Preparation method of crisaborole

A technology of crisaborol and solvent, which is applied in the field of preparation of crisaborol, can solve problems such as cost increase, heavy metal pollution, and high cost, and achieve the effects of easy operation, high safety, and simple operation

Active Publication Date: 2021-04-30
HUBEI HENGAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the diaryl ether structure raw material market used in this method is difficult to obtain directly, and the boronation reaction requires the use of ex...

Method used

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  • Preparation method of crisaborole
  • Preparation method of crisaborole
  • Preparation method of crisaborole

Examples

Experimental program
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Effect test

preparation example Construction

[0045]The preparation method includes:

[0046](1) 5-bromophenate in formula VII

[0047]

[0048]For the starting material, in the first solvent, the first base is etherified with an etherification reaction to obtain a compound of formula VI;

[0049]

[0050](2) The hydrolysis reaction of the formula Vi compound in the second solvent, the presence of the first acid or the second base is obtained by the formula V compound;

[0051]

[0052](3) Reacting the formula IV compound in the presence of the formula V compound in the third solvent, the alkali is reacted with the hydroxyl protective reagent;

[0053]

[0054]The PG is a hydroxy protecting group;

[0055](4) The compound of formula IV is carried out in a condensing agent under a fourth solvent, and the reaction is obtained by condensation of N-hydroxyphthalimide under the condensation agent;

[0056]

[0057](5) The compound of formula III is carried out under the fifth solvent, and the presence of the light source is irradiated, and the presence of the boron co...

Embodiment 1

[0109]Example 1: Preparation of a compound of formula VI

[0110]60.0 g (0.28 mol) 5-bromide (compound), 50.0 g (0.42 mol) 4-cyanophenol, 116.0 g (0.84 mol) potassium carbonate and 300 ml DMF were added to the reaction bottle, stirring and warming up to 95 ~ 100 ° C reacted for about 12 hours, cooling, adding water crystalline, filtration, drying, gauge white solid powder 58.2g, that is, the formula Vi compound 5- (4-nitrile phenoxy) phenylphaxire, yield 82.2% .

[0111]Nuclear magnetic data of the resulting solid:1H-NMR (400MHz, CDCL3: Δ7.97 (D, 1H), 7.74 (m, 2H), 7.22 (DD, 1H), 7.18 (m, 2H), 7.11 (D, 1H), 5.31 (S, 2H). ,

Embodiment 2

[0112]Example 2: Preparation of a compound of formula V

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Abstract

The invention provides a preparation method of crisaborole. More specifically, 5-bromophthalide is used as an initial raw material, and is subjected to etherification, hydrolysis, hydroxyl protection, condensation reaction, photoreaction boronation and cyclization to obtain the crisaborole. The preparation method has the advantages of readily available raw materials, mild reaction conditions, avoidance of metal catalysis and harsh conditions due to adoption of photoreaction for boronizing, low cost, convenience in operation and suitability for industrial production.

Description

Technical field[0001]The invention belongs to the field of medical chemical, involving a method of preparing a micro-boronone.Background technique[0002]Micro Note (English Name: crisaborole), chemical name is 4 - [(1,3-dihydro-1-hydroxy-2,1-benzoxy boron-5-yl)] oxygen group Benzonitrile, chemical structural formula is shown in Formula I.[0003][0004]Kli Boron is a non-steroidal, phosphate, a phosphate (PDE4) inhibitor, which is developed by Anacor Medicine Co., Ltd., has a broad spectrum of anti-inflammatory activity. On December 14, 2016, FDA was approved by FDA, which was used for mild to moderate allergic dermatitis at 2 years and older, and the trade name is Eucrisa. In 2020, the United States expanded the age limit of children with mild to moderate specific dermatitis for mild to moderate specific dermatitis, and children aged 3 months. In 2019, the drug was also included in NMPA in the "second batch clinical urgent need for new drugs".[0005]There are different preparation metho...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D209/48
CPCC07F5/025C07D209/48Y02P20/55
Inventor 赵宇陈放邹青
Owner HUBEI HENGAN PHARMA
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