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
• Article Data: 15

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

Description

(S)-6-(3-CHLORO-2-FLUOROBENZYL)-1-(1-HYDROXY-3-METHYLBUTAN-2-YL)-7-METHOXY-4-OXO-1,4-DIHYDROQUINOLINE-3-CARBOXYLIC ACID, also known as Elvitegravir, is a quinolone antibiotic that serves as an HIV integrase inhibitor. It is characterized by its off-white to pale yellow solid appearance and is used in combination therapy for the treatment of HIV-1 infection. Elvitegravir works by inhibiting the integrase of HIV-1, blocking the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. It is the second of three marketed HIV integrase strand transfer inhibitors (INSTIs), including raltegravir and dolutegravir.

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

• 697762-62-2 (S)-ethyl 6-(3-chloro-2-fluorobenzyl)-7-fluoro-1-(1-(methoxycarbonyloxy)-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 
• 697762-61-1 (S)-ethyl 7-fluoro-6-iodo-1-(1-(methoxycarbonyloxy)-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 
• 869893-91-4 3-chloro-2-fluorobenzyl zinc bromide 
• 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 
• 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 
• 124-41-4 sodium methylate 
• 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 

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 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 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