Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design

Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design

Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide

Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide CO to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and <i>in vitro</i> properties of the parent drugs, with an important exception: oxetane analog <b>2</b> displays a clear differentiation with respect to human plasma stability. The prospect of limiting <i>in vivo</i> stability/metabolism, blocking <i>in vivo</i> racemization, and potentially altering teratogenicity is appealing

Development of a Streamlined Manufacturing Process for the Highly Substituted Quinazoline Core Present in KRAS G12C Inhibitor <i>Divarasib</i>

A streamlined process for the synthesis of a highly functionalized quinazoline that enabled late-stage preparation of KRAS G12C inhibitor divarasib is presented herein. The highlights of the synthesis are a telescoped four-step preparation of the key 2-amino-4-bromo-3-fluorobenzonitrile intermediate, a critical aromatic chlorination using NCS and catalytic HCl, a cyclization to a quinazoline dione employing CO2 and DBU, and a DABCO−MsOH-catalyzed Halex reaction to form target quinazoline fluoride 2. In the chlorination step, we encountered an unusual halogen scrambling, resulting in critical 4,5-dichloro and 4,5-dibromo impurities that needed to be controlled down to low levels due to minimal purging power in downstream chemistry. The manufacturing process was demonstrated by the preparation of >500 kg of quinazoline 2 in 39% overall yield and 99.5 area % HPLC purity over nine chemical steps and five isolations