Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl

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Org. Process Res. Dev. 2020, 24, 1735 − 1742. DOI: 10.1021/acs.oprd.0c00358 ◆ For a recent project at Idorsia Pharmaceuticals, a robust and scalable route to 1-(pyrimidin-2-yl)cyclopropan-1-amine (1) needed to be developed ◆ An attractive option is to synthesize 1 from the corresponding carboxylic acid 4 via Curtius rearrangement. ◆ Unfortunately, all efforts were fruitless and very complex reaction mixtures were normally obtained. ◆ Functionalization of 2-cyclopropyl pyrimidine 11 was identified as another viable option to generate 1. The functionalization of 11 seemed to be challenging and the approach was finally abandoned. ◆ Retrosynthetically, the pyrimidine ring was envisioned to be formed from amidine 14 and a suitable 1,3-aldehyde synthon ◆ Direct conversion of the nitrile functionality of 15 into amidine 14 was difficult. Therefore, a stepwise Pinner reaction approach was developed ◆ While the development of the first three steps of the synthetic sequence was ………………………………