Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, cis-to-trans Epimerization, and Saponification

The rapid development of a stereoselective route for CXCR7 antagonist ACT-1004-1239 was needed, as the large-scale chromatographic separation of enantiomers was not a viable option for a resupply campaign that targeted >30 kg of API. The key to success was the stereoselective reduction of a chiral enamine derived from inexpensive (S)-α-methylbenzylamine. The reduction showed good selectivity for the desired cis-3R,4S-isomer, and the pure diastereomer (d.r. >98:2) was isolated as its TFA salt. After removal of the ethylbenzyl group and amide coupling with 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid, the enantiopure cis-3R,4S-amide was isolated. The subsequent epimerization of the 3-position adjacent to the methyl ester turned out to be a formidable challenge, as the standard conditions with NaOMe led to the formation of a thermodynamic mixture of the cis and trans isomers (final ratio of ∼1:4). Therefore, a new procedure was developed in which the methyl ester was transesterified in situ to the isopropyl ester with KOiPr in iPrOH, followed by epimerization to the trans-iPr-ester (final cis:trans ratio 5:95). After saponification with aqueous KOH, the desired trans-3S,4S-acid was isolated in overall 76% yield. After amide coupling and Boc deprotection, the final reductive amination with cyclopropanecarboxaldehyde was also vastly improved. A novel NaBH(OAc)3 solution in DMSO was used for the reaction and cleanly provided the API with high purity after simple aqueous quench without the need for any solvent switches or aqueous workups. As a proof of concept, 240 g of API was produced in house with the novel stereoselective route, which was then also used to produce over 30 kg of GMP material at an external manufacturer for Phase 2 clinical studies.