ABT450

Paritaprevir hydrate, a second-generation NS3/4A protease inhibitor, is a component of the all-oral, interferon-free hepatitis C virus combination therapy developed by Enanta Pharmaceuticals and AbbVie. The fixed-dose tablet of paritaprevir, ombitasvir (XXV, NS4A replication complex inhibitor), and ritonavir (cytochrome P450 inhibitor) taken in combination with dasabuvir (X, NS5B polymerase inhibitor) was approved for the treatment of chronic HCV genotype 1 in the USA and EU in 2014, and further approved for treatment of genotype 4 chronic HCV infection without cirrhosis by the US FDA in 2015. After 12 weeks of combination treatment, high sustained virological response rates have been demonstrated in clinical trials.205 Paritaprevir joins other marketed NS3/4A inhibitors, including telaprevir, boceprevir, simeprevir, and vaniprevir (XXXVIII), which inhibit a critical enzymatic complex for HCV replication. It exhibits potent antiviral activity against HCV genotype 1a and 1b strains, with EC50 values of 1.0 and 0.21 nM respectively. As paritaprevir is metabolized by CYP3A4, ritonavir, a CYP3A inhibitor with no direct HCV antiviral properties, is dosed concurrently to boost paritaprevir exposure, raising the mean plasma half-life to ca. 5.5 h and allowing for once-daily dosing. While several development routes for paritaprevir have been published in the patent literature, no process route has been disclosed to date. Perceptibly the most scalable route is described below; no yields for this route have been reported. Notably, the synthesis of a closely related compound that shares the same macrocylic core has been reported by AbbVie on kilogram scale.

Paritaprevir is a pharmaceutical drug that is used in the treatment of hepatitis C virus in patients with HCV genotype 1 infection. It inhibits an important viral phosphoprotein, NS5A, which is involved in viral replication, assembly, and secretion.

ChEBI: An azamacrocycle which is used which is in combination with dasabuvir sodium hydrate, ombitasvir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver.

Commercial (2S,4R)-N-Boc-4-hydroxyproline (219) was reacted with 6-chlorophenanthridine (220) in NMP in the presence of sodium t-butoxide. Acid 221 was then coupled with commercial vinylcyclopropylamine fragment 222 using o-(7-azabenzotriazol-1-yl)-N,N,N0 ,N0-tetramethyluronium hexafluorophosphate (HATU) and DIPEA to afford peptide 223 following Boc deprotection. The product could be crystallized upon neutralizing with NaOH. Amine 223 was subsequently coupled with acid 224 using EDC and N-hydroxy-5-norbornene-2,3-di-carboximide (HONB) in the presence of N,N-dimethylethylene diamine to afford linear tripeptide 225. Acid 224 was formed from Boc- (2S)-amino-non-8-eic acid (229) and 5-methyl-2-pyrazine carboxylic acid (230) via Boc deprotection and peptide coupling, using N,N0-disuccinimidyl carbonate and 4-dimethylaminopyridine (DMAP) to pre-activate acid 230.
Linear trieptide 225 was Boc protected and then subjected to ring closing metathesis using Zhan-B catalyst (226) in toluene, using imidazole to quench the catalyst after the reaction. On kilo-scale, a closely-related ring closing metathesis reaction provided the desired Z isomer in 61% yield.211 Removal of the Boc carbamate then provided macrocyclic intermediate 227. Ester hydrolysis with lithium hydroxide followed by acidification gave acid 228 which was coupled with cyclopropylsulfonamide (33) using CDI and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The isolated product was dissolved in i-PrOAc and diluted with ethanol. Water was added portion-wise and the solid isolated by filtration to afford crystalline paritaprevir hydrate (XXVII).