A Novel, Practical, and Efficient Synthetic Process for Chiral 10-Aza-isoergoline Scaffold of the Antipsychotic Candidate IHCH7041

A novel, practical, and scalable synthetic route has been developed for (S)-N1, the pivotal chiral 10-aza-isoergoline scaffold of the antipsychotic candidate IHCH7041. This process features a concise, chromatography-free synthesis of racemic N1 from commercially available starting materials with a significantly increased yield of 24.9%, followed by its first successful optical resolution via diastereomeric salt formation with dibenzoyl-L-tartaric acid. Through systematic optimization of each step, the route was successfully executed on a multikilogram scale, delivering (S)-N1 in high yield with excellent chemical purity (>99%) and enantiomeric excess (>98.5%). Key advantages include operational simplicity, mild conditions, avoidance of specialized equipment or hazardous reagents, and significant cost reduction, making it highly suitable for large-scale production.