138729-47-2

Basic information

• Product Name: Eszopiclone
• Synonyms: ESOPICLONE;ESZOPICLONE;(S)-(+)-ZOPICLONE;Eszppiclone98.5%~100.5%;Eszppiclone;[(9S)-8-(5-Chloropyridin-2-yl)-7-oxo-2,5,8-triazabicyclo[4.3.0]nona-1,3,5-trien-9-yl]4-methylpiperazine-1-carboxylate;Lunesta;ESZOPICLONE CIV
• CAS NO: 138729-47-2
• Molecular Formula: C₁₇H₁₇ClN₆O₃
• Molecular Weight: 388.81
• EINECS: 202-303-5
• Product Categories: Sedative, Hypnotic;Intermediates & Fine Chemicals;Pharmaceuticals;GABA/Glycine receptor
• Mol File: 138729-47-2.mol

Chemical Properties

• Melting Point: 202-204°C
• Boiling Point: 580.7 °C at 760 mmHg
• Flash Point: 305 °C
• Appearance: White or slightly yellowish powder
• Density: 1.54 g/cm³
• Vapor Pressure: 1.78E-13mmHg at 25°C
• Refractive Index: 1.688
• Storage Temp.: -20°C Freezer
• PKA: 6.70±0.10(Predicted)
• CAS DataBase Reference: Eszopiclone(CAS DataBase Reference)
• NIST Chemistry Reference: Eszopiclone(138729-47-2)
• EPA Substance Registry System: Eszopiclone(138729-47-2)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38-62
• Safety Statements: 26-36
• Hazardous Substances Data: 138729-47-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Eszopiclone is used as a hypnotic and sedative agent for the treatment of insomnia. It helps in addressing difficulty falling asleep, maintaining sleep, frequent awakenings during the night, waking up too early, inability to fall back asleep, and not feeling refreshed upon waking up in the morning.
Eszopiclone is used as a long-term treatment option for insomnia, as it does not lead to tolerance development in patients even after 6 months of use. This makes it a preferred choice for managing chronic insomnia.
Additionally, Eszopiclone is used as an active ingredient in various brand-name medications, such as Lunesta (Sepracor) and Ortho-EST (Sun), which are prescribed to patients suffering from insomnia.

References

https://en.wikipedia.org/wiki/Eszopiclone http://www.medicinenet.com/eszopiclone/article.htm https://pubchem.ncbi.nlm.nih.gov/compound/969472#section=Top

Originator

Aventis (France)

Mechanism of action

The cyclopyrrole zopiclone is described as a “superagonist” at BZRs with the subunit composition α1β2γ2 and α1β2γ3, because it potentiates the GABA-gated current more than the benzodiazepine (flunitrazepam) reference agonist. Racemic zopiclone has been available in Europe since 199,2 and the higher affinity S-enantiomer (eszopiclone) was marketed in the United States in 2005, primarily to treat insomnia, because of its rapid onset and moderate duration (half-life, ~6 hours) of hypnotic-sedative effect. Less than 10% of orally administered eszopiclone is excreted unchanged, because it undergoes extensive CYP3A4- and CYP2E1-catalyzed oxidation and demethylation to metabolites excreted primarily in urine. "

Pharmacokinetics

Zoplicone was originally marketed as a racemic mixture; however, because the sedative activity is primarily associated with the S-isomer, only the S-isomer is currently marketed in the United States (as esozoplicone) (36). It is soluble in dilute mineral acids. Unlike zolpidem and zaleplon, eszoplicone is not as specific for the α1 subunit of GABAA, but it binds broadly, like the benzodiazepines (Table 19.2). Its pharmacological and pharmacodynamic activities, however, are more closely related to those of the nonbenzodiazepines. It is rapidly absorbed, with an oral bioavailability of approximately 80%, reaching peak concentrations in 1 h and having a relatively long elimination half-life of approximately 6 hours (Table 19.2). Eszopliclone is primarily metabolized to (S)-zoplicone N-oxide and (S)-N-desmethylzoplicone by the CYP3A4. (S)-Ndesmethylzopiclone binds to GABA receptors with substantially lower potency than eszopiclone, and (S)-zopiclone-N-oxide shows no significant binding to this receptor. It does not accumulate with once-daily administration, and it exhibits linear (dose-proportional) pharmacokinetics over the range of 1 to 6 mg. Eszopiclone is weakly bound to plasma protein (52–60%), suggesting that eszopiclone distribution should not be affected by drug–drug interactions caused by protein binding. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. A similar excretion profile would be expected for eszopiclone. Less than 10% of the orally administered eszopiclone dose is excreted in the urine as unchanged drug. After a high-fat meal, peak plasma concentrations can be delayed by approximately 1 hour without affecting its half-life.

