WO2009101634A2 - A novel process for the preparation of eszopiclone - Google Patents

A novel process for the preparation of eszopiclone Download PDF

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WO2009101634A2
WO2009101634A2 PCT/IN2009/000097 IN2009000097W WO2009101634A2 WO 2009101634 A2 WO2009101634 A2 WO 2009101634A2 IN 2009000097 W IN2009000097 W IN 2009000097W WO 2009101634 A2 WO2009101634 A2 WO 2009101634A2
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eszopiclone
solvent
process according
acetonitrile
dibenzoyl
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PCT/IN2009/000097
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French (fr)
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WO2009101634A3 (en
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Rajesh Kumar Thaper
Mano J Devilalji Prabhavat
Suman Ralhan
Dnyaneshwar Tukaram Singare
Smite Shivaji Bhosale
Akshat Kumar Bhatnagar
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for the preparation of eszopiclone (II) and novel crystalline form B of eszopiclone dibenzoyl-D-tartarate salt.
  • Zopiclone is chemically known as (+)-4-methyl-l-piperazinecarboxylic acid 6-(5-chloro-2- pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester (I) is a short acting hypnotic agent used in the treatment of insomnia.
  • Zopiclone belongs to novel chemical class of cyclopyrrolone derivative, which is structurally unrelated to existing hypnotics such as benzodiazepines .
  • zopiclone exists as racemic mixture, consisting of a equimolar quantities of levorotatory and dextrorotatory isomers.
  • a racemic product it is known that, often, one of the two enantiomers is therapeutically active and the other enantiomer is usually less active or inactive and more toxic.
  • the patent US 6,319,926 discloses that the dextrorotatory isomer of zopiclone (II) is twice as active as the racemate, and the levorotatory isomer is both inactive and more toxic than the racemate.
  • Eszopiclone which is the S-enantiomer of zopiclone (dextrorotary isomer), possesses more activity and less toxicity than the racemic zopiclone and represented by formula (II).
  • US Pat. No. 3,862,149 describes a process for preparing zopiclone (I) by the reaction of 6-(5- chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with l-chlorocarbonyl-4-methylpiperazine (CMP) (IV) in the presence of N,N-dimethyl- formamide as a solvent and sodium hydride as a base for more than 3 hours. After chromatographic purification and recrystallization from a mixture of acetonitrile and diisopropyl ether, zopiclone is obtained with a yield of 14.7%.
  • Eszopiclone (I) can be obtained by conventional techniques such as optical resolution of zopiclone, separation of enontiomers by chiral phase chromatography, steroselective enzymatic catalysis by means of suitable microorganism and asymmetric synthesis.
  • optical resolution of zopiclone separation of enontiomers by chiral phase chromatography
  • steroselective enzymatic catalysis by means of suitable microorganism and asymmetric synthesis.
  • the most common methods for obtaining eszopiclone is by optical resolution of zopiclone (I) using optically active acids.
  • optically active acids The methods known in the literature for the resolution of zopiclone by an optically active acid are discussed below.
  • the patent US 7,125,874 teaches a process for the resolution of zopiclone (I) that involves the formation of dibenzoyl-D-tartaric acid addition salt of zopiclone in dichloromethane followed by crystallization of distereomeric salt initially from acetonitrile, then further recrystallization of the resulting salt from a mixture of dichloromethane and acetonitrile.
  • the process for resolution taught in this patent is laborious as it involves two crystallization steps.
  • the yield of eszopiclone so obtained is less than or equal to 23%.
  • the patent US 6,339,086 describes a process for resolution of zopiclone with D-(+)-malic acid in a mixture of methanol and acetone with an yield of 72% with a purity of 99.9%.
  • the patent application US 2007/0203145 teaches a process for resolution of zopiclone with L-tartaric acid in a mixture of ethanol, dichloromethane and acetonitrile yielding eszopiclone in a very low yield such as 15.77% with a lower purity such as 98.85%.
  • Eszopiclone (II) in free base form and salt forms are disclosed in patents US 6,444,673 and US 6,864,257.
  • the patents US 6,444,673 and US 6,319,926 describe the resolution of zopiclone by using dibenzoyl-D-tartaric-acid by crystallization, initially from acetonitrile and then from mixture of acetonitrile/dichloromethane to give eszopiclone-dibenzoyl-D-tartaric acid salt.
  • the process as described in these patents involves the purification of eszopiclone dibenzoyl tartaric acid salt by multiple crystallizations, which not only makes the process cumbersome but also decreases the yield to 36%.
  • Another PCT application WO 2007083188 describes the resolution of racemic zopiclone with Di-p-toluyl-D-tartaric acid in solvents such as tetrahydrofuran, methanol and acetone.
  • the resulting eszopiclone di-p-toluyl tartaric acid salt is purified by crystallization from mixture of ethyl alcohol and isopropyl ether or a mixture of methanol and isopropyl ether or leaching the salt with acetone.
  • the process involves huge volumes of solvent for purification, moreover chiral purity of diastereomeric salt obtained after purification is 97%.
  • This PCT application describes the process for the purification of eszopiclone by crystallization of eszopiclone from acetone. However, this process requires huge volumes of solvent since the initial stages involves stripping with acetone. This PCT application also describes the purification of eszopiclone from a mixture of acetone and acetic anhydride with a purity not less than 99%. Acetic anhydride is not a suitable solvent for crystallization and moreover due to its lacrymetric property, it is difficult to handle on large scale.
  • the present invention is related to a novel process for the preparation of eszopiclone (II), having chiral purity greater 99.9% with less amounts of organic volatile impurities, that comprises the following steps: (a) preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7- oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro- carbonyl-4-methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases; (b) resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a n
  • the present invention further relates to a novel polymorphic form B of eszopiclone dibenzoyl-D-tartaric acid salt and process for its preparation.
  • Figure 1 X-ray powder diffractogram (XRPD) for Form B of eszopiclone dibenzoyl-D- tartarate salt.
