WO2011045648A2 - Process for preparing (s)-(-)-10-acetoxy-10,11-dihydro-5h-dibenz[b,f]azepine-5-carboxamide and its esters thereof - Google Patents

Process for preparing (s)-(-)-10-acetoxy-10,11-dihydro-5h-dibenz[b,f]azepine-5-carboxamide and its esters thereof Download PDF

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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
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carboxamide
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WO2011045648A3 (en
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Mofazzal Husain
Debashish Datta
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Matrix Laboratories Limited
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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

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  • 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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Abstract

Disclosed herein an enzymatic process for preparing (S)-(-)-10-acetoxy-10,11- dihydro-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) and its esters thereof. Further, the invention provides novel intermediates of eslicarbazepine and isomers thereof, enabling high purity and yield of eslicarbazepine.

Description

PROCESS FOR PREPARING (S)-(-)-10-ACETOXY-10,ll-DIHYDRO-5H- DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE AND ITS ESTERS THEREOF
Field of the Invention
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. In particular, the present invention provides a novel enzymatic process for the preparation of eslicarbazepine and its esters thereof. Further, 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.
Background of the Invention
Eslicarbazepine acetate (ESL) [(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. Eslicarbazepine acetate is structurally represented as shown in formula I
Figure imgf000002_0001
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 synthesis and improved anticonvulsant properties of (S)-(-)- 10-acetoxy- 10,1 1 - dihydro-5H-dibenz/b,f/azepine-5-carboxamide (BIA 2-093), and (R)-(+)-l 0-acetoxy- 10, 11- dihydro-5H-dibenz/b,f/azepine-5-carboxamide (BIA 2-059), both single-isomer drugs specifically designed to avoid such formation of racemic mixtures of active metabolites have been described in U.S. Pat. No. 5,753,646 and Benes, J. et al., J. Med. Chem., 42, 2582 2587 (1999). 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.
Both stereoisomers of MHD are known compounds and are commonly used as standards in studies of oxcarbazepine metabolism. The resolution of the racemic alcohol has been previously described in the chemical literature (Benes, J. et al., J. Med. Chem., 42, 2582-2587 (1999) and Volosov, A. et al., Epilepsia, 41(9), 1107 1111 (2000)). These methods involve the formation of diasteroisomeric menthoxyacetate-ester derivatives of (±)-MHD; by taking advantage of the different solubilities of these diasteroisomeric esters, separation is possible by fractional crystallisation and subsequent hydrolysis affords the individually pure stereoisomers; (S)-(+)-MHD and (R)-(-)-MHD. However, this method was utilized for the preparation of only rather small quantities of each stereoisomer and contains certain inherent disadvantages which preclude its use for the preparation of pilot- scale quantities and thereafter industrial production. The necessary optically pure resolving agents, (+) and (-)-menthoxyacetic acid are extremely expensive and are not readily available in sufficiently large quantities from commercial sources. Their preparation from cheaper, readily available optically pure (+) or (-)-menthol could be considered, but this preparation is tedious, slow and potentially dangerous. Furthermore, these menthoxyacetic acids require 'activation" in order to react with (±) MHD and form the key intermediate diastereoisomeric menthoxyacetate esters.
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. Alternatively, 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.
Therefore, there is a requirement to provide a process which is more economical and industrially feasible to achieve high purity and yield of eslicarbazepine. Hence the present invention provides a process for preparing eslicarbazepine, which avoids the drawback associated with the prior arts discussed above.
Objects and Summary of the Invention
It is a principal object of the present invention to provide a novel process for preparing (S)-(-)-l 0-acetoxy-l 0, 11 -dihydro-5H-dibenz[b,fJazepine-5-carboxamide
(eslicarbazepine) and its esters thereof, wherein the said process comprises enzyme catalytic conversion method thus making the process more economical and industrially feasible with high purity and yield of eslicarbazepine.
It is another object of the present invention to provide novel intermediates of (S)-(- )-l 0-acetoxy-l 0,1 l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide of formula I and their isomers thereof, which are highly reactive in giving the required purity and yield.
It is one other object of the present invention to provide a process for preparing said (S)-(-)-l 0-acetoxy-l 0,1 l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I intermediates and their isomers thereof.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after. In accordance with one embodiment of the present invention, there is provided 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 (PG) 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)-(-)- 10,1 1 -dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula II, esterifying the (S)-(-)-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula II to obtain the (S)-(-)-10-acetoxy-10,l 1- dihydro-5H-dibenz[b,fjazepine-5-carboxamide of formula I.
