CN108530476A - A kind of preparation method of gram of vertical boron sieve intermediate - Google Patents

Abstract

The invention discloses a preparation method of a crisborole intermediate. The preparation method of the crisborole intermediate comprises the following steps: (1) combining 2-bromo-5-hydroxybenzaldehyde with benzyl chloride or benzyl bromide In the organic solvent (i), under the presence of alkali, the compound shown in the formula II is reacted; (2) the compound shown in the formula II is mixed with triethyl orthoformate, trimethyl orthoformate or ethylene glycol in an organic solvent (ii) react under the action of medium and acidic catalysts to prepare the compound shown in formula III; Pentacycline or 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate with stock solution in organic After the reaction is complete in the solvent (Ⅲ) at a reaction temperature of 10°C to 30°C, hydrochloric acid is added to adjust the pH to ≤3 to quench the reaction, and then react at 20°C to 100°C to obtain the compound shown in formula IV.

Description

A kind of preparation method of crisborole intermediate

technical field

The invention relates to the technical field of pharmacy, in particular to a preparation method of a crisborole intermediate.

Background technique

Eczema is an allergic inflammatory skin disease caused by a variety of internal and external factors. It is characterized by symmetrical distribution of skin lesions, polymorphic lesions, severe itching, tendency to exudate, and repeated attacks. The disease is lingering and difficult to heal, and clinical treatment is difficult. , had a great impact on the physical and mental health of patients. At present, Western medicine is mainly based on symptomatic treatment such as antihistamines, glucocorticoids, and astringent and protective preparations. Although these drugs can control symptoms, they are prone to relapse after drug withdrawal, and long-term, repeated, and large-scale use can cause Children with local telangiectasia, skin pigmentation and other adverse reactions.

Criborole is a non-hormonal drug, which has the advantages of convenient use, less adverse reactions, and low recurrence rate, and has high clinical application value. The chemical structure of criborole intermediate 1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane is as follows:

Disclosed in the method of 1,3-dihydro-1,5 dihydroxy-2,1-benzoxaborolane in the related art, but this method has used organic palladium catalyst and bis-linked pinacol borate , the starting materials are expensive.

Contents of the invention

The main purpose of the present invention is to propose a preparation method of crisborole intermediate, aiming at solving the need to use organopalladium catalyst and double pinacol borate in the preparation reaction of crisborole intermediate, starting raw material An expensive question.

In order to achieve the above object, the present invention proposes a kind of preparation method of crisborole intermediate, comprising the following steps:

(1) 2-bromo-5-hydroxybenzaldehyde is reacted with benzyl chloride or benzyl bromide in an organic solvent (i) and in the presence of an alkali to obtain a compound shown in formula II;

(2) reacting the compound shown in the formula II with triethyl orthoformate, trimethyl orthoformate or ethylene glycol in the organic solvent (ii) and under the action of an acidic catalyst to prepare the compound shown in the formula III;

Wherein, R is -CH ₃ or -CH ₂ CH ₃ ;

(3) 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate react completely with the standby solution in organic solvent (Ⅲ) at a reaction temperature of 10°C to 30°C After that, add hydrochloric acid to adjust the pH value to ≤3 to carry out the quenching reaction, and react at 20°C to 100°C to obtain the compound shown in formula IV;

Wherein, the standby solution is to make the compound shown in formula III in the organic solvent (Ⅲ), add the tetrahydrofuran solution of isopropylmagnesium chloride under the condition that the reaction temperature is less than 0 ° C, after the addition is completed, the reaction temperature is adjusted to After the reaction is complete at 10°C to 25°C, the standby solution is obtained;

(4) reacting the compound shown in formula IV with sodium borohydride or potassium borohydride in organic solvent (iv) to prepare the compound shown in formula V;

(5) reducing the compound represented by formula V with 5-10% palladium carbon in an organic solvent (v) to prepare the intermediate represented by formula I.