  • Figure 2 IR spectrum for Form B of eszopiclone dibenzoyl-D-tartarate salt.
  • Figure 3 XRPD of eszopiclone-dibenzoyl-D-tartaric acid salt obtained as per process described in example 1 of US 6,444,673.
  • the present invention is related to a novel process for the preparation of eszopiclone (II), having chiral purity greater 99.9% with less amounts of organic volatile impurities, that comprises the following steps:
  • One of the aspect of the process of the present invention is in the step 1 wherein the reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5- OH-Py) (III) with chloro-carbonyl-4-methyl-piperazine (CMP) free base (IV) or as an acid addition salt is carried out in the presence of diazabicylo[5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.
  • DBU diazabicylo[5.4.0]undec-7-ene
  • step 1 of the present invention can be carried out in an organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof.
  • aromatic hydrocarbons like benzene, toluene and xylene
  • esters like ethyl acetate and isopropyl acetate
  • ethers such as ethyl ether, methyl t-but
  • Suitable bases that can be used in step 1 along with DBU in the reaction include but are not limited to: organic bases such as triethylamine, diethylamine, methyl amine, pyridine and imidazoles; inorganic bases such as alkali hydroxides likes sodium hydroxide, its carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates sodium bicarbonate.
  • organic bases such as triethylamine, diethylamine, methyl amine, pyridine and imidazoles
  • inorganic bases such as alkali hydroxides likes sodium hydroxide, its carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates sodium bicarbonate.
  • the most preferred base is pyridine.
  • step 1 can be carried out at the temperatures selected from 0°C to 100 0 C, preferably 10 0 C to 40 0 C and most preferably 20 0 C - 30 0 C.
  • the step 2 of the present invention provides an efficient process for the resolution of zopiclone (I) to obtain eszopiclone (II).
  • Suitable optically active acids for use herein include D-lactic acid, D-tartaric acid, 1 S-IO- camphor sulfonic acid, S-hydrotrophic acid, (S)-2-methoxy phenyl acetic acid, (R)-2- methoxy-2-trifluoromethyl phenyl acetic acid, D-mandelic acid, di-p-anisolyl-D-tartaric acid, di-p-anisolyl-L-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid and S (+)- l,l '-binapthalene-2,2'-dihydrogen phosphate.
  • the preferred optically active acid used for resolution is dibenzoyl-D-tartaric acid.
  • the suitable solvent for the resolution in step 2 is selected from the group comprising of alcohols selected from methanol, ethanol, propanol, isopropanol; ethers selected from dioxane, tetrahydrofuran; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; ketones selected from acetone or mixtures thereof.
  • the preferred solvents are methanol, ethanol and tetrahydrofuran.
  • Molar ratio of racemic zopiclone to dibenzoyl-(D)-tartaric acid is in the range of 1.0:0.9 to
  • Resolution in step 2 is carried out at temperature of ranging from 20°C to 80°C, more preferably at 30°C to 60°C, most preferably at 45°C to 50°C.
  • the resolution is carried out by stirring the mixture of dibenzoyl-D-tartaric acid and zopiclone for 0.5 to 4 hours, more preferably for one hour.
  • Precipitation of the dibenzoyl-D-tartaric acid salt of eszopiclone (V) is carried out by adding suitable solvent in which the solubility of dibenzoyl-D-tartaric acid salt of eszopiclone is less.
  • the preferred solvents for precipitation are ethers such as diethylether, diisopropylether; nitriles such as acetonitrile, propionitrile.
  • the most preferred solvent for precipitation is acetonitrile.
  • the dibenzoyl-D-tartaric acid salt of eszopiclone (V) obtained is optionally purified in step 3 by crystallization from suitable solvent selected from the group of lower alcohols such as methanol, ethanol, propanol, isopropanol; ketones such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; aliphatic esters such as ethylacetate, propyl acetate, isopropyl acetate; ethers such as diethylether, diisopropylether, dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile or any mixtures thereof.
  • suitable solvent for crystallization is a mixture of methanol-acetonitrile or mixture of methanol, acetone and acetonitrile.
  • the present invention in step 3 provides novel crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt (V).
  • the crystalline Form B is characterized by XRPD pattern as shown in figure 1.
  • the characteristic peaks in XRPD of eszopiclone-di- benzoyl-D-tartarate salt Form B are as shown in table 1.
  • the crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt (V) described herein is further identified by IR spectrum as shown in figure 2.
  • the IR spectrum of crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt described herein has characteristic bands at 3422.6, 1743.7, 1722.2, 1704.7, 1653 and 1622 cm "1 .
  • the pure dibenzoyl-D-tartaric acid salt (V) of eszopiclone thus obtained is treated with an alkaline solution to pH 11 in biphasic mixture of water and dichloromethane in step 4.
  • the alkaline solution herein used is preferably an aqueous sodium hydroxide solution.
  • the organic phase of the resultant biphasic mixture was separated and evaporated under vaccum.
  • the present invention relates to a novel process for the purification of eszopiclone (II) to obtain eszopiclone having chiral purity greater 99.9% with less amounts of organic volatile impurities in step 5.
  • the process for the preparation of pure eszopiclone comprises the steps of:
  • the nitrile solvent is selected from acetonitrile or propionitrile, most preferred being acetonitrile.
  • the ketone antisolvent is selected from acetone or methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, the most preferred being acetone.
  • the reaction temperature at which the reaction is cooled is 2°-15°C.
  • the preferred reaction temperature is 5-10 0 C.
  • the solid is isolated as per the conventional methods like filtration.
  • the solid obtained is further dried under reduced pressure at 50-70 0 C, more preferably at 60 0 C.
