WO2011117885A1 - Procédé de préparation d'énantiomères de licarbazépine - Google Patents

Procédé de préparation d'énantiomères de licarbazépine Download PDF

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Publication number
WO2011117885A1
WO2011117885A1 PCT/IN2011/000190 IN2011000190W WO2011117885A1 WO 2011117885 A1 WO2011117885 A1 WO 2011117885A1 IN 2011000190 W IN2011000190 W IN 2011000190W WO 2011117885 A1 WO2011117885 A1 WO 2011117885A1
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WO
WIPO (PCT)
Prior art keywords
solvent
rlicarbazepine
eslicarbazepine
licarbazepine
acetate
Prior art date
Application number
PCT/IN2011/000190
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English (en)
Inventor
Sanjay Jagdish Desai
Ashesh Kamalnayan Pandya
Sachin Panditrao Sawant
Krunalkumar Ramanlal Mehariya
Original Assignee
Intas Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2011117885A1 publication Critical patent/WO2011117885A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines

Definitions

  • the present invention relates to a novel process for preparation of eslicarbazepine acetate or rlicarbazepine acetate.
  • Carbamazepine (I) and its 10-keto analogue oxcarbazepine (II) are first-line established drugs used in the treatment of epilepsy.
  • oxcarbazepine (II) is rapidly metabolized to a pharmacologically active 4: 1 mixture of the (S) and (R) enantiomers of 10,11-dihydro- 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (III) which is also known as licarbazepine.
  • Licarbazepine exhibits comparable antiepileptic activity to the parent drug, but its oral administration is hampered by its low bioavailability and to overcome this licarbazepine was converted to its acetate.
  • the (S) enantiomer of licarbazepine acetate also known as eslicarbazepine acetate (XII) and R enantiomer which is also known as rlicarbazepine acetate (XIII) can be depicted by following structural formula.
  • Licarbazepine acetate including all its enantiomer is disclosed in US 5,723,646.
  • the process of '646 involves reaction of licarbazepine with acetyl chloride to prepare eslicarbazepine or rlicarbazepine acetate.
  • US 2007/0073057 discloses process to prepare optically pure (S)-(+)-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and (R)-(-)-10,l 1-dihydro-lO-hydroxy- 5H-dibenz[b,f]azepine-5-carboxamide by resolution of racemic ( ⁇ )-10,l l-dihydro-10- hydroxy-5H-dibenz[b,f]azepine-5-carboxamide using diacetyl tartaric anhydride. Diacetyl tartaric anhydride is not readily available in commercial quantity and is also unstable, thus it needs to be prepared. The synthesis of resolving agent increases the total synthetic steps and makes the overall process lengthy.
  • the process of present application is simple, cost effective and industrially viable which uses readily available reagents for resolution of licarbazepine and for acetylation of individual isomer.
  • the main object of the invention is to provide an improved process for the preparation of (S)-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide and (R)-(-)- 10,1 1 -dihydro- 10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.
  • a further object of the invention is to provide an improved process for the preparation of (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide and (R)-(+)-10- acetoxy-10,1 l -dihydro-5H-dibenz[b,f]azepine-5-carboxamide.
  • the present invention comprises preparation of eslicarbazepine acetate (XII) or rlicarbazepine acetate (XIII).
  • the process of present invention comprises resolution of licarbazepine by using (R)-(+)-acetyl mandelic acid or (S)-(+)-acetyl mandelic acid.
  • the present invention also provides diastereomeric esters having following structural formula
  • the process comprises preparing eslicarbazepine and rlicarbazepine acetate by using acetic acid as acetylating agent.
  • Licarbazepine is reacted with (R)-(-)-acetyl mandelic acid or (S)-(+)-acetyl mandelic acid in the presence of coupling agent to give mixture of esters [(S,R)- acetyl mandalate and (R,R)-acetyl mandelate or (R,S)-acetyl mandalate and (S,S)- acetyl mandalate]
  • esters of (R)-(-)-acetyl mandalic acid and (S)-(+)-acetyl mandalic acid are separated into -individual esters by treating with solvent and then hydrolysed using a base to give Eslicarbazepine or Rlicarbazepine.
  • the process of present application involves reacting racemic licarbazepine with (R)-(-)-acetyl mandelic acid in presence of coupling agent to obtain (VIII) and (IX) acetyl mandalate esters of licarbazepine.
  • Suitable coupling agent includes carbodiimide such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethyl)aminophenyl)carbodiimide or carbonyldiimidazole.
  • carbodiimide such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethyl)aminophenyl)carbodiimide or carbonyldiimidazole.
  • dicyclohexylcarbodiimide is used for the purpose of present process.
  • nucleophilic catalyst which can be selected from a group 1-hydroxybenzotriazole, 4-dimethylaminopyridine also known as ⁇ , ⁇ -dimethylaminopyridine; Preferably N,N-dimethylaminopyridine is used. If carbonyldiimidazole (CDI) is used as coupling agent the reaction can be carried out in absence of nucleophilic catalyst.
  • CDI carbonyldiimidazole
  • the reaction is carried out in presence of solvent selected from chlorinated solvents such as dichloromethane, dichloroethane, chloroform, ether such as tetrahydrofuran, diethylether, diisopropyl ether.
  • solvent selected from chlorinated solvents such as dichloromethane, dichloroethane, chloroform, ether such as tetrahydrofuran, diethylether, diisopropyl ether.
  • the process may further include heating the reaction mixture, the reaction mixture can be heated to 30 - 120 °C; preferably the reaction mixture is heated to reflux temperature of the solvent used.
