Merugu Srinivas Reddy, Selmer-Olsen Sigrid, Kaada Camilla Johansen, Sundby Eirik, Hoff Bård Helge
Department of Chemistry, Norwegian University of Science and Technology (NTNU), N-7491 Trondheim, Norway.
Department of Materials Science and Engineering, Norwegian University of Science and Technology (NTNU), N-7491 Trondheim, Norway.
Molecules. 2024 Oct 7;29(19):4743. doi: 10.3390/molecules29194743.
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.
7-氮杂吲哚是具有相当药用价值的化合物。在开发集落刺激因子1受体酪氨酸激酶（CSF1R）抑制剂的构效关系过程中，需要一种特定的2-芳基-1-吡咯并[2,3-]吡啶-4-胺。评估了两种不同的合成策略，其中关键的C-C和C-N交叉偶联步骤的顺序不同。最佳路线依赖于在2-碘-4-氯吡咯并吡啶中间体的C-2位进行化学选择性铃木-宫浦交叉偶联，随后在C-4位与仲胺进行布赫瓦尔德-哈特维希胺化反应。事实证明，对羟基和吡咯进行掩蔽对于成功进行后一种转化至关重要。最后的三甲基硅基乙氧基甲基（SEM）脱保护步骤具有挑战性，因为甲醛的释放会产生不同的副产物，最有趣的是一种三环八元7-氮杂吲哚。目标2-芳基-1-吡咯并[2,3-]吡啶-4-胺（化合物）的活性比参考抑制剂低20倍，这证实了吡咯并嘧啶母体化合物中N-3对于有效抑制CSF1R的重要性。