In accordance with another embodiment of the present invention, there is provided 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[b,f]azepine-5-carboxamide of formula II to obtain the (S)-(-)- 10-acetoxy- 10,1 1- dihydro-5H-dibenz[b,fjazepine-5-carboxamide of formula I, wherein the protecting group is selected from methoxyacetyl, ethyl oxalate, acetate or ethylcarbonate.
In accordance with one other embodiment of the present invention, there is provided 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-5H- dibenz[b,fJazepine-5-carboxamide of formula II to obtain the (S)-(-)- 10-acetoxy- 10,1 1- dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I, wherein the enzyme is selected from hydrolases.
In accordance with further embodiment of the present invention, there is provided 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[b,fJazepine-5-carboxamide of formula II to obtain the (S)-(-)- 10-acetoxy- 10,1 1- dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I, wherein the enzyme is selected from a protease.
In accordance with yet another embodiment of the present invention, there is provided 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[b,f]azepine-5-carboxamide of formula II to obtain the (S)-(-)- 10-acetoxy- 10,1 1- dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I, wherein the enzyme is Protex 6L protease. In accordance with yet another embodiment of the present invention, there is provided a process for preparing (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]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,fJazepine-5-carboxamide of formula II, esterifying the (S)-(-)-10,l l-dihydro-5H- dibenz[b,fjazepine-5-carboxamide of formula II to obtain the (S)-(-)-10-acetoxy-10,l l- dihydro-5H-dibenz[b,fjazepine-5-carboxamide of formula I, wherein the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride.
In accordance with still another embodiment of the present invention, there is provided a process for separation of compounds of formula V and VI from a mixture containing the same, wherein the process 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.
In accordance with still another embodiment of the present invention, there is provided a process for separation of compounds of formula V and VI from a mixture containing the same, wherein the process 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 alcoholwherein the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride.
In accordance with still another embodiment of the present invention, there is provided 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-dihydro-5H-dibenz[b,fjazepine-5-carboxamide of formula II to obtain the (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide of formula I and wherein the resultant compound the (S)-(-)- 10-acetoxy- 10,11 -dihydro-5H- dibenz[b,fJazepine-5-carboxamide is characterized by having enantiomeric purity greater than about 99%, preferably greater than about 99.99%..
In accordance with yet another embodiment of the present invention, there is provided an intermediate of formula VII for producing (S)-(-)- 10-acetoxy- 10, 1 1 -dihydro- 5H-dibenz[b,fJazepine-5-carboxamide.,
In accordance with yet another embodiment of the present invention, there is provided 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.
In accordance with yet another embodiment of the present invention, there is provided a compound (S)-(-)- 10-acetoxy- 10,l l-dihydro-5H-dibenz[b,fJazepine-5- carboxamide of formula I having enantiomeric purity greater than about 99%, preferably greater than about 99.99%.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
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,
Figure imgf000009_0001
Scheme 1
wherein R is HO-CO-CH2-CO- , HO-CO-CH2-CH2-CO- , HO-CO-CH2-CH2-CH2-
CO-, or the like.
According to the present invention, the process for preparing (S)-(-)-10-acetoxy- 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula I
Figure imgf000009_0002
comprising: a) protecting a compound of formula III
Figure imgf000010_0001
with a protecting group in the presence of a solvent to give a compound of formula IV;
Figure imgf000010_0002
b) hydrolysing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI;
Figure imgf000010_0003
c) 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
Figure imgf000010_0004
wherein R is HO-CO-CH2-CO- , HO-CO-CH2-CH2-CO- , HO-CO-CH2-CH2-CH2-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 Π;
Figure imgf000011_0001
e) esterifying the (S)-(-)-10,l l-dihydro-5H-dibenz[b,fjazepine-5- carboxamide of formula II to obtain the (S)-(-)- 10-acetoxy- 10,11 -dihydro-5H- dibenz[b,fJazepine-5-carboxamide of formula I.
The present invention encompasses novel intermediates of eslicarbazepine and its isomers thereof. The 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,
Figure imgf000011_0002
wherein R is HO-CO-CH2-CO- , HO-CO-CH2-CH2-CO- , HO-CO-CH2-CH2-CH2- 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
Figure imgf000011_0003
wherein the 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
Figure imgf000012_0001
wherein R is HO-CO-CH2-CO- , HO-CO-CH2-CH2-CO- HO-CO-CH2-CH2-CH2- CO-, or the like.
