Crisaborole ointment and production process thereof

Abstract

The invention discloses a crisaborole ointment and a production process thereof. The crisaborole ointment is prepared from crisaborole, white vaseline, liquid paraffin, glyceryl monostearate and glyceryl distearate, glycerol, propylene glycol, butylated hydroxytoluene, ethylenediamine tetraacetic acid disodium salt, dimethyl sulfoxide and benzalkonium chloride. The preparation method comprises the following steps: 1, synthesizing crisaborole; step 2, preparing an ointment matrix; step 3, preparing and mixing a solution; step 4, emulsifying and homogenizing; and step 5, filling and packaging. Step 6, quality control; the butylated hydroxytoluene is added as an antioxidant to effectively prevent the effective components in the ointment from being oxidized in the preparation and storage processes, and the ethylene diamine tetraacetic acid is added as a metal chelating agent to chelate metal ions, so that the potential adverse effects of the metal ions on the stability and curative effect of the ointment are effectively prevented, and the ointment is safe and reliable. The purity and the safety of the ointment are ensured, and the oxidation resistance and the metal ion interference resistance of the ointment are enhanced.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to crisaborole ointment and a production process. Background Art

[0002] Criborole Ointment (Sutamine) is a prescription drug for external use, mainly used for the local treatment of mild to moderate atopic dermatitis in patients aged 2 years and above. Criborole Ointment is a phosphodiesterase 4 inhibitor. After application, it can promote the conversion of cyclic adenosine monophosphate into adenosine monophosphate in the body, thereby achieving the purpose of reducing the production of inflammatory mediators in the body; after application, the drug can effectively inhibit immune and inflammatory cells, and can be used to treat various chronic inflammatory skin diseases and help patients reduce local inflammatory responses; at the same time, the drug can also block skin necrosis and achieve a certain analgesic effect.

[0003] The existing production process of crisaborole ointment has the following defects: First, the ointment is easily affected by oxidation during the preparation and storage process, which will cause the active ingredients of the ointment to degrade, thereby reducing its efficacy; in addition, the ointment is also easily affected by metal ions, which may come from raw materials, equipment or environment in the production process; the presence of metal ions will interfere with the stability of the ointment and may even cause adverse reactions, posing a potential threat to the health of patients; second, the synthesis process of crisaborole uses flammable and explosive dangerous reagents such as n-butyl lithium and borane. The use of these reagents not only increases the safety risks in the production process, but also may cause harm to the health of operators; at the same time, the storage and transportation of these dangerous reagents also require special safety measures, thereby increasing production costs; third, in the synthesis process of compound 2, there is an operation of directly adding solid sodium borohydride to the reaction solution; since sodium borohydride is a strong reducing agent, a large amount of heat will be released during the addition process, causing the system temperature to rise rapidly; this may not only cause the risk of material impact, but also destroy the stability of the reaction system, affecting the purity and quality of the final product. Summary of the invention

[0004] The object of the present invention is to provide crisaborole ointment and a production process to solve the problems raised in the above background technology.

[0005] To achieve the above-mentioned purpose, the present invention provides the following technical scheme: crisaborole ointment, the formula of which includes: crisaborole, white vaseline, liquid paraffin, glyceryl mono- and distearate, glycerol, propylene glycol, butylated hydroxytoluene, disodium ethylenediaminetetraacetic acid, dimethyl sulfoxide and benzalkonium chloride, and the mass percentages of the components are: 2% to 4% of crisaborole, 10% to 30% of white vaseline, 5% to 20% of liquid paraffin, 2% to 10% of glyceryl mono- and distearate, 5% to 20% of glycerol, 5% to 15% of propylene glycol, 0.1% to 0.5% of butylated hydroxytoluene, 0.1% to 0.4% of disodium ethylenediaminetetraacetic acid, 5% to 15% of dimethyl sulfoxide, and 0.1% to 0.2% of benzalkonium chloride.

[0006] As a further technical solution of the present invention, the mass percentages of the components are: 3.4% of crisaborole, 25% of white vaseline, 18% of liquid paraffin, 8% of mono- and distearic acid glyceryl, 20% of glycerol, 15% of propylene glycol, 0.3% of butylated hydroxytoluene, 0.2% of disodium ethylenediaminetetraacetate, 10% of dimethyl sulfoxide, and 0.1% of benzalkonium chloride.

