518048-05-0

Basic information

• Product Name: Raltegravir
• Synonyms: Raltegravir;N-((4-Fluorophenyl)methyl)-1,6-dihydro-5-hydroxy-1-methyl-2-(1-methyl-1-(((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl)amino)ethyl)-6-oxo-4-pyrimidinecarboxamide;N-(2-(4-(4-Fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide;N-(2-(4-(4-Fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)p;Raltegravir(R&D);Raltegravir(free base);N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-(2-methyl-1,3,4-oxadiazole-5-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide;N-((4-Fluorophenyl)methyl)-1,6-dihydro-5-hydroxy-1-methyl-2-(1-methyl-1-(((5-methyl-1,3,4-oxadiazol-2-yl)carbonyl)am
• CAS NO: 518048-05-0
• Molecular Formula: C₂₀H₂₁FN₆O₅
• Molecular Weight: 444.42
• EINECS: 1312995-182-4
• Product Categories: API;Isentress;Inhibitors
• Mol File: 518048-05-0.mol
• Article Data: 23

Chemical Properties

• Melting Point: 216 °C(Solv: isopropanol (67-63-0))
• Appearance: /
• Density: 1.46 g/cm³
• Refractive Index: 1.65
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Very Slightly)
• PKA: 4.50±1.00(Predicted)
• CAS DataBase Reference: Raltegravir(CAS DataBase Reference)
• NIST Chemistry Reference: Raltegravir(518048-05-0)
• EPA Substance Registry System: Raltegravir(518048-05-0)

Safety Data

• Hazardous Substances Data: 518048-05-0(Hazardous Substances Data)

Usage

Product Features

Merck's Raltegravir is the first HIV integrase strand transfer inhibitor (referred to as an integrase inhibitor). It is also known as MK-0518, which can treat human immunodeficiency virus (HIV)-1 infection combining with other antiretroviral (ARV) drugs. It slows HIV-1 infection by inhibiting the necessary HIV integrase for viral replication. When raltegravir combines with other anti-HIV drugs, it can reduce the amount of HIV in the blood, while it can increase the number of so-called CD4+ T cells that belong to white blood cells. It helps against other infections. The interaction between raltegravir and ritonavir, efavirenz, tipranavir and tenofovir indicates that there is no drug cross-resistance, and there is a synergistic effect with a variety of drugs. The most common adverse reactions are diarrhea, nausea, headache. In addition, blood tests show that the muscle enzymes abnormally increased in some of patients who taked this drug. The above information is edited by the lookchem of Kui Ming.

Description

Joining maraviroc as a unique approach to battling HIV-1, raltegravir, an inhibitor of HIV-1 integrase, represents the first in its class to be developed and launched as a combination treatment with other antiretroviral agents (NRTIs, NNRTIs, and PIs). HIV-1 integrase is essential for replication of the virus as a virally encoded enzyme that integrates the viral DNA into the genome of the host cell. Inhibition of HIV-1 integrase prevents the two-step process of endonucleolytic removal of the terminal dinucleotide from each 3′end of the viral DNA followed by the covalent integration of the viral DNA, at these modified 3′ends, into the host DNA, thereby representing a viable intervention in the viral life cycle. In vitro, raltegravir inhibited the strand transfer activity of HIV-1 integrase with an IC50 of 2–7nM with ＞ 1,000-fold selectivity over other phosphoryltransferases. In addition, its in vitro IC95 for HIV-1 in 10% fetal bovine serum and 50% human serum was 19 and 33 nM, respectively. Raltegravir was well tolerated with no dose-related toxicities and a safety profile comparable to placebo. The most common clinical adverse events were diarrhea, nausea, vomiting, fatigue, headache, flushing, pruritus, and injection-site reactions.

Uses

Different sources of media describe the Uses of 518048-05-0 differently. You can refer to the following data:
1. Raltegravir (MK-0518) is a potent integrase (IN) inhibitor for WT and S217Q PFV IN.
2. Raltegravir (MK-0518, Isentress) is a potent integrase (IN) inhibitor for WT and S217Q PFV IN with IC50 of 90 nM and 40 nM, respectively.

Brand name

Isentress

Acquired resistance

Several characteristic mutations leading to typical amino acid exchanges have been characterized in cell culture studies and confirmed in clinical trial participants with virological failure while receiving raltegravir in combination with other antiretrovirals. Virological failure has generally been associated with mutations at one of three residues – Y143, Q148 or N155 – usually in combination with at least one other mutation.

