Synthesis method of crisaborole

Abstract

The invention discloses a synthesis method of crisaborole, and belongs to the technical field of medicine synthesis. The method comprises the following steps: (1) under the action of a reducing agent, carrying out reduction reaction on a compound II in a solvent I to obtain a compound III; (2) protecting the compound III in a solvent II under the action of an acetylation reagent and an acid-binding agent to obtain a compound IV; (3) in the presence of an alkali reagent, carrying out substitution reaction on the compound IV and 4-fluorobenzonitrile in a solvent III to obtain a compound V; (4) in the presence of alkali and a palladium catalyst, carrying out coupling reaction on the compound V and bis (pinacolato) diboron in a solvent IV to obtain a compound VI; and (5) under an alkaline condition, hydrolyzing and cyclizing the compound VI in a solvent V to generate a compound I, namely crisaborole. The method has the advantages of mild reaction conditions, simple operation, few reaction byproducts and high product yield, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a synthesis method of crisaborole, belonging to the technical field of drug synthesis. Background Art

[0002] Crisaborole, chemically known as 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, was developed by Anacor Pharmaceuticals and is a phosphodiesterase 4 (PDE4) inhibitor. This inhibition leads to an increase in the concentration of intracellular cyclic adenosine monophosphate (cAMP). It is used to treat fungal infections and was approved by the FDA in 2016 for marketing under the trade name Eucrisa. In China, the drug has been included in the list of the Second Batch of Clinically Urgently Needed Overseas New Drugs and the 2021 National Medical Insurance Negotiation Catalogue (Class B).

[0003] There are several known preparation routes for crisaborole.

[0004] The original research route initially reported was a patent for a series of small molecule compounds containing boron applied for by Anacor Pharmaceuticals of the United States through the PCT route in 2006. The international publication number is WO 2006089067A21381. This route uses ethylene glycol to protect 2-bromo-5-hydroxybenzaldehyde. Water is produced during the reaction, and 2-bromo-5-hydroxybenzaldehyde undergoes self-condensation, making the reaction difficult to proceed. At the same time, n-butyl lithium is required in the route, and the safety performance is low. The reaction conditions are relatively harsh, which is not conducive to industrial-scale production.

[0005] .

[0006] In the synthetic route disclosed by Wang Qishuai et al. (Study on the Synthesis Process of Ciliborole, Chemical Reagents, 2020, 42(06), 722-725), 2-bromo-5-hydroxybenzaldehyde is used as the raw material to undergo a nucleophilic substitution reaction with 4-fluorobenzonitrile, and then further react to obtain Ciliborole. This reaction route is a significant improvement over the reaction route in the original research literature, and does not use n-butyl lithium that requires ultra-low temperature. However, the aldehyde group of 2-bromo-5-hydroxybenzaldehyde is not protected, and the reaction with 4-fluorobenzonitrile will produce more impurities, and the reaction is incomplete, with a low yield.

[0007] .

[0008] Patent CN116253756B reports the use of cheap m-cresol as a raw material to synthesize crisaborole through four steps of coupling, bromination, boration and hydrolysis, but the post-bromination treatment is relatively complicated and the yield is low.

[0009] .

[0010] In summary, the current preparation methods of crisaborole have many shortcomings in terms of yield, experimental operation, etc. Therefore, it is still a problem that needs to be solved to study a crisaborole preparation method with mild reaction conditions, simple operation process, high product yield and suitable for industrial production. Summary of the invention

[0011] In view of the deficiencies in the prior art, the present invention aims to provide a method for synthesizing crisaborole, which has mild reaction conditions, is easy to operate, has a high product yield, and is suitable for industrial production.

[0012] In order to solve the above technical problems, the technical solution provided by the present invention is: A method for synthesizing crisaborole comprises the following steps: (1) Under the action of a reducing agent, compound II undergoes a reduction reaction in solvent I to obtain compound III: ; (2) Under the action of acetylating agent and acid binding agent, compound III is protected in solvent II to obtain compound IV: ; (3) In the presence of an alkaline reagent, compound IV and 4-fluorobenzonitrile undergo a substitution reaction in solvent III to obtain compound V: ; (4) In the presence of a base and a palladium catalyst, compound V and biboric acid pinacol ester undergo a coupling reaction in a solvent IV to obtain compound VI: ; (5) Under alkaline conditions, compound VI is hydrolyzed and cyclized in solvent V to generate compound I, namely, crisaborole: .