[0007] As a further technical solution of the present invention, the mass percentages of the components are: 2.3% of crisaborole, 23% of white vaseline, 17% of liquid paraffin, 10% of glyceryl mono- and distearate, 18% of glycerol, 14% of propylene glycol, 0.25% of butylated hydroxytoluene, 0.25% of disodium ethylenediaminetetraacetate, 15% of dimethyl sulfoxide, and 0.2% of benzalkonium chloride.

[0008] The production process of crisaborole ointment includes step 1, synthesis of crisaborole; step 2, preparation of ointment base; step 3, solution preparation and mixing; step 4, emulsification and homogenization; step 5, filling and packaging; step 6, quality control;

[0009] In the above step 1, 2-bromo-5-hydroxybenzaldehyde and p-fluorobenzonitrile are used as raw materials to synthesize criborol;

[0010] In the above step 2, the ointment base oil phase required for the production of crisaborole ointment is prepared;

[0011] In the above step 3, a crisaborole aqueous solution is prepared and added to the ointment base;

[0012] In the above step 4, the water phase and the oil phase are emulsified, and crisaborole is added and homogenized;

[0013] In the above step 5, the homogenized ointment is filled into a suitable container, such as a soft tube or an aluminum tube, and the filled ointment is sealed and packaged;

[0014] In step six above, the finished product is subject to strict quality control, including testing of appearance, properties, content uniformity, microbial limits, etc., to ensure that the product meets quality standards.

[0015] As a further technical solution of the present invention, in the step 1, 2-bromo-5-hydroxybenzaldehyde, p-fluorobenzonitrile, potassium carbonate and N,N-dimethylformamide are added to the reaction bottle in sequence, mixed and stirred under nitrogen protection, and heated to 80-90°C, and stirred for 20 hours. After the reaction is completed, the reaction solution is cooled to 0-10°C, purified water is slowly added, and the stirring is continued for 30 minutes. The filter cake is filtered and washed with purified water. The filter cake is dissolved with dichloromethane and separated. The aqueous phase is back-extracted with dichloromethane once, the organic phases are combined, anhydrous sodium sulfate and activated carbon are added to the organic phase, stirred for 5-6 hours, and the filtrate is collected by filtration. The filtrate is concentrated until no liquid flows out, anhydrous methanol is added to pulp at room temperature for 6 hours, the filter cake is collected by filtration, and washed with anhydrous methanol. The filter cake is vacuum dried at 50°C for 12 hours to obtain an off-white solid compound 1.

[0016] As a further technical solution of the present invention, in the step 1, compound 1 and anhydrous methanol are added to the reaction bottle, mixed and stirred, cooled to -5 to 5°C, and an ethanol solution containing sodium borohydride is added dropwise, and the temperature is controlled below 15°C. After the addition is completed, the temperature is raised to room temperature and stirred for 3 hours. After the reaction is completed, the reaction solution is cooled to 0 to 10°C, and a 10% aqueous solution of ammonium chloride is slowly added. The mixture is kept warm and stirred for 1 hour, filtered, and the filter cake is washed with purified water. The filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 2.

[0017] As a further technical solution of the present invention, in the step 1, compound 2 and dichloromethane are added to a 2L reaction bottle, stirred and dissolved at room temperature, triethylamine is added dropwise, acetic anhydride is added after the addition, and stirred at room temperature for 5 hours. After the reaction is completed, purified water is added to the reaction solution, the liquid is separated, and the organic phase is washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, anhydrous sodium sulfate is added to the organic phase and dried for 2 hours, filtered, and the filtrate is collected. After the filtrate is concentrated, an off-white solid is obtained, isopropanol and purified water are added, the temperature is raised to 60°C and stirred until the solid is dissolved, the temperature is lowered to room temperature for crystallization, the filter cake is filtered and rinsed with purified water, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 3.