Pharmaceutical Applications

Formulated as the potassium salt for oral administration.

Pharmacokinetics

Oral absorption: Not known/available Cmax 400 mg twice daily: c. 2.17 mg/L Plasma half-life: c. 9 h Volume of distribution: Not known/available Plasma protein binding: c. 83% Absorption and distribution It may be administered without regard to food. There are few data regarding its capacity to penetrate into genital secretions or breast milk. A study of 25 HIV-infected individuals receiving raltegravir as a component of combination antiretroviral therapy found that 24 had detectable levels and that 50% of these reached a level exceeding the 95% inhibitory concentration reported to inhibit HIV-1 strains fully susceptible to integrase inhibition. Metabolism and excretion It is not a substrate, and does not appear to inhibit or induce the cytochrome P450 enzyme complex. It is primarily metabolized through hepatic glucuronidation mediated by the UGT-1A1 enzyme. It is excreted in the feces (51%) and the urine (32%) as unaltered compound and its glucuronide. There are no recommended dose adjustments for weight, sex and race, or for hepatic or renal insufficiency. The pharmacokinetic handling in children has not been determined.

Side effects

Its toxicity profile to date is remarkably benign. Clinical trial participants experienced similar types and frequencies of adverse events as those receiving placebo. The most frequently reported adverse events were nausea, diarrhea and headache and were mostly mild to moderate in intensity. Myopathy, rhabdomyolysis and elevations of creatinine phosphokinase have been noted in a few trial participants and it should be used cautiously in combination with drugs associated with muscle toxicity.

Synthesis

The synthesis of raltegravir begins with the treatment of acetone cyanohydrin with liquid ammonia in a pressure vessel. The resulting aminonitrile is protected as the benzyl carbamate before reaction of the nitrile moiety with hydroxylamine to afford the amidoxime. The pyrimidone ring is then constructed by condensation with dimethyl acetylenedicarboxylate and subsequent cyclization in hot xylene. Methylation of the pyrimidone is performed next with iodomethane and magnesium methoxide in dimethylsulfoxide followed by conversion of the methyl ester to an amide with 4-fluorobenzylamine. The amine, liberated from hydrogenolytic removal of the carbobenzyloxy-protecting group, is acylated with oxadiazolecarbonyl chloride, prepared in three steps from 5-methyltetrazole, to afford raltegravir.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin, consider increasing raltegravir dose. Antivirals: avoid with fosamprenavir. Orlistat: absorption of raltegravir possibly reduced. Ulcer-healing drugs: concentration increased by omeprazole and famotidine.

Metabolism

Metabolised via glucuronidation, catalysed by the enzyme uridine diphosphate glucuronosyltransferase. Raltegravir is excreted in both urine and faeces as unchanged drug and metabolites.

InChI:InChI=1/C20H21FN6O5/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30)

Upstream product

• 1236352-55-8 C₁₄H₁₇N₅O₆ 
• 140-75-0 para-fluorobenzylamine 
• 1292804-07-9 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide sodium salt 
• 518048-03-8 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide 
• 1328839-28-6 C₂₄H₂₃FN₈O₇ 
• 889131-28-6 5-methyl-1,3,4-oxadiazole-2-carboxylic acid chloride 
• 888504-28-7 5-methyl-1,3,4-oxadiazole-2-carboxylic acid potassium salt 
• 1391918-13-0 N-(2-cyanopropan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide 

Downstream Products

• 1337990-95-0 raltegravir diethylamine salt 
• 1337990-96-1 raltegravir diisopropylamine salt 
• 1337990-94-9 raltegravir tert-butylamine salt 
• 1292804-07-9 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide sodium salt 
• 1337990-92-7 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide lithium salt 
• 1370588-52-5 4-(4-fluorobenzylcarbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl methanesulfonate 
• 1370588-51-4 4-(4-fluorobenzylcarbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl acetate 
• 1391918-17-4 C₂₀H₂₃FN₆O₆ 
• 1538603-90-5 ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate 
• 1538604-11-3 ((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)methyl pivalate 
• 1402232-17-0 ammonium salt of raltegravir 
• 1356906-11-0 L-arginine salt of raltegravir 
• 1337990-98-3 meglumine salt of raltegravir 
• 1356906-13-2 tris salt of raltegravir 

Relevant articles and documents

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.

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.

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.