Preparation method of crisaborole intermediate

A technology of crisborole and intermediates, applied in the field of drug synthesis, can solve the problems of undisclosed preparation methods, increased reaction energy consumption, inconvenient operation, etc., to reduce the reaction temperature and the use of water separators, reduce content, Effect of improving product yield and purity

Pending Publication Date: 2021-12-17
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the reaction, water is produced, which affects the progress of the reaction. The temperature should be further raised to remove the water produced in the reaction by toluene to increase the yield. This will undoubtedly greatly increase the energy consumption of the reaction, and the operation is also extremely inconvenient.
[0017] Although CN108659025A discloses 4-(4-bromo-3-(1,3-dioxolan-2-yl) phenoxy) benzonitrile compound, its preparation method is not disclosed, while referring to the above method with 4-( 4-bromo-3-formylphenoxy)benzonitrile is used as the starting material to react with ethylene glycol under acidic conditions at high temperature for a long time to prepare 4-(4-bromo-3-(1,3-dioxolane- In addition to the above-mentioned problems when 2-yl)phenoxy)benzonitrile, there are still a small amount of cyanohydrolysis impurities, which are difficult to refine
[0018] In summary, there are many deficiencies in the preparation methods of the relevant glyoxal intermediates in the current crisborol preparation process in terms of product purity, yield, and test operations. The preparation method suitable for industrialized production of glyoxal protection intermediate with high product yield and high purity is still a problem to be solved at present

Method used

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  • Preparation method of crisaborole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] At room temperature, 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), butanone ethylene glycol ketal (MED, 15.10g, 0.13mol), p-toluenesulfonic acid (0.86g, 0.005 mol) was added to dry dichloromethane (300ml), and the temperature was controlled at 20-25°C until the reaction was completed. Then, saturated sodium bicarbonate solution (150ml) was added and stirred for 10-15min, and then the organic layer was separated and purified water (150ml×3 ), washed with saturated brine (150ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 4-bromo-3-(1,3-dioxolane-2-yl)phenol. The yield is 97.5%, and the purity is 99.83%.

Embodiment 2

[0041] At room temperature, 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (12.78g, 0.11mol), 1R-(-)-10-camphorsulfonic acid (1.16g, 0.005mol ) was added into dry dichloromethane (300ml), and the temperature was controlled at 20-25°C until the reaction was completed. Then, saturated sodium bicarbonate solution (150ml) was added and stirred for 10-15min, then the organic layer was separated and purified water (150ml×3) Washing, washing with saturated brine (150ml), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness under reduced pressure is 4-bromo-3-(1,3-dioxolan-2-yl)phenol, yield 96.9%, 99.79% pure.

Embodiment 3

[0043] At room temperature, 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (11.62g, 0.10mol), 1S-(+)-10-camphorsulfonic acid (1.16g, 0.005mol ) was added into dry dichloromethane (300ml), and the temperature was controlled at 20-25°C until the reaction was completed. Then, saturated sodium bicarbonate solution (150ml) was added and stirred for 10-15min, then the organic layer was separated and purified water (150ml×3) Washing, washing with saturated brine (150ml), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness under reduced pressure is 4-bromo-3-(1,3-dioxolan-2-yl)phenol, yield 96.7%, 99.77% pure.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a crisaborole intermediate. MED is used for replacing ethylene glycol in the prior art for acetal protection, so that the reaction temperature and the use of a water segregator can be obviously reduced, the reaction operation is simplified, and the energy consumption is reduced. Compared with the prior art, the preparation process provided by the invention has the advantages that the product yield and purity are higher, and the preparation process is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of a crisborole intermediate. Background technique [0002] Crisaborole, developed by Anacor Pharmaceuticals, is a phosphodiesterase 4 (PDE4) inhibitor that results in increased intracellular cyclic adenosine monophosphate (cAMP) levels, used in Topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older holds great promise. On December 14, 2016, it was approved by the U.S. Food and Drug Administration (FDA) for marketing. The trade name is Eucrisa, and its chemical structure is as follows: [0003] [0004] 克立硼罗的制备方法已有研究报道,CN109456347A、IN201821000974、WO2019138422A1、US2019241585A1、WO2019120637A1、IN201741016807、CN109517003A、CN108864160A、WO2018224923A1、WO2018216032A1、WO2018207216A1、CN108659024A、WO2018150327A1、WO2018115362A1、CN108047261A、CN107759625A、US20170305936A1、CN106928264A、US20070286822A1、 It has bee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/22C07D317/20
CPCC07D317/22C07D317/20
Inventor 张乃华鲍广龙刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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