[0018] As a further technical scheme of the present invention, in the step 1, compound 3, DMF, diboronic acid pinacol ester, and potassium acetate are added to the reaction bottle, stirred for 30 minutes under nitrogen protection, palladium dichloride is added, nitrogen protection is applied, the temperature is raised to 90°C and stirred for 4 hours. After the reaction is completed, ethyl acetate and purified water are added to the reaction solution, stirred for 30 minutes, allowed to stand for separation, the organic phase is collected, washed twice with saturated sodium chloride aqueous solution, anhydrous sodium sulfate is added and dried for 2 hours, filtered, and the filtrate is collected. After the filtrate is concentrated, a brown solid is obtained, which is added to n-heptane, heated to 90-95°C and dissolved, activated carbon is added and stirred for 1 hour, filtered while hot, the filtrate is collected, cooled to room temperature and stirred for crystallization for 2 hours, filtered, the filter cake is rinsed with n-heptane, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 4.

[0019] As a further technical scheme of the present invention, in the step 1, compound 4 and tetrahydrofuran are added to the reaction bottle, stirred and dissolved, cooled to -5 to 5°C, concentrated hydrochloric acid is slowly added dropwise, and the temperature is raised to 40 to 50°C and stirred for 5 hours after the addition. After the reaction is completed, the temperature is cooled to room temperature, purified water and ethyl acetate are added, the liquids are separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, and the organic phases are washed with saturated sodium bicarbonate solution and sodium chloride solution respectively, the organic phases are collected, anhydrous sodium sulfate is added and dried for 2 hours, the filtrate is collected by filtration, and after the filtrate is concentrated, purified water and n-heptane are added and stirred for 2 hours, solids are precipitated, the filter cake is washed with n-heptane, the filter cake is collected, the filter cake is dissolved in methanol, heated to reflux until the solid is dissolved, and then the temperature is slowly reduced to 0 to 10°C for crystallization, filtered, the filter cake is washed with n-heptane, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain criborol.

[0020] As a further technical solution of the present invention, in the step three, a prescribed amount of dimethyl sulfoxide solvent is taken, placed in a beaker, heated to 45° C. and kept warm, butylated hydroxytoluene and disodium ethylenediaminetetraacetate are added, and stirred until completely dissolved to form an aqueous phase solution, and the prepared aqueous phase solution is slowly added to the prepared oil phase, while continuing to stir, so that the aqueous phase and the oil phase are fully mixed to form a cream-like substance.

[0021] Compared with the prior art, the present invention has the following beneficial effects: the present invention effectively prevents the active ingredients in the ointment from being oxidized during the preparation and storage process by adding butylated hydroxytoluene as an antioxidant, and chelates metal ions by adding disodium ethylenediaminetetraacetic acid as a metal chelating agent, effectively preventing the potential adverse effects of metal ions on the stability and efficacy of the ointment, ensuring the purity and safety of the ointment, enhancing the anti-oxidation performance and anti-metal ion interference ability of the ointment, providing patients with a more lasting and stable therapeutic effect, and at the same time improving the synthesis process of crisaborole, selecting a cheaper 2 -Bromo-5-hydroxybenzaldehyde and p-fluorobenzonitrile are used as raw materials, which reduces the production cost and improves the production efficiency. At the same time, the optimized synthesis process avoids the use of inflammable and explosive dangerous reagents such as n-butyl lithium and borane, significantly reducing the safety risks in the production process. At the same time, in the synthesis of compound 2, sodium borohydride is first dissolved in ethanol and then added dropwise, which can better control the reaction temperature and avoid the rapid temperature increase and material impact caused by directly adding solid sodium borohydride. It not only ensures the yield of the product, but also ensures the stability of the reaction system, providing high-quality raw material guarantee for the subsequent ointment preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The figure is a flow chart of the method of the present invention. DETAILED DESCRIPTION

[0023] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] Please see attached Figure 1 , a technical solution provided by the present invention:

[0025] Embodiment 1:

