- 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir
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Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.
- Ziegler, Robert E.,Desai, Bimbisar K.,Jee, Jo-Ann,Gupton, B. Frank,Roper, Thomas D.,Jamison, Timothy F.
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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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- 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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- 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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- Synthesis of two diastereomeric impurities of a fluorinated antiretroviral drug dolutegravir
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The study of drug impurities constitutes an important area of process research and development. In the current study the synthesis of two diastereomeric impurities namely R,R- and S,S-isomer of recently approved antiretroviral drug dolutegravir was explored. Accordingly, a simple and scalable process has been developed for the first time for the synthesis of said impurities starting from a common intermediate, e.g. ethyl 5-((2,4-difluorobenzyl)carbamoyl)-3-ethoxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate. The methodology involved individual treatment of this common ester with (S)- and (R)-3-amino-1-butanol separately to afford the corresponding target compound in good yield. The IR, 1H, 13C and 19F NMR and Mass spectral data as well as HPLC and HRMS analysis were used to characterize the synthesized impurities. Both the impurities were prepared in gram scale suggesting scale-up potential of the methodology developed. Besides being economical as well as free from the use of expensive catalyst, the methodology involved the use of mild reaction conditions and workup procedure. Additionally, the reaction conditions adopted in the current approach are suitable for the laboratory as well as industrial applications. The current study would be of considerable interest to researchers engaged in the process development for accessing chemically pure dolutegravir.
- Amasa, Srinivasulu Reddy,Garrepalli, Sailaja,Gudipati, Ramesh,Pal, Manojit,Ravindhranath, Kunta
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- NOVEL PYRROLE AND PYRIDONE DERIVATIVES AND USES THEREOF
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Pyrrole and pyridine derivatives and methods of synthesizing the derivatives/analogs are provided. In particular, the compounds are useful for the treatment of antiviral infections such as HIV and influenza.
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- Method for synthesizing diastereomer impurity in dolutegravir raw material
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The invention provides a method for synthesizing a diastereomer impurity in a dolutegravir raw material, which comprises the following steps: 1, carrying out condensation reaction on SM1 serving as araw material and 2,4-difluorobenzylamine to generate a compound I; 2, reacting the compound I with an alkali in a reaction solvent to generate a compound II; 3, hydrolyzing the compound II under an acidic condition to generate a compound III; 4, carrying out acid catalytic reaction on the compound III and R-aminobutanol in a reaction solvent to generate a compound IV; 5, generating a compound V from the compound IV in a reaction solvent under the catalysis of a condensing agent; and 6, demethylating the compound V under the action of an alkali metal salt to generate an impurity VI. The synthetic method of the diastereoisomer impurity in the dolutegravir raw material is simple in process and available in raw material, and the prepared new impurity can provide a reference substance for quality analysis of dolutegravir, so that the quality standard of dolutegravir is improved.
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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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- A kind of improved lu tewei preparation process (by machine translation)
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The present invention provides anti-aids drugs lu tewei improved preparation process, and for lu tewei bulk drug process control study of the diastereoisomeric synthetic intermediates 6' and its preparation method. The process for preparing the simple routes, simplified for intermediate purification processing, in addition this invention obtained the diastereoisomeric synthetic intermediates 6' help for lu tewei raw material preparation process of quality research. (by machine translation)
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- Improved method for synthesizing dolutegravir
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The invention relates to an improved method for synthesizing dolutegravir and belongs to the field of medicinal chemistry. The method takes maltol (compound 1) as a raw material, and a target is synthesized by the following route. The process raw material is cheap and easy to obtain, a reaction solvent can be recycled, the post-treatment operation is simple, the yield and the purity are high, especially the carbamoylation and debenzylation reaction are carried out in one step, the synthesis route is simplified, the cost is reduced, and the large-scale industrial production is facilitated.
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Paragraph 0032; 0040
(2019/03/30)
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- A new method for preparing lu Tewei (by machine translation)
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A process for preparing lu Tewei (E) new method, relates to the field of pharmaceutical chemistry, comprising the following steps: step 1) by the compound (A) with 2, 4 - two fluorine animal pen amine condensation reaction to obtain compound (B) steps 2) compound (B) removing the aldehyde protecting group to obtain the compound (C) step 3) compound (C) with R - 3 - amino - 1 - butanol on the ring by the reaction of the compound (D) step 4) compound (D) by the methylation reaction to occur after lu Tewei (E). This invention adopts the new line, and to the continuous optimization of the reaction conditions, so that the overall yield is raised greatly, as the compound (A) as a starting material and calculate the total yield is 75% or more, in a single reaction yield is 90% or more. (by machine translation)
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- PROCESS FOR THE PREPARATION OF HIV INTEGRASE INHIBITORS
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The present invention provides compound of formula (XVII), wherein P is hydroxyl protecting group; R2 and R3 are independently lower alkyl or R2 and R3 can be alkyl and joined to form a 5-, 6- or 7-membered ring; R4 is lower alkyl, and process for its preparation.
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Page/Page column 13; 14
(2017/07/14)
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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
(2016/10/07)
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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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- 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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- 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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Page/Page column 24; 25
(2015/02/02)
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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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Paragraph 00276-00278
(2015/12/17)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DOLUTEGRAVIR
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The present invention provides (R)-3-Amino-1-butanol (D)-tartarate (lIb); process for its preparation and its conversion to Dolutegravir. The present invention also provides an improved process for the preparation of Dolutegravir (I) or pharmaceutically acceptable salts wherein compound (XVI) is reacted with an optically active acid addition salt of (R)-3-amino-1-butanol (lla).
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Page/Page column 22-23
(2014/09/03)
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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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- 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 19-20
(2010/07/02)
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- POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY
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The present invention is to provide a novel compound (I), having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. Compound (I) wherein Z1 is NR4; R1 is hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R2 is optionally substituted aryl; R3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R4 and Z2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.
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Page/Page column 116
(2010/11/24)
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