posted on 2021-03-29, 18:33authored byMatthew Burns, Dave Perkins, Lai C. Chan, Michael J. Pilling, Anna Jawor-Baczynska, Alexander K. Mullen, Alan Steven, Chris Wimsey, Ahmed Elmekawy, Alex Lamacraft, Benjamin C. Dobson, Angus E. McMillan, David R. J. Hose, Phillip A. Inglesby, Steven A. Raw, Martin F. Jones
Route design and process development
of the small nitrogen heterocycle 2·HCl, a constituent
of AZD5718 (1), is
described. The novel synthetic sequence to 2.HCl involves
a desymmetrizing alkylation of 4-nitropyrazole, a non-cryogenic lithiation-alkoxycarbonylation,
and a global reduction-cyclization. This new synthetic route was implemented
in the manufacture of 2.HCl and was able to deliver over
1000 kg of product with a yield of 77% over the three stages.