Elvitegravir

Base Information

• Chemical Name: Elvitegravir
• CAS No.: 697761-98-1
• Molecular Formula: C23H23ClFNO5
• Molecular Weight: 447.88
• European Community (EC) Number: 691-248-4
• UNII: 4GDQ854U53
• ChEMBL ID: CHEMBL204656
• DSSTox Substance ID: DTXSID101021650
• Metabolomics Workbench ID: 65913
• NCI Thesaurus Code: C76493
• Nikkaji Number: J2.543.801I
• RXCUI: 1306286
• Wikidata: Q2740966
• Wikipedia: Elvitegravir
• Mol file: 697761-98-1.mol

Synonyms:elvitegravir;GS 9137;GS-9137;GS9137;JTK 303;JTK-303;JTK303;Vitekta

Chemical Property of Elvitegravir

Chemical Property:

• Vapor Pressure: 2.06E-16mmHg at 25°C
• Melting Point: 93-96°C
• Refractive Index: 1.603
• Boiling Point: 623.6 °C at 760 mmHg
• PKA: 0.44±0.20(Predicted)
• Flash Point: 330.9 °C
• PSA: 88.76000
• Density: 1.357 g/cm³
• LogP: 4.28100
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 5.3
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 7
• Exact Mass: 447.1248787
• Heavy Atom Count: 31
• Complexity: 702

Purity/Quality:

99% ^*data from raw suppliers

Elvitegravir ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC(C)C(CO)N1C=C(C(=O)C2=C1C=C(C(=C2)CC3=C(C(=CC=C3)Cl)F)OC)C(=O)O
• Isomeric SMILES: CC(C)[C@@H](CO)N1C=C(C(=O)C2=C1C=C(C(=C2)CC3=C(C(=CC=C3)Cl)F)OC)C(=O)O
• Recent ClinicalTrials: Two Part Study to Evaluate Pharmacokinetics, Safety, and Antiviral Activity of Elvitegravir Administered With a PI/r Background Regimen for ARV Treatment-Experienced Pediatric Participants
• Recent EU Clinical Trials: A Phase 3 Randomized, Active-Controlled, Open-Label Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-1 Virologically Suppressed on Antiretroviral Therapy
• Description: In November 2013, the European Medicines Agency (EMA) approved elvitegravir (also known as GS 9137 and JTK 303) as a single agent to be used as part of an antiviral regimen that includes a ritonavir-boosted protease inhibitor for the treatment of HIV-1 in adults without mutations indicative of elvitegravir resistance. Elvitegravir is the second of three marketed HIV integrase strand transfer inhibitors (INSTIs) including raltegravir and dolutegravir (this volume of ARMC). Elvitegravir was discovered by modification of a literature naphthyridine HIV integrase inhibitor in which the naphthyridine core served as a bioisostere for the diketo acid moiety in an original series. Serendipitously, a 4-quinolone-3-carboxylic acid precursor en route to the desired bioisosteric glyoxylic acid demonstrated modest integrase inhibition (IC50=1600 nM). Further derivatization led to elvitegravir with enhanced inhibition of integrase strand transfer (IC50=7.2 nM) and significant antiviral activity (EC50=0.9 nM). Elvitegravir was prepared in seven synthetic steps from 2,4-difluoro-5-iodobenzoic acid. The corresponding acid chloride was coupled to ethyl 3-(dimethylamino) acrylate and further substituted with S-valinol. Base promoted cyclization afforded the quinolone which was protected as silyl ether. Negishi coupling installed the 2-fluoro-3-chlorobenzyl moiety. Subsequent hydrolysis and methoxylation afforded elvitegravir.
• Uses: Elvitegravir (EVG, JTK-303/GS-9137) is an HIV integrase inhibitor for HIV-1 IIIB, HIV-2 EHO and HIV-2 ROD with IC50 of 0.7 nM, 2.8 nM and 1.4 nM, respectively. A novel inhibitor of human immunodeficiency virus type 1 integrase. Elvitegravir is a quinolone antibiotic that inhibits the integrase of HIV-1 (IC50 = 7.2 nM). It blocks the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. Elvitegravir is used in combination with a pharmacoenhancer and nucleoside/nucleotide reverse transcriptase inhibitors to block HIV-1 replication in vivo.[Cayman Chemical]

Technology Process of Elvitegravir

There total 67 articles about Elvitegravir 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: 99.3%

1-[(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (949465-85-4) → elvitegravir (697761-98-1)

Guidance literature:

1-[(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester; With sodium hydroxide; water; isopropyl alcohol; at 70 ℃; for 3h;

With hydrogenchloride; water; In 3-methyl-butan-2-one; Product distribution / selectivity;

Reference yield: 89.8%

(S)-ethyl 6-(3-chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxoquinoline-3-carboxylate → elvitegravir (697761-98-1)

Guidance literature:

(S)-ethyl 6-(3-chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxoquinoline-3-carboxylate; With sodium hydroxide; ethanol; water; at 20 - 55 ℃; for 0.5h;

With hydrogenchloride; water; In ethanol; at 20 ℃; Product distribution / selectivity;

Reference yield: 86.0%

3-chloro-2-fluorobenzyl zinc bromide (869893-91-4) + (S)-6-bromo-1,4-dihydro-1-(1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxoquinoline-3-carboxylic acid + N,N-bis(trimethylsilyl)acetamide (10416-58-7) → elvitegravir (697761-98-1)

Guidance literature:

(S)-6-bromo-1,4-dihydro-1-(1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxoquinoline-3-carboxylic acid; N,N-bis(trimethylsilyl)acetamide; In tetrahydrofuran; at 25 ℃; for 0.166667h;

3-chloro-2-fluorobenzyl zinc bromide; With bis(triphenylphosphine)palladium(II)-chloride; In tetrahydrofuran; at 60 ℃; for 2.5h;

With hydrogenchloride; In tetrahydrofuran; water; at 25 ℃; for 0.5h;

upstream raw materials:

6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-((S)-1-hydroxymethyl-2-methylprop-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

sodium methylate

C₂₄H₂₄ClF₂NO₄

3-chloro-2-fluorobenzyl zinc bromide

Refernces

• 1、 -. "A NEW PROCESS FOR THE PREPARATION OF ELVITEGRAVIR". . . Retrieved 2015/02/02.
• 2、 -. "A NEW PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR". Page/Page column 20. . Retrieved 2014/05/07.