Rolapitant, a spirocyclic neurokinin NK1 receptor antagonist comprisingthree stereogenic centers originated in the laboratories of Schering-Plough, and wasapproved for the treatment of chemotherapy-induced nausea and vomiting in 2015.The drug’s syntheses are primarily featured in the patent literat.

The original synthesis of rolapitant patented by Schering-Plough relies on the supply of the key building block 159. Synthetically, the latter can be traced back to (S)-phenylglycine over eight synthetic operations, including the preparation of oxazolidinone 160, as detailed further below. Cyclic enamine 159 was subjected to standard hydroboration–oxidation conditions, to afford alcohol 161, which was oxidized to ketone 162 under the Swern conditions. Ketone 162 was involved in a standard hydantoin synthesis with potassium cyanide and ammonium carbonate, to afford spirocyclic compound 163. The latter was Boc-protected, hydrolyzed and Boc-protected again to giveα-amino acid 164. The carboxylic group in 164 was reduced via a mixed anhydride to give amino alcohol 165 which was oxidized (again under the Swern conditions) and involved, without protection of the amino group, in a Horner–Wadsworth–Emmons olefination, to give the acrylate ester 166. The latter turned out to be a direct precursor of rolapitant, and was converted to the drug by hydrogenation (accompanied by lactam formation) and protecting group removal.

Fig1:Schering-Plough synthesis of rolapitant

As to the synthesis of key building block 159 from (S)-phenylglycine ((S)-Phg), it was accomplished as follows. (S)-Phg was converted to diastereomerically pure oxazolidinone 160 on condensation with benzaldehyde and Cbz-protection. Oxazolidinone 160 was C-alkylated in diastereoselective fashion with chiral bromide 167. The carbonyl group of the resulting intermediate 168 was reduced by lithium alumohydride, and the lactol 169was obtained. The aldehyde form of the latter reacted with phosphonium ylide generated from the alkyl phosphonium bromide 170, and the elaborate olefinic building block 171was obtained. It was hydrogenated over platinum dioxide and the resulting acetal 172 was treated with p-toluene sulfonic acid in refluxing ethanol. This led to the removal of the acetal protecting group and the cyclization of the Cbz-protected amino group onto the liberated aldehyde carbonyl group, to give the target key intermediate 159.

Fig2:Preparation of key building block 159 for the synthesis of rolapitant.

Reference:

[1] NAZAR MOSHNENKO. Synthetic Routes to Approved Drugs Containing a Spirocycle.[J]. Molecules, 2023, 28 10. DOI:10.3390/molecules28104209.