[0013] According to the invention, 2-bromo-5-hydroxybenzaldehyde is reduced and then the hydroxyl group is protected. Due to the difference in properties between the alcohol hydroxyl group and the phenolic hydroxyl group, the phenolic ester is preferentially hydrolyzed and reacts with 4-fluorobenzonitrile in the presence of potassium carbonate. The reaction by-products are small, the product yield and quality are high, and the post-treatment is simple. The problem that more impurities will appear in the prior art due to the direct reaction of 2-bromo-5-hydroxybenzaldehyde with 4-fluorobenzonitrile without protecting the aldehyde group is solved.

[0014] Furthermore, in step (1), the reducing agent is one of sodium borohydride, sodium triacetyl borohydride or sodium cyanoborohydride, preferably sodium borohydride; the solvent I is one or more of methanol, ethanol or isopropanol, preferably methanol; the molar ratio of compound II to the reducing agent is 1:(0.2-0.5), preferably 1:0.4; the ratio of compound II to solvent I is 1 mol:1L; the temperature of the reduction reaction is 0-20°C, and the time of the reduction reaction is 1-2h.

[0015] Furthermore, step (1) is carried out as follows: compound II is added to solvent I, stirred until dissolved, cooled to below 20°C, a reducing agent is added in five batches, reacted at 0-20°C for 1-2h, a mixed solution of 30wt.% concentrated hydrochloric acid and deionized water is slowly added, and the mixture is concentrated and dried under reduced pressure to obtain compound III; wherein the ratio of reducing agent, concentrated hydrochloric acid and deionized water is 1mol:(1-2)mol:50mL.

[0016] Furthermore, in step (2), the acid-binding agent is one of triethylamine, pyridine, 4-dimethylaminopyridine or diisopropylethylamine, preferably triethylamine; the solvent II is one of ethyl acetate or dichloromethane, preferably ethyl acetate; the acetylating agent is one of acetyl chloride or acetic anhydride, preferably acetic anhydride; the molar ratio of compound III, acetylating agent and acid-binding agent is 1:(2-3):(3-4), preferably 1:2.2:3; the ratio of compound III to solvent II is 1 g:(5-7) mL.

[0017] Furthermore, step (2) is carried out as follows: Compound III and an acid-binding agent are added to solvent II, stirred until dissolved, cooled to below 20°C and then dropwise added with an acetylating agent, wherein the solution temperature is controlled to be less than 20°C during the dropwise addition of the acetylating agent, reacted at 5-15°C for 2-3h, separated, and the organic phase washed with an 18wt.% aqueous KHCO3 solution and a 20wt.% aqueous NaCl solution in turn, concentrated under reduced pressure and dried to obtain compound IV.

[0018] Furthermore, in step (3), the base is one of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, preferably potassium carbonate; the solvent III is one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide or butanone, preferably DMSO; the molar ratio of compound IV, 4-fluorobenzonitrile and base is 1:(1-3):(1-3), preferably 1:2:2; the ratio of compound IV to solvent III is 1 g:(2.5-3) mL; the reaction temperature is 80-90°C, and the reaction time is 16-20 h.

[0019] Furthermore, step (3) is carried out as follows: Compound IV, 4-fluorobenzonitrile and a base are added to solvent III for reaction, the temperature is raised to 80-90°C for reaction for 16-20h, the temperature is lowered to below 30°C, water and ethyl acetate are added, the liquids are separated, the organic phase is washed with a 20wt.% sodium chloride aqueous solution, and then concentrated and dried under reduced pressure to obtain compound V.

[0020] Further, in step (4), the base is one of potassium acetate or sodium acetate, preferably potassium acetate; the palladium catalyst is one of tetrakistriphenylphosphine palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex or bis(triphenylphosphine)palladium chloride, preferably dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex; the solvent IV is one of 2-methyltetrahydrofuran, tetrahydrofuran, N,N-dimethylformamide (DMF), ‌N-methylpyrrolidone (NMP) or toluene, preferably 2-methyltetrahydrofuran; the molar ratio of compound V, base, palladium catalyst and diboronic acid pinacol ester is 1:(1-5):(0.001-0.005):(1-3), preferably 1:3:0.003:2; the ratio of compound V to solvent IV is 1 g:(5-7) mL.

