906673-24-3

Usage

Uses

Used in Pharmaceutical Industry:
AN2728 is used as an anti-inflammatory agent for the treatment of mild to moderate atopic dermatitis (AD) in patients aged two years and older. It is being studied for its potent activity both in vitro and in vivo, and its ability to suppress the release of proinflammatory cytokines such as TNF-α, IL-2, INF-γ, IL-5, and IL-10.
Used in Inflammatory Research:
AN2728 is used as a research tool to study the inhibitory activity of PDE4 and cytokine release, providing insights into the development of new anti-inflammatory drugs and therapies.

Biochem/physiol Actions

Crisaborole is a non-steroidal anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor. Crisaborole has an IC50 value of 490 nM for PDE4 with similar IC50 values for release of cytokines TNF-α, IL-2, and IFN-γ, and shows little inhibition against other PDE isozymes. Crisaborole has been approved as a topical treatment for atopic dermatitis.

Synthesis

Several disclosures describing synthetic approaches to ethereal boron-containing anti-inflammatory compounds have been published by Anacor. Commercially available bromobenzaldehyde 134 was protected as the corresponding acetal upon subjection to warm ethylene glycol in the presence of catalytic p-toluenesulfonic acid. This was followed by nucleophilic aromatic substitution involving 4-fluorobenzonitrile and subsequent acetal deprotection to furnish diaryl ether 136. Although multiple approaches to crisaborole have been reported from this intermediate diaryl ether 136, the published literature approach involves the following sequence: reduction of the aldehyde with sodium borohydride followed by THP protection to furnish bromobenzene 137, which then underwent lithium-halogen exchange prior to quenching with triisopropyl borate and acidification to arrive at crisaborole (XIII). Alternatively, patents from Anacor describe a general approach employing a Miyaura coupling of 136, enabling the installation of the corresponding pincacol borane, which could then be exposed to reduction conditions using sodium borohydride followed by boric acid wash, aqueous workup, and lyophilization to furnish XIII.

Synthetic route

4-Cyanochlorobenzene (623-03-0) + 1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane (1187190-70-0) → AN2728 (906673-24-3)

Conditions	Yield
With caesium carbonate In dimethyl sulfoxide at 60℃; Reagent/catalyst; Temperature; Solvent;	95%

1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane (1187190-70-0) + 4-fluorobenzonitrile (1194-02-1) → AN2728 (906673-24-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12h; Reagent/catalyst; Temperature;	95%
With potassium carbonate In dimethyl sulfoxide at 60 - 70℃; for 4h; Reagent/catalyst; Temperature; Solvent; Inert atmosphere;	76.9%

1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane (1187190-70-0) + 4-bromobenzenecarbonitrile (623-00-7) → AN2728 (906673-24-3)

Conditions	Yield
With caesium carbonate In dimethyl sulfoxide at 60℃; Reagent/catalyst; Solvent; Temperature;	93.3%

5-(4-cyanophenoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 40℃; Reagent/catalyst; Solvent; Temperature;	93%
With sodium hydroxide at 15 - 45℃;	91%

4-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride In water at 80℃; for 4h;	93%

C25H30BNO5 → AN2728 (906673-24-3)

Conditions	Yield
With methanesulfonic acid In ethanol; water at 20 - 30℃; for 24h; Solvent; Reagent/catalyst;	92%

2,6-dichloro-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile → AN2728 (906673-24-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen; potassium hydroxide In ethanol; water under 760.051 - 3800.26 Torr; for 1h;	90%

pinacol 4-(4-cyanophenoxy)-2-bromomethylphenylborate → AN2728 (906673-24-3)

Conditions	Yield
With water; potassium hydroxide at 55 - 65℃; for 2h; Inert atmosphere;	90%

4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile + water (7732-18-5) → AN2728 (906673-24-3)

