Crisaborole

Description Crisaborole is a phosphodiesterase- 4 (PDE4) inhibitor that was approved by the USFDA for the treatment of mild to moderate atopic dermatitis (AD) in patients aged two years and older. The drug, which was developed by Anacor Pharmaceuticals and later acquired and marketed by Pfizer, is delivered as a 2% ointment, which is applied topically. The unique employment of boron within the chemical structure of the drug is designed to enable selective engagement of PDE4 (an enzyme involved in the conversion of cAMP into AMP, which signals for downstream inflammatory events), effective penetration of the drug through human skin, and rapid clearance to limit systemic circulation.
Chemical 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.