Preparation method of crisaborole and intermediate product thereof

A technology of crisborol and its products, which is applied in the field of preparation of crisborol and its intermediate products, can solve the problems of harsh reaction conditions and unfavorable scale-up production, and achieve short reaction steps, reduced by-products, and mild reaction conditions Effect

Pending Publication Date: 2022-01-28
SHANGHAI GAOZHUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The common method for preparing aryl boronic acid or borate is to introduce boron atom through metal exchange between Grignard reagent or lithium substance and triisopropyl borate. The reaction conditions of this method are relatively harsh, which is not conducive to industrial scale-up production. Therefore, it is expected to seek a synthetic route with mild reaction conditions, high yield and suitable for industrial scale production by changing the protection of some groups and improving and optimizing the method of synthesizing aryl boronic acid or boronic acid ester.

Method used

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  • Preparation method of crisaborole and intermediate product thereof
  • Preparation method of crisaborole and intermediate product thereof
  • Preparation method of crisaborole and intermediate product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The reaction formula for the preparation of compound III is as follows:

[0066]

[0067] Add compound II (5.0 g, 0.023 mol) and methanol (40 mL) into the three-necked flask, and add 10 drops of concentrated sulfuric acid dropwise. After the addition, the temperature of the reaction system is raised to 60° C., and the reaction is stopped after the completion of the reaction as detected by TLC;

[0068] The reaction solution was concentrated under reduced pressure, 25ml of ethyl acetate and 15ml of water were added to the concentrate, and 15ml of saturated NaHCO was added to the organic layer after liquid separation. 3 After solution washing and liquid separation, the organic layer was washed with 15 ml of saturated brine. After liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid (5.04 g, 96.7% yield); 1 H-NMR (400Hz, DMSO-d 6 )δ (ppm) 3.81 (s, 3H), 6.89 (dd, J = 2.0, 2...

Embodiment 2

[0070] The reaction formula for the preparation of compound III is as follows:

[0071]

[0072] Add compound II (50.0 g, 0.23 mol) and methanol (400 mL) to the three-necked flask, and add 7.5 ml of concentrated sulfuric acid dropwise. After the addition, the temperature of the reaction system is raised to 60° C., and the reaction is stopped after TLC detects that the reaction is complete;

[0073] Concentrate the reaction solution under reduced pressure, add 250ml ethyl acetate and 150ml water to the concentrate, add 150ml saturated NaHCO to the organic layer after liquid separation 3 After solution washing and separation, the organic layer was washed with 150 ml of saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid (51.3 g, 96.4% yield).

Embodiment 3

[0075] The reaction formula of compound IV preparation is as follows:

[0076]

[0077] Add compound III (4.9g, 0.021mol), N,N-dimethylformamide (15mL), potassium carbonate (5.86g), p-fluorobenzonitrile (5.14g) into the three-necked flask, and the temperature of the reaction system rises after the addition is complete To 110°C, stop the reaction after TLC detects that the reaction is complete;

[0078] Filtrate, add the filtrate to ml water to quench, filter to obtain off-white solid (6.52g, 95.6% yield); 1 H-NMR (400Hz, DMSO-d 6 )δ (ppm) 3.82 (s, 3H), 7.18 (d, J = 8.4Hz, 2H), 7.26 (dd, J = 2.8, 2.4Hz, 1H), 7.49 (d, J = 2.4Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.86 (d, J=8.8Hz, 2H).

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Abstract

The invention discloses a preparation method of a crisaborole intermediate product. The crisaborole intermediate product has a structure represented by a general formula A1. The preparation method comprises the following steps: S1, adding a compound represented by a chemical formula II into an organic solvent, adding an acidic material, and carrying out a reaction to obtain a compound represented by a chemical formula III. The invention also discloses a preparation method of the crisaborole, which comprises the preparation method of the intermediate product of the crisaborole, and further comprises the following steps: adding the compound represented by a chemical formula VI into an organic solvent, carrying out contact reaction on the compound and bis (pinacolato) diboron under an alkaline condition and a palladium catalyst, and cyclizing under an acidic condition to obtain the crisaborole. According to the present invention, the yield and the safety performance of the whole process can be improved, the process production process is optimized, the excellent mass production method is provided for the crisaborole, and the crisaborole can be well applied to the industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, in particular to a preparation method of crisborole and its intermediate product. Background technique [0002] Crisaborole is a novel non-steroidal phosphodiesterase 4 (PDE4) inhibitor developed by Anacor Pharmaceuticals (now acquired by Pfizer) in the United States , this inhibition leads to increased intracellular concentrations of cyclic adenosine monophosphate (cAMP) and reduced release of pro-inflammatory cytokines for the treatment of fungal infections. In 2016, it was approved by the US Food and Drug Administration (FDA) as a topical ointment for the treatment of mild to moderate atopic dermatitis (AD) aged 2 and over, with the trade name Eucrisa. The chemical name of Crisaborole is 4-[(1,3-dihydro-1-hydroxyl-2,1-benzoxaborolane-5-yl)oxy]benzonitrile, and the English name is 4-[ (1,3-Dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, the chemical structural formula is as shown...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/54C07C67/08C07C69/84C07D309/12C07F5/02
CPCC07C253/30C07C67/08C07D309/12C07F5/025C07C69/84C07C255/54
Inventor 华岳庭高东李维华王江淮
Owner SHANGHAI GAOZHUN PHARMA CO LTD
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