Preparation method of crisaborole impurity

A creborone and impurity technology, which is applied in the field of preparation of creborone impurities, can solve the problems of difficult separation, impurity of degradation products, and low amount of target products, and achieves the effect of simple preparation method and high purity

Pending Publication Date: 2022-07-08
武汉绿合医药科技有限公司
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Problems solved by technology

[0008] At present, there is no relevant literature report on the synthesis method of the impurity crisaborole A, and by conventional methods, the impurities are degraded under strong alkali conditions, and then separated by means of column purification and liquid phase preparation. Miscellaneous, low yield of target product, difficult separation, etc.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of preparation method of criborole impurity A, reaction scheme is such as figure 1 shown, it includes the following steps:

[0035] S1. Preparation of Criborone Impurity II:

[0036] Weigh 2,5-dihydroxybenzaldehyde (10.00g, 72mmol), p-fluorobenzonitrile (8.77g, 72mmol), anhydrous K 2 CO 3 (15.01 g, 109 mmol), N,N-dimethylformamide (100 mL) was added, and the mixture was heated to 100° C. and stirred for 5 h. The sampling point board monitors the disappearance of the p-fluorobenzonitrile point, stops heating, and cools down to room temperature. 300 mL of purified water was added, and an oily substance was precipitated. Let stand, pour out the supernatant, add 50 mL of ethyl acetate to the remaining oil, stir and heat to reflux until clear, cool to room temperature and stir for 1-2 h, let stand, pour out the supernatant to obtain viscous solid cleaborol impurity Ⅱ crude product 11.24g.

[0037] S2. Liquid phase preparation and purification:

[0038] Get the ...

Embodiment 2

[0046] A kind of preparation method of Criborone impurity A, it comprises the steps:

[0047] S1. Preparation of Criborone Impurity II:

[0048] Weigh 2,5-dihydroxybenzaldehyde (5.00g, 36mmol), p-fluorobenzonitrile (4.38g, 36mmol), anhydrous K 2 CO 3 (7.50 g, 54 mmol), acetonitrile (50 mL) was added, and the reaction was heated to reflux for 6 h. The sampling point board monitors the disappearance of the p-fluorobenzonitrile point, stops heating, and cools down to room temperature. Suction filtration, and the filtrate was concentrated under reduced pressure to dryness to obtain an oily substance. Add 30 mL of anhydrous ethanol to the oil, stir and heat to 45°C to dissolve, then cool to room temperature after dissolving, slowly add 120 mL of ice water, stir and crystallize for 0.5 to 1 h, filter with suction, and blow dry the filter cake to obtain 6.90 g of a yellow-brown solid.

[0049] S2. Liquid phase preparation and purification:

[0050]Take the yellow-brown solid, ad...

Embodiment 3

[0054] A kind of preparation method of Criborone impurity A, it comprises the steps:

[0055] S1. Preparation of Criborone Impurity II:

[0056] Weigh 2,5-dihydroxybenzaldehyde (3.00g, 22mmol), p-fluorobenzonitrile (3.16g, 26mmol), anhydrous K 2 CO 3 (9.05 g, 65 mmol), added acetonitrile (30 mL), heated to reflux for 6 h. Sampling point plate monitoring 2,5-dihydroxybenzaldehyde point basically completes the reaction, stop heating, and cool down to room temperature. Suction filtration, and the filtrate was concentrated under reduced pressure to dryness to obtain an oily substance. Add 30 mL of anhydrous ethanol to the oil, stir and heat to 45°C to dissolve, then cool to room temperature after dissolving, slowly add 120 mL of ice water, stir and crystallize for 0.5 to 1 h, filter with suction, and blow dry the filter cake to obtain 4.30 g of a yellow-brown solid.

[0057] S2. Liquid phase preparation and purification:

[0058] Take the yellow-brown solid, add acetonitrile ...

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Abstract

The invention relates to a preparation method of a crisaborole impurity A. The preparation method comprises the following steps: S1, taking 2, 5-dihydroxybenzoic acid and p-halobenzonitrile as raw materials to react, and after the reaction is completed, separating reaction liquid to generate a crisaborole impurity II crude product; s2, purifying the crisaborole impurity I crude product by adopting liquid phase preparation to obtain a refined product; and S3, reducing the crude product of the crisaborole impurity II by using sodium borohydride, and after the reaction is completed, separating and purifying the reaction liquid to obtain the crisaborole impurity A. The preparation method has the advantages that 2, 5-dihydroxybenzoic acid and p-halobenzonitrile are used as raw materials, the raw materials react to generate a crisaborole impurity II, the crisaborole impurity II is purified and then reduced by hydroboration, and the crisaborole A is obtained, so that the preparation method is simple, and the obtained impurity A is high in purity and can be used as a standard substance for the quantitative detection process of crisaborole A; the used reagent raw materials are cheap and easy to obtain, and the crisaborole impurity II with high purity can be prepared in the synthesis route.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a preparation method of cleaborol impurity. Background technique [0002] Criborole was developed by Anacor, and Pfizer acquired Anacor at a high price. In December 2016, Criborole was approved by the US FDA, becoming the first new drug approved by the US FDA for the treatment of atopic dermatitis (AD) in the past 15 years. molecular entities. In July 2020, Criborone ointment was approved for marketing in China, becoming the first and only topical hormone-free PDE-4 inhibitor suitable for the treatment of mild to moderate atopic dermatitis in children and adults aged 2 years and above. prescription. [0003] The structural formula of Criborone is as follows: [0004] [0005] As a drug on the market, its quality must be effectively controlled. Among them, the impurity content of the drug is the key inspection index in the drug. Some impurities exceeding the st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C253/34C07C255/54
CPCC07C253/30C07C253/34C07C255/54Y02P20/584
Inventor 王大鹏雷帅刘迁秦志平万梦
Owner 武汉绿合医药科技有限公司
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