Conditions	Yield
Stage #1: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-formylphenoxy]benzonitrile With sodium tetrahydroborate; ethanol at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: water With hydrogenchloride at 40 - 45℃; for 0.5h; Inert atmosphere;	89.4%
Stage #1: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-formylphenoxy]benzonitrile With methanol; sodium tetrahydroborate at 0 - 15℃; for 1h; Inert atmosphere; Stage #2: water With hydrogenchloride pH=4 - 6; Temperature;	76.5%

C26H36BNO4Si → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 40℃; for 5h;	87%

C26H36BNO4Si → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 40℃; for 5h;	87%

diisobutyl 4-(4-cyanophenoxy)-2-bromomethylbenzeneborate → AN2728 (906673-24-3)

Conditions	Yield
With water; potassium hydroxide at 40 - 50℃; for 6h; Inert atmosphere;	85%

4-(4-cyanophenoxy)-2-chloromethylbenzeneboronic acid → AN2728 (906673-24-3)

Conditions	Yield
With triethylamine In water at 50 - 60℃; for 10h; Inert atmosphere;	84%

Triisopropyl borate (5419-55-6) + [5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane + water (7732-18-5) → AN2728 (906673-24-3)

Conditions	Yield
Stage #1: Triisopropyl borate; [5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane With n-hexyllithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Stage #2: water With hydrogenchloride In tetrahydrofuran; hexane pH=1 - 2; Inert atmosphere;	82%

4-(4-cyanophenoxy)-2-formylbenzeneboronic acid → AN2728 (906673-24-3)

Conditions	Yield
With sodium tetrahydroborate In methanol at 4℃; for 25h;	81%

pinacol 4-(4-cyanophenoxy)-2-methylphenylborate → AN2728 (906673-24-3)

Conditions	Yield
Stage #1: pinacol 4-(4-cyanophenoxy)-2-methylphenylborate With 5,5-dibromohydantoin In chlorobenzene at 75℃; for 2h; Stage #2: With water; sodium hydroxide In chlorobenzene at 45℃; for 1h;	80.9%

tetrahydroxydiboron (13675-18-8) + 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (906673-45-8) → AN2728 (906673-24-3)

Conditions	Yield
With (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); potassium acetate; ethylene glycol; XPhos In methanol at 64 - 66℃; Reagent/catalyst; Inert atmosphere; Sealed tube;	80%

tetrahydroxydiboron (13675-18-8) + 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile → AN2728 (906673-24-3)

Conditions	Yield
Stage #1: 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile With hydrogenchloride; sodium nitrite In methanol; water at 0℃; for 0.5h; Stage #2: tetrahydroxydiboron In methanol; water for 1h;	75%

2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1195-66-0) + [5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane → AN2728 (906673-24-3)

Conditions	Yield
Stage #1: [5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane With isopropylmagnesium chloride In tetrahydrofuran at -20 - 20℃; for 3h; Inert atmosphere; Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at 0 - 25℃; for 8h; Inert atmosphere;	72%

C25H32BNO5 → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride; water In tetrahydrofuran at 20℃; for 3h;
With hydrogenchloride In methanol at 20 - 30℃; for 24h;

Reaxys ID: 32488018 → AN2728 (906673-24-3)

4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (906673-45-8) + Trimethyl borate (121-43-7) → AN2728 (906673-24-3)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at -78℃;	Ca. 17 g

4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (906673-45-8) + Triisopropyl borate (5419-55-6) → AN2728 (906673-24-3)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at -78℃;	Ca. 1.8 g

4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (906673-45-8) → AN2728 (906673-24-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: dmap / tetrahydrofuran / 1 h / 20 °C 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 85 °C / Inert atmosphere 3: hydrogenchloride / tetrahydrofuran; water / 40 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 20 °C 2: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 80 °C / Inert atmosphere 3: sodium hydroxide / 15 - 45 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine / dichloromethane / 20 °C 2: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 80 °C / Inert atmosphere 3: sodium hydroxide; methanol / 20 °C 4: hydrogenchloride / water / 4 h / 80 °C View Scheme