[0026] A crisaborole ointment, the formula of which includes: crisaborole, white vaseline, liquid paraffin, glyceryl mono- and distearate, glycerol, propylene glycol, butylated hydroxytoluene, disodium edetate, dimethyl sulfoxide and benzalkonium chloride, the mass percentages of the components being: 3.4% crisaborole, 25% white vaseline, 18% liquid paraffin, 8% glyceryl mono- and distearate, 20% glycerol, 15% propylene glycol, 0.3% butylated hydroxytoluene, 0.2% disodium edetate, 10% dimethyl sulfoxide and 0.1% benzalkonium chloride;

[0027] The production process of crisaborole ointment includes step 1, synthesis of crisaborole; step 2, preparation of ointment base; step 3, solution preparation and mixing; step 4, emulsification and homogenization; step 5, filling and packaging; step 6, quality control;

[0028] Wherein, in the above step 1, 2-bromo-5-hydroxybenzaldehyde and p-fluorobenzonitrile are used as raw materials to synthesize cresborole. In step 1, 2-bromo-5-hydroxybenzaldehyde, p-fluorobenzonitrile, potassium carbonate and N,N-dimethylformamide are added to the reaction bottle in sequence, and mixed and stirred under nitrogen protection, and the temperature is raised to 80-90°C, and the mixture is kept warm and stirred for 20 hours. After the reaction is completed, the reaction solution is cooled to 0-10°C, purified water is slowly added, and the mixture is kept warm and stirred for 30 minutes. The filter cake is washed with purified water after filtering, and the filter cake is dissolved with dichloromethane, and the liquid is separated. The aqueous phase is back-extracted with dichloromethane once, and the organic phases are combined, anhydrous sodium sulfate and activated carbon are added to the organic phase, and the mixture is stirred for 5-6 hours, and the filtrate is collected by filtering. The filtrate was concentrated until no liquid flowed out, anhydrous methanol was added to the room temperature for 6 hours, the filter cake was collected by filtration, washed with anhydrous methanol, and the filter cake was vacuum dried at 50°C for 12 hours to obtain an off-white solid compound 1; compound 1 and anhydrous methanol were added to the reaction bottle, mixed and stirred, cooled to -5 to 5°C, and an ethanol solution containing sodium borohydride was added dropwise, and the temperature was controlled below 15°C. After the addition was completed, the temperature was raised to room temperature and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 to 10°C, and 10% ammonium chloride aqueous solution was slowly added, and the mixture was kept warm and stirred for 1 hour, filtered, and the filter cake was washed with purified water. The filter cake was vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 2; 2L reaction Compound 2 and dichloromethane were added to the bottle, stirred at room temperature to dissolve, triethylamine was added dropwise, acetic anhydride was added after the addition, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, purified water was added to the reaction solution, and the liquid was separated. The organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn. Anhydrous sodium sulfate was added to the organic phase and dried for 2 hours. The filtrate was collected and concentrated to obtain an off-white solid. Isopropanol and purified water were added, the temperature was raised to 60°C and stirred until the solid was dissolved, and the temperature was lowered to room temperature for crystallization. The filter cake was filtered and rinsed with purified water, and the filter cake was collected. The filter cake was vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 3. Compound 3, DMF, diboric acid pinacol ester, and ethyl acetate were added to the reaction bottle. Potassium chloride was added under nitrogen protection, stirred for 30 minutes, palladium chloride was added, nitrogen protection was applied, the temperature was raised to 90°C and stirred for 4 hours. After the reaction was completed, ethyl acetate and purified water were added to the reaction solution, stirred for 30 minutes, allowed to stand for separation, the organic phase was collected, washed twice with saturated sodium chloride aqueous solution, dried for 2 hours with anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated to obtain a brown solid, which was added to n-heptane, heated to 90-95°C to dissolve, activated carbon was added and stirred for 1 hour, filtered while hot, the filtrate was collected, cooled to room temperature and stirred for crystallization for 2 hours, filtered, the filter cake was rinsed with n-heptane, the filter cake was collected, and the filter cake was vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 4;Compound 4 and tetrahydrofuran were added to the reaction flask, stirred and dissolved, cooled to -5 to 5°C, concentrated hydrochloric acid was slowly added dropwise, and the temperature was raised to 40 to 50°C and stirred for 5 hours after the addition. After the reaction was completed, the temperature was lowered to room temperature, purified water and ethyl acetate were added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, and washed with saturated sodium bicarbonate solution and sodium chloride solution, respectively. The organic phases were collected, anhydrous sodium sulfate was added and dried for 2 hours, and the filtrate was collected by filtration. After the filtrate was concentrated, purified water and n-heptane were added and stirred for 2 hours. Solids were precipitated, and the filter cake was washed with n-heptane and the filter cake was collected. The filter cake was dissolved in methanol, heated to reflux until the solid was dissolved, and then the temperature was slowly lowered to 0 to 10°C for crystallization, filtered, and the filter cake was washed with n-heptane. The filter cake was collected and dried in vacuo at 45°C for 12 hours to obtain crisaborole;

