WO2011117885A1

WO2011117885A1 - Process for preparation of enantiomers of licarbazepine

Info

Publication number: WO2011117885A1
Application number: PCT/IN2011/000190
Authority: WO
Inventors: Sanjay Jagdish Desai; Ashesh Kamalnayan Pandya; Sachin Panditrao Sawant; Krunalkumar Ramanlal Mehariya
Original assignee: Intas Pharmaceuticals Limited
Priority date: 2010-03-23
Filing date: 2011-03-22
Publication date: 2011-09-29

Abstract

The present invention provides a process for the preparation of eslicarbazepine and rlicarbazepine and their acetates by resolution of racemic licarbazepine using acetyl mandelic acid.

Description

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation of eslicarbazepine acetate or rlicarbazepine acetate.

BACKGROUND OF THE INVENTION

Carbamazepine (I) and its 10-keto analogue oxcarbazepine (II) are first-line established drugs used in the treatment of epilepsy.

After administration in humans, 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.

Benes, J. et al., J. Med. Chem., 42, 2582-2587 (1999) and Volosov A. et. al., Epilepsia, 41(9), 1107-1111 (2000) discloses resolution of racemic 10,1 l -dihydro-10-hydroxy-5H- dibenz[b,f]azepine-5-carboxamide (also known as (±)-MHD) into its separate optically pure stereoisomers i.e. (S)-(-)-10-acetoxy- 10,11 -dihydro-5H-dibehz[b,f]azepine-5- carboxamide, also known as ((S))-(-)-MHD, and (R)-(+)-10-acetoxy-10, l 1 -dihydro-5H- dibenz[b,f]azepine-5-carboxamide (R)-(+)-MHD). These methods involve the formation of diastereomeric methoxyacetoacetate ester derivatives of (±) MHD, by taking advantage of the different solubility of these diasteromeric esters, separation is possible by fractional crystallisation and subsequent hydrolysis affords the individually pure stereo isomers, (S)-(-)-MHD and (R)-(+)-MHD. However, this method was utilized for the preparation of only small quantities of each stereoisomer and is not suitable for industrial production. The optically pure resolving agents (+) and (-)-methoxyacetic acid are expensive and are not readily available in commercially required quantity.

Furthermore these methoxyacetic acid require 'activation' in order to react with (±)- MHD. This activation is normally achieved via conversion of the free acids to the acid chlorides, an extra synthetic step which requires the use of thionyl chloride or oxalyl chloride, also leads to formation of undesired impurities. A further limitation of above method is relatively low yield obtained of the optically pure methoxyacetate ester which is isolated after crystallisation; it yields usually only marginally 20%. 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.

Thus, there is still need in the art for an improved process to prepare eslicarbazepine and rlicarbazepine acetate while using inexpensive and readily available reagents.

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.

OBJECTS OF THE INVENTION

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.

SUMMARY OF THE INVENTION

In one general aspect the present invention comprises preparation of eslicarbazepine acetate (XII) or rlicarbazepine acetate (XIII). In an aspect 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

In another aspect the process comprises preparing eslicarbazepine and rlicarbazepine acetate by using acetic acid as acetylating agent.

DETAILED DESCRIPTION

Accordingly there is provided a process to prepare eslicarbazepine or rlicarbazepine using optically active acetyl mandelic acid comprising the steps of:

1. 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]

2. The mixture of 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 is summarized in the following scheme:

Scheme 1

In an embodiment, 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. Preferably dicyclohexylcarbodiimide is used for the purpose of present process.

The reaction is advantageously carried out in presence of nucleophilic catalyst which can be selected from a group 1-hydroxybenzotriazole, 4-dimethylaminopyridine also known as Ν,Ν-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.

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. 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.

Once the reaction is complete the 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.

From the organic layer collected after acid-base treatment desired diastereomers are separated by treating with solvent. Thus, 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.

Preferably 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 characteristics details of compound of formula (VIII) are given below:

1H-NMR (DMSO-d6, 400MHz, 8ppm) 2.12 (s,3H), 7.062-7.44( m,13 Ar-H), 6.33 (s,lH),

5.89 (s, 2H), 3.33 9 (d, 2H, J=14.4Hz), 6.4 (s,lH).

IR 1739.8 cm-1, 1681.93cm- 1 ; Mass 431.45 (m+1)

The ester (VIII) can be hydrolysed to give desired isomer of licarbazepine i.e. eslicarbazepine.

In another embodiment 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.

In another embodiment present invention provides -process for acetylation of eslicarbazepine and rlicarbazepine. The process can be summarized as following:

Rlicarbazepine Rlicarbazepine acetate

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.

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. After completion of reaction 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. After acid-base treatment the reaction mixture is concentrated and the residue is purified from organic solvent. 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.

The use of 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.

The starting material, Licarbazepine can be prepared by following the process mentioned in US 3,637,661 or according to the process of US 7,119,197.

In the following section embodiments are described by a way of examples to illustrate the process of. invention. However, these are not intended in any way to limit the scope of present invention. Several variants of these examples would be evident to present person ordinarily skilled in the art.