4-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile + water (7732-18-5) → AN2728 (906673-24-3)

Conditions	Yield
With hydrogenchloride at 0℃;	0.4 g

4-(4-bromo-3-formaldehydephenoxy)benzonitrile (906673-54-9) → AN2728 (906673-24-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; water; sodium tetrahydroborate / methanol / 1 h / 0 °C / Inert atmosphere 2: potassium acetate; XPhos; (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); ethylene glycol / methanol / 64 - 66 °C / Inert atmosphere; Sealed tube View Scheme
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 2-methyltetrahydrofuran / 2 h / 80 °C / Inert atmosphere 2: methanol; sodium tetrahydroborate / 0.5 h / 0 - 20 °C 3: hydrogenchloride / 0 °C View Scheme
Multi-step reaction with 4 steps 1: sodium tetrahydroborate; methanol / 10 - 30 °C 2: pyridine / dichloromethane / 20 °C 3: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 80 °C / Inert atmosphere 4: sodium hydroxide / 15 - 45 °C View Scheme

2-bromo-5-hydroxybenzaldehyde (2973-80-0) → AN2728 (906673-24-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide; toluene / 8 h / 115 °C / Inert atmosphere 2: sodium hydroxide; water; sodium tetrahydroborate / methanol / 1 h / 0 °C / Inert atmosphere 3: potassium acetate; XPhos; (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); ethylene glycol / methanol / 64 - 66 °C / Inert atmosphere; Sealed tube View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide; toluene / 8 h / 115 °C / Inert atmosphere 2: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 2-methyltetrahydrofuran / 2 h / 80 °C / Inert atmosphere 3: methanol; sodium tetrahydroborate / 0.5 h / 0 - 20 °C 4: hydrogenchloride / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 h / 75 - 85 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 65 - 70 °C 3.1: sodium tetrahydroborate; methanol / 1 h / 0 - 15 °C / Inert atmosphere 3.2: pH 4 - 6 View Scheme

4-fluorobenzonitrile (1194-02-1) → AN2728 (906673-24-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide; toluene / 8 h / 115 °C / Inert atmosphere 2: sodium hydroxide; water; sodium tetrahydroborate / methanol / 1 h / 0 °C / Inert atmosphere 3: potassium acetate; XPhos; (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); ethylene glycol / methanol / 64 - 66 °C / Inert atmosphere; Sealed tube View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide; toluene / 8 h / 115 °C / Inert atmosphere 2: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 2-methyltetrahydrofuran / 2 h / 80 °C / Inert atmosphere 3: methanol; sodium tetrahydroborate / 0.5 h / 0 - 20 °C 4: hydrogenchloride / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 h / 75 - 85 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 65 - 70 °C 3.1: sodium tetrahydroborate; methanol / 1 h / 0 - 15 °C / Inert atmosphere 3.2: pH 4 - 6 View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 80 - 90 °C 2.1: toluene-4-sulfonic acid / dichloromethane / 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -75 - 80 °C / Inert atmosphere 3.2: -75 - 80 °C 4.1: hydrogenchloride / methanol / 24 h / 20 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 80 - 90 °C 2: toluene-4-sulfonic acid / dichloromethane / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 20 h / 90 - 100 °C / Autoclave; Inert atmosphere 4: methanesulfonic acid / ethanol; water / 24 h / 20 - 30 °C View Scheme