  • the aforementioned process for the preparation of eszopiclone has the following advantages: i) purity is greater than 99.0%, ii) yield is greater than 80%, iii) simple and quick process, iv) easy to scale up, v) economical process, vi) avoids multiple crystallization in resolution, vii) avoids multiple work up procedures, viii) product contains lesser amounts of organic volatile impurities, ix) avoids chromatography, and x) toxic reagents are not used.
  • the principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples.
  • a solution of D-(+)-O,O-dibenzoyltartaric acid monohydrate (9.4 g) was prepared in tetrahydrofuran (60 ml) at 30-35 0 C.
  • To the solution zopiclone (10 g) obtained in step 1 was added at 30-35 0 C with stirring.
  • Acetonitrile (150 ml) was slowly added at 30-35 0 C to the mixture and then slowly cooled to 20-25 0 C. The obtained solid was filtered and dried.
  • step 2 The crude salt (10 g) obtained in step 2 was dissolved in methanol (300 ml) at 55-60°C. After a clear solution was obtained, acetonitrile (300 ml) was added at 55-60°C. The mixture was stirred and cooled slowly to 20-25 0 C. The solid was filtered and dried.
  • step 2 The crude salt (10 g) obtained in step 2 was dissolved in mixture of methanol (100 ml) and acetone (30 ml) at 40-45°C. After a clear solution was obtained, acetonitrile (120 ml) was added at 40-45°C. The mixture was stirred and cooled slowly to 20-25°C. The solid was filtered and dried. Yield: 9 g
  • Step 5 Purification of crude eszopiclone
  • Example 1 Purification as per example 1 in product patent US 6,444,673
  • a solution of Zopiclone-dibenzoyl-D-tartarate salt (50 g) obtained in step 3 was prepared in dichloromathane (500 ml) and water (500 ml).
  • the reaction mixture was alkalinized to pH 11 by slowly adding 20% NaOH at 5-10°C.
  • the dichloromethane layer was further extracted with water.
  • the aqueous layer was extracted with dichloromethane (2 x 75 ml).
  • Combined dichloromethane layer was distilled completely at 30-35°C, under reduced pressure (710 mm Hg) for 1 hr.
  • acetonitrile 500 ml was added.
  • the reaction mass was heated to dissolve the solid. After the dissolution the reaction mass was cooled slowly to 5°C.
  • a solution of Zopiclone-di-benzoyl-D-tartarate salt (160 g) obtained in step 3 was prepared in dichloromathane (4000 ml) and water (2400 ml). The reaction mixture was alkalinized to pH 11 by slowly adding 20% NaOH at 5-10°C. The dichloromethane layer was further extracted with water. The aqueous layer was extracted with dichloromethane (400 ml). Combined dichloromethane layer was distilled off completely at 30-35°C, under reduced pressure (710 mm Hg) for 3 hr. Acetonitrile (2 x 160 ml) was added and distilled at 60°C, at 760 mm vaccum to strip dichloromethane completely.

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Abstract

The present invention is related to a novel process for the preparation of eszopiclone (II), that comprises the following steps: (a) preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo- 5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro-carbonyl-4- methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases; (b) resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent; (c) optional purification of dibenzoyl-D-tartaric acid addition salt of eszopiclone by dissolution in solvent selected from alcohols, ketones or mixture thereof followed by the precipitation by adding a nitrile solvent; (d) conversion of the dibenzoyl-D-tartaric acid addition salt of eszopiclone to obtain the eszopiclone free base (II) by treating with an alkaline solution; (e) purification of eszopiclone by dissolving in nitrile solvent followed by addition of ketonic solvent. The eszopiclone (II) obtained by the process of the present invention has chiral purity greater than 99.9% and less amounts of organic volatile impurities. The present invention further provides novel crystalline form B of eszopiclone- Dibenzoyl-D-tartarate salt (V) and its preparation.

Description

A NOVEL PROCESS FOR THE PREPARATION OF ESZOPICLONE
Field of the Invention:
The present invention relates to a novel process for the preparation of eszopiclone (II) and novel crystalline form B of eszopiclone dibenzoyl-D-tartarate salt.
Background of the invention:
Zopiclone is chemically known as (+)-4-methyl-l-piperazinecarboxylic acid 6-(5-chloro-2- pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester (I) is a short acting hypnotic agent used in the treatment of insomnia. Zopiclone belongs to novel chemical class of cyclopyrrolone derivative, which is structurally unrelated to existing hypnotics such as benzodiazepines .
Figure imgf000002_0001
As a result of the presence of an asymmetric carbon atom denoted by asterisk (*), zopiclone exists as racemic mixture, consisting of a equimolar quantities of levorotatory and dextrorotatory isomers. In a racemic product, it is known that, often, one of the two enantiomers is therapeutically active and the other enantiomer is usually less active or inactive and more toxic. The patent US 6,319,926 discloses that the dextrorotatory isomer of zopiclone (II) is twice as active as the racemate, and the levorotatory isomer is both inactive and more toxic than the racemate. Eszopiclone, which is the S-enantiomer of zopiclone (dextrorotary isomer), possesses more activity and less toxicity than the racemic zopiclone and represented by formula (II).
US Pat. No. 3,862,149 describes a process for preparing zopiclone (I) by the reaction of 6-(5- chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with l-chlorocarbonyl-4-methylpiperazine (CMP) (IV) in the presence of N,N-dimethyl- formamide as a solvent and sodium hydride as a base for more than 3 hours. After chromatographic purification and recrystallization from a mixture of acetonitrile and diisopropyl ether, zopiclone is obtained with a yield of 14.7%.
Figure imgf000003_0001
(I)
The process as described in U.S. Pat. No. 3,862,149 involves the purification of the crude product by column chromatography, followed by crystallization, which not only makes the process cumbersome, but also provides zopiclone (I) in very low yield 14.7%.