According to one embodiment, 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.
Further, the present invention encompasses enantiomerically pure eslicarbazepine having enantiomeric purity of about 99% preferably about 99.99% enantiomeric excess.
According to the present invention, the hydroxy-protecting group can be one of the protective groups used in the alcohol chemistry, typically an acyl group, e.g. a Ci-C6 alkanoyl group, preferably a C1-C4 alkanoyl group, in particular formyl, acetyl or propionyl; an aryl-C]-C6 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. from halogen, in particular chlorine, bromine or iodine, and cyano; an aryl-Ci-C6 alkyl group, e.g. benzyl, phenylethyl or naphthalenylmethyl; or a tri (Ci-C6) alkyl-silyl group, e.g. trimethylsilyl, tert-butyl-dimethylsilyl. Preferably a -Cg alkanoyl group, more preferably a C -Ce alkanoyl group, in particular formyl or acetyl, methoxyacetyl, ethyl oxalate, ethylcarbonate. In one embodiment, 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.
1. Hydrolases are in many cases relatively stable enzymes that can be stored as concentrated aqueous solutions or freeze dried powders.
2. Many hydrolases are available in bulk as standard products that already have large applications.
3. The high stability of many hydrolases display activity in water or co=solvent mixtures or even neat organic solvents. Apart form solubility, the enzymes also allow other reactions than the natural reaction, such as lipases convert esters to amides if they are offered ammonia in an anhydrous medium.
According to present invention, 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. saitoi, 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, Alcalase, Savinase Everlase and Esperas,Lipase A.A.niger, Lipas AKP. Fluorescens,DF cone, LipasF-AP15 R.oryzae, LipasG.P.camemberti,Lipase MM.javanicus, LipaseC.rugosa, LipaseAP6, LipaseR.arrhizus, LipaseR niveus, LipasePF, LipaseC.cylindracea, LipaseRM, LipaseHog pancreas, Lipase porcinepancreas, LipaseAlcaligenes(PL), LipaseAlcaligenes(QLM), Lipase C.cylindracea (MY), Lipase C.cylindracea (OF), Lipase B.cepacia(SL), Lipase Ps.stutzeri(TL), Lipase wheat germ, Polarzyml2T, EST-811, EST- 812, EST-813, EST-814, EST-815, EST-816, Estrase BS2, Estrase BS3, Estrase PL, Estrase RM, Estrase RN, Estrase RO, Estrase SD, Estrase TL, Lipase CRL-1, Multifect LI 10L, Multifect LI 12L, Lipase Achromobacter, peptidase Rhizopus, BS Lipase, Acid protease, Neutral protease, Alkaline protease, Bacterial protease.
In another embodiment, 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.
Figure imgf000014_0001
The different proteases that were screened with the licarbazepine methoxy acetate briefed below in Table 2
Figure imgf000014_0002
Figure imgf000015_0001
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. In yet another embodiment, the best protease enzyme identified was Protex 6L.
The different rescreening of active proteases under biphasic conditions were briefed below in Table 3.
Figure imgf000016_0001
Screening of remaining hydrolases on licarbazepine methoxyacetate was carried out but did not yield additional hits of significance. The hydrolases screened are listed in Table 4 below.
Table 4
Figure imgf000017_0001
Figure imgf000018_0001
In yet another embodiment, the 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.
The different hydrolases that were screened with the licarbazepine acetate were briefed below in Table 5.
Figure imgf000018_0002
Screening of remaining hydrolases on licarbazepine acetate was carried out but did not yield additional hits of significance. The hydrolases screened are listed in Table 6 below.
Figure imgf000018_0003
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0002
In yet another embodiment, 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 different hydrolases that were screened with the licarbazepine ethylcarbonate are briefed below in Table 7.
Table 7
Figure imgf000022_0001
According to the present invention, the suitable solvent used in the above given scheme in various steps is selected from Ci-C6 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, chloro benzene, dimethyl formamide, water and mixtures thereof.
In yet another embodiment, 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.
Table 8
Figure imgf000023_0001
In yet another embodiment, under slightly lower temperature, the 2-methyl tetrahydrofuran showed slightly better enantioselectivity than the ethylacetate as shown in Table 9.
