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

A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor

We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor <b>GDC-0980</b>. The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH₃ was employed to replace Na­(OAc)₃BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with (<i>S</i>)-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC

Development of an Efficient Manufacturing Process for Reversible Bruton’s Tyrosine Kinase Inhibitor GDC-0853

Efforts toward the process development of reversible Bruton’s tyrosine kinase (BTK) inhibitor GDC-0853 (<b>1</b>) are described. A practical synthesis of GDC-0853 was accomplished via a key highly regioselective Pd-catalyzed C–N coupling of tricyclic lactam <b>5</b> with 2,4-dichloronicotinaldehyde (<b>6</b>) to afford the C–N coupling product <b>3</b>, a Suzuki–Miyaura cross-coupling of intermediate <b>3</b> with boronic ester <b>4</b> derived from a Pd-catalyzed borylation of tetracyclic bromide <b>7</b>, to generate penultimate aldehyde intermediate <b>2</b> and subsequent aldehyde reduction and recrystallization. Process development of starting materials <b>5</b>, <b>6</b>, and <b>7</b> is also discussed

A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate

We report a practical synthesis of PI3K inhibitor <b>GDC-0941</b>. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API