697761-98-1 Usage
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.
Chemical Properties
Off-White to Pale Yellow Solid
Originator
Torii Pharmaceuticals
(subsidiary of Japan Tobacco) (Japan)
Uses
Different sources of media describe the Uses of 697761-98-1 differently. You can refer to the following data:
1. 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.
2. A novel inhibitor of human immunodeficiency virus type 1 integrase.
3. 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]
Definition
ChEBI: A quinolinemonocarboxylic acid that is 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid substited at position 1 by a 1-hydroxy-3-methylbutan-2-yl group and at position 6 by a 3-chloro-2-fluorobenzyl group (the S-enantiomer). It is us
d in combination therapy for the treatment of HIV-1 infection.
Brand name
Vitekta? (Europe), Stribild?
(as combo in the United States
and Japan)
Synthesis
Commercial 2,4-dimethoxy-5-bromo benzoic acid (61) was
reacted with 0.5 equiv of butylethylmagnesium to generate the
dimagnesium salt in THF, which was then lithiated at 20 ℃ to
give the aryl lithium species. The aryl lithium species was then
reacted with the 2-fluoro-3-chloro benzaldehyde (62) to give alcohol 63. Treatment with triethylsilane in TFA resulted in
removal of the hydroxyl functionality to provide benzoic acid 64.
This acid was then reacted with carbonyldiimidazole and subsequently
magnesium malonate 65 to give ketoester 66 after
workup. Next, condensation with DMF–DMA converted ketoester
66 to the vinylogous amide 67, and this material was immediately
subjected to an addition–elimination reaction involving (S)-valinol
(68) in toluene at ambient temperature to provide intermediate 69.
Warming the resulting intermediate 69 in the presence of N,Obistrimethylsilyl
acetamide (BSA) and potassium chloride in DMF
furnished the ring-closed quinolone 70. The ester 70 was saponified
with potassium hydroxide in aqueous isopropanol and then
acidified and crystallized with the use of seed crystals. Upon
cooling, the crystalline product elvitegravir (IX) was collected by
filtration.
Check Digit Verification of cas no
The CAS Registry Mumber 697761-98-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,9,7,7,6 and 1 respectively; the second part has 2 digits, 9 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 697761-98:
(8*6)+(7*9)+(6*7)+(5*7)+(4*6)+(3*1)+(2*9)+(1*8)=241
241 % 10 = 1
So 697761-98-1 is a valid CAS Registry Number.
InChI:InChI=1/C23H23ClFNO5/c1-12(2)19(11-27)26-10-16(23(29)30)22(28)15-8-14(20(31-3)9-18(15)26)7-13-5-4-6-17(24)21(13)25/h4-6,8-10,12,19,27H,7,11H2,1-3H3,(H,29,30)
697761-98-1Relevant articles and documents
An Improved Synthesis of Elvitegravir
Rádl, Stanislav,Stach, Jan,Pí?a, Ond?ej,Cinibulk, Josef,Havlí?ek, Jaroslav,Zajícová, Markéta,Pekárek, Tomá?
, p. 1738 - 1749 (2016/11/23)
An improved process for the active pharmaceutical ingredient of a new HIV integrase inhibitor elvitegravir (1) has been developed. It starts from commercially available 2,4-dimethoxyacetophenone, which is selectively halogenated into the position 5. The 5-halo acetophenones are condensed with dialkyl carbonates to give the corresponding benzoylacetates. Their treatment with N,N-dimethylformamide dimethyl acetal followed by (S)-valinol then provided the corresponding intermediate benzoyl acrylates. Cyclization to the required 1,4-dihydroquinolin-4-oxo derivatives by aromatic nucleophilic substitution of the 2-methoxy group was achieved by treatment with N,O-bis(trimethylsilyl)-acetamide, which also protected the OH group as the trimethylsilyl derivative. Finally, the Negishi coupling with 2-fluoro-3-chlorobenzylzinc bromide and the following hydrolysis provided elvitegravir (1). The preferred variant, the seven-step procedure starting from 2,4-dimethoxyacetophenone, provides elvitegravir in 29.3% yield.
A NEW PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR
-
Page/Page column 21, (2014/05/07)
The present solution relates to an improved production method of elvitegravir of formula I, which is being clinically evaluated for treatment of HIV infection. Elvitegravir of formula I is produced via the intermediate of formula II, the preparation of which is also an object of the present solution.
AN IMPROVED PROCESS FOR THE PREPARATION OF ELVITEGRAVIR
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Page/Page column 36, (2011/02/24)
The present invention relates to improved process for the preparation of elvitegravir (12), wherein the compound of formula (6) is protected with suitable protecting agents and further reacted with formula (9) in the presence of tetrakis(triphenylphosphin
