Method for preparing crisaborole

Abstract

The invention discloses a method for preparing crisaborole shown as a formula I. The preparation method disclosed by the invention comprises the following steps: carrying out the following reaction between a compound IV and bis(pinacolato)diboron in a solvent in the presence of alkali and a catalyst, thereby obtaining the compound V. The preparation method disclosed by the invention has the characteristics of being readily available in raw materials, simple in steps, mild in reaction conditions, controllable in quality, environmental-friendly, low in cost and the like. The industrial production of the bulk drug is facilitated, and development of the economic technology is promoted. The structural formula is as shown in the specification.

Description

Technical field

[0001] The present invention relates to a preparation method of crenzaboron. Background technique

[0002] Crisaborole was developed by Anacor Pharmaceuticals. It is a phosphodiesterase 4 (PDE4) inhibitor. This inhibition leads to increased levels of intracellular cyclic adenosine monophosphate (CAMP). The topical treatment of mild to moderate allergic dermatitis in patients 2 years and older has broad prospects. On December 14, 2016, it was approved by the U.S. Food and Drug Administration (FDA) under the trade name Eucrisa.

[0003] The chemical name of Creisaboron is 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborolan-5-yl)oxy]benzonitrile I, which The structural formula is:

[0004]

[0005] The preparation method of cresarboron has been reported. In Bioorganic&Medicinal Chemistry Letters 19(2009) 2129-2132, Tsutomu Akama et al. reported that 2-bromo-5-hydroxybenzaldehyde is used as the raw material, and the aromatic ring is protected. Nucleophilic substitution, depr...

Examples

Embodiment 1

[0056] For the preparation of Intermediate III, the reaction formula is as follows:

[0057]

[0058] Add 2-bromo-5-hydroxybenzyl alcohol II (374g, 1.84mol), N,N-dimethylformamide (2.2L), potassium carbonate (509g, 2mol) and p-fluorobenzonitrile ( 223.1g, 1.84mol), after the addition, the reaction system was heated to 80-90°C for reaction, TLC monitored until the reaction was complete, and the system was slowly added to water (4.4L) for quenching.

[0059] Filtration and drying to obtain an off-white solid, ie Intermediate III, with an HPLC purity of 96.5% and a yield of 95.7%; 1 HNMR(300MHz, CDCl 3 )δ(ppm): 4.75(s, 2H), 6.88(dd, J=8.5, 2.9Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.26(d, J=2.6Hz, 1H) , 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H).

Embodiment 2

[0061] For the preparation of Intermediate III, the reaction formula is as follows:

[0062]

[0063] Add 2-bromo-5-hydroxybenzyl alcohol II (20.3g, 0.1mol), N,N-dimethylformamide (50mL), potassium carbonate (27.6g, 0.2mol) and p-fluorobenzene to a three-necked flask in sequence Nitrile (14.5g, 0.12mol), after the addition, the reaction system was heated to 80-90°C for reaction, TLC monitored until the reaction was complete, and the system was slowly added to water (250mL) for quenching.

[0064] After filtration and drying, an off-white solid, ie Intermediate III, was obtained with an HPLC purity of 93.5% and a yield of 96.2%.

Embodiment 3

[0066] For the preparation of Intermediate IV, the reaction formula is as follows:

[0067]

[0068] Intermediate III (30.4g, 0.1mol), dichloromethane (300ml), 2,3-dihydropyran (16.8g, 0.2mol) and p-toluenesulfonic acid monohydrate (1.9g, 0.01 mol), stirring overnight at room temperature.

[0069] Add 100ml of 1% ammonia water to the system, stir to separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow oil. Add petroleum ether to crystallize to obtain an off-white solid, ie Intermediate IV, with a purity of 98.7% by HPLC , The yield is 88%; 1 HNMR(300MHz, CDCl 3 )δ(ppm) 1.64~1.86(m, 6H), 3.55(m, 1H), 3.88(m, 1H), 4.53(d, J=10.5Hz, 1H), 4.77(d, J=10.2, 2.7Hz , 2H), 6.84 (dd, J = 8.7, 4.2 Hz, 1H), 7.01 (dd, J = 6.6, 3.6 Hz, 2H), 7.27 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 6.3 Hz, 1H), 7.60 (dd, J=6.6, 3.6 Hz, 2H).

