Fit-for-purpose synthesis of dual leucine zipper kinase (DLK) inhibitor GNE-834. Issue 43 (22nd October 2020)

• Record Type: Journal Article
• Authors: Xu, Jie; Carrera, Diane E.; Beaudry, Danial; Siu, Michael; Huestis, Malcolm P.; Liu, Wendy; Angelaud, Rémy; Gosselin, Francis
• Is Part Of: Tetrahedron letters. Volume 61:Issue 43(2020)
• Publication Date: 2020-10-22
• Subjects: Suzuki coupling -- Reductive amination -- Resolution -- DLK inhibitor -- ALS; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2020.152430
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: A fit-for-purpose synthesis of DLK inhibitor. Suzuki–Miyaura coupling at 500 g scale. Separation of diastereomers by resolution. Abstract: A practical fit-for-purpose synthesis of dual leucine zipper kinase (DLK) inhibitor GNE-834 (1) was developed. The key CC bond was constructed via a Suzuki–Miyaura cross-coupling of iodopyrazole 2 and pyridine boronic ester 3 to afford ketone 12 . Subsequent selective reductive amination of ketone 12 with morpholine followed by a resolution via tosylate salt formation provided GNE-834 (1) in 39% overall yield from iodide 2 with 98.9 A% HPLC purity.