[0021] Further, step (4) is carried out as follows: Compound V and biboric acid pinacol ester are added to solvent IV, and a base and a palladium catalyst are added under nitrogen protection, and the temperature is raised to 75-80°C for reflux reaction for 18-24 hours, and after cooling to 50-60°C, N-acetyl-L-cysteine, deionized water and activated carbon are added, and the mixture is stirred for 30 minutes at the temperature, filtered, and the filtrate is allowed to stand for stratification, and the organic phase is treated with a KHCO3 aqueous solution with a concentration of 18wt.%, a KHCO3 aqueous solution with a concentration of 20wt. % sodium chloride aqueous solution, washed once each, concentrated under reduced pressure, added with anhydrous ethanol, stirred, heated to 50-60°C to dissolve, then cooled to 10-20°C to crystallize for 3-6h, filtered, rinsed with a mixed solution of anhydrous ethanol and deionized water in a volume ratio of 1:1, and dried to obtain compound VI; wherein the molar ratio of compound V to N-acetyl-L-cysteine ​​is 1:1; the ratio of compound V, activated carbon, and water is 1g: (0.05-0.08)g: (5-7)mL.

[0022] Furthermore, in step (5), the base is one of potassium hydroxide or sodium hydroxide, preferably sodium hydroxide; the solvent V is one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide or acetone, preferably methanol; the molar ratio of compound VI to the base is 1:1-3, preferably 1:2; the ratio of compound VI to solvent V is 1 g: (4-6) mL.

[0023] Furthermore, step (5) is carried out as follows: Compound VI is added to solvent V, and then a sodium hydroxide solution with a concentration of 0.08-0.12 g / mL is added, the temperature is raised to 40-50°C for reaction for 2-4 hours, the temperature is lowered to below 30°C, dilute hydrochloric acid is slowly added, crystallization is carried out for 12-16 hours, filtration is carried out, and drying is carried out to obtain compound I, i.e., crisaborole; the dilute hydrochloric acid is obtained by mixing concentrated hydrochloric acid with a concentration of 30 wt.% and deionized water in a ratio of 1 g:1 mL.

[0024] Furthermore, the drying is all air-force drying, and the temperature is all 45-55°C.

[0025] Compared with the prior art, the present invention has the following beneficial effects: (1) The method of the present invention uses 2-bromo-5-hydroxybenzaldehyde as a raw material, has mild reaction conditions, short steps, simple operation, simple reaction treatment, few reaction by-products, high product yield, and is more suitable for industrial production.

[0026] (2) The present invention uses 2-bromo-5-hydroxybenzaldehyde as a raw material, and after protecting compound III, reacts with 4-fluorobenzonitrile, so that the product has a high yield and high purity, which solves the problem that in the prior art, 2-bromo-5-hydroxybenzaldehyde is used as a raw material, but the aldehyde group is not protected, and the reaction with 4-fluorobenzonitrile produces a large amount of impurities, and the reaction is incomplete, resulting in a low yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound III prepared in Example 1; Figure 2 is the hydrogen nuclear magnetic resonance spectrum of compound IV prepared in Example 2; Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound V prepared in Example 3; Figure 4 is the hydrogen nuclear magnetic resonance spectrum of compound VI prepared in Example 4; Figure 5 is the HPLC detection spectrum of compound Ⅰ prepared in Example 5; Figure 6 is the MS spectrum of compound Ⅰ prepared in Example 5; Figure 7 is the hydrogen nuclear magnetic resonance spectrum of compound Ⅰ prepared in Example 5; Figure 8 This is the carbon NMR spectrum of compound Ⅰ prepared in Example 5. DETAILED DESCRIPTION

[0028] Example 1: Preparation of Compound III Compound II (301.5 g, 1.50 mol) was added to 1.5 L of anhydrous methanol, stirred until dissolved, cooled to below 20°C, and sodium borohydride (22.6 g, 0.60 mol) was added in five batches. The mixture was reacted at 10°C for 1.5 h. The reaction of compound II was completed by TLC monitoring. 30 wt.% concentrated hydrochloric acid (91.3 g, 0.75 mol) and 75 mL of deionized water were slowly added. The organic solvent was removed by concentration under reduced pressure, and 1.8 L of deionized water was added. The mixture was slurried at 15°C for 1.5 h, filtered, and the filter cake was dried at 50°C to obtain 277.96 g of an off-white solid, namely compound III, with a yield of 91.9% and a HPLC purity of 98.86%.