[0029] In the above step 2, the ointment base oil phase required for the production of crisaborole ointment is prepared;

[0030] In the above step 3, a crisaborole aqueous solution is prepared and added to the ointment base, a prescribed amount of dimethyl sulfoxide solvent is taken, placed in a beaker and heated to 45° C. and kept warm, butylated hydroxytoluene and disodium ethylenediaminetetraacetate are added, and stirred until completely dissolved to form an aqueous solution, and the prepared aqueous solution is slowly added to the prepared oil phase, while continuing to stir, so that the aqueous phase and the oil phase are fully mixed to form a cream-like substance;

[0031] In the above step 4, the water phase and the oil phase are emulsified, and crisaborole is added and homogenized;

[0032] In the above step 5, the homogenized ointment is filled into a suitable container, such as a soft tube or an aluminum tube, and the filled ointment is sealed and packaged;

[0033] In step six above, the finished product is subject to strict quality control, including testing of appearance, properties, content uniformity, microbial limits, etc., to ensure that the product meets quality standards.

[0034] Embodiment 2:

[0035] The invention discloses a crisaborole ointment, the formula of which includes crisaborole, white vaseline, liquid paraffin, glyceryl mono- and distearate, glycerol, propylene glycol, butylated hydroxytoluene, disodium edetate, dimethyl sulfoxide and benzalkonium chloride, the mass percentages of the components being: 2.3% crisaborole, 23% white vaseline, 17% liquid paraffin, 10% glyceryl mono- and distearate, 18% glycerol, 14% propylene glycol, 0.25% butylated hydroxytoluene, 0.25% disodium edetate, 15% dimethyl sulfoxide and 0.2% benzalkonium chloride; the production method thereof is the same as that of Example 1.

[0036] Embodiment 3:

[0037] The invention discloses a crisaborole ointment, the formula of which includes crisaborole, white vaseline, liquid paraffin, glyceryl mono- and distearate, glycerol, propylene glycol, butylated hydroxytoluene, disodium edetate, dimethyl sulfoxide and benzalkonium chloride, wherein the mass percentages of the components are respectively: 3% crisaborole, 24% white vaseline, 16% liquid paraffin, 9% glyceryl mono- and distearate, 19% glycerol, 13% propylene glycol, 0.5% butylated hydroxytoluene, 0.3% disodium edetate, 15% dimethyl sulfoxide and 0.2% benzalkonium chloride; the ointment is consistent with Example 1.

[0038] The specific composition ratios of each embodiment are shown in the following table:

[0039]

[0040] Based on the above, the advantages of the present invention are: the present invention effectively prevents the active ingredients in the ointment from being oxidized during the preparation and storage process by adding butylated hydroxytoluene as an antioxidant, and can chelate metal ions by adding disodium ethylenediaminetetraacetic acid as a metal chelating agent, effectively preventing the potential adverse effects of metal ions on the stability and efficacy of the ointment, ensuring the purity and safety of the ointment, enhancing the anti-oxidation performance and anti-metal ion interference ability of the ointment, and providing patients with a more lasting and more stable therapeutic effect; white vaseline, as one of the matrix components of the ointment, has excellent moisturizing properties, can reduce skin dryness, and improve the moisturizing effect of the ointment; glycerin helps to keep the skin moisturized, increases the moisture content of the stratum corneum, thereby improving skin health, and also has a moisturizing effect, which can increase the moisturizing properties of the ointment and make the skin The skin is softer and smoother. Glyceryl mono- and distearate as emulsifier can help the oil phase and water phase in the ointment to mix better to form a stable cream-like substance. At the same time, the synthesis process of crisoborole is improved, and cheaper 2-bromo-5-hydroxybenzaldehyde and p-fluorobenzonitrile are selected as raw materials, which reduces the production cost and improves the production efficiency. At the same time, the optimized synthesis process avoids the use of inflammable and explosive dangerous reagents such as n-butyl lithium and borane, and significantly reduces the safety risk in the production process. At the same time, in the synthesis of compound 2, sodium borohydride is first dissolved in ethanol and then added dropwise, which can better control the reaction temperature and avoid the rapid temperature increase and material impact caused by the direct addition of solid sodium borohydride. It not only ensures the yield of the product, but also ensures the stability of the reaction system, providing high-quality raw material guarantee for the subsequent ointment preparation.

