Cyclopenta(c)pyrrole-1-carboxamide, (2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino)oxoacetyl)butyl)octahydro-, (1S,3aR,6aS)-

Synthesis

For preparation of bulk API, a convergent synthetic strategy was utilized as described in the scheme. Retrosynthetically the penultimate intermediate 212, which was coupled with amine 213 for the final step, was prepared by coupling bicyclic amine 217 with amino acids 216 and 215 and then with pyrazine acid 214. In the early stages of development, the cyclopropyl amide fragment 213 was made using a MCR coupling sequence by reacting aldehyde 218 with cyclopropyl isocyanide (219) and triflouroacetic acid to give amide alcohol 220 in 85% yield. Removal of the Cbz group was accomplished via hydrogenolysis to provide key cyclopropyl amide alcohol 213 in 95% yield. While this route was shorter in terms of steps, it was not amenable to large-scale preparation due to difficulties associated with the handling of isocyanide 219.Thus, for large-scale synthesis, the route depicted in Scheme 35 was utilized. Commercially available Cbz-protected amino acid 221 was converted to the corresponding Weinreb amide 222 using CDI as the activating agent. This was followed by LAH reduction to give aldehyde 218 in 73% yield from 221. Aldehyde 218 was reacted with sodium cyanide under neutral to mildly basic conditions allowing for easy workup of the cyanohydrin, which was immediately hydrolyzed by refluxing in 4 N hydrochloric acid in dioxane to deliver hydroxy acid HCl salt 223. Since the formation of the acyloin resulted in removal of the Cbz protecting group, reinstallation of this protecting group preceded conventional amide bond formation through the intermediacy of the succinate ester of 224. This provided the desired amide alcohol 220 in 56% yield from 223. Hydrogenolysis of Cbz carbamate 220 then furnished the requisite intermediate amine (213) in 73% yield.The large-scale synthesis of bicyclic pyrrolidine 231 was accomplished as described in the following scheme. Commercially available 3-azabicyclo[ 3.3.0]nonane hydrochloride (225) was first protected as the corresponding Boc carbamate 226 in 90% yield. Deprotonation of the bicyclic pyrrolidine carbamate 226 with sec-BuLi and sequential quench with bubbling carbon dioxide gas followed by sodium hydrogensulfate resulted in racemic acid 227 in 80% yield. Racemate 227 was resolved using (S)-tetrahydronapthalamine (228) in ethyl acetate and isopropanol at 70–75°C. This mixture was allowed to cool down slowly to effect the crystallization of the optically enriched chiral salt 229 in 83% yield with greater than 99.5% ee. This enatioenriched salt was free based with sodium hydrogen sulfate and converted to t-butyl ester 230 using Boc anhydride and DMAP. The secondary amine of 230 was liberated using methane sulfonic acid at room temperature followed by salt formation with oxalic acid in isopropyl acetate to give oxalic acid salt 231 in 81% yield over 3 steps.With the synthesis of the key intermediates complete, sequential coupling events were then executed to complete the synthesis of teleprevir (following scheme). Fragment 217 was coupled with the Cbz-protected valine (216) using EDCI and HOBt to give intermediate 232 in 87% yield. Similarly, after removal of the Cbz group of 232 via catalytic hydrogenolysis, the resulting amine was coupled with cyclohexyl amino acid 215 to give dipeptide intermediate 233 in 89% yield over 2 steps. Sequential cleavage of the Cbz group in 233 followed by CDI-mediated coupling with commercially available pyrazine acid 214 gave rise to the expected pyrazine amide intermediate. Subsequent hydrolysis of the t-butyl ester through the use of concentrated acid in DCM provided the key intermediate tripeptidic acid (212) in 68% over 3 steps. The tripeptide 212 was then coupled with cyclopropyl amide amine 213 using EDCI, HOBt and N-methyl morpholine (NMM) to provide penultimate intermediate alcohol 234 in 95% yield. Subjection of 234 to Dess–Martin periodinane (DMP) oxidation in t-butanol and DCM furnished telaprevir (XXI) in 85% yield.

Drug interactions

Potentially hazardous interactions with other drugs Alpha-blockers: avoid with alfuzosin. Analgesics: risk of ventricular arrhythmias with methadone. Anti-arrhythmics: risk of ventricular arrhythmias with amiodarone and disopyramide - avoid; risk of ventricular arrhythmias with flecainide andpropafenone - use with caution; use IV lidocaine with caution. Antibacterials: concentration of both drugs increased with clarithromycin, erythromycin and telithromycin, increased risk of ventricular arrhythmias; avoid with rifabutin and rifampicin (concentration significantly reduced by rifampicin). Anticoagulants: concentration of warfarin possibly affected; avoid with apixaban; possibly increased dabigatran concentration. Antidepressants: possibly increased trazodone concentration; avoid with St John’s wort. Antiepileptics: avoid with carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone. Antifungals: concentration of both drugs possibly increased with ketoconazole, increased risk of ventricular arrhythmias; possibly increased itraconazole concentration; possibly increased posaconazole concentration - increased risk of ventricular arrhythmias; possibly altered voriconazole concentration - increased risk of ventricular arrhythmias. Antipsychotics: avoid with pimozide; possibly increases lurasidone and quetiapine concentration - avoid. Antivirals: concentration possibly reduced by atazanavir; concentration of atazanavir possibly increased; avoid with darunavir, fosamprenavir and lopinavir; concentration of daclatasvir and possibly olaparib increased - reduce daclatasvir and olaparib dose; concentration reduced by efavirenz - increase telaprevir dose; concentration possibly reduced by ritonavir; concentration of tenofovir possibly increased. Anxiolytics and hypnotics: possibly increased midazolam concentration - risk of prolonged sedation, avoid concomitant use with oral midazolam. Beta-blockers: risk of ventricular arrhythmias with sotalol - avoid. Ciclosporin: concentration of both drugs increased, reduce ciclosporin dose. Cilostazol: possibly increases cilostazol concentration. Colchicine: possibly increased risk of colchicine toxicity - suspend or reduce colchicine dose, avoid in hepatic or renal impairment. Cytotoxics: possibly increases bosutinib concentration - avoid or consider reducing dose of bosutinib; reduce dose of ruxolitinib. Domperidone: possibly increased risk of ventricular arrhythmias - avoid. Ergot alkaloids: avoid concomitant use. Guanfacine: possibly increases guanfacine dose - halve dose of guanfacine. Lipid-regulating drugs: avoid with lomitapide, simvastatin and atorvastatin. Oestrogens: possibly reduced ethinylestradiol concentration and contraceptive effect. Sildenafil: avoid concomitant use. Sirolimus: concentration of both drugs increased, reduce sirolimus dose. Beta2 sympathomimetics: avoid with salmeterol - risk of ventricular arrhythmias. Tacrolimus: concentration of both drugs increased, reduce tacrolimus dose. Tadalafil: avoid with high dose tadalafil. Vardenafil: avoid concomitant use.

Metabolism

Extensively metabolised in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in faeces, plasma and urine.

Definition

ChEBI: An oligopeptide consisting of N-(pyrazin-2-ylcarbonyl)cyclohexylalanyl, 3-methylvalyl, octahydrocyclopenta[c]pyrrole-1-carboxy, and 3-amino-N-cyclopropyl-2-oxohexanamide residues joined in sequence. Used f r treatment of chronic hepatitis C virus genotype 1 infection.

Brand name

Incivek