Synthetic Approaches to the New Drugs Approved During 2022

Abstract

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review. ■ SIGNFICANCEWith a brief discussion on the disease target and development background, this review focuses on synthetic routes to access new chemical entities including small molecules, antibody drug conjugates, and this year, a radioligand therapeutic. Drugs approved worldwide are included in the review.

Rational Molecular Editing: A New Paradigm in Drug Discovery

“…William and co-workers exploited the RCM chemistry to optimize the heavily patented pyrimidine-based scaffold, generating the macrocycle pacritinib (Figure ). Pacritinib, a JAK2 (Janus Kinase 2) and FLT3 (fms-like tyrosine kinase-3) dual inhibitor with good selectivity against JAK1 and JAK3, was approved in 2022 for myelo­fibrosis in patients with low platelet counts . Zotiraciclib and SB1578, under clinical assessment, were also obtained by this transformative strategy. , In drug discovery practice, the U-shaped lead compounds, after installing functional handles, could potentially undergo macrocyclization, resulting in the generation of diverse macrocycles.…”

Visible-Light-Mediated Azidation of α-Diazoesters with TMSN3 via Direct Photoexcitation and SH2 Mechanism

“…Organic azides are extensively used in pharmaceuticals, bioorthogonal labeling, biological imaging, and materials synthesis . Meanwhile, they are versatile organic synthons to synthesize N-heterocycles, amines and miscellaneous compounds via diverse transformations, such as well-known azide–alkyne cycloaddition (AAC), C–H amination, and C–N 3 retention reactions .…”