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Preparation method of crisaborole

A technology of crisborol and borohydride, which is applied in the field of preparation of crisborol, can solve the problems of harsh reaction conditions of butyllithium or tert-butyllithium, expensive organic palladium catalyst, high process cost, etc. The effect of cheap price, low price and low process cost

Inactive Publication Date: 2018-10-16
WUHAN POLYTECHNIC UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] like figure 1 and figure 2 As shown, the existing synthesis of 4-((1-hydroxyl-1,3-dihydrobenzo[C][1,2]oxaborolan-5-yl)oxy)benzonitrile (criborole ) method, some use organic palladium for coupling to generate borate, and some use butyllithium or tert-butyllithium to react with trimethyl borate or triisopropyl borate at -78°C to generate phenyl Borate ester; in the above-mentioned preparation method, there is an expensive organic palladium catalyst, which leads to product palladium residue, harsh reaction conditions of butyllithium or tert-butyllithium, and problems such as high process cost

Method used

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  • Preparation method of crisaborole

Examples

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preparation example Construction

[0023] Such as image 3 As shown, the invention provides a kind of preparation method of crisborole, and this preparation method comprises the steps:

[0024] (1) In the presence of the first solvent, the compound shown in formula I is contacted with an alkali metal borohydride to obtain the compound shown in formula II;

[0025]

[0026] (2) In the presence of a second organic solvent and a base, the compound shown in formula II and compound a are subjected to a contact reaction to obtain a compound shown in formula III; or in the presence of a second organic solvent and a catalyst, the The compound shown in the formula II and dihydropyran are subjected to a contact reaction to obtain the compound shown in the formula III; wherein, the compound a is trimethylchlorosilane, tert-butyldimethylsilyl chloride or chloromethyl methyl ether ;

[0027]

[0028] Wherein, R is trimethylsilyl, tert-butyldimethylsilyl, methyl methyl ether or tetrahydropyranyl;

[0029] (3) In the...

Embodiment

[0039] This embodiment provides a preparation method of crisborole, the preparation method comprising the following steps:

[0040] (1) Preparation of 4-[(4-bromo-3-hydroxymethyl)phenoxy)]benzonitrile (compound shown in formula II)

[0041] With 30.2g (0.1mol) 4-[(4-bromo-3-formyl) phenoxy group)] benzonitrile (compound shown in formula I), 400ml methyl alcohol join in the reactor, add 1.89g ( 0.1mol) sodium borohydride, after adding, continue to stir at 25°C for 4h until the reaction of the raw materials is complete, recover methanol, add 1000ml of water for beating, filter, and dry to obtain a solid of 27.8% with a yield of 92%;

[0042] (2) Preparation of [5-(4-cyanophenoxy)-2-bromophenyl-1-methoxy]-trimethylsilane (compound shown in formula III)

[0043] 30.2g (0.1mol) 4-[(4-bromo-3-hydroxymethyl)phenoxy)]benzonitrile, 300ml dichloromethane, 30.3g triethylamine (0.3mol) were added to the reactor, Cool to 0-10°C, add 12.96g of trimethylchlorosilane dropwise, control the t...

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Abstract

The invention discloses a preparation method of crisaborole. The method comprises the steps as follows: a compound shown in a formula I and alkali metal borohydride are subjected to a contact reaction, and a compound shown in a formula II is obtained; the compound shown in the formula II and a compound a are subjected to a contact reaction, and a compound III is obtained; or the compound shown inthe formula II and dihydropyran are subjected to a contact reaction, and a compound III is obtained, wherein the compound a is trimethylchlorosilane, tert-butyldimethylsilyl chloride or chloromethyl methyl ether; the compound shown in the formula III and an isopropylmagnesium chloride solution are subjected to a contact reaction, and a standby solution is obtained; then, the standby solution is added to a mixed solution of a compound b and a third organic solvent for a contact reaction, hydrochloric acid is added for a contact reaction, and crisaborole, namely, a compound shown in a formula IV, is obtained, wherein the compound b is 2-alkoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, triisopropyl borate or trimethyl borate.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and more specifically relates to a preparation method of crisborole. Background technique [0002] 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-hor...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 赵玲杨博
Owner WUHAN POLYTECHNIC UNIVERSITY
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