Route Design to Manufacture: Synthesis of the Heterocyclic
Fragment of AZD5718 Using a Non-cryogenic Lithiation-Alkoxycarbonylation
Reaction

Burns, Matthew; Perkins, Dave; Chan, Lai C.; Pilling, Michael J.; Jawor-Baczynska, Anna; Mullen, Alexander K.; Steven, Alan; Wimsey, Chris; Elmekawy, Ahmed; Lamacraft, Alex; Dobson, Benjamin C.; McMillan, Angus E.; Hose, David R. J.; Inglesby, Phillip A.; Raw, Steven A.; Jones, Martin F.

doi:10.1021/acs.oprd.0c00533.s001

op0c00533_si_001.pdf (348.13 kB)

Route Design to Manufacture: Synthesis of the Heterocyclic Fragment of AZD5718 Using a Non-cryogenic Lithiation-Alkoxycarbonylation Reaction

journal contribution

posted on 2021-03-29, 18:33 authored by Matthew 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.