4-cyanophenol (767-00-0) → AN2728 (906673-24-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water; 1,4-dioxane / 0.5 h / 20 °C 1.2: 3 h / 55 °C 2.1: hydrogenchloride / 1 h / 20 °C 3.1: sodium tetrahydroborate / tetrahydrofuran 4.1: sodium nitrite; hydrogenchloride / methanol; water / 0.5 h / 0 °C 4.2: 1 h View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water; 1,4-dioxane / 0.5 h / 20 °C 1.2: 3 h / 55 °C 2.1: hydrogenchloride / 1 h / 20 °C 3.1: sodium tetrahydroborate / tetrahydrofuran 4.1: sodium nitrite; hydrogenchloride / methanol; water / 0.5 h / 0 °C 4.2: 1 h View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 95 - 100 °C 2.1: potassium carbonate / methanol; water / 1 h / 40 °C 3.1: 1H-imidazole / dichloromethane / 3 h / 25 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 1 h 4.2: 20 - 30 °C 5.1: cesium acetate; pyridine / ethyl acetate / 20 h / 30 - 35 °C / Inert atmosphere; Irradiation 6.1: hydrogenchloride / water; tetrahydrofuran / 5 h / 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 95 - 100 °C 2.1: potassium carbonate / methanol; water / 1 h / 40 °C 3.1: 1H-imidazole / acetone / 4 h / 30 - 40 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / tetrahydrofuran / 1 h 4.2: 5 h / 20 - 30 °C 5.1: cesium acetate; picoline / ethyl acetate / 16 h / 30 - 35 °C / Inert atmosphere; Irradiation 6.1: hydrogenchloride / water; tetrahydrofuran / 5 h / 40 °C View Scheme

AN2728 (906673-24-3) → 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzoic acid

Conditions	Yield
With sodium hydroxide; water In 1,4-dioxane; methanol for 144h; Reflux;	79%
With sodium hydroxide In ethanol for 3h; Heating / reflux;	8%
Stage #1: AN2728 With sodium hydroxide In ethanol for 3h; Heating / reflux; Stage #2: With hydrogenchloride Product distribution / selectivity;	8%
With water; sodium hydroxide In ethanol for 3h; Solvent; Temperature; Time; Reflux;	8%
Stage #1: AN2728 With sodium hydroxide In ethanol; water for 3h; Heating / reflux; Stage #2: With hydrogenchloride In ethanol; water	8%

AN2728 (906673-24-3) + butyric acid (107-92-6) → C18H16BNO4

Conditions	Yield
Stage #1: butyric acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60℃; for 1h; Stage #2: AN2728 In tetrahydrofuran for 2h;	76.32%

AN2728 (906673-24-3) + dimethylphosphoric acid (813-78-5) → C16H15BNO6P

Conditions	Yield
Stage #1: dimethylphosphoric acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60℃; for 1h; Stage #2: AN2728 In tetrahydrofuran for 2h;	66.58%

AN2728 (906673-24-3) + isobutyric Acid (79-31-2) → C18H16BNO4

Conditions	Yield
Stage #1: isobutyric Acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60℃; for 1h; Stage #2: AN2728 In tetrahydrofuran for 2h;	62.46%

AN2728 (906673-24-3) + 3-Phenylpropionic acid (501-52-0) → C23H18BNO4

Conditions	Yield
Stage #1: 3-Phenylpropionic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60℃; for 1h; Stage #2: AN2728 In tetrahydrofuran for 2h;	62.06%

AN2728 (906673-24-3) + diphenyl hydrogen phosphate (838-85-7) → C26H19BNO6P

Conditions	Yield
Stage #1: diphenyl hydrogen phosphate With 1,1'-carbonyldiimidazole In tetrahydrofuran at 60℃; for 1h; Stage #2: AN2728 In tetrahydrofuran for 2h;	43.38%

AN2728 (906673-24-3) → 5-(4-(1H-tetrazol-5-yl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol (947162-19-8)

Conditions	Yield
With sodium azide; ammonium chloride In N,N-dimethyl-formamide at 80℃; for 48h;	23%

AN2728 (906673-24-3) → 1-hydroxy-5-[4-(tetrazole-1-yl)phenoxy]-2,1-benzoxaborole

Conditions	Yield
With sodium azide; ammonium chloride In N,N-dimethyl-formamide at 80℃; for 48h;	23%
With sodium azide; ammonium chloride In N,N-dimethyl-formamide at 80℃; for 48h;	23%
With sodium azide; ammonium chloride In N,N-dimethyl-formamide at 80℃; for 48h;	23%

