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

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

Uses

1. Used in HIV Treatment:
Raltegravir is used as an antiretroviral agent for the treatment of HIV-1 infection. It is particularly effective against both wild-type and S217Q PFV IN strains of the virus, with IC50 values of 90 nM and 40 nM, respectively. By inhibiting the HIV-1 integrase enzyme, Raltegravir disrupts the viral life cycle and helps control the progression of the infection.
2. Used in Combination Therapy:
Raltegravir is used as a component of combination therapy with other antiretroviral agents, such as NRTIs, NNRTIs, and PIs. This approach helps to enhance the overall effectiveness of the treatment and reduce the likelihood of the virus developing resistance to the drugs.
3. Used in Research and Development:
Raltegravir is also used in research and development for the study of HIV-1 integrase and the development of new antiretroviral drugs. Its high potency and selectivity make it a valuable tool for understanding the mechanisms of HIV-1 replication and the design of novel therapeutic strategies.

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.

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

• 140-75-0 para-fluorobenzylamine 
• 1172131-65-5 C₂₉H₃₃FN₄O₆ 
• 1193687-88-5 ethyl (2-(4-(4-fluorobenzylcarbamoyl)-1,6-dihydro-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl)propan-2-ylcarbamoyl)formate 
• 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 
• 1328839-28-6 C₂₄H₂₃FN₈O₇ 
• 518048-03-8 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide 

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 
• 1370588-53-6 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 2,4,6-trimethylbenzenesulfonate 
• 1172131-68-8 4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-((5-methyl-1,3,4-oxadiazol-2-yl)carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl benzoate 
• 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 

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 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.

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.

PROCESS FOR THE PREPARATION OF RALTEGRAVIR

The present invention refers to a process for the preparation of Raltegravir and pharmaceutically acceptable salts thereof.

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.

(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.

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.

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.

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).

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.