WO2009101634A2 - Nouveau procédé de préparation de l'eszopiclone - Google Patents

Nouveau procédé de préparation de l'eszopiclone Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
eszopiclone
solvent
process according
acetonitrile
dibenzoyl
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PCT/IN2009/000097
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English (en)
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WO2009101634A3 (fr
Inventor
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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Publication of WO2009101634A2 publication Critical patent/WO2009101634A2/fr
Publication of WO2009101634A3 publication Critical patent/WO2009101634A3/fr

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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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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un nouveau procédé de préparation de l'eszopiclone (II), qui comprend les étapes suivantes : (a) la préparation de zopiclone (I) par réaction de la 6-(5-chloropyridin-2-yl)-5-hydroxy-7-oxo-5,6-dihydropyrrolo[3,4-b]pyrazine-5-one (5-OH-Py) (III) avec la chlorocarbonyl-4-méthylpipérazine (CMP) sous forme de base libre (IV) ou son sel d'addition avec un acide en présence de diazabicyclo[5.4.0]undéc-7-ène (DBU) ou d'un mélange de DBU et d'autres bases ; (b) la résolution de la zopiclone racémique par de l'acide dibenzoyl-D-tartrique dans un solvant approprié, le sel d'addition avec l'acide dibenzoyl-D-tartrique de l'eszopiclone étant séparé par l'ajout d'un solvant nitrile ; (c) la purification facultative du sel d'addition avec l'acide dibenzoyl-D-tartrique de l'eszopiclone par dissolution dans un solvant choisi parmi les alcools, les cétones ou leurs mélanges suivie par la précipitation par ajout d'un solvant nitrile ; (d) la conversion du sel d'addition avec l'acide dibenzoyl-D-tartrique de l'eszopiclone pour obtenir l'eszopiclone (II) sous forme de base libre par traitement par une solution alcaline ; (e) la purification de l'eszopiclone par dissolution dans un solvant nitrile suivie par l'ajout de solvant cétonique. L'eszopiclone (II) obtenue par le procédé de la présente invention a une pureté chirale supérieure à 99,9 % et des quantités inférieures d'impuretés volatiles organiques. La présente invention porte en outre sur une nouvelle forme cristalline B du sel dibenzoyl-D-tartrate d'eszopiclone (V) et sur sa préparation.
PCT/IN2009/000097 2008-02-13 2009-02-11 Nouveau procédé de préparation de l'eszopiclone WO2009101634A2 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
IN246KO2008 2008-02-13
IN246/KOL/2008 2008-02-13
IN602/KOL/2008 2008-03-03
IN602KO2008 2008-03-03
IN1200/MUM/2008 2008-06-05
IN1200MU2008 2008-06-05
IN1200/KOL/2008 2008-07-14
IN1200KO2008 2008-07-14

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WO2009101634A3 WO2009101634A3 (fr) 2014-10-16

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010052475A1 (fr) * 2008-11-07 2010-05-14 Cipla Limited Procédé pour la résolution optique de la zopiclone
EP2345654A1 (fr) 2010-01-05 2011-07-20 LEK Pharmaceuticals d.d. Particules d'eszopiclone et leur procédé de préparation
JP2020007252A (ja) * 2018-07-05 2020-01-16 アクティブファーマ株式会社 エスゾピクロンジベンゾイル−ｄ−酒石酸塩の製造方法、エスゾピクロンの製造方法、及びエスゾピクロンジベンゾイル−ｄ−酒石酸塩の結晶
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125874B2 (en) * 1991-01-17 2006-10-24 Sepracor Inc. Optically active 5H-pyrrolo[3,4-b] pyrazine derivative, its preparation and pharmaceutical compositions containing same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125874B2 (en) * 1991-01-17 2006-10-24 Sepracor Inc. Optically active 5H-pyrrolo[3,4-b] pyrazine derivative, its preparation and pharmaceutical compositions containing same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010052475A1 (fr) * 2008-11-07 2010-05-14 Cipla Limited Procédé pour la résolution optique de la zopiclone
US8461334B2 (en) 2008-11-07 2013-06-11 Cipla Limited Process for resolving zopiclone
EP2345654A1 (fr) 2010-01-05 2011-07-20 LEK Pharmaceuticals d.d. Particules d'eszopiclone et leur procédé de préparation
JP2020007252A (ja) * 2018-07-05 2020-01-16 アクティブファーマ株式会社 エスゾピクロンジベンゾイル−ｄ−酒石酸塩の製造方法、エスゾピクロンの製造方法、及びエスゾピクロンジベンゾイル−ｄ−酒石酸塩の結晶
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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