697761-98-1

Basic information

• Product Name: (S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID
• Synonyms: (S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID;(S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-2,3-DIMETHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID;Elvitegravir(GS-9137,JTK-303);Elvitegravir;6-(3-Chloro-2-fluorobenzyl)-1-[1(S)-(hydroxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;(S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO;6-[(3-chloro-2-fluorophenyl)Methyl]-1-[(2S)-1-hydroxy-2,3-diMethylbutan-2-yl]-7-Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;GS 9137
• CAS NO: 697761-98-1
• Molecular Formula: C23H23ClFNO5
• Molecular Weight: 447.888
• EINECS: 1592732-453-0
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitor;API
• Mol File: 697761-98-1.mol

Chemical Properties

• Melting Point: 93-96°C
• Boiling Point: 623.6 °C at 760 mmHg
• Flash Point: 330.9 °C
• Appearance: /
• Density: 1.357 g/cm³
• Vapor Pressure: 2.06E-16mmHg at 25°C
• Refractive Index: 1.603
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 0.44±0.20(Predicted)
• CAS DataBase Reference: (S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID(697761-98-1)
• EPA Substance Registry System: (S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID(697761-98-1)

Safety Data

• Hazardous Substances Data: 697761-98-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Elvitegravir is used as an antiviral agent for the treatment of HIV-1 in adults without mutations indicative of elvitegravir resistance. It is often used in combination with a ritonavir-boosted protease inhibitor and other antiviral drugs to enhance the treatment regimen's efficacy.
Used in HIV Treatment:
Elvitegravir is used as a component of combination therapy for the treatment of HIV-1 infection. It is effective against various strains of HIV, including HIV-1 IIIB, HIV-2 EHO, and HIV-2 ROD, with IC50 values of 0.7 nM, 2.8 nM, and 1.4 nM, respectively.
Brand Names:
Elvitegravir is marketed under the brand names Vitekta in Europe and Stribild (as a part of a combination therapy) in the United States and Japan.

Originator

Torii Pharmaceuticals (subsidiary of Japan Tobacco) (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.

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)

Upstream product

• 697762-66-6 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-[1-(S)-tert-butyldimethylsilyloxymethyl-2-methylprop-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 
• 124-41-4 sodium methylate 
• 1598387-86-0 methyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropanoate 
• 85070-47-9 1-(bromomethyl)-3-chloro-2-fluorobenzene 
• 182056-48-0 1-(5-bromo-2,4-dimethoxyphenyl)ethan-1-one 
• 869893-91-4 3-chloro-2-fluorobenzyl zinc bromide 
• 829-20-9 2',4'-dimethoxyacetophenone 
• 1598387-97-3 (R)-methyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-bromo-2,4-dimethoxybenzoyl)acrylate 
• 1598387-89-3 methyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-(dimethylamino)acrylate 
• 1177256-74-4 1-((2R)-1-tert-butyldimethylsilyloxy-3-methylbutan-2-yl)-6-(3-chloro-2-fluorobenzyl)-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 
• 28314-83-2 5-bromo-2,4-difluoro-benzoic acid 
• 934161-50-9 6-bromo-7-fluoro-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 
• 934161-52-1 6-bromo-1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 
• 697762-61-1 (S)-ethyl 7-fluoro-6-iodo-1-(1-(methoxycarbonyloxy)-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 

Relevant articles and documents

An Improved Synthesis of Elvitegravir

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 PROCESS FOR THE PREPARATION OF ELVITEGRAVIR

The invention relates to a process for the production of elvitegravir of formula (I), which is obtained by reaction of the general intermediate of formula (V) with 3-chloro-2-fluorobenzyl zinc bromide, producing the intermediate of formula (VII), which is

A NEW PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR

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 PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR

The present solution relates to an improved production method of elvitegravir of formula (I), which is being subjected to clinical trials for treatment of HIV infection. Elvitegravir of formula (I) is produced via the intermediate of formula (I)I, the pre

AN IMPROVED PROCESS FOR THE PREPARATION OF ELVITEGRAVIR

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

PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors

Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto - enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited-marked antiretroviral activity. Here, we show the synthesis and the detailed structure - activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3- dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nMin the strand transfer assay and an ED50 of 0.6 nMin the antiviral assay, and 6-(3-chloro-2-fluorobenzyl) -1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid 49, which had an IC50 of 7.2 nMand an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrasecatalyzed strand transfer processes than 3′-processing reactions, as is the case with the keto - enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.

PROCESS FOR PRODUCTION OF 4-OXOQUINOLINE COMPOUND

The present invention provides a compound useful as a synthetic intermediate for an anti-HIV agent having an integrase inhibitory activity, a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate. Specifi

METHOD FOR PRODUCING 4-OXOQUINOLINE COMPOUND

The present invention provides a compound useful as a synthetic intermediate for an anti-HIV agent having an integrase inhibitory activity, and a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate. Spe

PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.