AN2728 (906673-24-3) → 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzamide

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; water / ethanol / 3 h / Reflux 2: 1,1'-carbonyldiimidazole; ammonium bicarbonate / N,N-dimethyl-formamide / 20 °C View Scheme

Upstream product

• 906673-45-8 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile 
• 7732-18-5 water 
• 13675-18-8 tetrahydroxydiboron 
• 906673-54-9 4-(4-bromo-3-formaldehydephenoxy)benzonitrile 
• 2973-80-0 2-bromo-5-hydroxybenzaldehyde 
• 1194-02-1 4-fluorobenzonitrile 
• 767-00-0 4-cyanophenol 
• 73183-34-3 bis(pinacol)diborane 
• 94527-39-6 1-bromo-4-methoxy-2-(methoxymethyl)benzene 
• 1451392-22-5 4-(methoxy)-2-(methoxymethyl)benzeneboronic acid 
• 1187190-70-0 1,3-dihydro-1,5-dihydroxy-2,1-benzoxaborolane 
• 2737-20-4 (2-bromo-5-hydroxybenzene)methanol 

Downstream Products

• 1187187-13-8 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzoic acid methyl ester 
• 947162-19-8 5-(4-(1H-tetrazol-5-yl)phenoxy)benzo[c][1,2]oxaborol-1(3H)-ol 

Relevant academic research and scientific papers

Preparation method of crisaborole

The invention discloses a preparation method of crisaborole. The preparation method comprises the following steps: by taking m-methylphenol as a raw material, firstly coupling the m-methylphenol with 4-halogenated-cyanophenyl, and then under the action of a halogenating reagent, increasing the yield of an intermediate product 4-(4-halogen-3-methylphenoxy) cyanophenyl; and carrying out halogen-metal exchange, halogenation, ring closing and other reactions to prepare the crisaborole. Compared with the prior art, the method has advantages that the raw materials are cheap and easy to obtain, and expensive reagents and raw materials in the prior art are not used; the reaction is mild, and ultralow-temperature reaction in the prior art can be avoided; the method is short in reaction time, free of column chromatography purification, simple in process, convenient to operate and suitable for industrial production.

Preparation method of benzoxaborole compound

The invention discloses a preparation method of a benzoxaborole compound. The preparation method comprises the following steps: (1) reacting raw materials containing halogenated hydrocarbon and boric acid ester under an alkaline condition, acidifying and hydrolyzing to obtain an intermediate VI; and (2) reacting a raw material containing the intermediate VI with halogenated cyanophenyl to obtain the benzoxaborole compound. The raw materials are low in price, the preparation cost of the benzoxaborole compound is reduced, the steps of protection and de-protection of organic groups are not needed in the preparation process, the reaction process is simplified, and yield reduction caused by group protection is avoided; and meanwhile, the method is mild in reaction condition, low in equipment requirement and easy for large-scale industrial production.

Preparation method of crisaborole

The invention discloses a preparation method of crisaborole, which comprises the following steps: S1, reacting 2-bromo-5-hydroxybenzaldehyde with a hydroxyl protecting reagent in a solvent in the presence of alkali to obtain a compound I; S2, reducing the compound I in a solvent in the presence of a reducing agent to obtain a compound I I; S3, reacting the compound I with a hydroxyl protection reagent in a solvent in the presence of alkali to obtain a compound IV; S4, reacting the compound IV with boric acid ester in a solvent in the presence of alkali to obtain a compound V; S5, removing a hydroxyl protecting group from the compound V to obtain a compound VI; and S6, reacting the compound IV with p-fluorobenzonitrile to obtain crisaborole. A hydroxyl protecting group which is more beneficial to removal is adopted in the route, synthesis of boric acid ester is facilitated, side reactions are reduced, the yield is obviously increased, and the method is easy to operate, low in cost and beneficial to industrial production.

