Narlaprevir

Base Information

• Chemical Name: Narlaprevir
• CAS No.: 865466-24-6
• Molecular Formula: C36H61N5O7S
• Molecular Weight: 707.976
• UNII: 2857LA2O07
• ChEMBL ID: CHEMBL1255891
• DSSTox Substance ID: DTXSID801025746
• Metabolomics Workbench ID: 144552
• NCI Thesaurus Code: C166554
• Wikidata: Q27254268
• Wikipedia: Narlaprevir
• Mol file: 865466-24-6.mol

Synonyms:narlaprevir;SCH 900518;SCH-900518;SCH900518

Chemical Property of Narlaprevir

Chemical Property:

• PKA: 11.84±0.20(Predicted)
• PSA: 186.21000
• Density: 1.21
• LogP: 6.46740
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 5.4
• Hydrogen Bond Donor Count: 4
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 15
• Exact Mass: 707.42917048
• Heavy Atom Count: 49
• Complexity: 1400

Purity/Quality:

99% ^*data from raw suppliers

Narlaprevir ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CCCCC(C(=O)C(=O)NC1CC1)NC(=O)C2C3C(C3(C)C)CN2C(=O)C(C(C)(C)C)NC(=O)NC4(CCCCC4)CS(=O)(=O)C(C)(C)C
• Isomeric SMILES: CCCC[C@@H](C(=O)C(=O)NC1CC1)NC(=O)[C@@H]2[C@@H]3[C@@H](C3(C)C)CN2C(=O)[C@H](C(C)(C)C)NC(=O)NC4(CCCCC4)CS(=O)(=O)C(C)(C)C
• Recent ClinicalTrials: Efficacy and Safety of All-Oral Combination of Narlaprevir/Ritonavir and Sofosbuvir in Treatment-na?ve Patients With Chronic Hepatitis C Genotype 1
• Description: Narlaprevir was approved as a treatment for genotype 1 HCV and serves as a class 2 HCV NS3 serine protease inhibitor. In clinical trials, it showed a rapid and steady decline in HCV-RNA levels in both previously treated and treatment-naive patients when used in combination with ritonavir and PEG-IFN-α. This combination ultimately led to ≥50% of patients with undetectable HCV-RNA levels after a second period of treatment. Narlaprevir also has demonstrated activity against HCV mutations resistant to other treatments such as boceprevir and telaprevir. The unique activity of this drug can be attributed to a critical electrophilic α-keto-amide “warhead”, which covalently reacts with an HCV NS3 protease active-site serine residue involved in the HCV viral replication process. Because of their essential roles in viral replication, HCV NS3 and NS5B proteases have recently become key targets for HCV drug development. Strategically, the development of narlaprevir stems specifically from the pursuit of a single-diastereomer, second generation HCV protease inhibitor, which would provide in vitro potency and pharmacokinetic profile improvements over the structurally related antiviral drug boceprevir,which exists as a mixture of diastereomers. After the R-Pharm pharmaceutical group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute.
• Uses: Narlaprevir is an NS3/4A protease inhibitor used in the treatment of hepatitis C virus, HCV.

Technology Process of Narlaprevir

There total 26 articles about Narlaprevir 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: 82.7%

C36H63N5O7S (1256345-29-5) → narlaprevir (865466-24-6)

Guidance literature:

With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium acetate; acetic acid; In tert-butyl methyl ether; acetic acid methyl ester; water; at 5 - 15 ℃; for 2h; Industry scale;

Reference yield:

pentanal (110-62-3) → narlaprevir (865466-24-6)

Guidance literature:

Multi-step reaction with 10 steps

1.1: pyridine / 60 h / 5 - 35 °C / Industry scale

1.2: 30 °C / Industry scale

2.1: sulfuric acid / n-heptane / 18 h / 19 - 25 °C / Industry scale; Sealed vessel

