Vaniprevir

Description

Vaniprevir, which was approved in Japan in 2014 and sold under the trade name Vanihep®, is one of several structurallyrelated macrocycles developed for the treatment of patients afflicted with the hepatitis C virus. Specifically, the drug is indicated for patients with untreated, interferon-unresponsive, or relapsed genotype 1 chronic hepatitis C. Similar to asunaprevir (IV), vaniprevir is a NS3/4A protease inhibitor, and thus has a comparable mechanism of action.

The Uses of Vaniprevir

Vaniprevir is an antiviral therapy against hepatitis C.

Synthesis

Beginning with commercial bis-benzylbromide 311, subjection to benzylamine under basic conditions followed by acidification afford the isoindoline as the toluene sulfonic acid salt 312. This salt was then freebased and acylative removal of the benzyl protecting group took place through the use of acetyl chloride. Hydrochloric acid in refluxing methanol removed the acetamide to liberate indoline 313, which was isolated as the HCl salt. Next, exposure of 313 to alcohol 314 in the presence of CDI and warm DMF gave rise to carbamate 315. This was followed by Heck installation of n-hexenyl fragment 316 and subsequent hydrogenation of the olefin with concomitant removal of the benzoyl carbamate protecting group delivered macrocycle precursor 317. Next, an intramolecular lactamization reaction furnished the macrocyclic system and this was followed by saponification of the prolinate ester to give 318. This acid was then coupled with cyclopropylamine 319 under standard coupling conditions to furnish vaniprevir in 87% yield.
The preparation of hexenyl fragment 316 started with the lithiation of commercially available ethyl isobutyrate (320) and alkylative quench with 1-bromo-4-butene to provide hexenyl ester 321. Next, DIBAL reduction followed by CDI-mediated carbamate formation with L-t-leucine and subsequent treatment with dicyclohexylamine (DCHA) furnished the key hexenyl fragment 316.

The assembly of cyclopropylamine 319 stems from cyclopropyl fragment 34, whose synthesis was described in Scheme 5. Hydrogenation of this system to saturate the double bond was followed by treatment with toluenesulfonic acid to remove the Boc group, furnishing the tosylate salt in good yield for the two step sequence.