500287-72-9

Basic information

• Product Name: 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino]benzonitrile
• Synonyms: 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino]benzonitrile;Rilpivirine;4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile;R 278474;TMC 278;4-[[4-[[4-[(E)-2-Cyanovinyl]-2,6-diMethylphenyl]aMino]pyriMidin-2-yl]aMino]benzonitrile;4-{[4-({4-[(1E)-2-cyanoeth-1-en-1-yl]-2,6-diMethylphenyl}aMino)pyriMidin-2-yl]aMino}benzonitrile;Rilpivirine(R 278474
• CAS NO: 500287-72-9
• Molecular Formula: C₂₂H₁₈N₆
• Molecular Weight: 366.43
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 500287-72-9.mol
• Article Data: 13

Chemical Properties

• Melting Point: 245℃
• Boiling Point: 634.1 °C at 760 mmHg
• Flash Point: 337.3 °C
• Appearance: /
• Density: 1.27
• Vapor Pressure: 5.56E-16mmHg at 25°C
• Refractive Index: 1.665
• Storage Temp.: Refrigerator
• Solubility: Acetone (Slightly), Chloroform (Slightly), DMSO (Slightly), Water (Very Slightly
• PKA: 4.56±0.10(Predicted)
• CAS DataBase Reference: 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino]benzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino]benzonitrile(500287-72-9)
• EPA Substance Registry System: 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl-phenyl]amino]pyrimidin-2-yl]amino]benzonitrile(500287-72-9)

Safety Data

• Hazardous Substances Data: 500287-72-9(Hazardous Substances Data)

Usage

Description

In May 2011, the U.S. FDA approved rilpivirine in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV) 1 infection in treatment-naive adult patients. Rilpivirine is a member of the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of anti-HIV agents. It is highly potent against a range of wild-type HIV strains (EC50=0.07–1.0 nM),～10–20 timesmore potent than the NNRTI efavirenz (Sustiva), and active against HIV strains resistant to other NNRTIs. The discovery of rilpivirine was guided by molecular modeling and X-ray crystallography of HIV-1 RT complexed with inhibitors. The synthesis of rilpivirine is accomplished by an efficient 6-step route in which the key step is coupling of 4-((4-chloropyrimidin-2-yl)amino)benzonitrile with (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile.

Chemical Properties

N/ABright Yellow Solid

Originator

Janssen (Belgium)

Uses

Different sources of media describe the Uses of 500287-72-9 differently. You can refer to the following data:
1. A novel non-nucleoside reverse transcriptase inhibitor. Rilpivirine seems to be well tolerated with less CNS disturbance than Efavirenz, and has non-teratogenic potential. An anti-HIV agent.
2. A novel non-nucleoside reverse transcriptase inhibitor. Rilpivirine seems to be well tolerated with less CNS disturbance than Efavirenz, and has non-teratogenic potential.

Definition

ChEBI: An aminopyrimidine that is pyrimidine-2,4-diamine in which the amino groups at positions 2 and 4 are substituted by 4-cyanophenyl and 4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl groups respectively. Used for treatment of HIV.

Brand name

Edurant

Clinical Use

Non-nucleoside reverse transcriptase inhibitor: Treatment of progressive or advanced HIV infection in combination with at least two other antivirals

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with clarithromycin and erythromycin - concentration possibly increased; concentration decreased by rifampicin and rifabutin - avoid with rifampicin, increase dose of rilpivirine to 50 mg daily. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, primidone and phenytoin - avoid. Corticosteroids: avoid with dexamethasone (except as a single dose). Orlistat: absorption possibly reduced by orlistat. Ulcer-healing drugs: concentration possibly reduced by esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole - avoid; avoid histamine H2 -antagonists for 12 hours before and 4 hours after rilpiverine.

Metabolism

Primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. 85% excreted via the faeces (25% as unchanged drug) and 6% via the urine.

references

[1] moss d m, liptrott n j, curley p, et al. rilpivirine inhibits drug transporters abcb1, slc22a1, and slc22a2 in vitro. antimicrobial agents and chemotherapy, 2013, 57(11): 5612-5618.[2] garvey l, winston a. rilpivirine: a novel non-nucleoside reverse transcriptase inhibitor. 2009.[3] weiss j, haefeli w e. potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. international journal of antimicrobial agents, 2013, 41(5): 484-487.[4] baert l, van’t klooster g, dries w, et al. development of a long-acting injectable formulation with nanoparticles of rilpivirine (tmc278) for hiv treatment. european journal of pharmaceutics and biopharmaceutics, 2009, 72(3): 502-508.

