1206524-79-9

Basic information

• Product Name: 1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)-
• Synonyms: 1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)-;(2S,4R)-1-tert-butyl 2-Methyl 4-((3-chloro-7-Methoxyquinoxalin-2-yl)oxy)pyrrolidine-1,2-dicarboxylate;Grazoprevir Intermediate 2;1-(tert-Butyl) 2-methyl (2S,4R)-4-((3-chloro-7-methoxyquinoxalin-2-yl)oxy)pyrrolidine-1,2-dicarboxylate
• CAS NO: 1206524-79-9
• Molecular Formula: C₂₀H₂₄ClN₃O₆
• Molecular Weight: 437.87406
• Mol File: 1206524-79-9.mol

Chemical Properties

• Boiling Point: 524.2±50.0 °C(Predicted)
• Appearance: /
• Density: 1.324±0.06 g/cm3(Predicted)
• PKA: -1.42±0.48(Predicted)
• CAS DataBase Reference: 1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)-(CAS DataBase Reference)
• NIST Chemistry Reference: 1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)-(1206524-79-9)
• EPA Substance Registry System: 1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)-(1206524-79-9)

Safety Data

• Hazardous Substances Data: 1206524-79-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-dimethylethyl) 2-methyl ester, (2S,4R)is used as a reagent in the discovery of MK-5172 (M424985), a macrocyclic analog that functions as an antiviral protease inhibitor. This makes it a valuable component in the development of treatments for viral infections.
Used in Chemical Research:
1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-Methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-diMethylethyl) 2-Methyl ester,(2S,4R)is also utilized as a reagent in the discovery of quinoxaline-based metathesis catalysts, which are crucial in the synthesis of Grazoprevir, an antiviral medication used to treat hepatitis C virus infection. Its role in the synthesis process highlights its importance in the advancement of pharmaceutical chemistry.
Used in COVID-19 Research:
1,2-Pyrrolidinedicarboxylic acid, 4-[(3-chloro-7-methoxy-2-quinoxalinyl)oxy]-, 1-(1,1-dimethylethyl) 2-methyl ester, (2S,4R)is classified as a COVID-19-related research product. This indicates its potential involvement in the development of treatments, vaccines, or diagnostic tools for the novel coronavirus, further emphasizing its significance in contemporary medical research.

Upstream product

• 1206524-78-8 3-chloro-6-methoxyquinoxalin-2-ol 
• 438452-29-0 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromo-phenyl)sulfonyl]oxy}-pyrrolidine-1,2-dicarboxylate 
• 31910-18-6 2,3-dihydroxy-6-methoxyquinoxaline 
• 59548-39-9 4-methoxyphenylene-1,2-diamine dihydrochloride 
• 39267-04-4 2,3-dichloro-6-methoxyquinoxaline 
• 74844-91-0 1-tert-butyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate 
• 1263814-66-9 3-chloro-7-methoxyquinoxalin-2(1H)-one 
• 31910-18-6 2,3-dioxo-6-methoxy-1,2,3,4-tetrahydroquinoxaline 
• 96-96-8 4-methoxy-2-nitroaniline 
• 102-51-2 4-methoxy-1,2-phenylenediamine 

Downstream Products

• 1361028-94-5 methyl (4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate hydrochloride 
• 1350514-68-9 grazoprevir 
• 1206524-84-6 methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxa-diazacyclononadecino[11,12-b]quinoxaline-8-carboxylate 
• 1206524-85-7 (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradeca-hydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylic acid hydrate 
• 1206524-81-3 (2S,4R)-methyl 4-((3-chloro-7-methoxyquinoxalin-2-yl)oxy)-1-((S)-3,3-dimethyl-2-((((1R,2R)-2-(pent-4-en-1-yl)cyclopropoxy)carbonyl)amino)butanoyl)pyrrolidine-2-carboxylate 
• 1206524-83-5 methyl (1aR,5S,8S,10R,18E,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate 
• 1425038-23-8 methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-18,19-didehydro-1,1a,3,4,5,6,9,10,20,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3, 6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate 

Relevant articles and documents

Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants

A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants.

Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

HEPATITIS C VIRUS NS3/4A PROTEASE INHIBITORS

The invention provides novel classes of HCV therapeutics that are orally available, safe and effective HCV NS3/4A protease inhibitors and are less susceptible to drug resistance than existing therapeutics. The invention also relates to pharmaceutical composition of these compounds and methods of preparation and use thereof.

Synthesis of Grazoprevir, a Potent NS3/4a Protease Inhibitor for the Treatment of Hepatitis C Virus

An efficient synthesis of grazoprevir is reported. Starting from four readily available building blocks, grazoprevir is prepared in 51% overall yield and >99.9% purity for pharmaceutical use.

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values ≤5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.

Process and intermediates for preparing macrolactams

The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams from the intermediates. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.

METHODS AND INTERMEDIATES FOR PREPARING MACROLACTAMS

The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.

MACROCYCLIC AND BICYCLIC INHIBITORS OF HEPATITIS C VIRUS

Compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein the various substituents are defined herein, methods of using said compounds, and pharmaceutical compositions containing said compounds.

Inhibitors of nedd8-activating enzyme

The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.

Development of a practical, asymmetric synthesis of the hepatitis C virus protease inhibitor MK-5172

The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.