Technical field

[0001] The present invention relates to a preparation method of crenzaboron. Background technique

[0002] Crisaborole was developed by Anacor Pharmaceuticals. It is a phosphodiesterase 4 (PDE4) inhibitor. This inhibition leads to increased levels of intracellular cyclic adenosine monophosphate (CAMP). The topical treatment of mild to moderate allergic dermatitis in patients 2 years and older has broad prospects. On December 14, 2016, it was approved by the U.S. Food and Drug Administration (FDA) under the trade name Eucrisa.

[0003] The chemical name of Creisaboron is 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborolan-5-yl)oxy]benzonitrile I, which The structural formula is:

[0004]

[0005] The preparation method of cresarboron has been reported. In Bioorganic&Medicinal Chemistry Letters 19(2009) 2129-2132, Tsutomu Akama et al. reported that 2-bromo-5-hydroxybenzaldehyde is used as the raw material, and the aromatic ring is protected. Nucleophilic substitution, depr...

Examples

Embodiment 1

[0056] For the preparation of Intermediate III, the reaction formula is as follows:

[0057]

[0058] Add 2-bromo-5-hydroxybenzyl alcohol II (374g, 1.84mol), N,N-dimethylformamide (2.2L), potassium carbonate (509g, 2mol) and p-fluorobenzonitrile ( 223.1g, 1.84mol), after the addition, the reaction system was heated to 80-90°C for reaction, TLC monitored until the reaction was complete, and the system was slowly added to water (4.4L) for quenching.

[0059] Filtration and drying to obtain an off-white solid, ie Intermediate III, with an HPLC purity of 96.5% and a yield of 95.7%; 1 HNMR(300MHz, CDCl 3 )δ(ppm): 4.75(s, 2H), 6.88(dd, J=8.5, 2.9Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.26(d, J=2.6Hz, 1H) , 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H).

Embodiment 2

[0061] For the preparation of Intermediate III, the reaction formula is as follows:

[0062]

[0063] Add 2-bromo-5-hydroxybenzyl alcohol II (20.3g, 0.1mol), N,N-dimethylformamide (50mL), potassium carbonate (27.6g, 0.2mol) and p-fluorobenzene to a three-necked flask in sequence Nitrile (14.5g, 0.12mol), after the addition, the reaction system was heated to 80-90°C for reaction, TLC monitored until the reaction was complete, and the system was slowly added to water (250mL) for quenching.

[0064] After filtration and drying, an off-white solid, ie Intermediate III, was obtained with an HPLC purity of 93.5% and a yield of 96.2%.

Embodiment 3

[0066] For the preparation of Intermediate IV, the reaction formula is as follows:

[0067]

[0068] Intermediate III (30.4g, 0.1mol), dichloromethane (300ml), 2,3-dihydropyran (16.8g, 0.2mol) and p-toluenesulfonic acid monohydrate (1.9g, 0.01 mol), stirring overnight at room temperature.

[0069] Add 100ml of 1% ammonia water to the system, stir to separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow oil. Add petroleum ether to crystallize to obtain an off-white solid, ie Intermediate IV, with a purity of 98.7% by HPLC , The yield is 88%; 1 HNMR(300MHz, CDCl 3 )δ(ppm) 1.64~1.86(m, 6H), 3.55(m, 1H), 3.88(m, 1H), 4.53(d, J=10.5Hz, 1H), 4.77(d, J=10.2, 2.7Hz , 2H), 6.84 (dd, J = 8.7, 4.2 Hz, 1H), 7.01 (dd, J = 6.6, 3.6 Hz, 2H), 7.27 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 6.3 Hz, 1H), 7.60 (dd, J=6.6, 3.6 Hz, 2H).

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