Telescoped Two-Step Continuous-Flow Synthesis of Nevirapine Enabled by the On-Demand Generation of NaHMDS
Maksim Vasilev, Rajasekar Reddy Annapureddy, Chengfeng Ye, Sridhar Regati, Praveen Kumar Gajula, Jonathan Bietsch, Zhirui Wang, Jack D. Brown, Gopal Sirasani, Aravind S. Gangu, Paul Guo, Bo Qu, Chris H. SenanayakeAbstract
A telescoped two-step fully continuous-flow process for the synthesis of nevirapine (trade name: Viramune), a key therapeutic agent for the prevention and treatment of HIV-1 infection, has been developed. The process employs, for the first time, sodium bis(trimethylsilyl)amide (NaHMDS) as a homogeneous, process-friendly base for both reaction stages and enables direct conversion of methyl 2-(cyclopropylamino)nicotinate and 2-chloro-3-amino-4-picoline to nevirapine without isolation of the cyclization intermediate. The optimized process operates with a total residence time of 10 min and delivers crude nevirapine in 91.9% overall isolated yield across two reaction steps, with a space-time yield of ∼365 g/h/L and 99.6 A% HPLC purity. Furthermore, we developed an on-demand continuous generation of NaHMDS in diglyme (up to ∼2.0 M) using a sodium packed-bed column reactor. Using on-demand generated NaHMDS, the telescoped synthesis yielded crude nevirapine in 90.7% isolated yield (∼340 g/h/L space-time yield and 99.5 A% purity), providing a scalable and cost-effective alternative to NaH applied in the current commercial synthesis.