3.1: n-hexyllithium / n-heptane; tetrahydrofuran / 0.5 h / -65 - -55 °C / Industry scale

3.2: 1.5 h / -65 - -55 °C / Industry scale

4.1: (1S)-(+)-(10-camphorsulfonyl)-oxaziridine / n-heptane; tetrahydrofuran / 6 h / -65 - -55 °C / Industry scale

4.2: -60 - -40 °C / Industry scale

5.1: trifluoroacetic acid / toluene / 25.5 h / 50 °C / Industry scale

5.2: 15 - 20 °C / pH 5 - 6 / Industry scale

6.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / 2-methyltetrahydrofuran / 0.08 h / 0 - 10 °C / Industry scale

6.2: 4 h / 0 - 35 °C / Industry scale

7.1: hydrogen; acetic acid / palladium on carbon / methanol / 7 h / 60 °C / 4137.29 Torr / Industry scale

8.1: hydrogenchloride / water; tert-butyl methyl ether / 3 °C / Industry scale; Reflux

9.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / ethyl acetate; acetonitrile; water / -5 - 30 °C / Industry scale

10.1: sodium acetate; sodium hypochlorite; acetic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetic acid methyl ester; water; tert-butyl methyl ether / 2 h / 5 - 15 °C / Industry scale

With pyridine; hydrogenchloride; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; hydrogen; sodium acetate; n-hexyllithium; (1S)-(+)-(10-camphorsulfonyl)-oxaziridine; benzotriazol-1-ol; acetic acid; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; sulfuric acid; palladium on carbon; In tetrahydrofuran; 2-methyltetrahydrofuran; methanol; n-heptane; tert-butyl methyl ether; acetic acid methyl ester; water; ethyl acetate; toluene; acetonitrile;

Reference yield:

methyl cyclohexylcarboxylate (4630-82-4) → narlaprevir (865466-24-6)

Guidance literature:

Multi-step reaction with 10 steps

1.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 2 h / -10 °C / Industry scale

1.2: -10 - 25 °C

2.1: zinc dibromide / dichloromethane / 1.5 h / 20 - 45 °C / Industry scale

3.1: sodium hydroxide; water / methanol / 16 h / 70 °C / Industry scale

3.2: 10 °C / pH ~ 1.5 / Industry scale

4.1: Oxone / dichloromethane / 24 h / 15 °C / Industry scale

5.1: triethylamine; diphenyl phosphoryl azide / toluene / 9 h / 80 °C / 760.05 Torr / Industry scale; Reflux

6.1: triethylamine / toluene; water / 7 h / 0 - 20 °C / Industry scale

7.1: benzotriazol-1-ol; 4-methyl-morpholine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / acetonitrile; water / 5 h / 5 - 40 °C / Industry scale

8.1: sodium hydroxide; water / 2-methyltetrahydrofuran / 7 h / 20 - 60 °C / Industry scale

8.2: 0.17 h / 20 - 30 °C / pH 1.5 - 3 / Industry scale

9.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide / ethyl acetate; acetonitrile; water / -5 - 30 °C / Industry scale

10.1: sodium acetate; sodium hypochlorite; acetic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / acetic acid methyl ester; water; tert-butyl methyl ether / 2 h / 5 - 15 °C / Industry scale

With 4-methyl-morpholine; Oxone; sodium hypochlorite; n-butyllithium; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; diphenyl phosphoryl azide; water; sodium acetate; benzotriazol-1-ol; acetic acid; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; diisopropylamine; N-ethyl-N,N-diisopropylamine; sodium hydroxide; zinc dibromide; In tetrahydrofuran; 2-methyltetrahydrofuran; methanol; dichloromethane; tert-butyl methyl ether; acetic acid methyl ester; water; ethyl acetate; toluene; acetonitrile; 5.1: Curtius Rearrangement;

upstream raw materials:

C₃₆H₆₃N₅O₇S

pentanal

cyclohexanone

methyl cyclohexylcarboxylate