The publication Claude Jeanmart et al, Rhone-Poulenc Rech., France, Comptes Rendus des Sciences del' Academie des Sciences, Series C: Sciences Chimiques (1978), 287(9), 377-378 discloses the use of triethylamine and pyridine in the process for the preparation of zopiclone (I) by reacting 5 -OH-Py (III) with CMP (IV) hydrochloride salt in dichloromethane. On repeating this reaction, the present inventors obtained zopiclone in 62% yield having a purity of99.6% by HPLC. The patent application US2007/0054914 discloses preparation of zopiclone (I) by the reaction of 5-OH-Py (III) and CMP (IV) hydrochloride salt in the presence of either potassium carbonate and t-butyl ammonium bromide, or N,N-dimethylformamide and sodium hydride for more than 18 hours, yielding 50.49% of zopiclone with a purity of 99.65%. These reaction conditions require longer time for completion of the reaction, moreover the yield of zopiclone is poor.
The patent application US 2008/0015197 discloses the preparation of zopiclone (I) by the reaction of 5 -OH-Py (III) with CMP (FV) or its acid addition salt in 4-N,N-dimethylamino- pyridine (DMAP) and a base such as triethylamine for more than 6 hours yielding zopiclone in 97.42% yield with a purity of 98.69%. Although the yield of this process is better, but the purity is below 99.0%.
Eszopiclone (I) can be obtained by conventional techniques such as optical resolution of zopiclone, separation of enontiomers by chiral phase chromatography, steroselective enzymatic catalysis by means of suitable microorganism and asymmetric synthesis. The most common methods for obtaining eszopiclone is by optical resolution of zopiclone (I) using optically active acids. The methods known in the literature for the resolution of zopiclone by an optically active acid are discussed below.
The patent US 7,125,874 teaches a process for the resolution of zopiclone (I) that involves the formation of dibenzoyl-D-tartaric acid addition salt of zopiclone in dichloromethane followed by crystallization of distereomeric salt initially from acetonitrile, then further recrystallization of the resulting salt from a mixture of dichloromethane and acetonitrile. The process for resolution taught in this patent is laborious as it involves two crystallization steps. Moreover, the yield of eszopiclone so obtained is less than or equal to 23%.
The patent US 6,339,086 describes a process for resolution of zopiclone with D-(+)-malic acid in a mixture of methanol and acetone with an yield of 72% with a purity of 99.9%. The patent application US 2007/0203145 teaches a process for resolution of zopiclone with L-tartaric acid in a mixture of ethanol, dichloromethane and acetonitrile yielding eszopiclone in a very low yield such as 15.77% with a lower purity such as 98.85%.
Another patent application US 2007/0054914 describes a process for resolution of zopiclone with di-p-toluoyl-D-tartaric acid in acetonitrile in better yield and purity, but the resolving agent di-p-toluoyl-D-tartaric acid is costlier than dibenzoyl-D-tartaric acid.
The publication Blascheke G et al, Chirality (1993), 5, 419-421 describes the resolution of zopiclone with D-(+)-maleic acid from a mixture of methanol and acetone.
Eszopiclone (II) in free base form and salt forms are disclosed in patents US 6,444,673 and US 6,864,257. The patents US 6,444,673 and US 6,319,926 describe the resolution of zopiclone by using dibenzoyl-D-tartaric-acid by crystallization, initially from acetonitrile and then from mixture of acetonitrile/dichloromethane to give eszopiclone-dibenzoyl-D-tartaric acid salt. The process as described in these patents involves the purification of eszopiclone dibenzoyl tartaric acid salt by multiple crystallizations, which not only makes the process cumbersome but also decreases the yield to 36%.
The PCT application WO 2007088073 describes the resolution of zopiclone in acetonitrile with L-tartaric acid, the purity of eszopiclone-L-tartarate salt obtained was only 96%.
Another PCT application WO 2007083188 describes the resolution of racemic zopiclone with Di-p-toluyl-D-tartaric acid in solvents such as tetrahydrofuran, methanol and acetone. The resulting eszopiclone di-p-toluyl tartaric acid salt is purified by crystallization from mixture of ethyl alcohol and isopropyl ether or a mixture of methanol and isopropyl ether or leaching the salt with acetone. The process involves huge volumes of solvent for purification, moreover chiral purity of diastereomeric salt obtained after purification is 97%. This PCT application describes the process for the purification of eszopiclone by crystallization of eszopiclone from acetone. However, this process requires huge volumes of solvent since the initial stages involves stripping with acetone. This PCT application also describes the purification of eszopiclone from a mixture of acetone and acetic anhydride with a purity not less than 99%. Acetic anhydride is not a suitable solvent for crystallization and moreover due to its lacrymetric property, it is difficult to handle on large scale.
The patents US 6,339,086, US 6,458,791, US 6,506,753 and US 6,946464 describe the crystallization of eszopiclone from ethyl acetate to give eszopiclone with an enantiomeric purity of 99.9% .
US 6,969, 767 describes the purification of eszopiclone by flash chromatography on silica gel using acetone. The eszopiclone obtained has enantiomeric purity greater than 99%. However, purification using flash chromatography is industrially not feasible.
The patent applications US 20070054914 and WO 2007/088073 and the patents US 6,444,673 and US 6,319,926 describe purification of eszopiclone by recrystallization from acetonitrile. We observed that the crystallization from acetonitrile gives eszopiclone with greater than 900 ppm of acetonitrile as OVI (organic volatile impurity), even after prolonged drying for 40 hours under reduced pressure at 600C. It should be noted that as per pharmacopial requirement, allowed maximum limit for acetonitrile content is 410 ppm in a drug substance.
Thus the prior art methods for the preparation of eszopiclone (II) that are discussed above suffer from the following several disadvantages: i) lower purity, ii) lower yield, iii) cumbersome purification process for the removal of impurities, iv) use of hazardous reagent such as sodium hydride, v) requires longer reaction time, vi) involves several steps of crystallizations, thereby making process laborious, cumbersome, vii) large quantity of solvents, viii) low purity of diastereomeric salt, obtained in resolution. ix) more amounts of acetonitrile as OVI in the final product than allowed by pharmacopial limits, x) use of lacrymetric regents like acetic anhydride and xi) use of chromatographic methods, which are not industrially feasible.
