- Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis
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A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.
- Aoyama, Yasunori,Hakogi, Toshikazu,Fukui, Yuki,Yamada, Daisuke,Ooyama, Takao,Nishino, Yutaka,Shinomoto, Shoji,Nagai, Masahiko,Miyake, Naoki,Taoda, Yoshiyuki,Yoshida, Hiroshi,Yasukata, Tatsuro
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p. 558 - 564
(2019/04/30)
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- Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium
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A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atom-economical synthetic method for preparing this potent anti-HIV agent.
- Yasukata, Tatsuro,Masui, Moriyasu,Ikarashi, Fumiya,Okamoto, Kazuya,Kurita, Takanori,Nagai, Masahiko,Sugata, Yoshihide,Miyake, Naoki,Hara, Shinichiro,Adachi, You,Sumino, Yukihito
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p. 565 - 570
(2019/03/26)
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- Identification and Control of Critical Process Impurities: An Improved Process for the Preparation of Dolutegravir Sodium
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A four-stage manufacturing route for the preparation of dolutegravir sodium (1) was assessed and optimized leading to a higher yielding, simpler and scalable process. Key improvements in the process include the development of mild workup procedure by selective derivatization of a difficult to remove a process impurity using tert-butyldimethylsilyl chloride. Metal-based hydrogenation-free O-debenzylation is optimized, and the critical isomeric impurity formed was identified and eliminated from the process by the establishment of a proper control strategy.
- Sankareswaran, Srimurugan,Mannam, Madhavarao,Chakka, Veerababu,Mandapati, Srirami Reddy,Kumar, Pramod
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p. 1461 - 1468
(2016/08/30)
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- Intermediate of these pyridonecarboxylic carbamoylalkanoic and HIV integrase inhibitor
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A synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II: whereby a final product such as AA: can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.
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- DOLUTEGRAVIR SALTS
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Dolutegravir potassium salt and solid state forms thereof are provided, as well as methods of making and interconverting these forms. The Dolutegravir potassium forms, and pharmaceutical compositions containing them, may be used to treat subjects in need
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- PROCESS FOR THE PREPARATION OF INTERMEDIATE OF DOLUTEGRAVIR
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The present invention provides a novel processes for preparation of methyl 3- (benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyiridine-2- carboxylate using novel intermediates.
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- PROCESS FOR PREPARING COMPOUND HAVING HIV INTEGRASE INHIBITORY ACTIVITY
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A process for preparing a compound represented by formula (Y1) or (Y2) [wherein Rx is an optionally substituted carbocyclyl lower alkyl, or the like] or a salt thereof, using a novel process for preparing a pyridone derivative represented by formula (X4) [wherein R1d is hydrogen, halogen, or the like; R2d is hydrogen, a lower alkyl optionally substituted with substituent E, or the like; R4d is a lower alkyl optionally substituted with substituent E, or the like; and R6d is a lower alkyl group optionally substituted with substituent group E, or the like].
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- Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744)
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We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
- Johns, Brian A.,Kawasuji, Takashi,Weatherhead, Jason G.,Taishi, Teruhiko,Temelkoff, David P.,Yoshida, Hiroshi,Akiyama, Toshiyuki,Taoda, Yoshiyuki,Murai, Hitoshi,Kiyama, Ryuichi,Fuji, Masahiro,Tanimoto, Norihiko,Jeffrey, Jerry,Foster, Scott A.,Yoshinaga, Tomokazu,Seki, Takahiro,Kobayashi, Masanori,Sato, Akihiko,Johnson, Matthew N.,Garvey, Edward P.,Fujiwara, Tamio
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p. 5901 - 5916
(2013/08/23)
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- PROCESSES AND INTERMEDIATES FOR CARBAMOYLPYRIDONE HIV INTEGRASE INHIBITORS
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Processes are provided which create an aldehyde methylene, or hydrated or hemiacetal methylene attached to a heteroatom of a 6 membered ring without going through an olefinic group and without the necessity of using an osmium reagent. In particular, a comopound of formula (I) can be produced from (II) and avoid the use of an allyl amine: (formulae I and II) where R, P 1 P3, R3 and Rx are as described herein.
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Page/Page column 19
(2010/07/02)
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