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Synthesis method of crisaborole

A technology of crisborole and synthetic method, which is applied in the field of preparation of pharmaceutical compounds, and can solve the problems of unfavorable industrial production, heavy metal pollution, expensive raw materials or catalysts, etc.

Pending Publication Date: 2021-09-14
ANHUI POLY PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are still some disadvantages in the current synthetic process route, such as expensive raw materials or catalysts, or the need to react at a lower temperature, higher requirements for production conditions and equipment, and the problem of heavy metal pollution in the final product. It is beneficial to industrial production. Therefore, it is necessary to further optimize the synthetic route of crisborole in order to obtain a relatively mild reaction condition, which can reduce synthetic costs, and is green and environmentally friendly, and is suitable for industrial production.

Method used

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  • Synthesis method of crisaborole

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preparation example Construction

[0040] According to the present invention, there is provided a synthetic method of crisborole, which uses 4-bromo-3-methylphenol as a raw material, undergoes borylation and ring closure, and then reacts with halogenated benzonitrile to obtain crisborol Ro. The method comprises the steps of:

[0041] Step 1. Add 4-bromo-3-methylphenol and benzyl halide to solvent I to react to obtain compound I.

[0042]

[0043] The benzyl halide is preferably benzyl bromide or benzyl chloride.

[0044] The solvent I is selected from amide solvents, alcohol solvents, sulfone solvents, ketone solvents or nitrile solvents, preferably selected from N,N-dimethylformamide, dimethyl sulfoxide, methanol, isopropanol , acetone, butanone or acetonitrile, more preferably N,N-dimethylformamide and / or acetone.

[0045] Preferably, the reaction is carried out in the presence of an alkaline substance selected from organic or inorganic bases, preferably selected from trimethylamine, triethylamine, pota...

Embodiment 1

[0101] Add 3mol 4-bromo-3-methylphenol, 3000mL acetone, and 3.3mol potassium carbonate into the reaction kettle, add 3.6mol benzyl chloride under stirring, and reflux for 10 hours. After recovering the solvent, add 3000mL water, beat and wash, and filter Afterwards, it was dried in vacuo to obtain solid compound I with a molar yield of 96.4%.

[0102] Dissolve 2 mol of the prepared compound I in 14.5 L of carbon tetrachloride, add 2 mol of NBS and 0.44 mol of BPO under stirring conditions, react at 80°C for 10 h, cool to room temperature, add 14 L of water, stir and mix, then set aside to separate layer, separate the organic phase and add anhydrous sodium sulfate to dry, remove the solvent by rotary evaporation, add ethyl acetate and petroleum ether for crystallization, the volume ratio of ethyl acetate and petroleum ether is 1:1, and compound II (wherein X is bromine ), the molar yield is 86.9%.

Embodiment 2

[0104] Take 1.5 mol of compound II prepared in Example 1 and add it into 3 L of N,N-dimethylformamide to dissolve, add 8 mol of sodium acetate under stirring condition, and stir at 80° C. for 3 h. After the reaction, cool to room temperature, add 12.5L deionized water to the reaction solution, stir, add ethyl acetate for extraction, separate the organic phase, add anhydrous sodium sulfate to dry, filter, and evaporate to remove the solvent to obtain compound III , the molar yield was 90.9%.

[0105] Take 1.2 mol of the prepared compound III, 2.4 mol of double-linked pinacol borate, and 3.6 mol of potassium acetate, and add them to 6 L of 1,4-dioxane, and then add 60 mmol of [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ), under the protection of nitrogen, reacted at 105° C. for 6 h, heated and concentrated the reaction solution, added deionized water to stir, then stood still, and suction filtered to obtain a filter cake. Add the filter cake into ...

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Abstract

The invention provides a synthesis method of crisaborole. The method comprises the following steps: by taking 4-bromo-3-methylphenol as a raw material, carrying out boronation and cyclization, and reacting with halogenated cyanophenyl to obtain crisaborole. According to the method, the cost of starting materials can be reduced, by optimizing the synthesis process and carrying out subsequent reaction after boryl cyclization, side reactions are effectively reduced, the product quality is improved, the post-treatment process is effectively simplified, the reaction conditions are mild, preparation and synthesis of crisaborole are realized, and the method is particularly suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the preparation of pharmaceutical compounds, in particular to a preparation method of crisborole, which belongs to the field of pharmaceutical synthesis methods and techniques. Background technique [0002] Criborole is an effective agent for the treatment of the rare skin disease atopic dermatitis. Its chemical name is 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborolan-5-yl)oxy]benzonitrile. Its structural formula is as follows: [0003] [0004] Criborole can effectively inhibit the activity of phosphodiester-4, thereby inhibiting the production of pro-inflammatory mediators. It has been approved for marketing in many countries and has broad market prospects. [0005] At present, the synthetic method of criborol mainly uses 2-bromo-5-(4-cyanophenoxy)benzaldehyde as raw material to synthesize an intermediate with aldehyde group protection, and under the effect of n-butyllithium and boric acid Trimethyl ester is reacted at -78°...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCC07F5/025Y02P20/584
Inventor 范敏华周胜军吴族悌陆翠军聂良邓
Owner ANHUI POLY PHARM CO LTD
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