Crisaborole intermediate preparation method

A technology of crisborole and intermediates, applied in the field of pharmacy, can solve the problems of high price of 2-bromo-5-hydroxybenzaldehyde, increase of preparation cost of crisborole intermediates, low selectivity of bromination reaction, etc. Achieve the effects of cheap raw materials, improved bromination reaction selectivity, and short preparation steps

Pending Publication Date: 2019-11-19
WUHAN POLYTECHNIC UNIVERSITY
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Problems solved by technology

[0004] In order to better prepare crisborole, people have carried out extensive research on the synthesis of crisborole intermediates; for example, the synthetic routes of two crisborole intermediates shown respectively in formula 1 and formula 2; Wherein, the price of the used reaction raw material 2-bromo-5-hydroxybenzaldehyde of the method shown in formula 1 is expensive, has increased the preparation cost of crisborole intermediate; The method shown in formula 2, 2-bromo-5- The selectivity of the bromination reaction in the preparation process of hydroxybenzaldehyde is low, and the yield is low

Method used

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preparation example Construction

[0024] The invention provides a method for preparing a crisborole intermediate, the crisborole intermediate has the structure shown in formula IV,

[0025] This preparation method comprises the steps:

[0026] (1) In the presence of the first organic solvent and the first base, the compound shown in formula I is contacted with p-fluorobenzonitrile to obtain the compound shown in formula II;

[0027]

[0028] (2) In the presence of a second solvent, the compound represented by the formula II and the alkali metal borohydride are subjected to a contact reaction to obtain the compound represented by the formula III;

[0029]

[0030] (3) In the presence of a third organic solvent and a catalyst, the compound represented by the formula III and the bromination reagent are subjected to a contact reaction to obtain the compound represented by the formula IV;

[0031]

[0032] According to the present invention, preferably, in step (1), the first organic solvent is at least o...

Embodiment 1

[0047] As shown in Formula 3, this embodiment provides a preparation method of the crisborole intermediate, and the specific preparation method is as follows:

[0048] (1) Preparation of 4-(3-(formyl)phenoxy)benzonitrile (compound shown in formula II)

[0049] Add 122g (1mol) of m-hydroxybenzaldehyde (compound shown in formula I), 400ml of DMF, and 276g (2mol) of potassium carbonate into the reaction kettle, add 182g (2mol) of p-fluorobenzonitrile under stirring, react at 110°C for 16h, cool, Add 2000ml of water, extract with ethyl acetate three times, recover ethyl acetate, beat with methanol, filter, and dry to obtain 203g of brown solid, yield 91%;

[0050] (2) Preparation of 4-(3-(hydroxymethyl)phenoxy)benzonitrile (compound shown in formula III)

[0051] 223g (1mol) of 4-(3-(formyl)phenoxy)benzonitrile (compound shown in formula II), 2000ml methanol was added to the reaction kettle, and then 18.9g (1mol) sodium borohydride was added to the reaction in batches Kettle, af...

Embodiment 2

[0054] As shown in Formula 3, this embodiment provides a preparation method of the crisborole intermediate, and the specific preparation method is as follows:

[0055] (1) Preparation of 4-(3-(formyl)phenoxy)benzonitrile (compound shown in formula II)

[0056]Add 122g (1mol) of m-hydroxybenzaldehyde (compound shown in formula I), 400ml of DMF, and 276g (2mol) of potassium carbonate into the reaction kettle, add 182g (2mol) of p-fluorobenzonitrile under stirring, react at 110°C for 16h, cool, Add 2000ml of water, extract with ethyl acetate three times, recover ethyl acetate, beat with methanol, filter, and dry to obtain 203g of brown solid, yield 91%;

[0057] (2) Preparation of 4-(3-(hydroxymethyl)phenoxy)benzonitrile (compound shown in formula III)

[0058] 223g (1mol) of 4-(3-(formyl)phenoxy)benzonitrile (compound shown in formula II), 2000ml methanol was added to the reaction kettle, and then 18.9g (1mol) sodium borohydride was added to the reaction in batches Kettle, aft...

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Abstract

The invention discloses a crisaborole intermediate preparation method, wherein the crisaborole intermediate has a structure represented by a formula IV. The preparation method comprises: in the presence of a first organic solvent and a first alkali, carrying out a contact reaction on a compound represented by a formula I and p-fluorobenzonitrile to obtain a compound represented by a formula II; inthe presence of a second solvent, carrying out a contact reaction on the compound represented by the formula II and an alkali metal borohydride to obtain a compound represented by a formula III; andin the presence of a third organic solvent and a catalyst, carrying out a contact reaction on the compound represented by the formula III and a bromination reagent to obtain a compound represented bya formula IV. According to the present invention, with the preparation method, the reaction raw material p-fluorobenzonitrile is used as the ortho-position steric hindrance group, such that the use ofprotective groups is eliminated, the selectivity of the bromination reaction is improved, the process cost is low, the raw material price is cheap, and the method can be well used for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and more specifically, relates to a preparation method of a crisborole intermediate. 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 the clinical treatment is difficult, which has a great impact on the physical and mental health of patients. [0003] 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 r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/54
CPCC07C253/30C07C255/54Y02P20/55
Inventor 赵玲杨博
Owner WUHAN POLYTECHNIC UNIVERSITY
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