Synthesis

The synthesis of eszopicolone involves enzymatic resolution of a zopicolone derivative to give the chiral compound as depicted in the Scheme 12. Pyrazine-2,3- dicarboxylic acid anhydride was reacted with 2-amino- 5-chloropyridine (61) in refluxing acetonitrile to generate 3- (5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (62) in 95% yield. Compound 62 was cyclized by treating with refluxing SOCl2 to give 6-(5-chloropyrid-2-yl)-5,7- dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (63) in 79% yield.Compound 63 was subjected to partial reduction with KBH4 in dioxane-water at low temperature to give 6-(5-chloro-2- pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (64) in 64% yield, which was esterified with vinyl chloroformate in pyridine to give corresponding vinyl acetate 65 in 75% yield. The racemic 65 was then subjected to kinetic resolution by a highly enantioselective enzymatic hydrolysis process. Chiral vinyl acetate 67 with desired stereochemistry was obtained when candida antarctica lipase was employed for hydrolysis of 65 in dioxane/water at 60oC for 2 days. Interestingly, the enzymatic hydrolysis stopped at 50% conversion and the hydrolyzed alcohol was recovered as the starting substrate 65 because of spontaneous racemization of the alcohol in the reaction medium. Therefore, although a maximum yield of kinetic resolution is 50%, the overall efficiency of this enzymatic process is 100% because of substrate recycling. Finally, the chiral vinyl acetate 67 was condensed with methyl piperazine in acetone to give eszopicolone (IX).

Metabolism

The effects of eszoplicone on sleep onset may be reduced if it is taken either with or immediately after a high-fat/heavy meal. In elderly subjects, the elimination half-life was prolonged to approximately 5 to 9 hours. Therefore, in elderly patients, the starting dose should be decreased to 1 mg, and the dose should not exceed 2 mg. No dose adjustment is necessary in patients with renal impairment, because less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug. Although no pharmacokinetic or pharmacodynamic or drug interactions have been reported for eszopiclone, potent inhibitors of CYP3A4 could increase plasma levels of eszopiclone. Eszopiclone does not alter the clearance of drugs metabolized by common CYP450 enzymes. Potential pharmacodynamic interactions (additive pharmacological effects) with CNS depressants such as alcohol, anticonvulsants, antihistamines, antidepressants, or other psychotropic drugs could occur. Dosage adjustment may be necessary when eszopiclone is administered with CNS depressants; concomitant use with alcohol should be avoided. The primary advantage of eszoplicone is that it has been shown to be effective in chronic insomnia (long-term treatment) in measures of sleep latency, total sleep time, and wake time after sleep onset without development of tolerance. Eszoplicone would appear to be most effectively used for patients who tend to awaken during the night rather than patients for whom the primary problem is initiating sleep.

InChI:InChI=1/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3/t16-/m0/s1

Upstream product

• 109-01-3 1-methyl-piperazine 
• 508169-20-8 (S)-(+)-7-(2-chloromethyloxycarbonyloxy)-6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 43200-80-2 zopiclon 
• 144025-93-4 eszopiclone dibenzoyl-D-tartrate 
• 1225275-19-3 eszopiclone diacetyl-L-tartaric acid salt 
• 1225275-18-2 eszopiclone di-p-anisolyl-L-tartaric acid salt 
• 138680-08-7 (-)-Zopiclone 
• 1072-98-6 5-chloro-2-pyridylamine 
• 4744-50-7 2,3-pyrazinedicarboxylic anhydride 
• 55112-42-0 4-methylpiperazine-1-carbonyl chloride monohydrochloride 
• 43200-82-4 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine 
• 43200-83-5 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid 
• 1020156-02-8 D(+)-O,O-dibenzoyl tartarate of zopiclone 
• 1107971-15-2 (S)-zopiclone N-acetyl-L-aspartate 

Downstream Products

• 138680-08-7 (-)-Zopiclone 
• 537036-14-9 (7S)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one 
• 43200-80-2 zopiclon 
• 151851-70-6 C₁₇H₁₇ClN₆O₄ 
• 1167990-52-4 (S)-zopiclone (R)-mandelate 
• 1216659-29-8 (S)-desmethylzopiclone hydrochloride 

Relevant articles and documents

Are Highly Stable Covalent Organic Frameworks the Key to Universal Chiral Stationary Phases for Liquid and Gas Chromatographic Separations?

