cas 518048-05-0, Raltegravir | Articles data

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Seeking for Selectivity and Efficiency: New Approaches in the Synthesis of Raltegravir
The present work describes the development of an improved synthesis of active pharmaceutical ingredient raltegravir. The isolation of a new process intermediate and the newly developed conditions solve the issue of selectivity typical of this production process, with no need for the use of protecting groups, making the present route more efficient and sustainable than what was reported before. Efficiency comparisons with the previous processes confirm the result here obtained.
Caputo, Francesco,Corbetta, Stefano,Piccolo, Oreste,Vigo, Daniele
p. 1149 - 1156
(2020/07/25)

A newfangled synthesis of integrase inhibitor drug substance raltegravir potassium
Raltegravir sodium synthesis was achieved from its one of the key starting materials with retro synthetic approach, in which without using its critical starting material chemically known as 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride and which is more unstable during the synthesis of raltegravir potassium. Almost all the existed literatures commonly using this starting material in its synthesis even it is having a stability issue and hence to achieve a stable and economically viable synthesis. The current research describes a new route of synthesis by constructing an oxadiazole ring in a retro synthetic manner.
Rao, S. Venkat,Potluri, Vamsi Krishna,Potluri, Ramesh Babu
p. 2618 - 2622
(2019/10/02)

A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
A facile, cost-effective, and commercially viable synthesis of Raltegravir Potassium (1) has been developed from 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide (9) with high purity and in good yields. In addition, a new approach for the synthesis of key amine intermediate (9) of Raltegravir Potassium (1) from commercially available 2-amino-2-methylpropanenitrile hydrochloride (2) is also described. The key features of the synthesis are fewer synthetic steps, employing the inexpensive reagents and eco-friendly.
Karumanchi, Kishore,Nangi, Gangadhara Bhima Shankar,Danda, Subba Reddy,Chavakula, Ramadas,Korupolu, Raghu Babu,Bonige, Kishore Babu
p. 2683 - 2690
(2019/08/21)

PROCESS FOR THE PREPARATION OF RALTEGRAVIR
The present invention refers to a process for the preparation of Raltegravir and pharmaceutically acceptable salts thereof.
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Page/Page column 23

(2019/06/09)

Preparation method of pyrimidinone amide type compound
The invention discloses a pyrimidinone amide type compound and a preparation method thereof. A pyrimidinone compound is taken as a starting material and is subjected to four-step chemical conversion to obtain TN-A005 and an analogue thereof, and an intermediate can be prepared from methyl tetrazole. A one-pot method is used for feeding in the whole preparation process, post-treatment purificationof each step is recrystallization or dispersion washing, the use of means such as silica gel column chromatography is avoided, the preparation technology is greatly simplified, the preparation efficiency is improved, and the total yield can reach 50%. The method is simple and convenient in preparation steps and can improve the preparation efficiency.
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Paragraph 0047; 0048; 0049

(2018/10/19)

(Chloromethyl)dimethylchlorosilane-KF: A Two-Step Solution to the Selectivity Problem in the Methylation of a Pyrimidone Intermediate en Route to Raltegravir
The present work describes a two-step process, namely, silylation with (chloromethyl)dimethylchlorosilane and desilylation, to address the selectivity problem in the N-methylation of a pyrimidone intermediate toward the synthesis of the raltegravir active pharmaceutical ingredient. The said methodology delivers the desired drug substance in which the O-methylated impurity content is below the detection limit by high-performance liquid chromatography analysis. Moreover, this two-step, one-pot procedure provides an apparent advantage in terms of environmental impact with respect to the optimum approach described in the literature, while it compares equally well in terms of cost and operational simplicity.
Stathakis, Christos I.,Gkizis, Petros L.,Alexandraki, Elli S.,Trakossas, Sakellarios,Terzidis, Michael,Neokosmidis, Efstratios,Zacharis, Constantinos K.,Vasiliadou, Christina,Vastardi, Elli,Andreou, Thanos,Zitrou, Asteria,Varvogli, Anastasia-Aikaterini,Koftis, Theocharis V.
p. 1413 - 1418
(2017/09/22)

PROCESS FOR PREPARING COMPOUNDS USEFUL AS INTERMEDIATES FOR THE PREPARATION OF RALTEGRAVIR
The invention discloses a novel and selective methylation process used in the preparation of Raltegravir and intermediates. Further disclosed is an improved method for the reaction of intermediate amine compound of formula IIb with oxadiazole intermediate compound of formula V.
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(2018/04/11)

AN IMPROVED PROCESS FOR THE PREPARATION OF RALTEGRAVIR
The present invention provides a process for the preparation of crystalline anhydrous compound of Formula (X), Further, the present invention relates to the use of compound of Formula (X) preparation of Raltegravir (I) or its pharmaceutically acceptable salt thereof.
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(2016/06/13)

