Work

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

Year: 2024

Type: article

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.

Source: Molecules

DOI: 10.3390/molecules29194743

Authors: Srinivas Reddy Merugu, Sigrid Selmer-Olsen, Camilla Johansen Kaada, Eirik Sundby, Bård Helge Hoff

Institution: Norwegian University of Science and Technology

Language: English

Topic: Catalytic Cross-Coupling Reactions

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: gold

Estimated APC paid: $3,069

Funder: Norges Forskningsråd