InChI:InChI=1/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+

Upstream product

• 4336-70-3 (cyanomethyl)triphenylphosphonium chloride 
• 500293-29-8 4-[4-(4-formyl-2,6-dimethylphenylamino)pyrimidin-2-ylamino]benzonitrile 
• 107-13-1 acrylonitrile 
• 374067-85-3 4-((4-((4-bromo-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile 
• 661489-23-2 (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile hydrochloride 
• 244768-32-9 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile 
• 87-62-7 2,6-dimethylaniline 
• 4102-53-8 4-iodo-2,6-dimethylaniline 
• 1228671-28-0 4-((4-methoxypyrimidin-2-yl)amino)benzonitrile 
• 189956-45-4 4-[(4-hydroxy-2-pyrimidinyl)amino]benzonitrile 
• 1538550-43-4 (E)-3-(4-((2-chloropyrimidin-4-yl)amino)-3,5-dimethylphenyl)acrylonitrile 
• 873-74-5 4-Aminobenzonitrile 
• 500288-66-4 (E)- 3-{4-[2-(4-(cyanophenylamino)-1-oxo-pyrimidin-4-yl)amino]-3,5-dimethylphenyl}acrylamide 
• 500292-86-4 3-(4-amino-3,5-dimethylphenyl)acrylonitrile 

Downstream Products

• 882054-49-1 C₂₂H₁₇BrN₆ 
• 1399384-91-8 rilpivirine tosylate salt 
• 700361-47-3 Rilpivirine hydrochloride 
• 882054-59-3 C₂₅H₂₂N₆O₂ 

Relevant articles and documents

Method for preparing high-purity ribavirin intermediate by one-pot method (by machine translation)

The invention relates to the technical field of chemical medicine, in particular to a method for preparing a high-purity ribavirin intermediate by a one-pot method. The method comprises the following steps: (1) replacing the compound I with the compound II to obtain the reaction liquid of the compound III. (2) Acrylamide was added to III reaction liquid of the compound, and the reaction liquid of compound IV was obtained under Heck reaction conditions. (3) In the reaction solution of Compound IV, activated carbon is first added for decolorization treatment, and then a poor solvent is added for crystallization to obtain a white compound IV, i.e. a ripe intermediate. The method for preparing the high-purity ribavirin intermediate by one-pot method is scientific, reasonable, simple and feasible, improves product purity and yield, and is suitable for large-scale production. (by machine translation)

Method for effectively removing isomer of rilpivirine

The invention belongs to the field of chemical synthesis of medicines, and in particular discloses a method for effectively removing the isomer of rilpivirine. The method comprises the following steps: synthesizing organic acid salts of rilpivirine from rilpivirine and maleic acid, benzene sulfonic acid, p-methylbenzene sulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid and the like, performing recrystallization on the organic acid salts of the rilpivirine by using mixed solvents of methanol, ethanol, acetonitrile, acetic acid, N,N-dimethyl formamide and the like and water, furthermore freeing recrystallized organic acid salts of the rilpivirine by using alkali such as sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, potassium tert-butoxide and sodium ethoxide, thereby reducing the content of Z-isomer of rilpivirine to be 0.1% or below from about 12%. The method is simple and convenient to operate, gentle in reaction conditions, low in production cost, relatively small in loss of products in the purification process, good in reproducibility, stable in process, applicable to industrial amplification and great in practical values, and the content of the Z-isomer of the rilpivirine can be reduced to be 0.1% or below from 12-14% at a time.

RILPIVIRINE HYDROCHLORIDE

The present invention provides a novel process for the preparation of rilpivirine. The present invention also provides a novel process for the preparation of rilpivirine hydrochloride. The present invention further provides a rilpivirine hydrochloride monohydrate, process for its preparation and pharmaceutical compositions comprising it.