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

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.

Keywords: 8-membered 7-azaindole; Buchwald–Hartwig amination; CSF1R; SEM-deprotection; azaindole; chemoselective Suzuki–Miyaura.

Figure 1

The FDA approved drugs PLX3397 and PLX4032; examples of polycyclic azaindoles I–IV and azaindole dimer V. The coloured bonds show the essential bond forming steps in preparation of I–V.

Scheme 1

Structure of the CSF1R inhibitor 1, the less active thienopyrimidine 2 and 7-azaindole analogue 3c. The initial retrosynthetic plan (in the frame) is shown with red wavy bonds indicating disconnections. The numbering system of the different heterocycles is also shown.

Scheme 2

Initial route to 2-aryl-1H-pyrrolo[2,3-b]pyridine-4-amines, side products and structure of the RuPhos and XPhos Pd G2 catalyst.

Scheme 3

Synthesis of the model compound 14b by a chemoselective Suzuki–Miyaura cross-coupling. The 2,4-diarylated 15b is the major side product.

Scheme 4

Synthesis of the protected analogues 14d and 14e.

Scheme 5

SEM-deprotection of compounds 13a–b and 13d–e to 3a–c and the side products 16 and 17.

Figure 2

CSF1R inhibition (IC₅₀ curves) for the 7-azaindole 3c (red squares), pyrrolopyrimidine 1 (blue circles) and thienopyrimidine 2 (green triangles). The solid lines are regression curves generated from 20 data points each. The assay was performed at ThermoFisher (Invitrogen, San Diego, CA, USA) using the Z-lyte technology; ATP level was equal to K_M.