Route Design To Manufacture: Synthesis Of The Heterocyclic Fragment Of Azd5718 Using A Non-Cryogenic Lithiation-Alkoxycarbonylation Reaction

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.