Thus, there exist a need for the development of an economical process for the preparation of eszopiclone that is easy to operate on industrial scale to obtain highly pure eszopiclone (II) in better yield. The inventors of the present invention have developed a novel process for the preparation of eszopiclone (II) that involve a simple cost-effective, industrially feasible process, for the preparation of pure eszopiclone as per pharmacopial standards.
Summary of the Invention:
The present invention is related to a novel process for the preparation of eszopiclone (II), having chiral purity greater 99.9% with less amounts of organic volatile impurities, that comprises the following steps: (a) preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7- oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro- carbonyl-4-methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases; (b) resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent; (c) optional purification of dibenzoyl-D-tartaric acid addition salt of eszopiclone by dissolution in solvent selected from alcohols, ketones or mixture thereof followed by the precipitation by adding a nitrile solvent;
(d) conversion of the dibenzoyl-D-tartaric acid addition salt of eszopiclone to obtain the eszopiclone free base (II) by treating with an alkaline solution;
(e) purification of eszopiclone by dissolving in nitrile solvent followed by addition of ketonic solvent.
The present invention further relates to a novel polymorphic form B of eszopiclone dibenzoyl-D-tartaric acid salt and process for its preparation.
Description of the Drawings:
Figure 1 : X-ray powder diffractogram (XRPD) for Form B of eszopiclone dibenzoyl-D- tartarate salt. Figure 2: IR spectrum for Form B of eszopiclone dibenzoyl-D-tartarate salt.
Figure 3: XRPD of eszopiclone-dibenzoyl-D-tartaric acid salt obtained as per process described in example 1 of US 6,444,673.
Detailed Description of the Invention:
The present invention is related to a novel process for the preparation of eszopiclone (II), having chiral purity greater 99.9% with less amounts of organic volatile impurities, that comprises the following steps:
1. preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7- oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro- carbonyl-4-methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases; 2. resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent;
3. optional purification of dibenzoyl-D-tartaric acid addition salt of eszopiclone by dissolution in solvent selected from alcohols, ketones or mixture thereof followed by the precipitation by adding a nitrile solvent;
4. conversion of the dibenzoyl-D-tartaric acid addition salt of eszopiclone to obtain the eszopiclone free base (II) by treating with an alkaline solution;
5. purification of eszopiclone by dissolving in nitrile solvent followed by addition of ketonic solvent.
Figure imgf000009_0001
(D
Crude eszopiclone
Pure eszop
Figure imgf000009_0002
One of the aspect of the process of the present invention is in the step 1 wherein the reaction of 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5- OH-Py) (III) with chloro-carbonyl-4-methyl-piperazine (CMP) free base (IV) or as an acid addition salt is carried out in the presence of diazabicylo[5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.
The process of step 1 of the present invention can be carried out in an organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof. The most preferred solvent is benzene and dichloromethane.
Suitable bases that can be used in step 1 along with DBU in the reaction include but are not limited to: organic bases such as triethylamine, diethylamine, methyl amine, pyridine and imidazoles; inorganic bases such as alkali hydroxides likes sodium hydroxide, its carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates sodium bicarbonate. The most preferred base is pyridine.
The reaction of step 1 can be carried out at the temperatures selected from 0°C to 1000C, preferably 100C to 400C and most preferably 200C - 300C.
Molar ratio of the 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-dihydro-7-hydroxy-5H- pyrrolo[3,4-b]pyrazine-5-one (1) to that DBU in the range of 1 :0.1 to 1 :10, preferably 1:1 to
1:5. In a preferred embodiment, the step 2 of the present invention provides an efficient process for the resolution of zopiclone (I) to obtain eszopiclone (II).
Suitable optically active acids for use herein include D-lactic acid, D-tartaric acid, 1 S-IO- camphor sulfonic acid, S-hydrotrophic acid, (S)-2-methoxy phenyl acetic acid, (R)-2- methoxy-2-trifluoromethyl phenyl acetic acid, D-mandelic acid, di-p-anisolyl-D-tartaric acid, di-p-anisolyl-L-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid and S (+)- l,l '-binapthalene-2,2'-dihydrogen phosphate. The preferred optically active acid used for resolution is dibenzoyl-D-tartaric acid.
The suitable solvent for the resolution in step 2 is selected from the group comprising of alcohols selected from methanol, ethanol, propanol, isopropanol; ethers selected from dioxane, tetrahydrofuran; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; ketones selected from acetone or mixtures thereof. The preferred solvents are methanol, ethanol and tetrahydrofuran.
Molar ratio of racemic zopiclone to dibenzoyl-(D)-tartaric acid is in the range of 1.0:0.9 to
1.0 to 1.1, preferably 1:1.
Resolution in step 2 is carried out at temperature of ranging from 20°C to 80°C, more preferably at 30°C to 60°C, most preferably at 45°C to 50°C.The resolution is carried out by stirring the mixture of dibenzoyl-D-tartaric acid and zopiclone for 0.5 to 4 hours, more preferably for one hour. Precipitation of the dibenzoyl-D-tartaric acid salt of eszopiclone (V) is carried out by adding suitable solvent in which the solubility of dibenzoyl-D-tartaric acid salt of eszopiclone is less. The preferred solvents for precipitation are ethers such as diethylether, diisopropylether; nitriles such as acetonitrile, propionitrile. The most preferred solvent for precipitation is acetonitrile.
The dibenzoyl-D-tartaric acid salt of eszopiclone (V) obtained is optionally purified in step 3 by crystallization from suitable solvent selected from the group of lower alcohols such as methanol, ethanol, propanol, isopropanol; ketones such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; aliphatic esters such as ethylacetate, propyl acetate, isopropyl acetate; ethers such as diethylether, diisopropylether, dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile or any mixtures thereof. Preferred solvent for crystallization is a mixture of methanol-acetonitrile or mixture of methanol, acetone and acetonitrile.
