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WO2011045648A2 - Procédé de préparation de (s)-(-)-10-acétoxy-10,11-dihydro-5h-dibenz[b,f]azépine-5-carboxamide et ses esters - Google Patents

Procédé de préparation de (s)-(-)-10-acétoxy-10,11-dihydro-5h-dibenz[b,f]azépine-5-carboxamide et ses esters Download PDF

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Publication number
WO2011045648A2
WO2011045648A2 PCT/IB2010/002574 IB2010002574W WO2011045648A2 WO 2011045648 A2 WO2011045648 A2 WO 2011045648A2 IB 2010002574 W IB2010002574 W IB 2010002574W WO 2011045648 A2 WO2011045648 A2 WO 2011045648A2
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formula
protease
compound
process according
carboxamide
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WO2011045648A3 (fr
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Mofazzal Husain
Debashish Datta
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Mylan Laboratories Ltd
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Matrix Laboratories Ltd
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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
    • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11

Definitions

  • This invention in general relates to a process for preparing (S)-(-)-10-acetoxy- 10,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide (eslicarbazepine) and its esters thereof.
  • the present invention provides a novel enzymatic process for the preparation of eslicarbazepine and its esters thereof.
  • the invention provides novel intermediates of eslicarbazepine and isomers thereof, the process for preparing the same and the use of the same to prepare eslicarbazepine.
  • Eslicarbazepine acetate [(S)-(-)- 10-acetoxy- 10,11 -dihydro-5H- dibenz[b,fjazepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder.
  • ESL central nervous system
  • VGSC voltage-gated sodium channel
  • Eslicarbazepine acetate shares with carbamazepine and oxcarbazepine, the dibenzazepine nucleus bearing the 5-carboxamide substitute, but it is structurally different at the 10 and 11 -positions.
  • This molecular variation not only results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine- 10,1 1 epoxide but also avoids the unnecessary production of isomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity.
  • the key step of the synthesis of compounds BIA 2-093 and BIA 2-059 involves the resolution of racemic 10,l l-dihydro-10-hydroxy-5H-dibenz/b, f/azepine-5- carboxamide (( ⁇ )MHD) into its separate, optically pure stereoisomers, (S)-(+)- 10,11- dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((S)-(+)-MHD), and (R)-(-)- 10,1 l-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((R)-(-)-MHD), which are the principal intermediates.
  • This activation is normally achieved via conversion of the free acids to the acid chlorides (these acid chlorides are very expensive products when bought from commercial sources), an extra synthetic step which requires the use of unpleasant halogenating reagents such as for example thionyl chloride or oxalyl chloride.
  • this reaction can be accomplished using a coupling reagent such as for example dicyclohexylcarbodiimide.
  • This reagent is also expensive; additionally it is difficult to manipulate due to its low melting point and is indicated as a potent skin irritant, thus posing health risks for workers.
  • Often difficulties are encountered in removing the dicyclohexylurea by-product completely from the wanted product.
  • a further and very serious limitation of this method is the relatively low yield obtained of the optically pure menthoxyacetate ester which is isolated after crystallisation, in yields usually only marginally better than 20% (the maximum yield being 50% for each isomer).
  • WO 20020092572 granted as US 7,119,197 disclosed a process for the preparation of optically pure (S)-(+) -10, 1 l-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and (R)-(-)-10,l l-dihydro-10-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 tartaric acid anhydride.
  • This process includes large number of steps and chiral auxiliary like tartaric acid anhydride.
  • the present invention provides a process for preparing eslicarbazepine, which avoids the drawback associated with the prior arts discussed above.
  • a process for preparing (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5- carboxamide of formula I wherein the process comprises of protecting a compound of formula III with a protecting group in the presence of a solvent to give a compound of formula IV, hydrolysing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI, treating the mixture of the compound of formula V and formula VI with acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII, hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-(-)-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula II, esterifying the (S)-(-)-10,l l-dihydro-5H- dibenz
  • a process for preparing (S)-(-)-l 0-acetoxy- 10,11 -dihydro-5H-dibenz[b,fj azepine- 5-carboxamide of formula I wherein the process comprises of protecting a compound of formula III with a protecting group in the presence of a solvent to give a compound of formula IV, hydrolysing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI, treating the mixture of the compound of formula V and formula VI with acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII, hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-(-)-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula II, esterifying the (S)-(-)-l 0, 1 1 -dihydro-5
  • a process for preparing (S)-(-)- 10-acetoxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5- carboxamide of formula I wherein the process comprises of protecting a compound of formula III with a protecting group in the presence of a solvent to give a compound of formula IV, hydrolysing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI, treating the mixture of the compound of formula V and formula VI with acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII, hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-(-)-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula II, esterifying the (S)-(-)-10,l l-dihydro-5H- dibenz