High-performance liquid chromatography (HPLC) and gas chromatography (GC) over chiral stationary phases (CSPs) represent the most popular and highly applicable technology in the field of chiral separation, but there are currently no CSPs that can be used for both liquid and gas chromatography simultaneously. We demonstrate here that two olefin-linked covalent organic frameworks (COFs) featuring chiral crown ether groups can be general CSPs for extensive separation not only in GC but also in normal-phase and reversed-phase HPLC. Both COFs have the same 2D layered porous structure but channels of different sizes and display high stability under different chemical environments including water, organic solvents, acids, and bases. Chiral crown ethers are periodically aligned within the COF channels, allowing for enantioselective recognition of guest molecules through intermolecular interactions. The COF-packed HPLC and GC columns show excellent complementarity and each affords high resolution, selectivity, and durability for the separation of a wide range of racemic compounds, including amino acids, esters, lactones, amides, alcohols, aldehydes, ketones, and drugs. The resolution performances are comparable to and the versatility is superior to those of the most widely used commercial chiral columns, showing promises for practical applications. This work thus advances COFs with high stability as potential universal CSPs for chromatography that are otherwise hard or impossible to produce.

Method for synthesizing eszopiclone

The invention provides a method for synthesizing eszopiclone. According to the method, chiral imidazo thiazole is taken as a catalyst to catalyze a racemic hemiacetal intermediate and chloro-formic ester to produce kinetic resolution reaction, and (S)-hemiacetal carbonic ester with good yield and enantioselectivity is obtained. The (S)-hemiacetal carbonic ester is reacted with N-methyl piperazine, so that eszopiclone can be obtained. The method has the advantages that the chiral imidazo thiazole which is low in cost and easy to obtain is used as the catalyst, operation procedures are simple, the production cost is low, and the method has very high application value for the industrial preparation of eszopiclone.

Eszopiclone microcrystalline and its preparation method

The invention discloses an eszopiclone microcrystalline and a preparation method thereof. The preparation method comprises the following steps: (1) eszopiclone is dissolved in an acid solution containing an acidulant to obtain a medicated solution; or a water-soluble eszopiclone salt is dissolved in water to get a medicated solution; wherein the solvent of the acid solution containing the acidulant is a solvent A and / or water; the solvent A is an organic solvent capable of being mixedly dissolved in water in any proportion; and (2) under stirring, an alkalizing agent is added into the medicated solution. The eszopiclone microcrystalline prepared by the preparation method is free of residual organic solvent, microcrystalline particle size and particle size distribution are controllable, and the microcrystalline product can be directly used for the preparation of pharmaceutical formulations without further grinding, so that the dissolution rate and content uniformity of prepared pharmaceutical formulation products are increased, and bioavailability improvement and individual difference reduction can be facilitated.

A method for preparing eszopiclone

The invention relates to an eszopiclone preparation method comprising main steps that: zopiclone is subjected to a reaction with D-dibenzoyltartaric acid or a hydrate thereof, such that dextral zopiclone-D-dibenzoyltartrate is produced; and the salt is dissociated, such that eszopiclone is obtained. According to the method, D-dibenzoyltartaric acid with a substance amount of a quarter to a half of that of zopiclone is adopted. The reaction conditions are mild, operation is convenient, product yield is high, and product purity is high. The method is suitable for large-scale industrialized productions.