Preferably, said step (1) reacts 2-bromo-5-hydroxybenzaldehyde with benzyl chloride or benzyl bromide in the organic solvent (i) in the presence of a base to prepare the compound shown in formula II , the organic solvent (i) is one or more of N, N dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetone, butanone, acetonitrile; and/or,

The base is one or more of triethylamine, pyridine, DIPEA, tributylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide; and/or,

The amount of benzyl chloride or benzyl bromide is 1-1.5 equivalents.

Preferably, the step (1) is the step of preparing the compound shown in formula II by reacting 2-bromo-5-hydroxybenzaldehyde with benzyl chloride or benzyl bromide in the organic solvent (i) in the presence of a base, Specifically:

With 2-bromo-5-hydroxybenzaldehyde and benzyl chloride or benzyl bromide in the organic solvent (i), under the presence of a base, and adding a catalyst to react the compound shown in formula II, wherein the catalyst is potassium iodide , sodium iodide, tetrabutylammonium iodide in one or more.

Preferably, in the step (2), the compound represented by formula II is reacted with triethyl orthoformate, trimethyl orthoformate or ethylene glycol in an organic solvent (ii) under the action of an acidic catalyst to prepare the compound represented by formula III In the step of the shown compound, the organic solvent (ii) is one or more of methanol, ethanol, toluene, xylene; and/or,

One or more of the acidic catalyst p-toluenesulfonic acid, methanesulfonic acid, ammonium chloride, boron trifluoride ether; and/or,

The amount of the triethyl orthoformate, trimethyl orthoformate or ethylene glycol is 1-2 equivalents.

Preferably, the organic solvent (iii) in the step (3) is one or more of tetrahydrofuran, diethyl ether, methyl tetrahydrofuran, and ethylene glycol dimethyl ether; and/or,

The 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5-tetramethyl The amount of base-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate is 1 to 2.5 equivalents; and/or,

The amount of the isopropylmagnesium chloride is 1-2.5 equivalents.

Preferably, in the step (4) reacting the compound shown in formula IV with sodium borohydride or potassium borohydride in an organic solvent (iv) to prepare the compound shown in formula V, the organic solvent (iv ) is one or more of methanol, ethanol, isopropanol, water, tetrahydrofuran; and/or,

The amount of the sodium borohydride or potassium borohydride is 0.5-2 equivalents.

Preferably, said step (5) reduces the compound shown in formula V with 5-10% palladium carbon in organic solvent (v) to prepare the step of the intermediate shown in formula I, said organic solvent (v) is one or more of methanol, ethanol, isopropanol, n-butanol, water, and tetrahydrofuran.

Preferably, said step (5) reduces the compound shown in formula V with 5-10% palladium carbon in an organic solvent (v) to prepare the step of intermediate shown in formula I, specifically:

The compound represented by formula V is hydrogenated with 5-10% palladium carbon in an organic solvent (v) under pressure or a chemical reducing agent is used as a hydrogen source to completely react to prepare the intermediate represented by formula I.

The present invention has the following advantages:

(1) Grignard reagent is used to replace organic palladium catalyst in the process of preparing boric acid in the present invention, the price is low, the reaction conditions are mild, no palladium residue will be produced, and the use of noble metal catalysts and harsh reaction conditions is not involved in the process;

(2) the preparation method of the present invention does not need to react under severe cryogenic conditions;

(3) The preparation method of the present invention has low process cost and cheap raw materials, and can be better applied to industrial production.

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

Disclosed in the method of 1,3-dihydro-1,5 dihydroxy-2,1-benzoxaborolane in the prior art, but this method has used organic palladium catalyst and bis-linked pinacol boronic acid Esters, starting materials are expensive.

In order to solve the above problems, the present invention proposes a preparation method of a crisborole intermediate, wherein the crisborole intermediate is 1,3-dihydro-1,5-dihydroxy-2,1-benzoxygen Boronane, the chemical structural formula is as follows:

The preparation method of this crisborole intermediate comprises the steps:

Step S100, reacting 2-bromo-5-hydroxybenzaldehyde with benzyl chloride or benzyl bromide in an organic solvent (i) in the presence of a base to obtain a compound represented by formula II;

Further, the organic solvent (i) is one or more of N,N dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetone, butanone, and acetonitrile; and/ or,

The base is one or more of triethylamine, pyridine, DIPEA, tributylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide; and/or,

The amount of benzyl chloride or benzyl bromide is 1-1.5 equivalents, preferably, the amount of benzyl chloride or benzyl bromide is 1 equivalent.