  • a process for separation of compounds of formula V and VI from a mixture containing the same comprises of treating the mixture of the compound of formula V and formula VI with an acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII and hydrolyzing the resultant compound of formula VII in presence of a solvent to obtain a corresponding alcohol.
  • a process for separation of compounds of formula V and VI from a mixture containing the same comprises of treating the mixture of the compound of formula V and formula VI with an acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII and hydrolyzing the resultant compound of formula VII in presence of a solvent to obtain a corresponding alcohol
  • the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride.
  • a compound (S)-(-)- 10-acetoxy- 10, 1 1 -dihydro-5H-dibenz[b,f]azepine-5- carboxamide of formula I wherein the said compound is prepared by a process that comprises of protecting a compound of formula III with a protecting group in the presence of a solvent to give a compound of formula IV, hydrolysing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI, treating the mixture of the compound of formula V and formula VI with acid anhydride in the presence of a base and a solvent to obtain a mixture of compound of formula V and formula VII, hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-( ⁇ )-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula II, esterifying the (S)-(-)-10,l l-di
  • intermediates of formula IV for producing (S)-(-)- 10-acetoxy- 10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide, wherein said intermediates are protected by a protecting group selected from methoxyacetyl, ethyl oxalate or ethyl carbonate.
  • the present invention relates to a process for the preparation of eslicarbazepine acetate by enzymatic resolution of protected licarbazepine, a precursor to eslicarbazepine acetate
  • the present invention further relates to an enzymatic process for the preparation of eslicarbazepine (compound of formula II) and its acetate ester (compound of formula I) as shown in scheme 1,
  • R is HO-CO-CH 2 -CO- , HO-CO-CH 2 -CH 2 -CO- , HO-CO-CH 2 -CH 2 -CH 2 -
  • R is HO-CO-CH 2 -CO- , HO-CO-CH 2 -CH 2 -CO- , HO-CO-CH 2 -CH 2 -CO-, or the like; d) hydrolyzing the compound of formula V in presence of a base and a solvent to obtain (S)-(-)-10,l l-dihydro-5H-dibenz[b,fjazepine-5-carboxamide of formula ⁇ ;
  • the present invention encompasses novel intermediates of eslicarbazepine and its isomers thereof.
  • novel intermediates of the present invention include activated esters which were screened against the hydrolase enzyme using appropriate solvent system.
  • the present invention provides an intermediate of formula VII for producing (S)-(- )-l O-acetoxy-10, 1 1 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide,
  • R is HO-CO-CH 2 -CO- , HO-CO-CH 2 -CH 2 -CO- , HO-CO-CH 2 -CH 2 -CH 2 - CO-, or the like.
  • the present invention provides intermediates of formula IV for producing (S)-(-)- 10-acetoxy- 10, 1 1 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide
  • PG is selected from methoxyacetyl, ethyl oxalate or ethyl carbonate.
  • the present invention encompasses the separation of compounds of formula V and VI by treating with appropriate acid anhydrides to give compounds of formula V and VII
  • R is HO-CO-CH 2 -CO- , HO-CO-CH 2 -CH 2 -CO- HO-CO-CH 2 -CH 2 -CH 2 - CO-, or the like.
  • the hydrolysis of the protected compound of formula V is carried out in the presence of a catalyst such as dimethylaminopyridine, buffer/co-solvent mixture wherein in the buffer is selected from sodium phosphate buffer, potassium phosphate buffer, tris(hydroxymethyl)-aminomethane and the like.
  • a catalyst such as dimethylaminopyridine, buffer/co-solvent mixture wherein in the buffer is selected from sodium phosphate buffer, potassium phosphate buffer, tris(hydroxymethyl)-aminomethane and the like.
  • the present invention encompasses enantiomerically pure eslicarbazepine having enantiomeric purity of about 99% preferably about 99.99% enantiomeric excess.
  • the hydroxy-protecting group can be one of the protective groups used in the alcohol chemistry, typically an acyl group, e.g. a Ci-C 6 alkanoyl group, preferably a C 1 -C4 alkanoyl group, in particular formyl, acetyl or propionyl; an aryl-C]-C 6 alkanoyl group, e.g. phenylacetyl, phenylpropionyl, or aroyl, e.g. benzoyl, wherein the phenol ring is optionally substituted with one to three substitutions independently selected e.g.
  • an acyl group e.g. a Ci-C 6 alkanoyl group, preferably a C 1 -C4 alkanoyl group, in particular formyl, acetyl or propionyl
  • an aryl-C]-C 6 alkanoyl group e.g. phenylacetyl, phenylpro
  • halogen in particular chlorine, bromine or iodine, and cyano
  • an aryl-Ci-C 6 alkyl group e.g. benzyl, phenylethyl or naphthalenylmethyl
  • a tri (Ci-C 6 ) alkyl-silyl group e.g. trimethylsilyl, tert-butyl-dimethylsilyl.
  • a -Cg alkanoyl group more preferably a C -Ce alkanoyl group, in particular formyl or acetyl, methoxyacetyl, ethyl oxalate, ethylcarbonate.
  • the enzymes that are suitable for the present invention and most investigated are hydrolases.
  • the commonly used hydrolases are lipases, proteases and esterases.
  • Hydrolases are a very large family of enzymes, which are able to perform reactions with water, but also in near anhydrous organic solvent.
  • Hydrolases have a number of specific advantages that make them very suitable for use in a chemical process.
  • Hydrolases are in many cases relatively stable enzymes that can be stored as concentrated aqueous solutions or freeze dried powders.
  • the suitable enzyme is selected from NZL101, NZL102, NZL103, NZL104, NZL105, NZL106, NZL107, NZL108, NZL109, NZPlOl, NZP 102, NZP103, NZP104, NZP106, Protease Alcalase, Protease Savinase, Protease Everlase, Protease Neutrase, ProteaseB.amyloliquifaciens, ProteaseA.oryzae, Protease N, ProteaseA.melleus, Protease A.
  • ProteaseB.polymyxa Protease S.griseus, Bromelain, Papain, Ficin, Rennet (M.Miehei), Protex6L, Protex7L, Protexl3FL, Protexl4L, Protexl5L, Protex30L, Protex40L, Protex40XL, Protex50FP, Protex51FP, Protex89L, Proteinase bact, ProtexB.subtillis,Novo porcine trypsine,Novocarne tender, Acid protease, Neutral protease, Alkaline protease, Bacterial protease,Alkaline protease, protease Alcalase, protease Savinase, Protease Everlase, Protease Esperase, Bacterial protease, CalA, CalB, R M, Lipolase, Lipexl00,NZ51032, Resinase, Lecitase Ultra, Al
