- An Improved Synthesis of Elvitegravir
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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.
- Rádl, Stanislav,Stach, Jan,Pí?a, Ond?ej,Cinibulk, Josef,Havlí?ek, Jaroslav,Zajícová, Markéta,Pekárek, Tomá?
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p. 1738 - 1749
(2016/11/23)
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- A NEW PROCESS FOR THE PREPARATION OF ELVITEGRAVIR
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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
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Page/Page column 10
(2015/02/02)
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- A NEW PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR
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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.
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Page/Page column 21
(2014/05/07)
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- AN IMPROVED PRODUCTION METHOD AND NEW INTERMEDIATES OF SYNTHESIS OF ELVITEGRAVIR
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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
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ELVITEGRAVIR
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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
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Page/Page column 36
(2011/02/24)
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- Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors
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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.
- Sato, Motohide,Kawakami, Hiroshi,Motomura, Takahisa,Aramaki, Hisateru,Matsuda, Takashi,Yamashita, Masaki,Ito, Yoshiharu,Matsuzaki, Yuji,Yamataka, Kazunobu,Ikeda, Satoru,Shinkai, Hisashi
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experimental part
p. 4869 - 4882
(2010/03/02)
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- PROCESS FOR PRODUCTION OF 4-OXOQUINOLINE COMPOUND
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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
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Page/Page column 53-54
(2009/12/28)
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- PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS
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The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.
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Page/Page column 18-19; 25-26
(2009/04/25)
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- METHOD FOR PRODUCING 4-OXOQUINOLINE COMPOUND
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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
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Page/Page column 83-84
(2008/12/09)
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- PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS
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The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.
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Page/Page column 21
(2008/06/13)
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- Novel HIV-1 integrase inhibitors derived from quinolone antibiotics
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The viral enzyme integrase is essential for the replication of human immunodeficiency virus type 1 (HIV-1) and represents a remaining target for antiretroviral drugs. Here, we describe the modification of a quinolone antibiotic to produce the novel integr
- Sato, Motohide,Motomura, Takahisa,Aramaki, Hisateru,Matsuda, Takashi,Yamashita, Masaki,Ito, Yoshiharu,Kawakami, Hiroshi,Matsuzaki, Yuji,Watanabe, Wataru,Yamataka, Kazunobu,Ikeda, Satoru,Kodama, Eiichi,Matsuoka, Masao,Shinkai, Hisashi
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p. 1506 - 1508
(2007/10/03)
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- STABLE CRYSTAL OF 4-OXOQUINOLINE COMPOUND
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The present invention provides a crystal of 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which shows a particular powder X-ray diffraction pattern of a characteristic diffractio
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Page/Page column 27-28; 32-33; 41; 44-45
(2010/02/14)
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- NOVEL 4-OXOQUINOLINE COMPOUND AND USE THEREOF AS HIV INTEGRASE INHIBITOR
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Provision of a compound having an anti-HIV activity, particularly an integrase inhibitory activity.A 4-oxoquinoline compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof: wherein each symbol is as defined in the specification.The present invention also relates to a pharmaceutical composition containing the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; an integrase inhibitor, an antiviral agent, anti-HIV agent and the like, which contains the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof as an active ingredient; an anti-HIV composition containing the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof, and one or more other kinds of anti-HIV activity substances as active ingredients; an anti-HIV agent containing the 4-oxoquinoline compound or a pharmaceutically acceptable salt thereof as an active ingredient, which is used for a multiple drug therapy with other anti-HIV agent(s), and the like.
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Page/Page column 115-116
(2008/06/13)
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- COMBINATIONS COMPRISING A 4-ISOQUINOLONE DERIVATIVE AND ANTI-HIV AGENTS
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The present invention relates to a combination therapy for treating an HIV infection or inhibiting integrase comprising (S)-6-(3-chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ("Compound A"
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- 4-OXOQUINOLINE COMPOUNDS AND UTILIZATION THEREOF AS HIV INTEGRASE INHIBITORS
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An anti-HIV agent containing, as an active ingredient, a 4-oxoquinoline compound represented by the following formula [I] wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.
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Page/Page column 61-62
(2008/06/13)
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