Further, the step S100 is specifically:

With 2-bromo-5-hydroxybenzaldehyde and benzyl chloride or benzyl bromide in the organic solvent (i), under the presence of a base, and adding a catalyst to react the compound shown in formula II, wherein the catalyst is potassium iodide , sodium iodide, tetrabutylammonium iodide in one or more.

During specific implementation, the step S100 may be:

After mixing 2-bromo-5-hydroxybenzaldehyde and organic solvent (ⅰ) in a certain proportion and adding to the reaction kettle, after adding a certain amount of alkali, add benzyl chloride or benzyl bromide, and heat the reaction (the heating temperature can be 80°C , can also be 100°C, the specific settings are set according to actual needs, and are not limited here), after the reaction is complete, the solvent is recovered, added an appropriate amount of water for beating, filtered, and dried to obtain the compound shown in formula II, wherein, during the reaction Catalysts may also be added.

Step S200, reacting the compound represented by formula II with triethyl orthoformate, trimethyl orthoformate or ethylene glycol in an organic solvent (ii) under the action of an acidic catalyst to prepare the compound represented by formula III;

Wherein, R is -CH ₃ or -CH ₂ CH ₃ ;

Preferably, the organic solvent (ii) is one or more of methanol, ethanol, toluene, xylene; and/or,

One or more of the acidic catalyst p-toluenesulfonic acid, methanesulfonic acid, ammonium chloride, boron trifluoride ether; and/or,

The amount of the triethyl orthoformate, trimethyl orthoformate or ethylene glycol is 1-2 equivalents.

During specific implementation, the step S200 may be:

After the intermediate II is mixed with the organic solvent (ii) in a certain proportion, one or more of triethyl orthoformate, trimethyl orthoformate, or ethylene glycol is added, an acidic catalyst is added, the reaction is heated, and the solvent is recovered. Filter and dry to obtain the compound represented by formula III.

In step S300, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate react completely with the standby solution in organic solvent (Ⅲ) at a reaction temperature of 10°C to 30°C After that, add hydrochloric acid to adjust the pH value to ≤3 to carry out the quenching reaction, and react at 20°C to 100°C to obtain the compound shown in formula IV;

Preferably, the reaction temperature is 15°C, 20°C or 25°C after the reaction is complete under the condition of 10°C to 30°C.

Wherein, the standby solution is to make the compound shown in formula III in the organic solvent (Ⅲ), add the tetrahydrofuran solution of isopropylmagnesium chloride under the condition that the reaction temperature is less than 0 ° C, after the addition is completed, the reaction temperature is adjusted to After the reaction is completed at 10°C to 25°C, the standby solution is obtained; preferably, the reaction temperature in adjusting the reaction temperature to complete the reaction at 10°C to 25°C is 15°C, 18°C, 20°C or 22°C.

Preferably, the organic solvent (iii) is one or more of tetrahydrofuran, diethyl ether, methyl tetrahydrofuran, and ethylene glycol dimethyl ether; and/or,

The 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5-tetramethyl The amount of base-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate is 1 to 2.5 equivalents; and/or,

The amount of the isopropyl magnesium chloride is 1-2.5 equivalents, preferably, the amount of the isopropyl magnesium chloride is 1.5 equivalents or 2 equivalents.

During specific implementation, the step S300 may be:

Make the compound represented by formula III in the organic solvent (Ⅲ), add -20°C to 0°C (preferably, -20°C to -10°C) under the condition that the reaction temperature is less than 0°C, add isopropylmagnesium chloride dropwise After the addition of the THF solution, adjust the reaction temperature to 10°C to 25°C to complete the reaction (usually 1 to 3 hours to complete the reaction) to obtain the standby solution.

