Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 (2)

Org. Process Res. Dev. 2024, 28, 2269−2283. DOI: 10.1021/acs.oprd.3c00492

◆Nucleophilic aromatic substitution (SNAr) and Buchwald−Hartwig type couplings did not deliver 22 in acceptable yield and/or purity, mainly due to regioselectivity issues

◆Therefore, we abandoned the original strategy and decided to prepare 4 via a 5-step sequence

◆Our first approach for the final steps to ACT-1014-6470 (1) relied on the formation of the advanced urea-intermediate 28 from which the crucial ring closure could be achieved by intramolecular alkylation with the primary alcohol in an activated form

◆Unfortunately, activation of the alcohol functionality in 28 by addition of either thionyl chloride or methanesulfonyl chloride proved unsuccessful

◆At this point we decided to focus on a more promising approach, i.e. the preparation of the advanced diamine precursor 27 from which API 1 could be formed by intramolecular urea formation

◆Alternatively, we wanted to test whether the coupling of carboxylic acid 32 with aminopiperidine 4 to form amide 35 was also a viable way to API 1

◆In contrast to the oily nature of the Weinreb amide route intermediates, amide 35 had the advantage of being a nicely crystalline solid