[0041] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

Claims

1. Cliborol ointment, the formula of which includes: Cresborole, white vaseline, liquid paraffin, glyceryl mono- and distearate, glycerol, propylene glycol, butylated hydroxytoluene, disodium edetate, dimethyl sulfoxide and benzalkonium chloride, characterized in that the mass percentages of the components are: 2% to 4% of Cresborole, 10% to 30% of white vaseline, 5% to 20% of liquid paraffin, 2% to 10% of glyceryl mono- and distearate, 5% to 20% of glycerol, 5% to 15% of propylene glycol, 0.1% to 0.5% of butylated hydroxytoluene, 0.1% to 0.4% of disodium edetate, 5% to 15% of dimethyl sulfoxide and 0.1% to 0.2% of benzalkonium chloride.

2. The crisaborole ointment according to claim 1, characterized in that: The mass percentages of the components are: 3.4% of crisaborole, 25% of white vaseline, 18% of liquid paraffin, 8% of mono- and distearic acid glyceryl, 20% of glycerol, 15% of propylene glycol, 0.3% of butylated hydroxytoluene, 0.2% of disodium ethylenediaminetetraacetate, 10% of dimethyl sulfoxide, and 0.1% of benzalkonium chloride.

3. The crisaborole ointment according to claim 2, characterized in that: The mass percentages of the components are: 2.3% of crisaborole, 23% of white vaseline, 17% of liquid paraffin, 10% of glyceryl mono- and distearate, 18% of glycerol, 14% of propylene glycol, 0.25% of butylated hydroxytoluene, 0.25% of disodium ethylenediaminetetraacetate, 15% of dimethyl sulfoxide, and 0.2% of benzalkonium chloride.

4. A process for producing crisaborole ointment, comprising step 1, synthesis of crisaborole; step 2, preparation of ointment base; step 3, solution preparation and mixing; step 4, emulsification and homogenization; step 5, filling and packaging; step 6, quality control; characterized in that: In the above step 1, 2-bromo-5-hydroxybenzaldehyde and p-fluorobenzonitrile are used as raw materials to synthesize criborol; In the above step 2, the ointment base oil phase required for the production of crisaborole ointment is prepared; In the above step 3, a crisaborole aqueous solution is prepared and added to the ointment base; In the above step 4, the water phase and the oil phase are emulsified, and crisaborole is added and homogenized; In the above step 5, the homogenized ointment is filled into a suitable container, such as a soft tube or an aluminum tube, and the filled ointment is sealed and packaged; In step six above, the finished product is subject to strict quality control, including testing of appearance, properties, content uniformity, microbial limits, etc., to ensure that the product meets quality standards.

5. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 1, 2-bromo-5-hydroxybenzaldehyde, p-fluorobenzonitrile, potassium carbonate and N,N-dimethylformamide are added to the reaction bottle in sequence, and the mixture is stirred and heated to 80-90° C. under nitrogen protection, and the mixture is kept warm and stirred for 20 hours. After the reaction is completed, the reaction solution is cooled to 0-10° C., purified water is slowly added, and the mixture is kept warm and stirred for 30 minutes. The filter cake is washed with purified water by filtration, and the filter cake is dissolved with dichloromethane for separation. The aqueous phase is back-extracted with dichloromethane once, and the organic phases are combined. Anhydrous sodium sulfate and activated carbon are added to the organic phases, and the mixture is stirred for 5-6 hours. The filtrate is collected by filtration, and the filtrate is concentrated until no liquid flows out. Anhydrous methanol is added and pulped at room temperature for 6 hours. The filter cake is collected by filtration and washed with anhydrous methanol. The filter cake is vacuum dried at 50° C. for 12 hours to obtain an off-white solid compound 1.

6. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 1, compound 1 and anhydrous methanol are added to a reaction bottle, mixed and stirred, cooled to -5 to 5°C, and an ethanol solution containing sodium borohydride is added dropwise, and the temperature is controlled below 15°C. After the addition is completed, the temperature is raised to room temperature and stirred for 3 hours. After the reaction is completed, the reaction solution is cooled to 0 to 10°C, and a 10% aqueous solution of ammonium chloride is slowly added. The mixture is kept warm and stirred for 1 hour, filtered, and the filter cake is washed with purified water. The filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 2.

7. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 1, compound 2 and dichloromethane are added to a 2L reaction bottle, stirred at room temperature to dissolve, triethylamine is added dropwise, acetic anhydride is added after the addition, and the mixture is stirred at room temperature for 5 hours. After the reaction is completed, purified water is added to the reaction solution, the liquid is separated, and the organic phase is washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence. Anhydrous sodium sulfate is added to the organic phase and dried for 2 hours. The organic phase is filtered and the filtrate is collected. The filtrate is concentrated to obtain an off-white solid, isopropanol and purified water are added, the temperature is raised to 60°C and stirred until the solid is dissolved, the temperature is lowered to room temperature for crystallization, the filter cake is filtered and rinsed with purified water, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 3.

8. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 1, compound 3, DMF, diboronic acid pinacol ester and potassium acetate are added to the reaction bottle, stirred for 30 minutes under nitrogen protection, palladium dichloride is added, nitrogen protection is applied, the temperature is raised to 90°C and stirred for 4 hours. After the reaction is completed, ethyl acetate and purified water are added to the reaction solution, stirred for 30 minutes, allowed to stand for separation, the organic phase is collected, washed twice with saturated sodium chloride aqueous solution, dried for 2 hours with anhydrous sodium sulfate, filtered, and the filtrate is collected. The filtrate is concentrated to obtain a brown solid, added to n-heptane, heated to 90-95°C to dissolve, activated carbon is added and stirred for 1 hour, filtered while hot, the filtrate is collected, cooled to room temperature and stirred for crystallization for 2 hours, filtered, the filter cake is rinsed with n-heptane, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain an off-white solid compound 4.

9. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 1, compound 4 and tetrahydrofuran are added to the reaction bottle, stirred and dissolved, cooled to -5 to 5°C, concentrated hydrochloric acid is slowly added dropwise, the temperature is raised to 40 to 50°C and stirred for 5 hours after the addition is completed, and the temperature is lowered to room temperature after the reaction is completed, purified water and ethyl acetate are added, the liquids are separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, and the organic phases are washed with saturated sodium bicarbonate solution and sodium chloride solution respectively, the organic phases are collected, anhydrous sodium sulfate is added and dried for 2 hours, the filtrate is filtered and collected, and after the filtrate is concentrated, purified water and n-heptane are added and stirred for 2 hours, solids are precipitated, the filter cake is washed with n-heptane, the filter cake is collected, the filter cake is dissolved in methanol, heated to reflux until the solid is dissolved, and the temperature is slowly lowered to 0 to 10°C for crystallization, filtered, the filter cake is washed with n-heptane, the filter cake is collected, and the filter cake is vacuum dried at 45°C for 12 hours to obtain criborol.

10. The process for producing crisaborole ointment according to claim 3, characterized in that: In the step 3, a prescribed amount of dimethyl sulfoxide solvent is taken, placed in a beaker, heated to 45° C. and kept warm, butylated hydroxytoluene and disodium ethylenediaminetetraacetate are added, and stirred until completely dissolved to form an aqueous phase solution, and the prepared aqueous phase solution is slowly added to the prepared oil phase, while continuing to stir, so that the aqueous phase and the oil phase are fully mixed to form a cream-like substance.

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