In one aspect, the present invention in step 3 provides novel crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt (V). The crystalline Form B is characterized by XRPD pattern as shown in figure 1. The characteristic peaks in XRPD of eszopiclone-di- benzoyl-D-tartarate salt Form B are as shown in table 1.
Table 1: XRPD of Form B of eszopiclone-di-benzoyl-D-tartarate salt
Figure imgf000012_0001
Figure imgf000013_0001
The crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt (V) described herein is further identified by IR spectrum as shown in figure 2. The IR spectrum of crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt described herein has characteristic bands at 3422.6, 1743.7, 1722.2, 1704.7, 1653 and 1622 cm"1.
The pure dibenzoyl-D-tartaric acid salt (V) of eszopiclone thus obtained is treated with an alkaline solution to pH 11 in biphasic mixture of water and dichloromethane in step 4. The alkaline solution herein used is preferably an aqueous sodium hydroxide solution. The organic phase of the resultant biphasic mixture was separated and evaporated under vaccum.
The present invention relates to a novel process for the purification of eszopiclone (II) to obtain eszopiclone having chiral purity greater 99.9% with less amounts of organic volatile impurities in step 5. The process for the preparation of pure eszopiclone comprises the steps of:
1. stirring crude eszopiclone in nitrile solvent,
2. heating to obtain a solution, 3. addition of an ketone antisolvent to the hot solution,
4. cooling the mixture,
5. isolation of the solid and
6. drying under reduced pressure at 50-70°C.
The nitrile solvent is selected from acetonitrile or propionitrile, most preferred being acetonitrile.
The ketone antisolvent is selected from acetone or methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, the most preferred being acetone.
The reaction temperature at which the reaction is cooled is 2°-15°C. The preferred reaction temperature is 5-100C.
The solid is isolated as per the conventional methods like filtration. The solid obtained is further dried under reduced pressure at 50-700C, more preferably at 600C.
The aforementioned process for the preparation of eszopiclone has the following advantages: i) purity is greater than 99.0%, ii) yield is greater than 80%, iii) simple and quick process, iv) easy to scale up, v) economical process, vi) avoids multiple crystallization in resolution, vii) avoids multiple work up procedures, viii) product contains lesser amounts of organic volatile impurities, ix) avoids chromatography, and x) toxic reagents are not used. The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The invention, which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
Step 1: Preparation of racemic Zopiclone (I) Example- 1
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (100 g), DBU (173.9 g), pyridine (90.25 g) and dichloromethane (1000 ml), 1- chlorocarbonyl-4-methylpiperazine hydrochloride (151.56 g) was added and stirred for 5 hours at 20-25 °C. On completion of the reaction, chilled water (1000 ml) was added to it to form a biphasic mixture and the organic phase was extracted. The aqueous phase was further extracted with dichloromethane (1000 ml). The organic phases were combined, washed with water (5 x 1000 ml) and evaporated under vacuum. The resultant solid residue was dissolved in acetonitrile (500 ml), charcoalized with activated carbon (5 gms), filtered on celite bed and washed with acetonitrile (2 x 50 ml). The filtrate and the acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and dried to obtain zopiclone. (Yield: 81%; Purity: 99.65% by HPLC).
Example-2
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (50 g), DBU (115.94 mg) and dichloromethane (500 ml), l-chlorocarbonyl-4- methylpiperazine hydrochloride (75.78 g) was added and stirred for 6 hours at 20-25 °C. On completion of the reaction, chilled water (500 ml) was added to it to form a biphasic mixture and the organic phase was extracted. The aqueous phase was further extracted with dichloromethane (500 ml). The organic phases were combined, washed with water (5 x 500 ml) and evaporated under vacuum. The resultant solid residue was dissolved in acetonitrile (250 ml), charcoalized with activated carbon (2.5 gms), filtered on celite bed and washed with acetonitrile (2 x 25 ml). The filtrate and the acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and dried to obtain zopiclone (Yield: 74.3%; Purity: 99.65% by HPLC).
Example-3
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (5 g), DBU (8.69 g), potassium hydroxide (3.19 g) and dichloromethane (50 ml), 1- chlorocarbonyl-4-methylpiperazine hydrochloride (7.58 g) was added and stirred for 5 hours at 20-25 °C. On completion of the reaction, chilled water (50 ml) was added to it to form a biphasic mixture and the organic phase was extracted. The aqueous phase was further extracted with dichloromethane (50 ml). The organic phases were combined, washed with water (5 x 50 ml) and evaporated under vacuum. The resultant solid residue was dissolved in acetonitrile (25 ml), charcoalized with activated carbon (0.25 gms), filtered on celite bed and washed with acetonitrile (2 x 25 ml). The filtrate and the acetonitrile washings were. combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and dried to obtain zopiclone. (Yield: 32.4%; Purity: 96.90% by HPLC).
Example-4
To a mixture of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine (5 g), triethylamine (5.76 g), pyridine (4.5 g) and dichloromethane (50 ml), 1- chlorocarbonyl-4-methylpiperazine hydrochloride (7.58 g) was added and stirred for 5 hours at 20-25 °C. On completion of the reaction, chilled water (50 ml) was added to it to form a biphasic mixture and the organic phase was extracted. The aqueous phase was further extracted with dichloromethane (50 ml). The organic phases were combined, washed with water (5 x 50 ml) and evaporated under vacuum. The resultant solid residue was dissolved in acetonitrile (25 ml), charcoalized with activated carbon (0.25 gms), filtered on celite bed and washed with acetonitrile (2 x 10 ml). The filtrate and the acetonitrile washings were combined, cooled, stirred for 2 hours at 5 - 10°C, filtered and dried to obtain zopiclone. (Yield: 62.1%; Purity: 99.62% by HPLC). Step 2: Resolution of racemic zopiclone (I) and preparation of eszopiclone-dibenzoyl-D- tartarate salt (V):
Example-1
Zopiclone (25 gms) obtained in step 1 was added to a solution of dibenzoyl-D-tartaric acid monohydrate (24.1 gms) in methanol (300 ml) at 45-50°C and stirred for 1 hour. Acetonitrile
(500 ml) was added to the reaction mixture and cooled slowly to 20-25°C. The precipitated solid was filtered and dried under vaccum. Yield: 24 gms (0.96 w/w); Purity: 94 %; [OC]D 20 = + 95 °.