Experimental Details:

Chiral HPLC method for identification of diastereomers:

Column Chiral Cel-OD-H(250x4.6mm, 5μ) Make: ,

Detector UV at 2 lOnm

Flow Rate 1.Oml/minute

Injection volume 5.0μ1

Column temp 25°C

Sample Cone. 1.Omg/ml

Mobile Phase n-hexane:Isopropanol (70:30)

Diluent Mobile Phase

Specific optical rotation: 20[a]D(c = 1, pyridine) Examples

Example 1 - Preparation of (10S)-10-[(2R)-(acetyIoxy)(phenyl)ethanoate]-10,ll- dihydro-5H-dibenzo[b,f] azepine -5-carboxamide (VIII)

Dichloromethane 2160 ml, 164.96 g (R)-(-)-acetyl mandelic acid, 180 g racemic licarbazepine, 86.48 g 4-dimethylamino pyrimidine and 175.28g dicyclohexylcarbodiimide were mixed in a round bottom flask and the resultant reaction mixture was refluxed for one hour. After completion of reaction the reaction mixture was filtered and the filtrate was -washed with aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was collected and it was concentrated. To the residue thus obtained 1620ml of methyl isobutylketone was added. 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.

Example 2 - Preparation of (10S)-10-hydroxy-10,ll-dihydro-5H-dibenzo [b,f]azepine-5-carboxamide [Eslicarbazepine(X)]

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.

Example 3 - Preparation of (10S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo

[b,f]azepin-10yl-acetate [esclicarbazepine acetate, (XII)]

240 ml dichloromethane, 5.29 g, acetic acid, 20 g esclicarbazepine, 9.6 g 4- dimethylamino pyridine and 19.47 g dicyclohexylcarbodiimide were charged in a round bottom flask. The reaction mixture was refluxed for 1 hour, after completion of reaction the reaction mixture was filtered, and the filtrate was washed with aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was separated and it was concentrated, to the residue thus obtained isopropyl alcohol (140 ml) was added. The resultant mixture was heated to reflux for 30 minutes followed by cooling to 25 - 30 °C. The product thus separated and filtered to obtain 17g of title compound with 99.6% optical purity.

Example 4 - Preparation of (10R)-10-[(2S)-(acetyIoxy)(phenyl)ethanoate]-10,ll- dihydro-5H-dibenzo[b,f]azepine-5-carboxamide (VII )

Dichloromethane 4800 ml, 366.57 g (S)-(+)-acetyl mandelic acid, 400 g racemic licarbazepine, 192.2 g 4-dimethylaminopyrimidine and 389.51 g

dicyclohexylcarbodiimide were mixed in a round bottom flask and the resultant reaction mixture was refluxed for one hour. After completion of reaction the reaction mixture was filtered and the filtrate was washed with aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was collected and it was. concentrated. To the residue thus obtained 3600 ml of methyl isobutylketone was added. 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 methylisobutylketone at 60 - 65 °C to get title compound with 97.5 % of optical purity.

Example 5 - Preparation of (10R)-10-hydroxy-10,ll-dihydro-5H-dibenzo [b,f]azepine-5-carboxamide [Rlicarbazepine(XI)]

1415 ml water, 283 g compound obtained form example 4 and 283 g sodium hydroxide were added. 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 148.5 g of title compound. Example 6 - Preparation of (10R)-5-carbamoyl-10,ll-dihydro-5H-dibenzo [b,f]azepin-10yl-acetate (Rlicarbazepine acetate, (XIII) )

1764 ml dichloromethane, 38.89 g, acetic acid, 147 g rlicarbazepine, 70.63 g 4- dimethylamino pyridine and 143.14 g dicyclohexylcarbodiimide were charged in a round bottom flask. The reaction mixture was refluxed for 1 hour, after completion of reaction the reaction mixture was filtered, and the filtrate was washed with aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was separated and it was concentrated, to the residue thus obtained isopropyl alcohol (1029 ml) was added. The resultant mixture was heated to reflux for 30 minutes followed by cooling to 25 - 30 °C. The product thus separated was filtered to obtain 123g of- title compound with 99_^8% optical purity.

Claims

Claims:

1. A process for the preparation of enantiomers of licarbazepine comprising: a. reacting racemic licarbazepine with (R)-(-)-acetyl mandelic acid or S- (+)-acetyl mandelic acid to obtain esters of formula (VIII ) and (IX) or esters of formula (VI) and (VII) respectively b. separating the desired ester obtained in step a); c. hydrolysing the ester obtained in step b) to eslicarbazepine or rlicarbazepine; d. optionally acetylating to obtain eslicarbazepine or rlicarbazepine respectively

2. The process as claimed in claim 1 , wherein the esterification step a) is conducted in a solvent and in the presence of a coupling agent or a nucleophilic catalyst.

3. The process as claimed in claim 1, wherein the separation step b) comprises treating mixture of esters with a solvent.

4. The process as claimed inxlaim 3, wherein solvent is selected from ketone.

5. The process as claimed in claim 4, wherein ketone is selected from acetone, methylethylketone, methylisobutylketone.

6. The process as claimed in claim 1, wherein hydrolysis is conducted in the presence of a base.

7. The compounds of formulae (VI ), (VII), (VIII) and (IX)

8. A process for preparation of eslicarbazepine acetate or rlicarbazepine acetate comprising acetylating eslicarbazepine or rlicarbazepine with acetic acid.

9. The process as claimed in claim 8, wherein the acetylation is conducted in a solvent and in the presence of a coupling agent or a nucleophilic catalyst.

10. The process as claimed in claim 2 or claim 9, wherein the coupling agent is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, l-ethy-3-(3- dimethylaminopropyl)carbodiimide or carbonyldiimidazole.

11. The process as claimed in claim 2 or claim 9, wherein the nucleophilic catalyst is selected from 4-dimethylaminopyridine or 1-hydroxybenzotriazole.

12. The process as claimed in claim 2 or claim 9, wherein solvent is selected from a group comprising of chlorinated solvents, ethers or mixture thereof.

13. The process as claimed in claim 12, wherein solvent is selected from dichloromethane, dichloroethane, chloroform, tetrahydrofuran, diethyl ether, diisopropyl ether or mixture thereof.