[0029] 1 H-NMR (DMSO-d6): δ9.614 (1H, s), δ7.298 (1H, d), δ7.001 (1H, d), δ6.593 (1H, dd), δ5.352 (1H, b), δ4.415 (2H, s). The hydrogen spectrum of compound III is attached. Figure 1 .

[0030] Example 2: Preparation of Compound IV Compound III (270.0 g, 1.33 mol) and triethylamine (403.0 g, 3.99 mol) were added to 1.5 L of ethyl acetate and stirred until dissolved. After cooling to below 20 °C, acetic anhydride (298.8 g, 2.926 mol) was added dropwise, and the temperature was controlled to be less than 20 °C during the addition process. The reaction was carried out at 10 °C for 2.5 h. The reaction of compound III was completed under TLC monitoring. 1.5 L of deionized water was added and stirred to separate the layers. The aqueous phase was removed and the organic phase was washed with KHCO3 aqueous solution and sodium chloride aqueous solution in turn. The concentrate was concentrated under reduced pressure at 50 °C. 840 mL of ethanol was added to the concentrate and stirred. The temperature was raised to 50 °C to dissolve. 840 mL of deionized water was slowly added. The temperature was lowered to 15 °C for crystallization for 18 h. The filter cake was dried at 50 °C with air blowing to constant weight to obtain 321.3 g of off-white solid, i.e., compound IV. The yield was 84.1% and the purity by HPLC was 99.25%.

[0031] 1 H-NMR (DMSO-d6): δ7.700 (1H, d), δ7.270 (1H, d), δ7.114 (1H, dd), δ5.103 (2H, s), δ2.282 (3H, s), δ2.114 (3H, s). The hydrogen spectrum of compound IV is attached. Figure 2 .

[0032] Example 3: Preparation of Compound V Compound IV (315.0 g, 1.1 mol), 4-fluorobenzonitrile (266.4 g, 2.2 mol), potassium carbonate (304.1 g, 2.2 mol) were added to 870 mL DMSO for reaction, and the temperature was raised to 85 °C for reaction for 18 h. The reaction of compound IV was completed by TLC monitoring, and the temperature was lowered to below 30 °C, and 1.9 L deionized water and 1.4 L ethyl acetate were slowly added for stirring and separation. The aqueous phase was extracted once with 630 mL ethyl acetate, and the organic phases were combined, washed with sodium chloride aqueous solution, and concentrated under reduced pressure at 50 °C. The concentrate was added with 950 mL anhydrous ethanol and stirred, and then 630 mL deionized water was added for stirring at 10 °C for crystallization for 2 h. Filter, and the filter cake was dried at 50 °C with air blast to constant weight to obtain 341.1 g of off-white solid, namely compound V, with a yield of 89.6% and HPLC purity of 98.74%.

[0033] 1 H-NMR (DMSO-d6): δ7.872-7.848 (2H, m), δ7.730 (1H, d), δ7.290 (1H, d), δ7.165-7.136 (2H, m), δ7.097 (1H, dd), δ5.104 (2H, s), δ2.088 (3H, s). The hydrogen spectrum of compound V is attached. Figure 3 .

[0034] Example 4: Preparation of Compound VI Compound V (330.0 g, 0.953 mol) and pinacol diboron (484.0 g, 1.906 mol) were added to 1.9 L 2-methyltetrahydrofuran, and potassium acetate (280.6 g, 2.859 mol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) dichloromethane complex (2.13 g, 0.00283 mol) were added under nitrogen protection. The temperature was raised to 75-80 ° C and refluxed for 22 h. The complete reaction of compound V was monitored by TLC. The temperature was lowered to 55 ° C, and N-acetyl-L-cysteine ​​(155.5 g, 0.953 mol), 1.65 L deionized water and 16.5 g activated carbon were added. The mixture was stirred for 30 min at room temperature and filtered. The filtrate was allowed to stand for stratification and 330 mL of filtrate was added. The organic phase was washed once with KHCO3 aqueous solution and sodium chloride aqueous solution, concentrated at 50 ° C under reduced pressure, 2.3 L of anhydrous ethanol was added to the concentrate, the temperature was raised to 55 ° C to dissolve, then the temperature was lowered to 15 ° C to crystallize for 5 h, filtered, and washed with 600 mL of anhydrous ethanol and deionized water in a volume ratio of 1:1 mixed solution, the filter cake was dried at 50 ° C to constant weight, and 319.6 g of off-white solid, i.e., compound VI, was obtained with a yield of 85.3% and HPLC purity of 99.13%.

