518048-03-8

Basic information

• Product Name: 2-(1-AMINO-1-METHYLETHYL)-N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE
• Synonyms: 2-(1-AMINO-1-METHYLETHYL)-N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE;2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;InterMediate B of Raltegravir;2-(2-AMinopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-ethyl-6-oxo-1,6-dihydropyriMidine-4-carboxaMide;2-(2-aMinopropan-2-yl)-N-[(4-fluorophenyl)Methyl]-5-hydroxy-1-Methyl-6-oxo-1,6-dihydropyriMidine-4-carboxaMide;2-(1-AMino-1-Methylethyl)-N-[(4-fluorophenyl)Methyl]-1,6-dihydro-5-hydroxy-1-Methyl-6-oxo-;N-(4-fluorobenzyl)-2-(2-aMinopropan-2-yl)-5-hydroxy-1-Methyl-6-oxo-1,6-dihydropyriMidine-4-carboxaMide;2-(2-Aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carbox
• CAS NO: 518048-03-8
• Molecular Formula: C₁₆H₁₉FN₄O₃
• Molecular Weight: 334.35
• EINECS: 1592732-453-0
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labelled Compounds;intermediate;Fluorine series
• Mol File: 518048-03-8.mol

Chemical Properties

• Melting Point: 105-107°C
• Boiling Point: 567.4 °C at 760 mmHg
• Flash Point: 311 °C
• Appearance: White solid (powder)
• Density: 1.35
• Refractive Index: 1.607
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Very Slightly, Heated), Pyridine (Slightly)
• PKA: 4.50±1.00(Predicted)
• CAS DataBase Reference: 2-(1-AMINO-1-METHYLETHYL)-N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(1-AMINO-1-METHYLETHYL)-N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE(518048-03-8)
• EPA Substance Registry System: 2-(1-AMINO-1-METHYLETHYL)-N-(4-FLUOROBENZYL)-5-HYDROXY-1-METHYL-6-OXO-1,6-DIHYDROPYRIMIDINE-4-CARBOXAMIDE(518048-03-8)

Safety Data

• Hazardous Substances Data: 518048-03-8(Hazardous Substances Data)

Usage

Uses

1. Pharmaceutical Industry:
2-(1-Amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide is used as an intermediate in the preparation of HIV-integrase inhibitors for the development of antiretroviral drugs. Its role in this process is to facilitate the creation of compounds that can effectively inhibit the integration of the HIV virus into the host's DNA, thus suppressing the viral replication process.
2. Research and Development:
In the field of research and development, this compound is used as a labeled intermediate in the preparation of labeled HIV-integrase inhibitors. This application is essential for studying the mechanism of action, pharmacokinetics, and pharmacodynamics of these inhibitors, as well as for the development of new and more effective antiretroviral therapies.
3. Chemical Synthesis:
As a white solid (powder), 2-(1-Amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide can also be used in various chemical synthesis processes, potentially leading to the development of new compounds with diverse applications in different industries.

InChI:InChI=1/C16H19FN4O3/c1-16(2,18)15-20-11(12(22)14(24)21(15)3)13(23)19-8-9-4-6-10(17)7-5-9/h4-7,22H,8,18H2,1-3H3,(H,19,23)

Upstream product

• 518048-02-7 {1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-1-methyl-ethyl}carbamic acid benzyl ester 
• 888504-27-6 2-(1-benzyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester 
• 140-75-0 para-fluorobenzylamine 
• 519028-33-2 benzyl 2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-ylcarbamate 

Downstream Products

• 518048-05-0 raltegravir 
• 518048-04-9 methyl {[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]amino}(oxo)acetate 
• 1064707-02-3 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-[(pyridin-2ylcarbonyl)amino]ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1064707-06-7 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-[(1,3-thiazol-5-ylcarbonyl)amino]ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1064707-04-5 N-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethyl]pyrimine-2-carboxamide 
• 1064707-07-8 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-{[(5-methyl-4H-1,2,4-triazol-3-yl)carbonyl]amino}ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1064706-92-8 2-(1-dimethylamino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1064706-95-1 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-[(methylsulfonyl)amino]ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 518049-93-9 N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-[(1H-imidazol-5-ylcarbonyl)amino]-1-methylethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1064706-97-3 2-(1-{[(dimethylamino)sulfonyl]amino}-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide 
• 1328839-28-6 C₂₄H₂₃FN₈O₇ 
• 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 
• 1193687-88-5 ethyl (2-(4-(4-fluorobenzylcarbamoyl)-1,6-dihydro-5-hydroxy-1-methyl-6-oxopyrimidin-2-yl)propan-2-ylcarbamoyl)formate 

Relevant articles and documents

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.

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.

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.

PROCESSES FOR THE PREPARATION OF INTERMEDIATES OF RALTEGRAVIR

The present disclosure provides a process for the preparation of 2-(2-amino propan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine- 4-carboxamide by debenzylation of benzyl(2-{4-[(4-fluorobenzyl)carbamoyl]-5- hydroxy-1-methyl-6-ox

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.

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.

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.