  • the methoxy acetate ester was screened against different hydrolase enzymes and it was found that lipases are not suitable substrates whereas proteases are the most preferred ones with respect to reactivity and obtaining the desired enantiospeficity and hydrolyzing the undesired (R)-enantiomer.
  • the different hydrolases that were screened on licarbazepine methoxy acetate are briefed below in Table 1.
  • the active proteases were again screened with slightly optimized conditions such as using a larger amount of organic solvent thus making the solution biphasic.
  • the hydrolytically sensitive substrate is mostly dissolved in the organic phase, reducing its exposure to water phase. This greatly improved the enantioselectivity of the enzymes tested.
  • the best protease enzyme identified was Protex 6L.
  • racemic acetate ester was screened using bulk hydrolases in a biphasic system and found that only proteases have shown the reactivity but at a much reduced rate.
  • licarbazepine ethylcarbonate was considered, as this can react on either side of the carbonyl group giving the same alcohol product. This was screened against bulk hydrolases and it was found that the enantioselectivity was quite low.
  • the suitable solvent used in the above given scheme in various steps is selected from Ci-C 6 alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, and t-butanol; ketones such as acetone, propanone, and 2-butanone; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, tetrahydrofuran, 2-methyl tetrahydrofuran and dioxane, chlorinated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride, hydrocarbons, toluene, xylene,
  • the solvent screening is done using a combination of licarbazepine methoxyacetate and Protex 6L against 2-methyl tetrahydrofuran and ethylacetate at relatively high temperature and higher substrate loading and the results were found comparable as shown in Table 8.
  • the 2-methyl tetrahydrofuran showed slightly better enantioselectivity than the ethylacetate as shown in Table 9.
  • isopropy acetate was tested at both high and low temperatures and it was found that at higher temperatures, the conversion is much superior than 2-methyl tetrahydrofuran and ethylacetate. At lower temperatures, the solubility of the substrate was lower in isopropylacetate although the enantiomeric ratio is by far the highest. Also observed is that a slight reduction in pH of the reaction mixture improves the performance of the 2-methyl tetrahydrofuran. Table 10 depicts the solvent comparison at lower and higher temperatures. Table 10
  • a base can be an organic base, for example an alkali metal Cj-C 6 alkoxide, such as sodium or potassium methoxide, ethoxide or tert- butoxide; l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO); or an inorganic base, e.g. an alkali or alkaline-earth metal hydroxide, carbonate or phosphate, e.g. sodium, potassium or barium hydroxide, sodium or potassium carbonate, or sodium or potassium phosphate or sodium hydride,.
  • an alkali metal Cj-C 6 alkoxide such as sodium or potassium methoxide, ethoxide or tert- butoxide
  • DBU l ,8-Diazabicyclo[5.4.0]undec-7-ene
  • DABCO l,4-diazabicyclo[2.
  • the base is preferably an inorganic base, more preferably an alkali or alkaline-earth metal phosphate; or organic base, for example pyridine or substituted pyridines or a base is typically an organic base, in particular a tertiary amine, for example a tri(Ci-C 6 )alkylamine, e.g. triethylamine or trimethylamine, a tri(Ci-C 6 )alkanolamine, e.g. triethanolamine, trimethanolamine or tripropanolamine, or diazabicyclooctane or diazabicycloundecene, or mixtures thereof.
  • organic base for example pyridine or substituted pyridines or a base is typically an organic base, in particular a tertiary amine, for example a tri(Ci-C 6 )alkylamine, e.g. triethylamine or trimethylamine, a tri(Ci-C 6 )alkanol
  • the selectivity is a delicate balance between temperatures, pH, type of co-solvent and amount of enzyme (thus determining the reaction time). At higher concentrations the buffer strength is not sufficient to compensate for all the acid liberates in the enzymatic hydrolysis.
  • a pH control system is adopted in the place of buffer.
  • the type of base used for pH control can have a major influence on the product quality and enzyme stability.
  • the preferred pH range is between 4 to 8 and the preferred buffer /solvent mixture range is 5 to 60%.
  • the buffer employed is selected from a group consisting of sodium phosphate buffer, potassium phosphate buffer, tris(hydroxymethyl)aminomethane or mixtures thereof, wherein the buffer used is in the range of about 10 to 500 mmoles.
  • the catalyst used in the process is preferably dimethyl amino pyridine.
  • temperature control is considered.
  • the solubility of the substrate and products is very limited; hence temperature control is very important.
  • the optimum temperature may well be higher than the optimum temperatures.
  • enzymatic hydrolysis is carried out at a temperature of about 20 to 50° C, preferably 25 to 40°C.
  • the third parameter is the incorporation of recycling strategies to reuse the undesired (R)-enantiomer.
  • the easiest way is to implement off-line racemisation of the (R)-alcohol separated /isolated as the hemi-succinate. This can be done by oxidation/reduction step via the achiral oxcarbazepine or via the chlorination approach of the expired patent EP 1477480.
  • the enzymatic resolution of licarbazepine is done using the methoxyacetate as best derivative and Protex 6L protease as most efficient enzyme.
  • This materia] (5.3 g) was dissolved in 75 ml 2-methyl tetrahydrofuran and mixed with 53 mg (1 wt% to total) of 4-dimethylaminopyridine, 1.5 g (15 mmol; 1.4 eq to alcohol) of succinic anhydride and 3 ml triethylamine (20 mmol; 1 eq to total).
  • This mixture was refluxed under argon while frequently sample using achiral HPLC. The heating was continued for a total of 8h, followed by overnight cooling.
  • a HPLC sample for the clear solution showed about 99.85 % conversion of the alcohol to hemi-succinate.
  • HPLC 99.4 % purity and 99.99 % ee of (5)-licarbazepine methoxyacetate.
  • the water phase was acidifying with HC1 (pH 3 -4) and the white solid precipitated out of (R)-enriched licarbazepine.
  • HPLC 99.5% purity and 99.99 % ee.

