748810-28-8

Usage

Uses

Used in Pharmaceutical Industry:
VERNAKALANT HYDROCHLORIDE is used as an antiarrhythmic agent for the treatment of patients with atrial fibrillation and atrial flutter. It works by selectively targeting atrial tissues, effectively and rapidly terminating the abnormal heart rhythm associated with these conditions.
Additionally, VERNAKALANT HYDROCHLORIDE is used as a therapeutic agent for the management of atrial fibrillation, providing a rapid and effective treatment option for patients suffering from this heart condition. Its atrial-selective action allows for targeted treatment with minimal side effects, making it a valuable addition to the arsenal of antiarrhythmic drugs.

Clinical Use

Vernakalant is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. The drug was initially developed by Cardiome Pharma under the trade names Kynapid ? and Brinavess ? and its intravenous formulation was further developed by Merck in April 2009. Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking the cardiac transient outward potassium current, with increased potency as the heart rate increases. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval, which may theoretically increase the risk of ventricular tachycardia.

Synthesis

The preparation of vernakalant entails the union of a prolinol derivative 150 with a 3,4-dimethoxyphenethyl alcohol (148) across a cyclohexanyl lynchpin 152 and is described in the scheme. Decarboxylation of commercially available (2S,4R)-4- hydroxyprolinol (150) was effected using cyclohexanol and cyclohexanone at elevated temperatures. Subsequent protection of the nitrogen atom and the oxygen atom within this system resulted in carbamate 151. Acid-mediated removal of the N-protective functionality preceded nucleophilic attack on epoxide 152 in hot water, and the ensuing mixture of diastereomers was separated by classical resolution via the tartrate salt. O-Benzylated vernakalant 154 was obtained when enantiomerically pure alcohol 153 was subjected to trichloroacetimidate 149 (which arose from the corresponding alcohol 148 under modified Williamson conditions. Acidic hydrogenolysis, which the authors report as separate steps, furnished vernakalant hydrochloride (XIV) in excellent overall yield.

Upstream product

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• 795281-92-4 (3R)-3-benzyloxy-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}pyrrolidine 
• 906802-36-6 (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)-2,5-dioxopyrrolidin-3-yl acetate 
• 822-87-7 2-Chlorocyclohexanone 
• 7417-21-2 2-(3,4-dimethoxyphenyl)ethyl alcohol 
• 1360728-96-6 2-(3,4-dimethoxyphenyl ethoxy)-cyclohexylammonium maleate 
• 1360728-87-5 (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol 
• 19398-47-1 (R)-1,4-dibromo-2-butanol 
• 1360617-31-7 2-(3,4-dimethoxyphenyl ethoxy)-cyclohexanone 
• 1360728-99-9 C₄H₆O₅*C₁₆H₂₅NO₃ 

Relevant academic research and scientific papers

Preparation method of vernakalant hydrochloride

The invention discloses a preparation method of vernakalant hydrochloride. The preparation method comprises the following steps: (1) adding a substrate (1R, 2R)- 2- (3, 4-dimethoxyphenethoxy) cyclohexylamine into a solvent; (2) adding an alkaline reagent, and controlling the temperature of the system; (3) adding an epoxy compound, controlling the temperature of the system, and raising the temperature to carry out cyclization reaction for a period of time; and (4) filtering to obtain a vernakalant solution, adding a hydrochloric acid solution to salify, concentrating under reduced pressure, andadding a crystallization solvent to crystallize, thereby obtaining the vernakalant hydrochloride. According to the invention, a chiral epoxy compound is adopted for cyclization reaction, the characteristics of high yield, short reaction time, simplicity and convenience in operation, mild conditions, convenience in post-treatment, easiness in industrial production and the like are realized, the use of heavy metals is avoided, and the development of injection medicines is facilitated.

A highly efficient asymmetric synthesis of vernakalant

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

PROCESS FOR PREPARING AMINOCYCLOHEXYL ETHER COMPOUNDS

The present invention relates to a process for preparing aminocyclohexyl ether compounds of Formula I: or the pharmaceutically acceptable salts and esters thereof. In particular, the instant invention is directed towards a process for preparing (1R,2R)-2-

SYNTHETIC PROCESSES FOR THE PREPARATION OF AMINOCYCLOHEXYL ETHER COMPOUNDS

This invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R3, R4 and R5 are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.

SYNTHETIC PROCESS FOR AMINOCYCLOHEXYL ETHER COMPOUNDS

Methods for the preparation of stereoisomerically substantially aminocyclohexyl ether compounds such as trans-(1R,2R)-aminocyclohexyl ether compounds and/or trans-(1S,2S)-aminocyclohexyl ether compounds as well as various intermediates and substrates are disclosed.

PRODUCTION METHOD OF OPTICALLY ACTIVE CYCLOHEXANE ETHER COMPOUNDS

The present invention relates to an industrial synthetic method of an optically active cyclohexane ether compound (IIIa) or a salt thereof, which is useful as a pharmaceutical agent, and an intermediate useful for the production method of the present invention. The production method of the present invention is as shown below: wherein each symbol is as defined in the specification. According to the production method of the present invention, efficient and stable supply of an optically active cyclohexane ether compound (IIIa) in a high yield at a lower cost can be afforded. Therefore, an optically active cyclohexane ether compound (IIIa) extremely useful as a pharmaceutical agent can be provided by an industrially highly advantageous method.