Table 9
Figure imgf000023_0002
In yet another embodiment, 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
Figure imgf000024_0001
According to the present invention, a base can be an organic base, for example an alkali metal Cj-C6 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,. 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-C6)alkylamine, e.g. triethylamine or trimethylamine, a tri(Ci-C6)alkanolamine, e.g. triethanolamine, trimethanolamine or tripropanolamine, or diazabicyclooctane or diazabicycloundecene, or mixtures thereof.
According to the present invention, 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. Hence 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%. According to the present invention, 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.
Further, the catalyst used in the process is preferably dimethyl amino pyridine.
As a second parameter, temperature control is considered. The solubility of the substrate and products is very limited; hence temperature control is very important. At high substrate loading, the optimum temperature may well be higher than the optimum temperatures. According to the present invention, 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.
According to the present invention, the enzymatic resolution of licarbazepine is done using the methoxyacetate as best derivative and Protex 6L protease as most efficient enzyme.
The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in any way.
Example 1
Preparation of Licarbazepine methoxyacetate
2.54 g (lOmmol) racemic licarbazepine was suspended in a mixture of 50ml anhydrous dichloromethane and 3 ml pyridine. A trace amount (ca 2Qmg) of dimethylaminopyridine (DMAP) was added. At ambient temperature a solution of 1.2 g methoxy acetyichloride (l lmmol) in 5 ml anhydrous dichloromethane was added dropwise. Stirred the reaction mass and added 0.1 g additional methoxyacetyl chloride, the mixture was stirred for 20 min, and then quenched the reaction mass with water. The organic phase was washed with dilute hydrochloric acid (75 ml), water and saturated sodium bicarbonate solution. The organic phase was extracted and dried on sodium sulfate, evaporated the solvent under reduces pressure to give 3.3 g of colorless foam. Further, added methyl tertiary butyl ether to give solidification. The suspension was filtered and air- dried to give a white solid (3.1g; 95%).
HPLC: 98% purity
Example 2
Preparation of Licarbazepine ethylcarbonate
. 2.54 g (lOmmol) racemic licarbazepine was suspended in a mixture of 75 ml anhydrous dichloromethane and 3 ml pyridine. At ambient temperature a solution of 1 Ag ethylchloro formate (13 mmol) in 5 ml anhydrous dichloromethane was added drop wise. Stirred the reaction mixture for lhr and reaction mixture was quenched with water. The organic phase was washed with sodium hydrogen sulfate solution, water and saturated sodium bicarbonate solution. The organic phase was extracted and dried on sodium sulfate, evaporated the solvent under reduced pressure to give viscous oil. The viscous oil was diluted with diethyl ether to give solidification. The suspension was filtered washed with diethyl ether and dried to give 1.27g white powder (72 %).
Example 3
Preparation of Licarbazepine ethyl oxalate
1.27 g (lOmmol) racemic licarbazepine was suspended in a mixture of 35 ml anhydrous dichloromethane and added 1.5 ml pyridine. At ambient temperature a solution of 1 g of freshly opened ethyl chlorooxalate in 5 ml anhydrous dichloromethane was added drop wise to the above mixture. The reaction mixture was stirred for one hour. The reaction mixture was quenched with water. The organic phase was washed with dilute sodium hydrogen sulfate solution, water and saturated sodium bicarbonate solution. The organic extract was dried on sodium sulfate and evaporated under reduced pressure to give viscous oil. The viscous oil was dissolved with diethyl ether to give solidification. The suspension was filtered, washed with diethyl ether and dried to give desired product.
Example 4
Preparation of Eslicarbazepine via enzymatic hydrolysis
6.52 g racemic licarbazepine methoxyacetate was suspended in a mixture of 30 ml 2-methyltetrahydrofuran and 75 ml 33 mM potassium phosphate buffer pH 7.3. To the mixture was added 1 ml of Protex 6L protease liquid. The tri-phasic mixture was stirred at 30 °C and pH 6.8 while the pH was controlled by automatic addition of 1 M sodium carbonate solution in a pH-stat set-up. The progress of reaction was monitored by HPLC and stopped the reaction after 53 % conversion [substrate 99.85 - 99.99% and 85% ee of the product alcohol]. The triphasic reaction mixture was extracted twice with dichloromethane to isolate the alcohol and ester. The organic phase was washed with saturated sodium chloride solution and dried on sodium sulfate, evaporated the solvent under reduced pressure to give 5.3 g white solid [HPLC: 99.99 % ee of (5)-ester).
