Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR.

ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date. Process development was conducted for large-scale pilot plant manufacturing, and obtaining the desired polymorph A04 was key after a synthetic route of ASP3026 was selected for scale-up. The effects of temperature and solvent species on induction time of polymorph transformation were investigated using in situ Raman spectroscopy, and selective transformation conditions of A02 to A03 and A04 were examined in detail. A04 was obtained at high temperatures using highly polar non-hydrogen-bond-donating solvents, while A03 was obtained at low temperatures using low-polarity or hydrogen-bond-donating solvents. Further, the desired polymorph A04 was successfully obtained in high purity in first stage scale-up manufacturing. Given these findings, this method of solvent-mediated polymorph transformation may aid in process development for obtaining desired polymorphs.

Azaspirene and related congeners, which possess various biological activities, have a unique spirocyclic core structure. However, there are few studies on the chemical properties of (−)-azaspirene, despite the fact that it may provide important insights into unveiling the biosynthetic pathway. Here, we report a nine-step chemical synthesis of an azaspirene analogue with a new finding that the natural (−)-azaspirene skeleton easily racemizes in neutral aqueous media.

ASP3026(N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date, and the most stable polymorph (A04) was selected for designing solid formulations. The influence of crystallization process parameters on nucleation of A03 and A04 was clarified for process development. A04 was obtained at relatively high temperatures and A03 at relatively low temperatures, regardless of the superaturation ratio. A03 and A04 were therefore able to be selectively obtained via temperature control, possibly due to temperature-dependent variations in the concentrations of conformers in solution. The relationship between polymorphs and solution structures before nucleation was investigated using in situ Raman spectroscopy. The relationship with the intensity ratios of nine Raman bands of both polymorphs and ASP3026 solution structures was investigated in detail. Our findings suggest that the solution structure shifted from a structure similar to that of A04 to one similar to that of A03 with decreasing temperature.

ASP3627 (1) is a potent Janus kinase inhibitor discovered and developed by Astellas Pharma Inc. Here, we report the development of a practical and scalable method for manufacturing ASP3627 featuring a six-reaction telescoping process consisting of DIBAL reduction, hydrolysis, Wittig reaction, cyclization, and a two-step sequence to remove the SEM group. In addition, a simple palladium removal procedure using l-cysteine is described. This method was used to successfully perform the first multikilogram synthesis of ASP3627, producing 30 kg with high purity in excellent overall yield.