[0035] 1H-NMR (DMSO-d6): δ7.882-7.860 (2H, m), δ7.785 (1H, d), δ7.173-7.151 (3H, m), δ7.069 (1H, dd), δ5.255 (2H, s), δ2.036 (3H, s), δ1.296 (12H, s). The hydrogen spectrum of compound VI is attached. Figure 4 .

[0036] Example 5: Preparation of Compound I Compound VI (213.7 g, 0.543 mol) was added to 1070 mL of anhydrous methanol, and then a sodium hydroxide solution with a concentration of 0.1 g / mL was added. The temperature was raised to 45°C for reaction for 3 h. The reaction of compound VI was completed under TLC monitoring. The temperature was lowered to below 30°C, and 276 g of dilute hydrochloric acid was slowly added. Crystallization took 14 h, and the mixture was filtered and rinsed with water. The filter cake was dried at 50°C to constant weight to obtain 119.93 g of a white solid, namely compound I (crisborole), with a yield of 87.9% and a HPLC purity of 99.933%. The dilute hydrochloric acid was obtained by mixing concentrated hydrochloric acid with a concentration of 30 wt.% with deionized water in a ratio of 1 g:1 mL.

[0037] The HPLC detection spectrum of compound I is shown in the attached Figure 5 .

[0038] MS (ESI (-), 75V) m / z: 250.39. The mass spectrum of compound Ⅰ is attached. Figure 6 .

[0039] 1 H-NMR (DMSO-d6): δ9.241 (1H, s), δ7.878-7.793 (3H, m), δ7.173-7.089 (4H, m), δ4.975 (2H, s). The hydrogen spectrum of compound I is attached. Figure 7 .

[0040] 13 C-NMR (DMSO-d6): δ161.101, δ157.546, δ157.145, δ135.161, δ133.078, δ119.438, δ119.137, δ113.195, δ105.990, δ70.148. The carbon spectrum of compound I is attached. Figure 8 .

Claims

1. A method for synthesizing crisaborole, characterized in that: The following steps are involved: (1) Under the action of a reducing agent, compound II undergoes a reduction reaction in solvent I to obtain compound III: ； (2) Under the action of acetylating agent and acid binding agent, compound III is protected in solvent II to obtain compound IV: ； (3) In the presence of an alkaline reagent, compound IV and 4-fluorobenzonitrile undergo a substitution reaction in solvent III to obtain compound V: ； (4) In the presence of a base and a palladium catalyst, compound V and biboric acid pinacol ester undergo a coupling reaction in a solvent IV to obtain compound VI: ； (5) Under alkaline conditions, compound VI is hydrolyzed and cyclized in solvent V to generate compound I, namely, crisaborole: 。 2. The method for synthesizing crisaborole according to claim 1, characterized in that: In step (1), the reducing agent is one of sodium borohydride, sodium triacetyl borohydride or sodium cyanoborohydride, preferably sodium borohydride; the solvent I is one or more of methanol, ethanol or isopropanol, preferably methanol; the molar ratio of compound II to the reducing agent is 1:(0.2-0.5), preferably 1:0.4; the ratio of compound II to solvent I is 1 mol:1L; the temperature of the reduction reaction is 0-20°C, and the time of the reduction reaction is 1-2h.

3. The method for synthesizing crisaborole according to claim 1, characterized in that: Step (1) is carried out as follows: Compound II is added to solvent I, stirred until dissolved, cooled to below 20°C, a reducing agent is added in five batches, reacted at 0-20°C for 1-2h, a mixed solution of 30wt.% concentrated hydrochloric acid and deionized water is slowly added, and the mixture is concentrated and dried under reduced pressure to obtain Compound III; wherein the ratio of the reducing agent, concentrated hydrochloric acid and deionized water is 1 mol: (1-2) mol: 50mL.

4. The method for synthesizing crisaborole according to any one of claims 1 to 3, characterized in that: In step (2), the acid binding agent is one of triethylamine, pyridine, 4-dimethylaminopyridine or diisopropylethylamine, preferably triethylamine; the solvent II is one of ethyl acetate or dichloromethane, preferably ethyl acetate; the acetylating agent is one of acetyl chloride or acetic anhydride, preferably acetic anhydride; the molar ratio of compound III, acetylating agent and acid binding agent is 1: (2-3): (3-4), preferably 1: 2.2: 3; the ratio of compound III to solvent II is 1 g: (5-7) mL.

