Synthesis of Asthma Drug Zafirlukast (Accolate) Using Intramolecular Oxidative Coupling via sp³ C–H Bond Activation

Abstract

The FDA-approved drug for the treatment of asthma, zafirlukast, is synthesized engaging multiple catalytic reactions including a new method for the construction of 3-aroylindoles via oxidative cyclization. The highlights include transition-metal and peroxide free C–H bond activation using the stoichiometric amount of sodium persulfate as an oxidizing agent in the construction of 3-aroylindole, avoiding transition metal, with over 28% overall yield. The complete process has a turnaround time of 28 h to get the target molecule starting from substituted aniline, with practically no protecting groups.

Growing Utilization of Radical Chemistry in the Synthesis of Pharmaceuticals

“…Ultimate ketonization of 64.3 into intermediate 64.4 , gave the desired compound 63.4 after oxidation (Scheme 64). The reported protocol constituted a speedy approach towards zafirlukast ( 63.9 ) by providing a turnaround time of 28 h to access the target molecule starting from substituted aniline ( 63.1 ), with practically no protecting groups [193] …”

“…The reported protocol constituted a speedy approach towards zafirlukast (63.9) by providing a turnaround time of 28 h to access the target molecule starting from substituted aniline (63.1), with practically no protecting groups. [193]…”

Application of N-Alkyl Amines as Versatile Building Blocks in Oxidative Coupling Reactions

“…Recently, Chandrasekhar and coworkers [57] reported a similar method using sodium persulfate as oxidant for the synthesis of 3-aroylindoles through intramolecular oxidative cyclization in the absence of copper catalyst. The product was further used as a starting martial for the synthesis of food and drug administration (FDA)-approved anti-asthma drug zafirlukast (Scheme 26).…”

Novel zafirlukast derivatives exhibit selective antibacterial activity againstPorphyromonas gingivalis

“…Several synthetic methods were reported for either linear or convergent synthesis of zafirlukast. 29,30,[33][34][35][36][37][38][39] Here, the concise and linear synthesis of zafirlukast derivatives involved C-C bond formation between various substituted indoles and benzoyl analogues followed by a subsequent sulfamidation step. The initial synthesis centered on creating zafirlukast derivatives 4a and 4b with variations in the arylsulfonamide domain as well as the elimination of the cyclopentyl carbamate of the indole of the parent molecule (Scheme 1).…”