SYNTHESIS OF RALTEGRAVIR
The present invention relates to a novel synthetic route for the preparation of raltegravir and pharmaceutically acceptable salts, starting from 2-amino-2-methylpropanenitrile and oxadiazole carbonyl chloride, through the formation of a pyrimidinone intermediate of formula (V).
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(2015/02/25)

Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors
A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.
Wang, Ziwen,Wang, Mingxiao,Yao, Xue,Li, Yue,Qiao, Wentao,Geng, Yunqi,Liu, Yuxiu,Wang, Qingmin
p. 361 - 369
(2012/06/30)

CRYSTALLINE SODIUM SALT OF AN HIV INTEGRASE INHIBITOR
The present invention refers to a crystalline sodium salt of a compound of formula I (INN: Raltegravir) or a hydrate/solvate thereof as well as a process for obtaining the same.
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Page/Page column 10

(2012/11/14)

Identification, synthesis, and strategy for minimization of potential impurities observed in raltegravir potassium drug substance
Multiple sources of anticipated degradation and process impurities of raltegravir potassium drug substance observed during the laboratory optimization and later during its bulk synthesis are described in this article. The impurities were monitored by UPLC, and their structures are tentatively assigned on the basis of fragmentation patterns in LC-MS and NMR spectroscopy. Most of the impurities are synthesized, and their assigned constitutions were confirmed by co-injection in UPLC. In addition to the formation, synthesis, and characterization, strategy for minimizing these impurities to the level accepted by ICH is also described. We feel that our study will be helpful to the generic industry for obtaining chemically pure raltegravir potassium.
Patil, Gulabrao D.,Kshirsagar, Siddheshwar W.,Shinde, Shivnath B.,Patil, Pankaj S.,Deshpande, Mangesh S.,Chaudhari, Ashok T.,Sonawane, Swapnil P.,Maikap, Golak C.,Gurjar, Mukund K.
p. 1422 - 1429
(2012/10/29)

PROCESSES FOR PREPARING RALTEGRAVIR AND INTERMEDIATES IN THE PROCESSES
The present invention provides a process for preparing benzyl-2-(4-(4- fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2- ylcarbamate (RLT-8), a process for preparing Raltegravir via RLT-8, a process for preparing methyl 2-(2-(benzyloxycarbonylamino)propan-2-yl)-5 -hydroxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxylate (RLT-7'), a process for preparing Raltegravir via RLT-7', and a process for preparing crystalline form V of Raltegravir potassium.
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(2012/08/08)

Development of a second-generation, highly efficient manufacturing route for the HIV integrase inhibitor raltegravir potassium
A manufacturing route for the synthesis of raltegravir potassium 1 was developed via a thermal rearrangement of amidoxime DMAD adducts 6 to construct the key, highly functionalized hydroxypyrimidinone core 7. Utilizing this route 1 was prepared in nine linear chemical steps with 22% overall yield. A second-generation synthesis was subsequently developed that solved the key chemical, productivity, and environmental impact issues of the initial synthesis. Highlights of the new synthesis include a highly selective methylation, 3-4-fold higher productivity, and a 65% reduction of combined organic and aqueous waste produced. The efficient second-generation manufacturing route provides raltegravir potassium 1 in 35% overall yield.
Humphrey, Guy R.,Pye, Philip J.,Zhong, Yong-Li,Angelaud, Remy,Belyk, Kevin M.,Maligres, Peter E.,Miller, Ross A.,Reamer, Robert A.,Askin, David,Mancheno, Danny E.,Weissman, Steven A.
experimental part
p. 73 - 83
(2011/09/16)

RALTEGRAVIR SALTS AND CRYSTALLINE FORMS THEREOF
The present invention includes new salts of Raltegravir and crystalline forms thereof, pharmaceutical compositions containing the salts or crystalline forms, methods of using the salts or crystalline forms or the compositions to treat HIV infection or to prepare medicament for treating HIV infection, and a process for preparing Raltegravir potassium.
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Page/Page column 27-28

(2011/10/13)

Radiosynthesis of the HIV integrase inhibitor [18F]MK-0518 (Isentress)
The human immunodeficiency virus integrase inhibitor, [18F]MK- 0518, was prepared via a three-step, one-pot radiosynthesis. [ 18F]4-Fluorobenzylamine was produced from the fluorination of 4-cyano-N,N,N-trimethylammonium triflate with [18F]fluoride and reduction with borane methylsulfide complex in 50-68% radiochemical yield. The final step, the coupling of [18F]4-fluorobenzylamine with an ester coupling partner, achieved an overall uncorrected radiochemical yield after HPLC purification of ～2%, based on the starting [18F]fluoride. In a typical run, the total synthesis time was about 90 min and gave 0.37-1.74 GBq (10-47 mCi) of [18F]MK-0518. The radiochemical purity of [ 18F]MK-0518 was >98% and the specific activity was 243-1275 Ci/mmol (EOS, n = 4). A convenient three-step, one-pot radiosynthesis of [ 18F]MK-0518 via [18F]4-fluorobenzylamine has been developed, giving sufficient quantities of [18F]MK-0518 for animal positron emission tomography studies. Copyright
Li, Wenping,Thompson, Wayne,Fisher, Thorsten,Wai, John S.,Hazuda, Daria,Burns, H. Donald,Hamilla, Terence G.
body text
p. 517 - 520
(2011/08/09)

