- Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium
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A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from (R)-3-amino-1-butanol and establishes the BC ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48-51% isolated yield (HPLC purity of 99.7-99.9%) over six linear steps.
- Dietz, Jule-Philipp,Lucas, Tobias,Gro?, Jonathan,Seitel, Sebastian,Brauer, Jan,Ferenc, Dorota,Gupton, B. Frank,Opatz, Till
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p. 1898 - 1910
(2021/08/01)
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- NOVEL CRYSTALLINE POLYMORPHS OF SODIUM (4R,12AS)-9-{[(2,4-DIFLUOROPHENYL) METHYL]CARBAMOYL}-4-METHYL-6,8-DIOXO-3,4,6,8,12,12A-HEXAHYDRO-2H-PYRIDO [1',2':4,5]PYRAZINO[2,1-B][1,3]OXAZIN-7-OLATE AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to novel crystalline polymorphs of sodium (4R,12aS)-9-{[(2,4-difluorophenyl) methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] pyrazino[2,1-b] [1,3] oxazin-7-olate represented by the following structural formula-1a and process for their preparation. The present invention further relates to novel solvated forms of sodium (4R,12aS)-9-{[(2,4-difluoro phenyl) methyl] carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5] pyrazino[2,1-b][1,3] oxazin-7-olate compound of formula-1a and process for their preparation.
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Page/Page column 19
(2020/08/22)
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- CONTINUES FLOW PROCESS FOR THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS - POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES AND INTERMEDIATES THEREOF
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The present invention discloses continues flow process for the preparation of polycyclic carbamoyl pyridone derivatives and intermediates thereof. In particular, the present invention discloses a process for the preparation of intermediate. Formule (V).
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Page/Page column 35; 36; 37; 38
(2019/09/04)
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- NEW POLYMORPHS OF DOLUTEGRAVIR SODIUM
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The present invention relates to new polymorphs of dolutegravir sodium and processes for the preparation of the new polymorphs of dolutegravir sodium. The present invention also provides pharmaceutical compositions comprising these new polymorphs, and medical uses of the polymorphs.
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Page/Page column 31; 32; 33; 34
(2019/04/10)
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- 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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- PROCESSES FOR PREPARING SOLID STATE FORMS OF DOLUTEGRAVIR SODIUM
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Disclosed are processes for preparing solvate forms of Dolutegravir sodium.
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Page/Page column 29
(2017/04/11)
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- NOVEL POLYMORPHS OF DOLUTEGRAVIR AND SALTS THEREOF
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The present invention relates to novel crystalline forms of dolutegravir, process for its preparation and pharmaceutical composition comprising them.
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Page/Page column 17
(2017/03/14)
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- PROCESS FOR THE PREPARATION OF DOLUTEGRAVIR
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Processes for the preparation of dolutegravir and pharmaceutically acceptable salts utilizing alkenylamine are disclosed. Intermediates in those synthetic schemes are also disclosed.
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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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Paragraph 0035; 0040
(2016/10/07)
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- NOVEL HYDRATES OF DOLUTEGRAVIR SODIUM
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The invention relates to novel hydrates of dolutegravir sodium and to processes for their preparation. Furthermore, the invention relates to a novel crystalline form of dolutegravir sodium, which is a useful intermediate for the preparation of one of the novel hydrates. In addition, the invention relates to the use of the novel hydrates for the production of pharmaceutical compositions. Finally, the invention relates to pharmaceutical compositions comprising an effective amount of the novel hydrates, to oral dosage forms comprising said pharmaceutical compositions, to a process for preparing said oral dosage forms, and to the use of said pharmaceutical compositions or dosage forms in the treatment of retroviral infections such as HIV-1 infections.
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Page/Page column 38
(2016/04/06)
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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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- PROCESS FOR PREPARING POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES AND INTERMEDIATES THEREOF
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The present invention relates to a novel process for the synthesis of polycyclic carbamoyl pyridone derivativesof formula (B): wherein Ar, W1, W2, W3, X, Y and Z are as defined in the specification; and to novel chemical intermediates for use in sucha process.
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- NOVEL PROCESS FOR THE PREPARATION OF DOLUTEGRAVIR AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to a novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof using novel intermediates.
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- PROCESS FOR THE PREPARATION OF DOLUTE-GRAVIR AND INTERMEDIATES THEREOF
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The present disclosure relates to processes for the preparation of dolutegravir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of dolutegravir.
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Page/Page column 17
(2015/02/25)
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- SOLID STATE FORMS OF DOLUTEGRAVIR SODIUM
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Solid state forms of Dolutegravir sodium, processes for preparation thereof and pharmaceutical compositions thereof are provided.
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Page/Page column 22; 23
(2015/10/05)
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- CRYSTALLINE FORMS OF DOLUTEGRAVIR SODIUM
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The present disclosure relates to novel crystalline dolutegravir sodium Form-M2, Form-M3, Form-M4 and process for the preparation thereof.
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Page/Page column 9
(2015/09/22)
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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 20
(2010/07/02)
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