Example-2
A solution of D-(+)-O,O-dibenzoyltartaric acid monohydrate (9.4 g) was prepared in tetrahydrofuran (60 ml) at 30-350C. To the solution zopiclone (10 g) obtained in step 1 was added at 30-350C with stirring. Acetonitrile (150 ml) was slowly added at 30-350C to the mixture and then slowly cooled to 20-250C. The obtained solid was filtered and dried.
Yield: 8.8 g
Chiral Purity: 98.04%.
MP: 133.1 to l33.6°C
[α]d 20 = 101.7° (c= 0.5, acetone)
Step 3: Purification eszopiclone-dibenzoyl-D-tartarate salt (V):
Example-1
The crude salt (10 g) obtained in step 2 was dissolved in methanol (300 ml) at 55-60°C. After a clear solution was obtained, acetonitrile (300 ml) was added at 55-60°C. The mixture was stirred and cooled slowly to 20-250C. The solid was filtered and dried.
Yield: (9 g)
Chiral Purity: 99.88%.
MP: 138.4 to 1400C
[α]d 20 = 106.8° (c= 0.5, acetone) Example-2
The crude salt (10 g) obtained in step 2 was dissolved in mixture of methanol (100 ml) and acetone (30 ml) at 40-45°C. After a clear solution was obtained, acetonitrile (120 ml) was added at 40-45°C. The mixture was stirred and cooled slowly to 20-25°C. The solid was filtered and dried. Yield: 9 g
Chiral Purity: 99.89%. MP: 139.2 to 140.3°C [α]d 20 = 105.3° (c= 0.5, acetone)
Step 4: Preparation of eszopiclone
Purified eszopiclone-dibenzoyl-D-tartarate salt obtained in Step-3 (15 gms) was dissolved in a biphasic mixture of dichloromethane (150 ml) and water (150 ml) and alkalinised to pH 11 by slowly adding 20 % aqueous sodium hydroxide at 5-10 °C. The organic phase was then separated and the aqueous phase was extracted with dichloromethane (2 x 75 ml). The combined dichloromethane extracts were dried under vaccum. The dried residue was dissolved in acetonitrile (150 ml) by refluxing, the solution was cooled slowly to 5°C and stirred for 2 hrs at 5-10 °C. Solid obtained was filtered and dried under vaccuni. Yield: 5.1 gms (0.34w/w).
Step 5: Purification of crude eszopiclone
Example 1: Purification as per example 1 in product patent US 6,444,673
A solution of Zopiclone-dibenzoyl-D-tartarate salt (50 g) obtained in step 3 was prepared in dichloromathane (500 ml) and water (500 ml). The reaction mixture was alkalinized to pH 11 by slowly adding 20% NaOH at 5-10°C. The dichloromethane layer was further extracted with water. The aqueous layer was extracted with dichloromethane (2 x 75 ml). Combined dichloromethane layer was distilled completely at 30-35°C, under reduced pressure (710 mm Hg) for 1 hr. To the resulting residue, acetonitrile (500 ml) was added. The reaction mass was heated to dissolve the solid. After the dissolution the reaction mass was cooled slowly to 5°C. The reaction was stirred for 2 hours at 5-10°C. The solid was filtered, dried at 60°C, under reduced pressure (760 mm) for 40 hours. Yield: 30.26g (0.34 w/w) Chiral Purity: 99.96% (by HPLC) Qualitative purity: 99.65% (by HPLC) Acetonitrile content: 975 ppm
Example 2: Purification as per the invention:
A solution of Zopiclone-di-benzoyl-D-tartarate salt (160 g) obtained in step 3 was prepared in dichloromathane (4000 ml) and water (2400 ml). The reaction mixture was alkalinized to pH 11 by slowly adding 20% NaOH at 5-10°C. The dichloromethane layer was further extracted with water. The aqueous layer was extracted with dichloromethane (400 ml). Combined dichloromethane layer was distilled off completely at 30-35°C, under reduced pressure (710 mm Hg) for 3 hr. Acetonitrile (2 x 160 ml) was added and distilled at 60°C, at 760 mm vaccum to strip dichloromethane completely. Water was added and the solid was stirred at 55-60°C and filtered to get crude eszopiclone. To the obtained crude eszopiclone (66 g) acetonitrile (660 ml) was added at reflux temperature. After the dissolution of the solid, acetone (330 ml) was added. The reaction mass was cooled slowly to 5°C. The reaction was stirred for 2 hrs at 5-10°C. The solid was filtered, dried at 60°C, under reduced pressure (760 mm Hg) for 20 hours. Yield: 56.1O g (0.85 w/w) Chiral Purity: 99.95% (by HPLC) Qualitative purity: 99.7% (by HPLC) Acetonitrile content: 280 ppm Acetone content: 186 ppm.

Claims

CLAIMS1) A process for the preparation of eszopiclone comprising the steps of:
1. preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2-yl)-5- hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro-carbonyl-4-methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases;
2. resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent;
3. optional purification of dibenzoyl-D-tartaric acid addition salt of eszopiclone by dissolution in solvent selected from alcohols, ketones or mixture thereof followed by the precipitation by adding a nitrile solvent; 4. conversion of the dibenzoyl-D-tartaric acid addition salt of eszopiclone to obtain the eszopiclone free base (II) by treating with an alkaline solution; 5. purification of eszopiclone by dissolving in nitrile solvent followed by addition of ketonic solvent.