2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5-tetramethyl -1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate and organic solvent (Ⅲ) are mixed in a certain proportion and added to the reaction kettle, keep the reaction temperature at 10°C to 30°C, drop Add spare solution, after the reaction is complete, add concentrated hydrochloric acid (or dilute hydrochloric acid, according to the specific choice) to quench the reaction, continue to complete the reaction at 20 ° C ~ 100 ° C (usually 1-3 hours to complete the reaction ), reclaim the organic solvent, and crystallization obtains the compound shown in formula IV.

Step S400, reacting the compound shown in formula IV with sodium borohydride or potassium borohydride in an organic solvent (iv) to prepare the compound shown in formula V;

Preferably, the organic solvent (iv) is one or more of methanol, ethanol, isopropanol, water, tetrahydrofuran; and/or,

The amount of the sodium borohydride or potassium borohydride is 0.5-2 equivalents, preferably, the amount of the sodium borohydride or potassium borohydride is 1.5 equivalents.

During specific implementation, the step S400 may be:

Add the compound shown in Formula IV and the organic solvent (ⅳ) into the reaction kettle according to a certain ratio, add sodium borohydride or potassium borohydride in batches, after the addition is completed, react at room temperature until the reaction of compound IV is complete, recover the solvent, and add hydrochloric acid to adjust the pH to below 3, stirred, filtered, and dried to obtain the compound represented by formula V.

Step S500, reducing the compound represented by formula V with 5-10% palladium carbon in an organic solvent (v) to prepare the intermediate represented by formula I.

The organic solvent (v) is one or more of methanol, ethanol, isopropanol, n-butanol, water, and tetrahydrofuran.

In specific implementation, the step S500 is specifically:

The compound represented by formula V is hydrogenated with 5-10% palladium carbon in an organic solvent (v) under pressure or using a chemical reducing agent as a hydrogen source until the reaction is complete to prepare the intermediate represented by formula I.

Preferably, the compound shown in formula V is pressurized hydrogenated with 5-10% palladium carbon in an organic solvent (v) or utilizes a chemical reducing agent such as ammonium formate, and cyclohexene replaces hydrogen as a hydrogen source until the reaction is complete to prepare The intermediate shown in formula I is obtained.

Wherein, the pressurized hydrogenation may be without pressure, or may be under low pressure or high pressure, which is determined according to the amount of raw materials and the reaction time, and no specific limitation is made here.

During specific implementation, the step S500 may be:

Add the compound shown in formula V and the organic solvent (ⅴ) into the reactor according to a certain ratio, add 5-10% palladium carbon, pressurize hydrogenation until the reaction is complete, filter, recover the solvent, add water and filter to obtain the compound shown in formula I intermediate.

The technical scheme provided by the present invention provides a new process for the preparation of crisborole intermediate 1,3-dihydro-1,6-dihydroxy-2,1-benzoxaborolane, and the process The method does not involve the use of precious metal catalysts and harsh reaction conditions, and does not need to use expensive organic palladium catalysts for borate coupling, which reduces process costs, improves environmental protection, and is more suitable for industrial production.

Example

This embodiment provides a preparation method of a crisborole intermediate, the preparation method of the crisborole intermediate comprises the following steps:

(1) Preparation of 5-benzyloxy-2-bromo-benzaldehyde (compound shown in formula Ⅱ)

Add 201g (1mol) of 2-bromo-5-hydroxy-benzaldehyde, 1000ml of acetone, and 276g (1.1mol) of potassium carbonate into the reaction kettle, add 152g (1.2mol) of benzyl chloride under stirring, reflux for 10h, and recover the solvent. Add 1000ml of water, make a slurry, filter, and dry under reduced pressure to obtain 279g of solid, with a yield of 96%;

(2) Preparation of 5-benzyloxy-2-bromo-benzaldehyde diethyl acetal (compound shown in formula III)