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. The clear solution was diluted with 3 volumes of water (total volume ca 300 ml) to precipitate the desired (S)-methoxyacetate ester. A white solid was obtained, however HPLC showed still significant amounts of ester in the filtrate (32 % methoxyacetate and 67 % hemi- succinate). The filtrate was extracted twice with 2-MeTHF and the organic extract mixed with the earlier isolated solid. The combined solution was dried and evaporated to give 2.6 g white solid (40 % overall) of eslicarbazepine.
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.
The purified (S)-licarbazepine methoxy actetate was hydrolyzed using aqueous sodium hydroxide by dissolving in ethanol/2-methyltetrahydrofuran to give Eslicarbazepine. HPLC: 99.6% purity and 99.99% ee.
Example 5
Preparation of Eslicarbazepine acetate
2.54 g (lOmmlo) eslicarbazepine was suspended in 40 ml anhydrous dichloromethane and a trace amount (25 mg) of dimethylaminopyridine (DMAP) was added. At ambient temperature a solution of 0.94 g (12mmoI) acetyl chloride in 5 ml was added drop wise, the mixture was stirred for 30 min, and then quenched the reaction mass with water and the organic phase was washed twice with dilute HCL, water and saturated sodium bicarbonate solution. The organic extract was dried on sodium sulfate, evaporated the solvent under reduced pressure to give 2.93 g (99%) solid of Eslicarbazepine.
HPLC: 99.5% purity and 99.99 % ee.
Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:
1. A process for preparing (S)-(-)-10-acetoxy-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide of formula I
Figure imgf000029_0001
wherein the process comprising:
a) protecting a compound of formula III
Figure imgf000029_0002
with a protecting group (PG) in the presence of a solvent to give a compound of formula IV,
Figure imgf000029_0003
wherein the PG group is selected from methoxyacetyl, ethyl oxalate or ethyl carbonate;
b) hydrolyzing the compound of formula IV employing an enzyme to obtain a mixture of compound of formula V and formula VI;
Figure imgf000029_0004
c) 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
Figure imgf000030_0001
wherein R is HO-CO-CH2-CO- , HO-CO-C¾-CH2-CO- , HO-CO-CH2-CH2-CH2-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 II;
Figure imgf000030_0002
e) esterifying the (S)-(-)-10, 1 l-dihydro-5H-dibenz[b,fjazepine-5- carboxamide of formula II to obtain the (S)-(-)-10-acetoxy-10, l l-dihydro-5H~ dibenz[b,f)azepine-5-carboxamide of formula I.
2. The process according to claim 1, wherein the protecting group is selected from methoxyacetyl, ethyl oxalate, acetate or ethylcarbonate.
3. The process according to claim 1, wherein the enzyme is selected from hydrolases.
4. The process according to claim 3, wherein the enzyme is selected from a protease.
5. The process according to claim 4, wherein the enzyme is selected from NZLlOl, NZL102, NZL103, NZL104, NZL105, NZL106, NZL107, NZL108, NZL109, NZPlOl, NZP102, NZP103, NZP104, NZP106, Protease Alcalase,Protease Savinase, Protease Everlase, Protease Neutrase, ProteaseB.amyloliquifaciens, ProteaseA.oryzae, Protease N, ProteaseA.melleus, ProteaseA.saitoi, 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, LipexlOO, NZ51032, Resinase, Lecitase Ultra, Alcalase, Savinase Everlase and Esperas, Lipase A.A.niger, Lipas AKP. Fluorescens,DF cone, LipasF-AP15 R.oryzae, LipasG.P.camemberti,Lipase MM.javanicus, LipaseC.rugosa, LipaseAP6, LipaseR.arrhizus, LipaseR niveus, LipasePF, LipaseC.cylindracea, LipaseRM, LipaseHog pancreas, Lipase porcinepancreas, LipaseAlcaligenes(PL), LipaseAlcaligenes(QLM), Lipase C.cylindracea (MY), Lipase C.cylindracea (OF), Lipase B.cepacia(SL), Lipase Ps.stutzeri(TL), Lipase wheat germ, Polarzyml2T, EST-811, EST-812, EST-813, EST-814, EST-815, EST-816, Estrase BS2, Estrase BS3, Estrase PL, Estrase RM, Estrase RN, Estrase RO, Estrase SD, Estrase TL, Lipase CRL-1, Multifect LI 10L, Multifect LI 12L, Lipase Achromobacter, peptidase Rhizopus, BS Lipase, Acid protease, Neutral protease, Alkaline protease or Bacterial protease
6. The process according to claim 4, wherein the enzyme is Protex 6L protease.
7. The process according to claim 1, wherein the step of hydrolyzing the compound of formula IV is carried out in the presence of a catalyst and a base and wherein said hydrolysis is performed with or without employing a buffer/co solvent or mixture of buffer/co solvent.
