Advances in the Synthesis of Ritlecitinib, a Novel Therapeutic Agent forAlopecia Areata

Ritlecitinib 1 is an oral selective JAK3/TEC kinase inhibitor developed by Pfizer Inc. It was approved for marketing in the US in June 2023 for the treatment of severe alopecia areata in adults and adolescents aged 12 years and older. This article reviews the research progress on the synthetic methods of ritlecitinib 1 reported to date, including routes starting from 5-amino-2- methylpyridine, Boc-D-pyroglutamic acid ethyl ester, and Boc-L-alaninal, and discusses the characteristics of each method (e.g., reaction steps, total yield, atom economy, production conditions, and cost). Among the summarized routes, Pfizer Inc.’s second-generation route (starting from 5-amino2-methylpyridine) has achieved mass production on a tens-of-kilograms scale, making it currently applicable for process scale-up. Additionally, Shandong Fuchang Pharmaceutical Co., Ltd.’s route a (starting from Boc-D-pyroglutamic acid ethyl ester) is highly competitive as a new process. It completely avoids the chiral resolution process, uses relatively low-cost chiral raw materials, and achieves a high total yield of 40.1%. If the hydrogen pressure required for reductive amination in this route can be further reduced and its process feasibility verified in large-scale production, it is expected to become another efficient option for industrial production. This review aims to provide comprehensive references for the industrial-scale production of ritlecitinib 1.