Strategy Approach for Direct Enantioseparation of Hyoscyamine Sulfate and Zopiclone on a Chiral αl-Acid Glycoprotein Column and Determination of Their Eutomers: Thermodynamic Study of Complexation

Rapid and simple isocratic high-performance liquid chromatographic methods with UV detection were developed and validated for the direct resolution of racemic mixtures of hyoscyamine sulfate and zopiclone. The method involved the use of αl-acid glycoprotein (AGP) as chiral stationary phase. The stereochemical separation factor (Greek small letter alpha with tonos) and the stereochemical resolution factor (Rs) obtained were 1.29 and 1.60 for hyoscyamine sulfate and 1.47 and 2.45 for zopiclone, respectively. The method was used for determination of chiral switching (eutomer) isomers: S-hyoscyamine sulfate and eszopiclone. Several mobile phase parameters were investigated for controlling enantioselective retention and resolution on the chiral AGP column. The influence of mobile phase, concentration and type of uncharged organic modifier, ionic strength, and column temperature on enantioselectivity were studied. Calibration curves were linear in the ranges of 1-10 μg mL-1 and 0.5-5 μg mL-1 for S-hyoscyamine sulfate and eszopiclone, respectively. The method is specific and sensitive, with lower limits of detection and quantifications of 0.156, 0.515 and 0.106, 0.349 for S-hyoscyamine sulfate and eszopiclone, respectively. The method was used to identify quantitatively the enantiomers profile of the racemic mixtures of the studied drugs in their pharmaceutical preparations. Thermodynamic studies were performed to calculate the enthalpic ΔH and entropic ΔS terms. The results showed that enantiomer separation of the studied drugs were an enthalpic process.

Preparation of a β-cyclodextrin-based open-tubular capillary electrochromatography column and application for enantioseparations of ten basic drugs

An open-tubular capillary electrochromatography column was prepared by chemically immobilized β-cyclodextrin modified gold nanoparticles onto new surface with the pre-derivatization of (3-mercaptopropyl)-trimethoxysilane. The synthesized nanoparticles and the prepared column were characterized by transmission electron microscopy, scanning electron microscopy, infrared spectroscopy and ultraviolet visible spectroscopy. When the column was employed as the chiral stationary phase, no enantioselectivity was observed for ten model basic drugs. So β-cyclodextrin was added to the background electrolyte as chiral additive to expect a possible synergistic effect occurring and resulting in a better separation. Fortunately, significant improvement in enantioselectivity was obtained for ten pairs of drug enantiomers. Then, the effects of β-cyclodextrin concentration and background electrolyte pH on the chiral separation were investigated. With the developed separation mode, all the enantiomers (except for venlafaxine) were baseline separated in resolutions of 4.49, 1.68, 1.88, 1.57, 2.52, 2.33, 3.24, 1.63 and 3.90 for zopiclone, chlorphenamine maleate, brompheniramine maleate, dioxopromethazine hydrochloride, carvedilol, homatropine hydrobromide, homatropine methylbromide, venlafaxine, sibutramine hydrochloride and terbutaline sulfate, respectively. Further, the possible separation mechanism involved was discussed.

CRYSTALLINE OF ESZOPICLONE, ITS COMPOSITION, PREPARATION AND USES THEREOF

The present invention disclosed a crystalline of S-zopiclone having a powder X-Ray diffraction spectrum using Cu-Ka radiation with characteristic peaks expressed in terms of 2θ at about 11.08°, about 12.38°, about 15.86°, about 17.88°, about 19.98° and ab

Process for Resolving Zopiclone

The present invention provides a process for the preparation of the dextrorotatory isomer of zopiclone (eszopiclone). The present invention also provides eszopiclone di-p-anisolyl-L-tartrate and eszopiclone diacetyl-L-tartrate, which are useful as interme

A process for racemisation of 6-(5-chloropyridin-2-yl)-7-(4-methyl-1-piperazinyl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine

The present invention provides a new process of recovering zopiclone from unwanted enantiomer by racemisation using aliphatic amines in amide solvents. The process of the present invention can give product in high yield with low amount of impurities and can be carried out on an industrial scale. The present invention provides also a method for resolving the enantiomers of zopiclone by means of chiral chromatography using stationary phase which comprises amylose tris (3,5-dimethylphenylcarbamate) immobilised on silica gel.

PROCESS FOR RESOLVING ZOPICLONE

The present invention provides a process for the preparation of the dextrorotatory isomer of zopiclone (eszopiclone). The present invention also provides eszopiclone di-p-anisolyl-L-tartrate and eszopiclone diacetyl-L-tartrate, which are useful as intermediates in a process for preparing eszopiclone.