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé enzymatique de préparation de (s)-(-)-10-acétoxy-10,11-dihydro-5H-dibenz[b,f]azépine-5-carboxamide (eslicarbazépine) et ses esters. En outre, l'invention concerne de nouveaux intermédiaires d'eslicarbazépine et leurs isomères, permettant d'obtenir une pureté élevée et un rendement élevé d'eslicarbazépine.
PCT/IB2010/002574 2009-10-12 2010-10-11 Procédé de préparation de (s)-(-)-10-acétoxy-10,11-dihydro-5h-dibenz[b,f]azépine-5-carboxamide et ses esters Ceased WO2011045648A2 (fr)

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IN2463CH2009 2009-10-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012156987A3 (fr) * 2011-05-19 2013-03-21 Glenmark Generics Limited Nouveau procédé de préparation d'eslicarbazépine
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

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US5753646A (en) 1995-06-30 1998-05-19 Portela & Ca., S.A. Substituted dihydrodibenzo/b,f/azepines, method of their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them
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
EP1477480A1 (fr) 2003-05-12 2004-11-17 Portela & Ca., S.A. Méthode de racémisation de (S)-(+)- et (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamides et de leurs mélanges optiquement actifs

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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
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EP1477480A1 (fr) 2003-05-12 2004-11-17 Portela & Ca., S.A. Méthode de racémisation de (S)-(+)- et (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamides et de leurs mélanges optiquement actifs

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012156987A3 (fr) * 2011-05-19 2013-03-21 Glenmark Generics Limited Nouveau procédé de préparation d'eslicarbazépine
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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