2) A process according to claim 1, wherein the solvent used in step 1 is selected from a group comprising of aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof.
3) A process according to claim 2 wherein most preferred solvent is benzene and dichloromethane. 4) A process according to claim 1 , wherein the other base used in step 1 is selected from group comprising of organic bases such as triethylamine, diethylamine, methyl amine, pyridine and imidazoles, inorganic bases such as alkali hydroxides likes sodium hydroxide, its carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates sodium bicarbonate.
5) A process according to claim I5 wherein the solvent used in step 2 is selected from a group comprising of alcohols selected from methanol, ethanol, propanol, isopropanol; ethers selected from dioxane, tetrahydrofuran; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; ketones selected from acetone or mixtures thereof.
6) A process according to claim 5 wherein the most preferred solvents are methanol, ethanol and tetrahydrofuran or mixtures thereof.
7) A process according to claim I5 wherein the precipitation solvent used in step 2 is selected from acetonitrile and propionitrile. 8) A process according to claim 7 wherein the most preferred solvent is acetonitrile.
9) A process according to claim 1 , wherein solvent used in step 3 for purification of dibenzoyl-D-tartaric-acid salt ofeszopiclone is selected from group comprising of lower alcohols such as methanol, ethanol, propanol, isopropanol; ketones such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; aliphatic esters such as ethylacetate, propyl acetate, isopropyl acetate; ethers such as diethylether, diisopropylether, dioxane, tetrahydrofuran; nitriles such as acetonitrile, propionitrile or any mixtures thereof.
10) A process according to claim 9 wherein the most preferred solvent is mixture of methanol-acetonitrile or mixture of methanol, acetone and acetonitrile. 11) A process according to claim I5 wherein nitrile solvent used in step 5 is selected from acetonitrile or propionitrile. 12) The process according to claim 11, wherein the preferred solvent is actonitrile. 13) A process according to claim 1, wherein ketone antisolvent used in step 5 is selected from acetone or methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.
14) The process according to claim 13, wherein the preferred ketone solvent is acetone.
15) A novel crystalline Form B of eszopiclone-di-benzoyl-D-tartarate salt.
16) A novel crystalline Form B of claim 15 characterized by XRPD as shown in figure 1.
17) A novel crystalline Form B of claim 15 having XRPD as shown below.
Figure imgf000022_0001
Figure imgf000023_0001
18) A process for the preparation of zopiclone (I) by reaction of 6-(5-chloropyridin-2- yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) with chloro-carbonyl-4-methyl-piperazine (CMP) free base (IV) or its acid addition salt in the presence of diazabicylo [5.4.0]undec-7-ene (DBU) or a mixture of DBU and other bases.
19) A process of claim 18 wherein the solvent used is selected from a group comprising of aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethylmethyl ketone; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform and mixtures thereof.
20) A process according to claim 19 wherein most preferred solvent is benzene and dichloromethane. 21) A process according to claim 18, wherein the base used is selected from group comprising of organic bases such as triethylamine, diethylamine, methyl amine, pyridine and imidazoles, inorganic bases such as alkali hydroxides likes sodium hydroxide, its carbonates likes sodium carbonate, its hydrides likes sodium hydride and its bicarbonates sodium bicarbonate.
22) A process for the preparation of eszopiclone by resolution of racemic zopiclone with dibenzoyl-D-tartaric acid in suitable solvent wherein dibenzoyl-D-tartaric acid addition salt of eszopiclone is separated by the addition of a nitrile solvent.
23) A process according to claim 22, wherein the optically active acid used is selected from a group comprising of D-lactic acid, D-tartaric acid, lS-10-camphor sulfonic acid, S-hydrotrophic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2- trifluoromethyl phenyl acetic acid, D-mandelic acid, di-p-anisolyl-D-tartaric acid, di-p-anisolyl-L-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid and S (+)-l,l '-binapthalene-2,2'-dihydrogen phosphate. 24) A process according to claim 23 wherein the most preferred acid is dibenzoyl-D- tartaric acid.
25) A process according to claim 23, wherein the solvent used is selected from a group comprising of alcohols selected from methanol, ethanol, propanol, isopropanol; ethers selected from dioxane, tetrahydrofuran; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; ketones selected from acetone or mixtures thereof.
26) A process according to claim 25 wherein the most preferred solvents are methanol, ethanol and tetrahydrofuran or mixtures thereof.
27) A process according to claim 26, wherein the precipitation solvent used in step 2 is selected from a group comprising of ethers such as diethylether, diisopropylether; nitriles such as acetonitrile, propionitrile.
28) A process according to claim 27 wherein the most preferred solvent is acetonitrile. 29) A process for purification of eszopiclone by dissolving eszopiclone in nitrile solvent followed by addition of ketonic solvent.
30) A process according to claim 29, wherein nitrile solvent is selected from acetonitrile or propionitrile. 31) The process according to claim 30, wherein the preferred solvent is actonitrile.
32) A process according to claim 29, wherein ketone antisolvent is selected from acetone or methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.
33) The process according to claim 32, wherein the preferred ketone solvent is acetone. 34) Eszopiclone obtained by the process as per claim 1.
35) Eszopiclone obtained by the process described in claim 1 having purity greater than 99.9% and acetonitrile content less than 40 ppm.
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EP2345654A1 (en) 2010-01-05 2011-07-20 LEK Pharmaceuticals d.d. Eszopiclone particles and a process for their preparation
JP2020007252A (en) * 2018-07-05 2020-01-16 アクティブファーマ株式会社 Method for producing eszopiclone dibenzoyl-D-tartrate, method for producing eszopiclone, and crystal of eszopiclone dibenzoyl-D-tartrate
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof

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WO2010052475A1 (en) * 2008-11-07 2010-05-14 Cipla Limited Process for resolving zopiclone
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