  • reaction mixture is filtered and the filtrate is taken further for separation of esters prepared in step (I) of the scheme I.
  • the filtrate can be washed with acid followed by alkali to remove unreacted starting materials like acetyl mandelic acid or 4-dimethylaminopyridine.
  • the acid and alkali are used as their aqueous solution and can be selected from acetic acid, phosphoric acid, hydrochloric acicLor any other acid suitable for suGh process; alkali can-be selected from sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate.
  • diastereomers are separated by treating with solvent.
  • the organic layer is treated with solvent and diastereomers can be separated based on their solubility in particular solvent.
  • the solvents used for the separation include but not limited to acetone, methyl ethyl ketone, methylisobutylketone.
  • the ester (VIII) can be hydrolyzed to give desired isomer of licarbazepine i.e. eslicarbazepine.
  • the said organic layer is treated with methylisobutyl ketone.
  • the desired ester (VIII) does not dissolve in the solvent hence can be separated by filtration or any other similar technique.
  • the ester of formula (IX) remains in filtrate and can be separated by complete removal of solvent.
  • the diastereomeric esters are identified by specific optical rotation and chiral HPLC.
  • the Specific optical rotation of compound of formula (VIII) is -123° and of formula (IX) is +121°.
  • Retention time is measured in minutes between injection of the sample on the column and elution of the particular component through the detector.
  • the retention time ("Rt") of ester of formula (VIII) is about 11.0 minute and of formula (IX) is about 14.0 minute.
  • the structure of compound of formula (VIII) was deduced with the help of 1H - NMR, IR spectroscopy, and Mass Spectrometry.
  • the ester (VIII) can be hydrolysed to give desired isomer of licarbazepine i.e. eslicarbazepine.
  • rlicarbazepine can be prepared by following the same process as disclosed above for eslicarbazepine; the process comprises use of (S)-(+)-acetyl mandelic acid as resolving agent.
  • present invention provides -process for acetylation of eslicarbazepine and rlicarbazepine.
  • the process can be summarized as following:
  • the process of acetylation comprises reacting (S)- or (R)-licarbazepine with acetic acid.
  • the process is carried out in presence of coupling agent selected from carbonyldiimidazole (CDI) or carbodiimide which can be selected from dicyclohexyl carbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethyl)aminophenyl) carbodiimide, preferably dicyclohexyl carbodiimide is used for the purpose of present process.
  • CDI carbonyldiimidazole
  • carbodiimide which can be selected from dicyclohexyl carbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3-dimethyl)aminophenyl) carbodiimide, preferably dicyclohexyl carbodiimide is used for the purpose of present process.
  • the reaction is advantageously carried out in presence of nucleophilic catalyst which can be selected from 4-dimethylaminopyridine, 1-hydroxybenzotriazole. If coupling agent is CDI, reaction can be carried out in absence of nucleophilic catalyst.
  • the reaction is carried out in a solvent; suitable solvents include chlorinated solvents such as dichloromethane, dichloroethane, chloroform; ether such as diethylether, diisopropyl ether or mixture thereof.
  • the reaction mixture can be heated to reflux temperature of the solvent.
  • the acetyl derivative of formula (XII) or (XIII) is isolated from reaction mixture by filtering the reaction mixture and subjecting the filtrate to acid/base treatment.
  • the acid/alkali treatment can be followed by purification from an organic solvent.
  • the acid is used as an aqueous solution and can be selected from acetic acid, phosphoric acid, hydrochloric acid; preferably acetic acid is used.
  • the base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate; preferably aqueous sodium bicarbonate.
  • the suitable solvent for purification of eslicarbazepine acetate or rlicarbazepine acetate can be selected from alcohols linear or branched chain.
  • the example of alcohol includes but not limited to ethyl alcohol, methyl alcohol or isopropyl alcohol preferably isopropyl alcohol is used for purification.
  • the present inventors have also tried an alternative route for resolution of licarbazepine; this process includes reacting licarbazepine with dicarboxylic acid followed by resolution of esters thus obtained by optically active phenyl ethyl amine.
  • the dicarboxylic acid can be selected from any aromatic or aliphatic dicarboxylic acid.
  • acetyl mandelic acid as the resolving agent makes the present process simple yet, efficient.
  • the product i.e. eslicarbazepine acetate or rlicarbazepine acetate is obtained with-good yield and high optical purity.
  • Licarbazepine can be prepared by following the process mentioned in US 3,637,661 or according to the process of US 7,119,197.
  • the resultant reaction mixture was heated at 60 - 65 °C for one hour and filtered at the same temperature.
  • the solid thus obtained was again purified by. using methyl isobutylketone at 60 - 65 °C to get title compound with 97.6% of optical purity.
  • reaction mixture 250 ml water, 50 g compound obtained form example 1 and 50 g sodium hydroxide were mixed in a round bottom flask. The resultant reaction mixture was heated at 80 -85 °C for 1 hour. After completion of reaction the reaction mixture was cooled to ambient temperature and the pH of the reaction mixture was adjusted to acidic to get 26 g of title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un procédé de préparation d'eslicarbazépine et de licarbazépine et leurs acétates par résolution de licarbazépine racémique au moyen d'acide acétyle mandélique.
PCT/IN2011/000190 2010-03-23 2011-03-22 Procédé de préparation d'énantiomères de licarbazépine WO2011117885A1 (fr)

