95635-55-5

Basic information

• Product Name: Ranolazine
• Synonyms: 1-Piperazineacetamide,N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-;N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]ethanamide;N-(2,6-diMethylphenyl)-2-{4-[(2R)-2-hydroxy-3-(2-Methoxyphenoxy)propyl]piperazin-1-yl}acetaMide;Ranolazine(Ranexa);1- 3-(2-Methoxyphenoxy)-2-hydroxypropyl -4- ...;Ranolazine N-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide;Ranolazine (100 mg);RANOLAZINE
• CAS NO: 95635-55-5
• Molecular Formula: C₂₄H₃₃N₃O₄
• Molecular Weight: 427.54
• EINECS: 1308068-626-2
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;RANEXA;Inhibitors;APIs;Antianginal;API
• Mol File: 95635-55-5.mol
• Article Data: 19

Chemical Properties

• Melting Point: 119-1200C
• Boiling Point: 624.1 °C at 760 mmHg
• Flash Point: 331.2 °C
• Appearance: white solid
• Density: 1.174 g/cm³
• Vapor Pressure: 1.94E-16mmHg at 25°C
• Refractive Index: 1.585
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 14.06±0.20(Predicted)
• CAS DataBase Reference: Ranolazine(CAS DataBase Reference)
• NIST Chemistry Reference: Ranolazine(95635-55-5)
• EPA Substance Registry System: Ranolazine(95635-55-5)

Safety Data

• Hazardous Substances Data: 95635-55-5(Hazardous Substances Data)

Usage

Description

Ranolazine, also known as N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide (Ranexa), is an antianginal medication that was approved by the Food and Drug Administration (FDA) in January 2006 for the treatment of chronic angina. It is an active piperazine derivative that was patented in 1986 and is available in oral and intravenous forms. Ranolazine is evidenced with anti-ischemic/antianginal properties in patients with chronic angina without clinically significant changes in heart rate or blood pressure. It is a white solid and is marketed under the brand name Ranexa (Sensus).

Uses

Used in Cardiovascular Medicine:
Ranolazine is used as an antianginal medication for the treatment of chronic angina, a common symptom of coronary artery disease. It helps to alleviate chronic chest pain by altering the transcellular late sodium current, which in turn affects the sodium-dependent calcium channels during myocardial ischemia. This mechanism indirectly prevents the calcium overload associated with cardiac ischemia.
Ranolazine is also used as an anti-ischemic agent, providing potential benefits in cardiovascular conditions such as heart failure, acute and chronic myocardial ischemia, certain types of cardiac sodium channel gene mutations, and ventricular and supraventricular arrhythmias.
Used in Chronic Stable Angina (CSA) Treatment:
In patients with CSA, Ranolazine is used as an extended-release drug to treat chronic angina in those who have not responded to prior angina therapy. It helps to correct the imbalance between myocardial oxygen demand and supply, typically without producing significant reductions in heart rate or blood pressure.

References

[1] Bernard R. Chaitman, Ranolazine for the Treatment of Chronic Angina and Potential Use in Other Cardiovascular Conditions, New Drugs and Technologies, 2006, vol. 113, 2462-2472 [2] Bernard R. Chaitman, Sandra L. Skettino, John O. Parker, Peter Hanley, Jaroslav Meluzin, Jerzy Kuch and Carl J. Pepine, Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina, Journal of the American College of Cardiology, 2004, vol. 43, 1375-1382

Clinical Use

Add on therapy for angina

Synthesis

Two syntheses, one from the inventors at Roche and other from a group in Hungary, of Ranolazine have been described in the patent literature. The original synthesis is highlighted in the Scheme. Reaction of 2,6-dimethylaniline 46 with chloroacetyl chloride (47) in the presence of triethylamine for 4h at 0oC gave amide 48 in 82% yield. This chloro amide 48 was reacted with piperazine in refluxing ethanol for 2 h to give piperazinyl amide 50. Reaction of amide 50 with epoxide intermediate 53, prepared by reacting 2-methoxy phenol 51 with epichlorohydrin, in refluxing isopropanol for 3 h followed by treatment with HCl/methanol gave ranolazine dihydrochloride (VII) in 73% yield.

Drug interactions

Potentially hazardous interactions with other drugs Anti-arrhythmics: avoid with disopyramide. Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid concomitant use; concentration reduced by rifampicin - avoid. Antifungals: concentration increased by ketoconazole and possibly itraconazole, posaconazole and voriconazole - avoid. Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir and tipranavir - avoid. Beta-blockers: avoid with sotalol. Ciclosporin: concentration of both drugs possibly increased. Grapefruit juice: concentration of ranolazine possibly increased - avoid. Statins: concentration of simvastatin increased - maximum dose of simvastatin is 20 mg. Tacrolimus: concentration of tacrolimus increased.

Metabolism

Extensively metabolised in the gastrointestinal tract and liver. Four main metabolites have been identified. Approximately 75% of a dose is excreted in the urine with the remainder in the faeces.

InChI:InChI=1/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29)

Upstream product

• 5294-61-1 N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide 
• 162712-35-8 CVT-2513 
• 1131-01-7 2-chloro-N-(2,6-dimethylphenyl)acetamide 
• 2210-74-4 2-(2-methoxy-phenoxymethyl)-oxirane 
• 90-05-1 2-methoxy-phenol 
• 87-62-7 2,6-dimethylaniline 
• 1427177-23-8 (RS)-2-(4-(3-chloro-2-hydroxyphenyl)piperazin-1-yl)-N-(2,6-dimethylphenyl)acetamide 
• 25772-81-0 1-chloro-3-(2-methoxyphenoxy)-2-propyl alcohol 
• 110-85-0 piperazine 

Downstream Products

• 1215206-15-7 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine tosylate 
• 1215206-11-3 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine maleate 
• 1080496-58-7 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine fumarate 
• 1215206-08-8 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine oxalate 
• 1215206-14-6 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine besylate 
• 142387-99-3 (R)-Ranolazine 
• 114246-81-0 (S)-Ranolazine 

Relevant articles and documents

A preparation method of Ranolazine

The present invention relates to the technical field of ranolazine, in particular to a ranolazine preparation method, the method comprises the following steps: piperazine through the hydroformylation reaction to obtain the 1 - formyl piperazine, then with 2 - chloro - N - (2, 6 - dimethyl-phenyl) acetamide for carrying out the alkylation reaction to obtain N - (2, 6 - dimethyl-phenyl) - 2 - (4 - formyl piperazine) acetamide, then through hydrolytic reaction to obtain N - (2, 6 - dimethyl-phenyl) - 2 - (1 - piperazinyl) acetamide, finally with 2 - (2 - methyl-phenoxymethyl) oxirane ring opening reaction to obtain the ranolazine. The invention preparation of the ranolazine purity is good, high yield.

NOVEL PROCESS FOR THE PREPARATION OF RANOLAZINE

The present invention relates to novel processes for the preparation of Ranolazine (I) and its acid addition salts and the novel process for the preparation of compound of formula (7).

Process for the Preparation of Ranolazine

A process for the preparation of ranolazine comprises the step of condensing N-(2,6-dimethylphenyl)-1-piperazinyl acetamide with a compound of formula (I) to obtain ranolazine, in which X is chlorine or bromine Ranolazine is prepared by condensing ring-opening halide which replaces epoxide in this process.