500287-72-9

Usage

Uses

1. Used in Pharmaceutical Industry:
Rilpivirine is used as an anti-HIV agent for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naive adult patients. It is a member of the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of anti-HIV agents and is highly potent against a range of wild-type HIV strains.
2. Used in HIV Treatment:
Rilpivirine is used as a component in combination therapies with other antiretroviral agents for the treatment of HIV-1 infection. It is effective against HIV strains resistant to other NNRTIs and has shown to be well-tolerated with less CNS disturbance than other NNRTIs like Efavirenz.
Brand Name:
Edurant

Originator

Janssen (Belgium)

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 
• 24596-19-8 4-bromo-2,6-dimethylphenylamine 
• 3095-47-4 4-amino-3,5-dimethylbenzoic acid ethyl ester 
• 661489-23-2 (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile hydrochloride 
• 244768-32-9 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile 
• 661489-23-2 (E)-3-(4-amino-3,5-dimethylphenyl)-2-acrylonitrile hydrochloride 
• 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 

Downstream Products

• 1399384-91-8 rilpivirine tosylate salt 
• 700361-47-3 Rilpivirine hydrochloride 
• 882054-59-3 C₂₅H₂₂N₆O₂ 
• 882187-59-9 C₂₃H₁₈N₆O₂ 

Relevant academic research and scientific papers

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.

A METHOD OF PRODUCING HIGHLY PURE RILPIVIRINE AND ITS SALTS

A method of preparing Rilpivirine of formula I, or a suitable salt thereof, comprising a reaction of a hydrogen halide of the aniline derivative of formula II with chloropyrimidine of formula III in methyl isobutyl ketone and in the presence of a polar additive.

Pharmaceutical compositions comprising a basic drug compound, a surfactant, and a physiologically tolerable water soluble acid

The invention provides a novel pharmaceutical composition comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base characterized in that the acid respectively base:drug compound ratio is at least 1:1 by weight.

PROCESS FOR RILPIVIRINE USING NOVEL INTERMEDIATE

The present invention provides a commercially viable process for preparing rilpivirine and its pharmaceutically acceptable acid addition salts thereof in high yields using novel intermediate.

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.

PROCESS FOR RILPIVIRINE

The present invention provides a novel process for the preparation of 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile. The present invention also provides a novel process for the preparation of 4-iodo-2,6-dimethyl benzenamine. The present invention further provides an improved process for the preparation of rilpivirine. The present invention further provides a tosylate salt of rilpivirine, process for its preparation and pharmaceutical compositions comprising it.

IMPROVED PROCESS FOR PREPARATION OF RILPIVIRINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

Disclosed is an improved process for the preparation of rilpivirine hydrochloride. The process comprises a) reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile hydrochloride and 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile in the presence of a phase transfer catalyst followed by saltification with an acid and b) converting the rilpivirine acid addition salt into rilpivirine hydrochloride salt.

RILPIVIRINE HYDROCHLORIDE

As used herein the term "room temperature" refers to a temperature of about 25°C to about 35°C. According to one aspect of the present invention, there IS provided a novel process for the preparation of rilpivirine, which comprises: a) condensing the (E)-3-( 4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride with 4-( 4-chloropyrimidin-2-ylamino )benzonitrile m the presence of Nmethylpyrrolidone; b) heating the contents obtained in step (a) at about 75 to 95°C to obtain a solution; c) cooling the solution obtained in step (b) at below 35°C; d) adding water to the reaction mass; and e) isolating rilpivirine. The reaction in step (b) may preferably be heated to 100 to 110°C. Step (c) may preferably be carried out at room temperature. Rilpivirine may be isolated in step (e) by the methods known such as Filtration or centrifugation.

PROCESS FOR RILPIVIRINE

The present invention provides a novel process for the preparation of 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile. The present invention also provides a novel process for the preparation of 4-iodo-2,6-dimethyl benzenamine. The present invention further provides an improved process for the preparation of rilpivirine. The present invention further provides a tosylate salt of rilpivirine, process for its preparation and pharmaceutical compositions comprising it.