Preparation method of crisaborole

A technology of criborole and nitrophenylboronic acid, which is applied in the field of preparation of criborole, can solve the problems of low total yield, low yield, many side reactions, etc., and achieves mild and controllable reaction, cheap and easy raw materials. The effect of obtaining, high yield

Active Publication Date: 2019-03-12
ANHUI QINGYUN PHARMA & CHEM
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  • Description
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Problems solved by technology

[0007] Although the starting materials of this route are easy to obtain, the reaction steps are long and the overall yield is low, especially the ultra-low temperature reaction that also uses n-butyllithium to participate, so that the yield of this route is low, the product purity is poor, and it is difficult to realize large-scale industrialization Production
[0008] To sum up, there are currently few synthetic routes for crisborole, only two routes, because the raw materials are not easy to obtain, ultra-low temperature reaction is used, there are many side reactions, and the product is poor in purity, so it is difficult to realize industrial production. Therefore, the development of green and environmental protection , The route of synthesizing crisborole with strong operability has broad prospects

Method used

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  • Preparation method of crisaborole
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preparation example Construction

[0043] The synthetic route of the preparation method of a kind of crisborole that the present invention proposes is as follows:

[0044] With reference to the above-mentioned route, a kind of preparation method of crisborole proposed by the present invention comprises the following steps:

[0045] S1, carrying out nitration reaction with o-cyanophenylboronic acid (2) and concentrated nitric acid to obtain 2-cyano-4-nitrophenylboronic acid (3);

[0046] S2. Reducing 2-cyano-4-nitrophenylboronic acid to obtain 2-formyl-4-nitrophenylboronic acid (4);

[0047] S3, reducing 2-formyl-4-nitrophenylboronic acid to obtain 2-hydroxymethyl-4-nitrophenylboronic acid (5);

[0048] S4, 2-hydroxymethyl-4-nitrophenylboronic acid obtains 2-hydroxymethyl-5-nitrophenylboronic acid half ester (6) through condensation reaction;

[0049] S5, 2-hydroxymethyl-5-nitrophenylboronic acid half ester undergoes reduction reaction, diazotization hydrolysis reaction to obtain 2-hydroxymethyl-5-hydroxypheny...

Embodiment 1

[0053] A preparation method of crisborole, comprising the steps of:

[0054] Synthesis of S1, 2-cyano-4-nitrophenylboronic acid: Add 1.67kg of concentrated sulfuric acid to a round-bottomed flask equipped with mechanical stirring, slowly add 1.07kg of fuming nitric acid dropwise under an ice-salt bath, and control the temperature of the reaction system Do not exceed 20°C. After the addition, add 500g of 2-cyanophenylboronic acid in batches. After the addition, raise the temperature to 80°C for 5 hours. TLC monitors the progress of the reaction. After the conversion of the raw materials is complete, cool to room temperature and pour the obtained reaction solution into In 5L of ice water, a large number of light yellow solids precipitated, filtered, dried, and recrystallized from absolute ethanol to obtain light yellow 2-cyano-4-nitrophenylboronic acid;

[0055] Synthesis of S2, 2-formyl-4-nitrophenylboronic acid: 0.5kg of 2-cyano-4-nitrophenylboronic acid was added in a round-b...

Embodiment 2

[0061] A preparation method of crisborole, comprising the steps of:

[0062] Synthesis of S1, 2-cyano-4-nitrophenylboronic acid: Add 1.336 kg of concentrated sulfuric acid to a round bottom flask equipped with mechanical stirring, slowly add 0.856 kg of fuming nitric acid dropwise in an ice-salt bath, and control the temperature of the reaction system Do not exceed 20°C. After the addition, add 500g of 2-cyanophenylboronic acid in batches. After the addition, raise the temperature to 40°C for 5 hours. TLC monitors the progress of the reaction. After the conversion of the raw materials is complete, cool to room temperature, and pour the obtained reaction solution In 5L of ice water, a large number of light yellow solids precipitated, filtered, dried, and recrystallized from absolute ethanol to obtain light yellow 2-cyano-4-nitrophenylboronic acid;

[0063] Synthesis of S2, 2-formyl-4-nitrophenylboronic acid: 0.5kg of 2-cyano-4-nitrophenylboronic acid was added in a round-bottom...

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Abstract

The invention relates to the technical field of crisaborole, in particular to a preparation method of crisaborole. The method comprises the following steps: carrying out nitration reaction on cyanophenylboronic acid and concentrated nitric acid to obtain 2-cyan-4-nitrobenzeneboronic acid; then carrying out reduction reaction to obtain 2-formoxyl-4-nitrobenzeneboronic acid; then carrying out reduction reaction to obtain 2-hydroxymethyl-4-nitrophenylboronic acid; carrying out condensation reaction to obtain 2-hydroxymethyl-5-nitrobenzeneboronicacidhemiester; carrying out reduction reaction and diazotization hydrolysis reaction to obtain 2-hydroxymethyl-5-hydroxy benzeneboronicacidhemiester; and finally, carrying out etherification reaction on the 2-hydroxymethyl-5-hydroxy benzeneboronicacidhemiester and fluorobenzonitrile to obtain the crisaborole. The preparation method of the crisaborole has the advantages that the purity of the prepared crisaborole is good, and the yield is high.

Description

technical field [0001] The invention relates to the technical field of crisborole, in particular to a preparation method of crisborole. Background technique [0002] Crisaboeole, the chemical name is 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborolan-5-yl)oxy]benzonitrile , is a phosphodiesterase inhibitor indicated for the treatment of fungal infections, especially for the treatment of fungal infections of the nails or skin. Developed by Anacro Pharmaceuticals and approved by the FDA in December 2016 for marketing in the United States, the trade name is Eucrisa, which is a topical ointment. [0003] At present, the synthetic route of crisborole mainly consists of the following two: [0004] Synthetic route 1 is a route reported by US Patent US2006234981A1. This route uses 4-(4-bromo-3-formylphenoxy)benzonitrile as the starting material, first reduced by sodium borohydride, and then chloromethyl ether Etherification, boration and cyclization to obtain criborole, the synthetic r...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCC07F5/02
Inventor 黄欢黄庆国李凯施亚琴
Owner ANHUI QINGYUN PHARMA & CHEM
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