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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Oct 16

PMID 39407670

Authors

Srinivas Reddy Merugu

Sigrid Selmer-Olsen

Camilla Johansen Kaada

Eirik Sundby

Bard Helge Hoff

Affiliations

Soon will be listed here.

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-1-pyrrolo[2,3-]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-1-pyrrolo[2,3-]pyridin-4-amine (compound ) 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.

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