ROLAPITANT HYDROCHLORIDE

Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents. Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000- fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro. In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy, rolapitant shows no inhibition of CYP3A4, eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h), providing potential opportunities for single- and prechemotherapy-based treatments. In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.

Rolapitant Hydrochloride Hydrate is a raw material for pharmaceutical formulations.

ChEBI: A hydrate that is the monohydrate form of rolapitant hydrochloride. Used for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy.

Rolapitant features a fascinating molecular architecture consisting of two tetrasubstituted stereogenic carbon centers situated at the 2- and 5-carbons within a central piperidine ring and a spirocyclic array residing at the 5-position and a phenyl ring and ethereal linkage branching from the 2-position. The overall synthetic strategy to secure rolapitant hydrochloride hydrate relies upon the union of two advanced chiral building blocks that contain functional groups capable of securing the central piperidine ring. These two key intermediates, pyroglutamate derivative 93 and allylic amine 94, each bear one of the essential stereocenters embedded within the structure of the active pharmaceutical ingredient.

The first of these advanced intermediates, amidoaldehyde 93, is generated directly by base-mediated decomposition of pyroglutamic aminal 92. Subjection of 92 to triethylamine in EtOH/H2O at ambient temperatures led to generation of chiral allyl aldehyde 93, which was not isolated but condensed immediately with amine 94 in the presence of refluxing toluene to provide divinyl imine 95, which underwent immediate reduction using NaBH(OAc)3 in AcOH/toluene to furnish the free amine. The free amine was converted to the corresponding tosylate monohydrate salt and triturated, providing 96 as a white crystalline powder after subjection to TsOH?¤H2O in i-PrOH/H2O. Divinyl amine 96 could then be reacted with a solution of TsOH in toluene, distilled, and directly combined with a toluene solution of Hoveyda-Grubbs second-generation catalyst (HG-II) under heating conditions, leading to the desired ring-closing metathesis product 97 as the HCl salt (85% yield over two steps) after filtration, distillation, and workup with 12N HCl. Washing of a toluene solution of 97 with aqueous NaOH and subsequent treatment of the resulting organic solution with H2, wet Pd/C, and additional granular activated carbon (Nuchar Aquaguard) led to the fully reduced piperidine product in high yield (95%). Rolapitant hydrochloride hydrate XIII was accessed thereafter by precipitation from a solution of EtOH/i-PrOH/H2O/HCl, providing the product as a white solid (91% yield).