Preparation method of crisaborole key intermediate

The invention discloses a method for preparing a crisaborole key intermediate with a structure as shown in a formula I. A synthetic route of the method is as shown in the specification, and the method specifically comprises the following steps: (1) reacting m-hydroxyl benzaldehyde-glycol acetal (II) with an iodine source in the presence of a catalyst to generate an iodinated product III; (2) in the presence of alkali, condensing III and a compound IV to generate V; and (3) in an inert gas atmosphere, carrying out a Miyaura boronation reaction between the compound V and the compound IV under the action of a catalyst to generate a compound VII, which does not need to be further purified, and removing the protection group under the action of acid to obtain a compound I, namely the crisaborole key intermediate. The method has the characteristics of cheap and easily available raw materials, low EHS risk of the used reagent and the synthesis process, simple and convenient separation and purification operation, suitability for industrial production and the like.

Preparation method of crisaborole

The invention provides a preparation method of crisaborole. More specifically, 5-bromophthalide is used as an initial raw material, and is subjected to etherification, hydrolysis, hydroxyl protection, condensation reaction, photoreaction boronation and cyclization to obtain the crisaborole. The preparation method has the advantages of readily available raw materials, mild reaction conditions, avoidance of metal catalysis and harsh conditions due to adoption of photoreaction for boronizing, low cost, convenience in operation and suitability for industrial production.

Crisaborole intermediate, preparation method and application of crisaborole intermediate in preparation of crisaborole

The invention discloses a crisaborole intermediate, a preparation method and application of the crisaborole intermediate in preparation of crisaborole. The crisaborole intermediate has a structure asshown in a formula I in the specification. The preparation method comprises the following steps: carrying out Grignard reaction on a compound shown in a structural formula VI in an organic solvent A or carrying out exchange reaction with a metal Grignard reagent, and reacting with borate to obtain a compound shown in a structural formula V; reacting the obtained compound with the structural formula V with pinacol in an organic solvent B to obtain a compound with a structural formula IV; removing a protecting group from the compound shown in the structural formula IV in an organic solvent C toobtain a compound shown in a structural formula III; and carrying out a coupling reaction on the compound shown in the structural formula III and 4-halogenated cyanophenyl shown in the structural formula II in an organic solvent D under an alkaline condition to obtain the crisaborole intermediate shown in the structural formula I. The method effectively solves the problems of high production costand low product purity, and is suitable for industrial large-scale production.

METHOD FOR PREPARING CRISABOROLE

The invention relates to a method for preparing Crisaborole of Formula I, comprising using m-methylphenol as the starting material to obtain a target product through a five-step reaction. The starting materials and the raw materials used in each step of the method according to the present invention are cheap and easy to obtain, and the process is simple. The reaction of introducing boron atoms into the benzene ring to form an oxygen boron heterocycle is novel, with high yield and mild conditions, and is suitable for industrial production.

PROCESS FOR THE PREPARATION OF CRISABOROLE

The present invention relates to a process for the preparation of crisaborole of formula (I): by preparing intermediates of formulas (II) and (III):

INTERMEDIATES AND PROCESS FOR THE PREPARATION OF A CRYSTALLINE FORM OF A TOPICAL ANTI-INFLAMMATORY AGENT

The present invention relates to a process for the preparation of an inhibitor of phosphodiesterase 4, in particular of phosphodiesterase 4B (PDE4B), and intermediates useful for its preparation.

A method for preparing [...]

The invention discloses a formula I shown in the preparation method of the [...]. Preparation method of this invention comprises the following steps: in the solvent, under the action of alkali and catalyst, the compound IV with the [...][...] alcohol ester as shown in the following reaction, to obtain the compound V can be. Preparation method of the invention, raw materials are apt, simple steps, mild reaction conditions, quality is controllable, is friendly to the environment, the cost is low and the like, and contributes to the industrial production of the raw material, to promote their economic and technological development.