5. The method for synthesizing crisaborole according to claim 4, characterized in that: Step (2) is carried out as follows: Compound III and an acid-binding agent are added to solvent II, stirred until dissolved, cooled to below 20°C and then dropwise added with an acetylating agent, wherein the solution temperature is controlled to be less than 20°C during the dropwise addition of the acetylating agent, reacted at 5-15°C for 2-3h, separated, and the organic phase washed with an 18wt.% aqueous KHCO3 solution and a 20wt.% aqueous sodium chloride solution in turn, concentrated under reduced pressure and dried to obtain compound IV.

6. The method for synthesizing crisaborole according to claim 1, characterized in that: In step (3), the base is one of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, preferably potassium carbonate; the solvent III is one of dimethyl sulfoxide, N,N-dimethylformamide or butanone, preferably dimethyl sulfoxide; the molar ratio of compound IV, 4-fluorobenzonitrile and base is 1:(1-3):(1-3), preferably 1:2:2; the ratio of compound IV to solvent III is 1g:(2.5-3)mL; the temperature of the substitution reaction is 80-90°C, and the time of the substitution reaction is 16-20h.

7. The method for synthesizing crisaborole according to claim 1, characterized in that: In step (4), the base is one of potassium acetate or sodium acetate, preferably potassium acetate; the palladium catalyst is one of tetrakistriphenylphosphine palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex or bis(triphenylphosphine)palladium chloride, preferably dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane complex; the solvent IV is one of 2-methyltetrahydrofuran, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone or toluene, preferably 2-methyltetrahydrofuran; the molar ratio of compound V, base, palladium catalyst and diboric acid pinacol ester is 1:(1-5):(0.001-0.005):(1-3), preferably 1:3:0.003:2; the ratio of compound V to solvent IV is 1 g:(5-7) mL.

8. The method for synthesizing crisaborole according to claim 6 or 7, characterized in that: Step (4) is carried out as follows: Compound V and bipyraclostrobin are added to solvent IV, and a base and a palladium catalyst are added under nitrogen protection, and the temperature is raised to 75-80°C for reflux reaction for 18-24 hours, and then the temperature is lowered to 50-60°C, and N-acetyl-L-cysteine, deionized water and activated carbon are added, and the mixture is stirred for 30 minutes at the temperature, filtered, and the filtrate is allowed to stand for stratification, and the organic phase is treated with an aqueous solution of KHCO3 having a concentration of 18 wt.%, a chloride having a concentration of 20 wt.%, and a precipitate of 10 wt.%. The sodium aqueous solution is washed once each, concentrated under reduced pressure, anhydrous ethanol is added with stirring, the temperature is raised to 50-60°C to dissolve, and then the temperature is lowered to 10-20°C for crystallization for 3-6 hours, filtered, rinsed with a mixed solution of anhydrous ethanol and deionized water in a volume ratio of 1:1, and dried to obtain compound VI; wherein the molar ratio of compound V to N-acetyl-L-cysteine ​​is 1:1; the ratio of compound V, activated carbon, and deionized water is 1g: (0.05-0.08)g: (5-7)mL.

9. The method for synthesizing crisaborole according to claim 8, characterized in that: In step (5), the base is one of potassium hydroxide or sodium hydroxide, preferably sodium hydroxide; the solvent V is one of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide or acetone, preferably methanol; the molar ratio of compound VI to the base is 1:(1-3), preferably 1:2; the ratio of compound VI to solvent V is 1 g:(4-6) mL.

10. The method for synthesizing crisaborole according to claim 1, characterized in that: Step (5) is carried out as follows: Compound VI is added to solvent V, and then a sodium hydroxide solution with a concentration of 0.08-0.12 g / mL is added, the temperature is raised to 40-50°C for reaction for 2-4 hours, the temperature is lowered to below 30°C, dilute hydrochloric acid is slowly added, crystallization is carried out for 12-16 hours, filtration is carried out, and drying is carried out to obtain compound I, i.e., crisaborole; the dilute hydrochloric acid is obtained by mixing concentrated hydrochloric acid with a concentration of 30 wt.% and deionized water in a ratio of 1 g:1 mL.

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