Regioselective assembly of fused pyrazole-azepine heterocycles: Synthesis of the 5-HT7 antagonist 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine

• Published in: Tetrahedron letters Vol. 67; p. 152843
• Main Authors: Dvorak, Curt A., Liang, Jimmy, Mani, Neelakandha S., Carruthers, Nicholas I.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 16.03.2021
• Subjects: 5-HT7 antagonist; Heterocycles; Pyrazole coupling; Pyrazolo[3,4-d]azepine; Heterocycles; Pyrazolo[3,4-d]azepine; Pyrazole coupling; 5-HT7 antagonist
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2021.152843

[Display omitted] •Selective pyrazole construction.•Regioselective fused azepine-pyrazole assembly.•Pyrazole triflate coupling.•Selective Ring expansion.•Selective 5-HT7 antagonist clinical candidate. The synthesis of the 5-HT7 antagonist 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine is described using a regioselective assembly of a pyrazole ring fused to an azepine ring. Two different approaches were examined for the construction of the fused pyrazole-azepine heterocyclic core. These were based on the timing and method of installation of the appended aryl ring and construction of the fused heterocycle. The team focused on a route that featured a palladium coupling reaction to introduce the aryl ring via a pyrazole triflate and a selective alkylation to set the position of benzyl moiety on the pyrazole nitrogen. This led to a scalable synthesis of 1 (JNJ-18038683) allowing the discovery team to select and advance a clinical candidate.