8. The process according to claim 7, wherein the catalyst is dimethyl amino pyridine.
9. The process according to claim 1 or 7, wherein the base is selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate.
10. The process according to claim 7, wherein the buffer, co-solvent or mixture of buffer/co solvent is used s about 5 to 60%.
1 1. The process according to claim 10, wherein the buffer employed is selected from a group consisting of sodium phosphate buffer, potassium phosphate buffer, tris(hydroxymethyl)aminomethane or mixtures thereof.
12. The process according to claim 11, wherein the buffer used is in the range of about 10 to 500 mmoles.
13. The process according to claim 1, wherein the hydrolyzing the compound of formula IV is carried out at a controlled pH.
14. The process according to claim 13, wherein the pH is varies between 4 to 8.
15. The process according to claim 1, wherein the hydrolyzing the compound of formula IV is performed at a temperature from about 25° C to 40° C.
16. The process according to claim 1, wherein the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride.
17. A process for separation of compounds of formula V and VI from a mixture containing the same,
Figure imgf000032_0001
wherein the process comprising:
a) treating the mixture of the compound of formula V and formula VI with an acid anhydride in the presence of a catalyst, base and a solvent to obtain a mixture of compound of formula V and formula VII
Figure imgf000032_0002
wherein R is HO-CO-CH2-CO- , HO-CO-CH2-CH2-CO- , HO-CO-CH2-CH2-CH2-CO-, or the like; and b) hydrolyzing the resultant compound of formula VII in presence of a solvent to obtain a corresponding alcohol.
18. The process according to claim 17, wherein the acid anhydride is selected from a group consisting of malonic anhydride, succinic anhydride, glutaric anhydride or aspartic anhydride.
19. The process according to claim 17, wherein the base is selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate.
20. The process according to claim 17, wherein the catalyst is dimethyl amino pyridine.
21. The process according to claim 17, wherein the solvents employed are selected from 2-methyl tetrahydrofuran, toluene, hexane, heptane, esters, chlorinated solvents, ethers, ketones or mixture thereof.
22. The process according to claim 21, wherein the solvents are ethylacetate, isopropyl acetate, dichloromethane, chlorobenzene, methyl tertirarybutyl ether, diisopropyl ether, dimethyl formamide, tetrahydrofuran, acetone, propanone, water or mixture thereof.
23. A (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide prepared by a process according to claim 1, wherein the (S )-(-)- 10-acetoxy- 10, 11 -dihydro- 5H-dibenz[b,f]azepine-5-carboxamide is characterized by having enantiomeric purity greater than about 99%.
24. The (S)-(-)-l 0-acetoxy- 10,11 -dihydro-5H-dibenz[b,f]azepine-5- carboxamide according to claim 23, wherein the enantiomeric purity is greater than about 99.99%.
25. Intermediate of formula VII for producing (S)-(-)-10-acetoxy-10,l l- dihydro-5H-dibenz[b,f]azepine-5-carboxamide,
Figure imgf000033_0001
whererin R is HO-CO-C¾-CO- , HO-CO-CH2-CH2-CO- , HO-CO-CH2-CH2-CH2-
CO-, or the like.
26. Intermediates of formula IV for producing (S)-(-)-10-acetoxy-10,l l- dihydro-5H-dibenz[b,f]azepine-5-carboxamide
Figure imgf000034_0001
wherein the PG is selected from methoxyacetyl, ethyl oxalate or ethyl carbonate.
27. A compound (S)-(-)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5 carboxamide of formula I having enantiomeric purity greater than about 99%
Figure imgf000034_0002
28. The compound according to claim 27, wherein the enantiomeric purity greater than about 99.99%.
PCT/IB2010/002574 2009-10-12 2010-10-11 Process for preparing (s)-(-)-10-acetoxy-10,11-dihydro-5h-dibenz[b,f]azepine-5-carboxamide and its esters thereof WO2011045648A2 (en)

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