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Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection

Synthetic Routes to 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amines: Cross-Coupling and Challenges in SEM-Deprotection

Authors :
Srinivas Reddy Merugu
Sigrid Selmer-Olsen
Camilla Johansen Kaada
Eirik Sundby
Bård Helge Hoff
Source :
Molecules, Vol 29, Iss 19, p 4743 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

7-Azaindoles are compounds of considerable medicinal interest. During development of the structure–activity relationship for inhibitors of the colony stimulated factor 1 receptor tyrosine kinase (CSF1R), a specific 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine was needed. Two different synthetic strategies were evaluated, in which the order of the key C-C and C-N cross-coupling steps differed. The best route relied on a chemoselective Suzuki–Miyaura cross-coupling at C-2 on a 2-iodo-4-chloropyrrolopyridine intermediate, and subsequently a Buchwald–Hartwig amination with a secondary amine at C-4. Masking of hydroxyl and pyrroles proved essential to succeed with the latter transformation. The final trimethylsilylethoxymethyl (SEM) deprotection step was challenging, as release of formaldehyde gave rise to different side products, most interestingly a tricyclic eight-membered 7-azaindole. The target 2-aryl-1H-pyrrolo[2,3-b]pyridin-4-amine (compound 3c) proved to be 20-fold less potent than the reference inhibitor, confirming the importance of the N-3 in the pyrrolopyrimidine parent compound for efficient CSF1R inhibition.

Details

Language :
English
ISSN :
14203049
Volume :
29
Issue :
19
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.2ab797ff510640988cffcaeaf2843f54
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules29194743