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
[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...
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Published in | Tetrahedron letters Vol. 67; p. 152843 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
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Elsevier Ltd
16.03.2021
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Abstract | [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. |
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AbstractList | [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. |
ArticleNumber | 152843 |
Author | Mani, Neelakandha S. Carruthers, Nicholas I. Liang, Jimmy Dvorak, Curt A. |
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SubjectTerms | 5-HT7 antagonist Heterocycles Pyrazole coupling Pyrazolo[3,4-d]azepine |
Title | 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 |
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