29.1g (0.1mol) 5-benzyloxy-2-bromo-benzaldehyde (compound shown in formula II), 100ml ethanol, 0.53g (0.01mol) ammonium chloride, 16.3g (0.11mol) triethyl orthoformate Heat the ester to reflux for 5 hours, cool, filter, recover the solvent, and rectify to obtain 32.5 g of oil, with a yield of 89%;

(3) Preparation of 4-benzyloxy-2-formylphenylboronic acid (compound shown in formula IV)

Add 36.5 g (0.1 mol) of 5-benzyloxy-2-bromo-benzaldehyde diethyl acetal (the compound represented by formula III) and 300 ml of THF into the reaction kettle. Add 2.0M isopropylmagnesium chloride solution (75ml, 0.15mol), the temperature does not exceed 0°C, add dropwise for about 2h, stir at 20°C for 1h, and prepare the solution for later use;

Add THF300ml, 23.7g (0.15mol) 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane into the reaction flask, cool to 0-10°C, Add the above standby solution dropwise for about 1.5 hours. After dropping, react at 25°C for 9h, add hydrochloric acid in an ice bath until the pH value is below 3, continue to react at 80°C for 2 hours, recover the organic solvent, crystallize, filter and dry to obtain 20g of the compound , yield 78%;

(4) Preparation of 5-benzyloxy 1,3-dihydro-1-hydroxyl-2,1-benzoxaborolane (compound shown in formula V)

Add 25.7g (0.1mol) of 4-benzyloxy-2-formylphenylboronic acid (compound shown in formula IV), 200ml of methanol into the reaction kettle, add 1.89g (0.1mol) of sodium borohydride in batches, and complete the addition , continue to stir at 25°C for 4 hours until the reaction of the raw materials is complete, recover methanol, add 50ml of 0.1M hydrochloric acid for beating for 6 hours, filter, and dry to obtain 23g of solid, with a yield of 97%;

(5) Preparation of 1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane (compound shown in formula I)

5-benzyloxy 1,3-dihydro-1-hydroxy-2,1-benzoxaborolane (compound represented by formula V) (25.6g, 0.1mol), ethanol 500ml, 5% Pd /C was added to the reaction kettle, hydrogenated at 1 bar pressure until the reaction was complete, filtered, recovered ethanol, added water, filtered, and dried to obtain 13.8 g of solids, with a yield of 92%.

¹ HNMR DMSO-d ₆ 9.32(s,1H)7,23(d,1H),7.12(d,1H),6.90(dd,1H)4.96(S,2H),ESI MH 149

The present invention has the following advantages:

(1) In the process of preparing boric acid in the present invention, the Grignard reagent is used to replace the organic palladium catalyst, the price is low, the reaction conditions are mild, and no palladium residue will be generated.

(2) The preparation method of the present invention does not need to react under severe cryogenic conditions.

(3) The preparation method of the present invention has low process cost and cheap raw materials, and can be better applied to industrial production.

The above are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of patent protection of the present invention.

Claims (8)

