Simeprevir

Base Information

• Chemical Name: Simeprevir
• CAS No.: 923604-59-5
• Molecular Formula: C₃₈H₄₇N₅O₇S₂
• Molecular Weight: 749.952
• Mol file: 923604-59-5.mol

Synonyms:(2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide;

Chemical Property of Simeprevir

Chemical Property:

• PKA: 4.47±0.40(Predicted)
• PSA: 193.51000
• Density: 1.38
• LogP: 6.99250
• Solubility.: insoluble in H2O; insoluble in EtOH; ≥18.75 mg/mL in DMSO

Purity/Quality:

98%, ^*data from raw suppliers

Simeprevir ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: In September 2013, simeprevir (also known as TMC435) was approved in Japan (trade name Sovriad?) for the treatment of genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). Simeprevir was approved for the same indication in November 2013 in the United States (trade name Olysio?) and Canada (trade name Galexos?). Simeprevir is the third HCV PI to receive approval and was discovered from an effort to optimize a novel series of cyclopentane-core macrocyclic HCV PIs. Unlike the earlier PIs, simeprevir does not rely on formation of a covalent intermediate to inhibit the enzyme, but instead gains binding affinity through a large P2 quinoline substituent that occupies an extended S2 subsite of HCV protease by induced fit. This pocket is not occupied by inhibitors such as telaprevir and boceprevir. Other key features of simeprevir are truncation of the P3 capping group (the N-methyl amide), use of an acylsulfonamide as an acid isostere, and incorporation of an isopropylthiazole group to give improved permeability. Simeprevir is a potent NS3/4A PI (Ki=0.36 nM), with antiviral activity in the HCV replicon assay (genotype 1b EC50=7.8 nM; genotype 1a EC50=28.4 nM). It is 25-fold less potent against HCV genotype 2, >1000 less potent for HCV genotype 3, but has 3-fold better potency for HCV genotype 4.
• Clinical Use: HCV NS3/4A serine protease inhibitor: Treatment of hepatitis C in combination with other treatment
• Drug interactions: Potentially hazardous interactions with other drugs Anti-arrhythmics: possible increased risk of bradycardia with amiodarone. Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration of both drugs increased with erythromycin - avoid; concentration reduced by rifampicin and possibly rifabutin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin and primidone - avoid. Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - avoid. Antivirals: concentration of both drugs increased with darunavir - avoid; concentration reduced by efavirenz; avoid with etravirine; concentration possibly reduced by nevirapine - avoid; concentration increased by ritonavir - avoid. Ciclosporin: avoid concomitant use, increased simeprevir concentration. Cobicistat: concentration possibly increased by cobicistat - avoid.

Technology Process of Simeprevir

There total 23 articles about Simeprevir which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 89.0%

cyclopropanesulphonamide (154350-29-5) + (2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid (923604-58-4) → simeprevir (923604-59-5)

Guidance literature:

(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid; With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; water; at 20 ℃; for 1h;

cyclopropanesulphonamide; With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 20 ℃; for 24h;

DOI:10.1021/acs.joc.8b03124

Reference yield: 71.0%

C38H49N5O8S2 → simeprevir (923604-59-5)

Guidance literature:

With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 27 ℃; for 24h;

Reference yield: 40.0%

cyclopropanesulphonamide (154350-29-5) + C35H40N4O5S (923604-55-1) → simeprevir (923604-59-5)

Guidance literature:

With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 50 ℃; for 15h;

upstream raw materials:

cyclopropanesulphonamide

C₃₅H₄₀N₄O₅S

(1R,4R,5R)-N-(hex-5-en-1-yl)-N-methyl-3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxamide

methyl (1R,2R,4R)-2-[5-hexen-1-yl-(methyl)carbamoyl]-4-hydroxycyclopentanecarboxylate

Refernces

• 1、 -. "HCV inhibitors of HCV inhibitors and intermediates prepared by the method of". . . Retrieved 2019/06/11.
• 2、 -. "POLYMORPHIC FORMS OF A MACROCYCLIC INHIBITOR OF HCV". Page/Page column 33-34. . Retrieved 2008/12/07.