PROCESS FOR PREPARING N-SUBSTITUTED HYDROXYPYRIMIDINONE CARBOXAMIDES
Processes for preparing certain N-arylalkyl-1-(alkyl or aralkyl)-2-acylaminoalkyl- 5-hydroxy -6-oxo-1,6-dihydropyrimidine-4-carboxamides are disclosed. In one embodiment, the process comprises acylating the free amine in the corresponding N-arylalkyl-1-(alkyl or aralkyl)- 2-aminoalkyl-5-ester protected hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide and then deprotecting the 5-hydroxy by base hydrolysis. The hydroxypyrimidinone carboxamide products of the process are HTV integrase inhibitors which are useful for treating HTV infection, treating AIDS, or delaying the onset or progression of AIDS. Certain esterified N-arylalkyl hydroxypyrimidinone carboxamides that can be employed as process intermediates are also disclosed.
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Page/Page column 47

(2009/09/04)

Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4- hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
Summa, Vincenzo,Petrocchi, Alessia,Bonelli, Fabio,Crescenzi, Benedetta,Donghi, Monica,Ferrara, Marco,Fiore, Fabrizio,Gardelli, Cristina,Paz, Odalys Gonzalez,Hazuda, Daria J.,Jones, Philip,Kinzel, Olaf,Laufer, Ralph,Monteagudo, Edith,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Scarpelli, Rita,Stillmock, Kara,Witmer, Marc V.,Rowley, Michael
experimental part
p. 5843 - 5855
(2009/09/25)

TASTE-MASKED TABLETS AND GRANULES
Orally administered, taste-masked tablets and granules contain (a) a hydroxypyrimidinone carboxamide, a hydroxy-tetrahydropyridopyrimidinone carboxamide, or a related carboxamide compound, or a pharmaceutically acceptable salt thereof, (b) a taste-masking polymer, (c) a superdisintegrant, and optionally other excipients. The carboxamide compound is an HIV integrase inhibitor, and the tablets and granules are suitable for use in the inhibition of HIV integrase, the treatment or prophylaxis of HIV infection, and the treatment or prophylaxis or delay in the onset of AIDS.
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Page/Page column 38-39

(2008/06/13)

USE OF ATAZANAVIR FOR IMPROVING THE PHARMACOKINETICS OF DRUGS METABOLIZED BY UGT1A1
A method for improving the pharmacokinetics of an orally administered drug that is directly metabolized by UGT1A1 comprises orally administering to a mammal in need of treatment with the drug a combination of the drug or a pharmaceutically acceptable salt thereof and atazanavir or a pharmaceutically acceptable salt thereof.
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Page/Page column 1.8.B

(2010/11/08)

PHARMACEUTICAL COMPOSITION CONTAINING AN ANTI-NUCLEATING AGENT
Pharmaceutical compositions suitable for oral administration in solid dosage forms are described. The compositions comprise an effective amount of a drug compound in the form of a salt, wherein the drug salt is characterized by conversion to a less soluble form of the drug compound under certain pH conditions, and an anti-nucleating agent.
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Page/Page column 36-37

(2010/11/08)

Potassium salt of an HIV integrase inhibitor
Potassium salts of Compound A and methods for their preparation are disclosed, wherein Compound A is of formula: Compound A is an HIV integrase inhibitor useful for treating or prophylaxis of HIV infection, for delaying the onset of AIDS, and for treating or prophylaxis of AIDS.
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Page/Page column 25-26

(2010/11/08)

PHARMACEUTICAL FORMULATION CONTAINING A RELEASE RATE CONTROLLING COMPOSITION
Pharmaceutical formulations suitable for oral administration in solid dosage forms are described. The compositions comprise an effective amount of a base salt of a compound of Formula (I) and a release rate controlling composition comprising a solubilizing agent, a gelling agent, and a water soluble filler; wherein R1, R2, R3 and R4 are defined herein. The formulations are suitable for use in the inhibition of HIV integrase, the treatment and prophylaxis of HIV infection, and the treatment, prophylaxis and delay in the onset of AIDS.
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Page/Page column 31-32

(2010/11/08)