1. a preparation method of crisborole intermediate, is characterized in that, comprises the following steps: (1) 2-bromo-5-hydroxybenzaldehyde is reacted with benzyl chloride or benzyl bromide in an organic solvent (i) and in the presence of an alkali to obtain a compound shown in formula II; (2) reacting the compound shown in the formula II with triethyl orthoformate, trimethyl orthoformate or ethylene glycol in the organic solvent (ii) and under the action of an acidic catalyst to prepare the compound shown in the formula III; Wherein, R is -CH ₃ or -CH ₂ CH ₃ ; (3) 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate react completely with the standby solution in organic solvent (Ⅲ) at a reaction temperature of 10°C to 30°C After that, add hydrochloric acid to adjust the pH value to ≤3 to carry out the quenching reaction, and react at 20°C to 100°C to obtain the compound shown in formula IV; Wherein, the standby solution is to make the compound shown in formula III in the organic solvent (Ⅲ), add the tetrahydrofuran solution of isopropylmagnesium chloride under the condition that the reaction temperature is less than 0 ° C, after the addition is completed, the reaction temperature is adjusted to After the reaction is complete at 10°C to 25°C, the standby solution is obtained; (4) reacting the compound shown in formula IV with sodium borohydride or potassium borohydride in organic solvent (iv) to prepare the compound shown in formula V; (5) reducing the compound represented by formula V with 5-10% palladium carbon in an organic solvent (v) to prepare the intermediate represented by formula I. 2. the preparation method of criborol intermediate as claimed in claim 1, is characterized in that, described step (1) with 2-bromo-5-hydroxybenzaldehyde and benzyl chloride or benzyl bromide in organic solvent (i) In the step of preparing the compound shown in formula II by reacting in the presence of a base, the organic solvent (i) is N,N dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropyl One or more of alcohol, acetone, butanone, acetonitrile; and/or, The base is one or more of triethylamine, pyridine, DIPEA, tributylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide; and/or, The amount of benzyl chloride or benzyl bromide is 1-1.5 equivalents. 3. the preparation method of criborol intermediate as claimed in claim 1, is characterized in that, described step (1) with 2-bromo-5-hydroxybenzaldehyde and benzyl chloride or benzyl bromide in organic solvent (i) in the presence of a base, react to prepare the step of the compound shown in formula II, specifically: With 2-bromo-5-hydroxybenzaldehyde and benzyl chloride or benzyl bromide in the organic solvent (i), under the presence of a base, and adding a catalyst to react the compound shown in formula II, wherein the catalyst is potassium iodide , sodium iodide, tetrabutylammonium iodide in one or more. 4. the preparation method of crisborole intermediate as claimed in claim 1 is characterized in that, described step (2) with the compound shown in formula II and triethyl orthoformate, trimethyl orthoformate or ethyl orthoformate In the step of preparing the compound shown in formula III by reaction of diol under the action of an acidic catalyst in the organic solvent (ii), the organic solvent (ii) is one or more of methanol, ethanol, toluene, xylene ;and / or, One or more of the acidic catalyst p-toluenesulfonic acid, methanesulfonic acid, ammonium chloride, boron trifluoride ether; and/or, The amount of the triethyl orthoformate, trimethyl orthoformate or ethylene glycol is 1-2 equivalents. 5. the preparation method of criborole intermediate as claimed in claim 1 is characterized in that, the organic solvent (iii) described in described step (3) is tetrahydrofuran, ether, methyltetrahydrofuran, ethylene glycol di One or more of methyl ethers; and/or, The 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-isopropoxy-4,4,5,5-tetramethyl The amount of base-1,3,2-dioxaborolane or trimethyl borate or triisopropyl borate is 1 to 2.5 equivalents; and/or, The amount of the isopropylmagnesium chloride is 1-2.5 equivalents. 6. the preparation method of criborole intermediate as claimed in claim 1 is characterized in that, described step (4) with the compound shown in formula IV and sodium borohydride or potassium borohydride in organic solvent (iv) In the step of preparing the compound shown in formula V, the organic solvent (iv) is one or more of methanol, ethanol, isopropanol, water, tetrahydrofuran; and/or, The amount of the sodium borohydride or potassium borohydride is 0.5-2 equivalents. 7. the preparation method of crisborole intermediate as claimed in claim 1 is characterized in that, described step (5) with the compound shown in formula V and the palladium carbon of 5-10% in organic solvent (v) In the step of preparing the intermediate shown in formula I by reduction reaction, the organic solvent (v) is one or more of methanol, ethanol, isopropanol, n-butanol, water, and tetrahydrofuran. 8. the preparation method of crisborole intermediate as claimed in claim 1 is characterized in that, described step (5) with the compound shown in formula V and the palladium carbon of 5-10% in organic solvent (v) The step of making the intermediate shown in formula I by middle reduction reaction, specifically: The compound represented by formula V is hydrogenated with 5-10% palladium carbon in an organic solvent (v) under pressure or a chemical reducing agent is used as a hydrogen source to completely react to prepare the intermediate represented by formula I.