Isolation and Characterization of Process Related Substances of an Antipsychotic Drug: Iloperidone

Reductive Hydroxymethylation of 4‐Heteroarylpyridines

“…This approach is highly modular and convergent: in step I aromatic and aliphatic components are joined together by alkylation, thus activating the pyridine; next, the dearomative functionalization reaction (step II) was performed which led to structures with ample functionality for further derivatisation and exploration of 3D chemical space (step III). Thus, a set of medicinal lead inspired 4‐heteroarylpyridines and functionalized alkyl iodides were heated together to furnish highly decorated pyridinium salts ( 1 aa–ad ) which were then subjected to the iridium‐catalyzed process, delivering the 3‐hydroxymethylated analogues 2 aa–ad in good yields [11–14] …”

“…[11][12][13][14] This synthetic sequence is operationally simple and delivers products bearing multiple new functional groups, such as an activated electron-deficient alkene andap rimarya lcohol, allowingm any possibilities for the additional functionalization reactionsw hich are essential fors tructure-activity relationship studies. This approach is highly modular and convergent:i ns tep Ia romatic and aliphatic components are joined togetherb ya lkylation,t hus activating the pyridine;n ext, the dearomativef unctionalization reaction (step II) was performed which led to structuresw ith ample functionality for further derivatisation and exploration of 3D chemical space (step III).…”

“…Thus, a set of medicinal lead inspired 4-heteroarylpyridines and functionalized alkyl iodides were heated together to furnish highly decorated pyridinium salts (1 aa-ad) which were then subjected to the iridium-catalyzed process, delivering the 3-hydroxymethylated analogues 2 aa-ad in good yields. [11][12][13][14] This synthetic sequence is operationally simple and delivers products bearing multiple new functional groups, such as an activated electron-deficient alkene and a primary alcohol, allowing many possibilities for the additional functionalization reactions which are essential for structure-activity relationship studies. Furthermore, in part due to the relatively mild conditions for transition-metal catalysis (45 8C and a mild base), a wide range of potentially sensitive functional groups, such as cyclic imides, aromatic halides, enolizable ketones, electronrich heterocycles, and aromatic ethers, were all tolerated under reaction conditions and do not hinder the catalytic reaction.…”