Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 (3)

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

◆While the saponification and amide coupling were successfully scaled up, a formidable challenge still remained: The subsequent amide reduction of 35 to diamine 27.

◆A wide range of different reduction conditions were tested, and a selection of obtained results were summarized

◆There was only a single reagent that provided full conversion and clean product formation: BH3·N,N-diethylaniline complex (DEANB) in toluene at 90−100 °C (entry 2).

◆During the 1.6 kg run, we observed formation of a precipitate in the receiving tank while methanol was distilled off. The distillate was transferred into a separate reactor and was quenched by addition of diluted aq. HCl.

◆We speculated that not only B(OMe)3 was distilling off, but also H2B(OMe) and HB(OMe)2 which could still release hydrogen gas.

◆As this posed a severe safety risk, it was decided for the 2.4 kg scale up to markedly prolong the reflux time after MeOH quench before the distillation of MeOH into the receiving tank was allowed.

◆The crystallization of 27-HCl completely depleted the des-HF impurity 39. A spiking test revealed that 39 is degraded during the amide reduction with DEANB. It was not possible to evaluate the nature of its degradation products.

◆There was a concern that the fluorine on the piperidine side chain might be cleaved during the DEANB reduction step forming impurity 42. However, stress tests of the DEANB reduction showed that this impurity 42 was not formed even under several days at reflux