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Method for preparing crisaborole

A technology of crisaborol and compounds, which is applied in the field of preparation of crisaborol, can solve the problems of high cost and low yield, and achieve the effects of low cost, high reaction yield and easier quality control

Active Publication Date: 2018-05-18
SUZHOU VIGONVITA LIFE SCIENCES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the literature, this route also has the problems of low yield and high cost, and the single-step yield of the ring-closing step is only about 30%, which has obvious defects

Method used

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  • Method for preparing crisaborole
  • Method for preparing crisaborole
  • Method for preparing crisaborole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1 Formula III compound (wherein X is bromine, PG is the synthesis of acetyl group)

[0063] Compound IV (30.00g, 98.7mmol, 1.0eq), acetic anhydride (12.08g, 118.4mmol, 1.2eq), THF (150mL) and DMAP (15.65g, 128.3mmol, 1.3eq) were added to the reaction flask respectively, The reaction was stirred at room temperature. After 1 h, TLC showed that the reaction of the raw materials was basically completed, and the post-treatment was carried out. Add 200mL of water and 200mLEA, separate the layers, wash the organic phase with water, dry, and concentrate to obtain a total of 32.36g of off-white solid, which is the target compound of formula III, namely 2-bromo-5-(4-cyanophenoxy)benzyl alcohol acetic acid Esters, yield 95%.

[0064] The nuclear magnetic data of gained white solid is as follows:

[0065] 1 H-NMR (400Hz, CDCl 3 ) δ (ppm) 2.15 (s, 3H), 5.18 (s, 2H), 6.92 (dd, J = 4Hz, 8Hz, 1H), 7.04 (m, 2H), 7.14 (d, J = 4Hz, 1H), 7.59 (d, J=8Hz, 1H), 7.64 (m, 2H). ...

Embodiment 2

[0066] Example 2 Synthesis of the compound of formula III (wherein X is bromine, and PG is 2,3,4-trimethoxybenzyl)

[0067] Dissolve compound IV (1.00g, 3.3mmol, 1.0eq) in DMF (15mL), add 60% sodium hydride (0.16g, 4.0mmol, 1.2eq), stir at room temperature for 30min, add 2,3,4-trimethyl Oxybenzyl chloride (1.00g, 4.6mmol, 1.4eq), heated to 85°C and stirred for reaction. After 6h, TLC showed that the reaction of the raw materials was basically completed, and the post-treatment was carried out. The reaction solution was cooled to room temperature, 20 mL of water was added to quench the reaction, extracted with 50 mL of EA, separated, the organic phase was washed with water, dried and concentrated, and the obtained crude product was purified by column chromatography to obtain 1.46 g of yellow oil, which was the target compound, with a yield of 76 %.

Embodiment 3

[0068] Synthesis of Example 3 Compound of Formula III (wherein X is bromine, and PG is trimethylsilyl)

[0069] Compound IV (3.00g, 9.9mmol, 1.0eq) and imidazole (1.34g, 19.7mmol, 2.0eq) were dissolved in dichloromethane (25mL), cooled to -15°C, and trimethylchlorosilane (1.60g, 14.7mmol, 1.5eq), the reaction was stirred. After 16h, TLC showed that the basic reaction of the raw materials was completed, and the post-treatment was carried out. The reaction was quenched by adding 50 mL of water, extracted with 50 mL of dichloromethane, separated, the organic phase was washed with water, dried, and concentrated. The obtained crude product was purified by column chromatography to obtain 3.26 g of a yellow oil, which was the target compound, with a yield of 88%.

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Abstract

The invention discloses a method for preparing crisaborole and an intermediate for preparing crisaborole. The method comprises the following steps: (1) enabling components such as 2-halogen-5-(4-cyanphenoxy) benzyl acetate and bis(pinacolato)diboron to react in the presence of an organic solvent and a palladium catalyst under an alkali condition so as to obtain components such as 2-acetoxyl methyl-4-(4-cyan phenoxy) phenylboronic acid pinacol ester; (2) enabling components such as the 2-acetoxyl methyl-4-(4-cyan phenoxy) phenylboronic acid pinacol ester to react in a solvent under an acid oralkali condition, thereby obtaining crisaborole. The method is gentle in reaction condition, easy to operate, high in reaction yield, simple in aftertreatment, relatively low in cost and applicable toindustrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of crisborole. Background technique [0002] Crisaborole, an inhibitor of phosphodiesterase 4 (PDE4), which results in increased intracellular levels of cyclic adenosine monophosphate (cAMP), is used in the treatment of fungal infections, more specifically Onychomycosis and / or fungal skin infections. The drug was approved by the U.S. Food and Drug Administration (FDA) in December 2016. It was developed by Anacor Pharmaceuticals and is responsible for marketing in the U.S. under the trade name The chemical name of Crisaborole is 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, and its English name is 4-(( 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile, the chemical structural formula is shown in formula (Ⅰ): [0003] [0004] At present, the compound has the following preparation methods. [0005] For example, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/02Y02P20/55
Inventor 田广辉吴建忠俞蒋辉庞珍强李俊永
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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