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IN803/MUM/2010 2010-03-23
IN803MU2010 2010-03-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3064490A1 (fr) 2015-03-06 2016-09-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé amélioré pour la préparation d'eslicarbazépine et d'acétate d'eslicarbazépine

Citations (7)

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US3637661A (en) 1970-03-04 1972-01-25 Ciba Geigy Corp 10-hydroxy-10 11-dihydro-dibenzazepine derivative
EP0751129A1 (fr) * 1995-06-30 1997-01-02 Portela & Ca., S.A. Dihydrobenzo(b,f)azepines substituées, leur préparation, leur utilisation dans le traitement des maladies du système nerveux central et compositions pharmaceutiques les contenant
US5723646A (en) 1991-01-24 1998-03-03 Bayer Aktiengesellschaft Substituted amino acid amide derivatives their preparation and use as fungicides
WO2002092572A1 (fr) * 2001-05-11 2002-11-21 Portela & Ca Sa Technique de preparation de (s)-(+)- et de (r)-(-)-10,11-dihydro-10-hydroxy-5h-dibenz/b,f/azepine-5-carboxamide
GB2416167A (en) * 2004-07-13 2006-01-18 Portela & Ca Sa Chiral inversion and esterification of (S)- and (R)-10-hydroxy-dibenzazepine carboxamides
GB2422149A (en) * 2005-01-14 2006-07-19 Portela & Ca Sa Process for the preparation of 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide
GB2437078A (en) * 2006-04-11 2007-10-17 Portela & Ca Sa 10-Acyloxy-5H-dibenzo[b,f]azepine-5-carboxamides & their asymmetric hydrogenation to the chiral 10,11-dihydro derivatives

Patent Citations (9)

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US3637661A (en) 1970-03-04 1972-01-25 Ciba Geigy Corp 10-hydroxy-10 11-dihydro-dibenzazepine derivative
US5723646A (en) 1991-01-24 1998-03-03 Bayer Aktiengesellschaft Substituted amino acid amide derivatives their preparation and use as fungicides
EP0751129A1 (fr) * 1995-06-30 1997-01-02 Portela & Ca., S.A. Dihydrobenzo(b,f)azepines substituées, leur préparation, leur utilisation dans le traitement des maladies du système nerveux central et compositions pharmaceutiques les contenant
WO2002092572A1 (fr) * 2001-05-11 2002-11-21 Portela & Ca Sa Technique de preparation de (s)-(+)- et de (r)-(-)-10,11-dihydro-10-hydroxy-5h-dibenz/b,f/azepine-5-carboxamide
US7119197B2 (en) 2001-05-11 2006-10-10 Portela & C.A., S.A. Method for preparation of (s)-(+)-and(r)-(-)10,11-dihydro-10-hydrodoxy-5h-dibenz/b,f/azephine-5-carboxamide
US20070073057A1 (en) 2001-05-11 2007-03-29 Portela & C.A.,S.A. Method for preparation of (S)-(+)- and (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide
GB2416167A (en) * 2004-07-13 2006-01-18 Portela & Ca Sa Chiral inversion and esterification of (S)- and (R)-10-hydroxy-dibenzazepine carboxamides
GB2422149A (en) * 2005-01-14 2006-07-19 Portela & Ca Sa Process for the preparation of 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide
GB2437078A (en) * 2006-04-11 2007-10-17 Portela & Ca Sa 10-Acyloxy-5H-dibenzo[b,f]azepine-5-carboxamides & their asymmetric hydrogenation to the chiral 10,11-dihydro derivatives

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BENES J ET AL: "Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 42, 1 January 1999 (1999-01-01), pages 2582 - 2587, XP002206156, ISSN: 0022-2623, DOI: 10.1021/JM980627G *
BENES, J. ET AL., J. MED. CHEM., vol. 42, 1999, pages 2582 - 2587
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VOLOSOV A., EPILEPSIA, vol. 41, no. 9, 2000, pages 1107 - 1111

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3064490A1 (fr) 2015-03-06 2016-09-07 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé amélioré pour la préparation d'eslicarbazépine et d'acétate d'eslicarbazépine
WO2016142164A1 (fr) 2015-03-06 2016-09-15 F.I.S. - Fabbrica Italiana Sintetici S.P.A. Procédé amélioré pour la préparation d'eslicarbazépine et d'acétate d'eslicarbazépine
US9845293B2 (en) 2015-03-06 2017-12-19 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for the preparation of eslicarbazepine and eslicarbazepine acetate

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