary pyridine.

[0039] Example 9: Preparation of compound VI (4-[(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboranecyclopenten-5-yl)oxy]benzonitrile) The difference between Example 9 and Example 3 is that the reducing agent was replaced with sodium borohydride. The yield of this step was 87.5%. Experimental results show that potassium borohydride has a better reducing effect than sodium borohydride. Compared with sodium borohydride, potassium borohydride has advantages such as better stability, milder and more controllable reaction, lower cost, and easier handling of byproducts.

[0040] Example 10: Preparation of compound VI (4-[(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboranecyclopenten-5-yl)oxy]benzonitrile) The difference between Example 10 and Example 3 lies in the molar ratio of hydrochloric acid to potassium borohydride reducing agent. Experimental results show that when the molar ratio of hydrochloric acid to potassium borohydride reducing agent is 0.5, the reducing agent quenching is incomplete, resulting in a yield of only 55%. Increasing the ratio to 2.0 ensures complete quenching, maintains a suitable pH, and produces a pure product with a yield of 97%. When the ratio is excessive to 2.5, the strong acid environment causes the precipitate to agglomerate into a viscous wet product, making filtration difficult and resulting in impurities, further reducing the yield to 86%. Therefore, controlling the molar ratio of hydrochloric acid to potassium borohydride reducing agent to around 2.0 ensures complete quenching while avoiding product decomposition and degradation, representing the optimal process balance.

Claims

1. A method for preparing creborol, characterized in that, The specific steps are as follows: S1. Starting with 3-hydroxybenzaldehyde and p-fluorobenzonitrile, an aromatic nucleophilic substitution reaction was carried out in solvent A in the presence of acid-binding agent A to obtain compound III. S2. Compound III obtained in S1 and tert-butylamine are added to solvent B and a condensation reaction is carried out in the presence of a dehydrating agent. After the reaction is completed, the temperature is lowered to room temperature, acid-binding agent B is added, and then boron tribromide is slowly added dropwise to carry out a boration reaction to obtain intermediate III-1. After the raw materials are completely converted, the insoluble matter is removed by filtration, and water and alkali are added to the filtrate to carry out hydrolysis to obtain compound V. S3. Dissolve compound V obtained in S2 in solvent C. Under the action of reducing agent and acid, the aldehyde group is reduced and cyclized, and creborone is obtained by separation. Its synthetic route is as follows: 。 2. The method for preparing creborol according to claim 1, characterized in that, In S1, the molar ratio of 3-hydroxybenzaldehyde, p-fluorobenzonitrile, and acid-binding agent A is 1:2 to 4:1 to 3, wherein the acid-binding agent A is selected from one or more of Li2CO3, Na2CO3, K2CO3, and Cs2CO3.

3. The method for preparing creborol according to claim 1, characterized in that, In S1, solvent A is selected from one or more of the following mixed solvents: toluene, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

4. The method for preparing creborol according to claim 1, characterized in that, In S1, the temperature for the aromatic nucleophilic substitution reaction is 90–110 °C, and the reaction time is 3–6 h.

5. The method for preparing creborone according to claim 1, characterized in that, In S2, the mass ratio of compound III to the dehydrating agent is 1:1 to 4, wherein the dehydrating agent is selected from one or more of the following: tris(2,2,2-trifluoroethyl)borate, tetraethyl titanate, anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous copper sulfate, 3Å molecular sieve and 4Å molecular sieve. The molar ratio of compound III to acid-binding agent B is 1:1 to 4, wherein acid-binding agent B is 2,6-dimethylpyridine; The molar ratio of compound III to the base is 1:2 to 5, wherein the base is selected from one or more of LiOH, NaOH, and KOH, and is a mixture thereof.

6. The method for preparing creborone according to claim 1, characterized in that, In S2, solvent B is selected from one or more of the following mixed solvents: toluene, acetonitrile, dichloromethane, dichloroethane, isopropanol, and tetrahydrofuran.

7. The method for preparing creborol according to claim 1, characterized in that, In S2, the condensation reaction temperature is 70–90℃ and the condensation reaction time is 4–6 h; the borylation reaction temperature is 20–40℃ and the borylation reaction time is 4–6 h; the hydrolysis reaction temperature is 0–20℃ and the hydrolysis reaction time is 0.5–3 h.

8. The method for preparing creborol according to claim 1, characterized in that, In S3, the molar ratio of compound V to reducing agent and acid is 1:0.2-1.0:0.5-2.5, wherein the reducing agent is selected from potassium borohydride, lithium borohydride and sodium borohydride, and the acid is selected from hydrochloric acid, sulfuric acid, citric acid and glacial acetic acid.

9. The method for preparing creborol according to claim 1, characterized in that, In S3, solvent C is selected from one or more mixed solvents composed of methanol, ethanol, isopropanol, and water.

10. The method for preparing creborol according to claim 1, characterized in that, In S3, the temperature for the reduction cyclization reaction is 0–20°C, and the reaction time is 0.5–3 h.

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