Field of the invention

The present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate.

Background of the Invention

Licarbazepine represented by formula I, is indicated to be suitable for the treatment of psychosomatic disturbances, epilepsy, trigeminal neuralgia and cerebral spasticity. It was demonstrated that the racemate of licarbazepine and both of its pure enantiomers are of equal efficacy against epilepsy

US application 20080139807 disclosed the process for the Preparation Of 10,11-Dihydro-10-Hydroxy-5H-Dibenz/B,F/Azepine-5-Carboxamide

US application 20080293934 disclosed the method for chiral Inversion of
(S)-(+)-and (RH-)-10,11-Dihydro-10-Hydroxy-5H-Dibenz/B,F/Azepine-6-
Carboxamide and Optically Enriched Mixtures Thereof

Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11dihydro-SH-
dibenz/b,f/azepine-5-carboxamlde ("BIA 2-093"). is a new drug currently being developed which is useful for the treatment of various conditions, such as. for example, epilepsy and affective brain disorders, as well as pain conditions and nervous function alterations in degenerative and post-ischemic diseases. Although chemically related to carbamazepine and oxcarbazepine, eslicarbazepine acetate is believed to avoid the production of certain toxic metabolites (such as, for example, epoxides) and to avoid the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity. See Benes et al., "Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-diben2[b,f]azepine-5-carboxamlde Derivatives," J. Med. Chem., 42, 2582-2587 (1999).

US applications 20060252746 and US 20060252745, disclosed the process for preparing pharmaceutical compositions comprising eslicarbazepine acetate and their methods of use

All the processes described in the prior art are long and involve chiral agents for resolution which may not be feasible at industrial level. Thus there is a need in the art for an improved process for preparing eslicarbazepine acetate which is cost effective and easy to make at industrial level.

Object and Summary of the Invention

The present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate,

In one aspect, the present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate, wherein the enzyme is selected from lipases.

Detail Description of the Invention

The invention provides an economically "green chemistry" process, which avoids the use of potentially harmful reagents.

The present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate.

In one embodiment the present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate wherein the enzyme is selected from lipases.

In another embodiment the present invention relates to an enzymatic process for the preparation of eslicarbazepine acetate as summarized in scheme 1

Racemic licarbazepine is acylated using suitable acylating agents such as vinyl acetate or isopropenyl acetate in the presence of suitable enzymes selected from lipases such as Candida antarctica lipase A (CAL-A) and suitable organic solvent such as chloroform to afford eslicarbazepine acetate.

The enzyme used in the present invention is selected from Lipozymes, Porcine Pancreatic Lipase, Candida antarctica lipase A (CAL-A), lyophilized Candida lipolytica Lipase, Geotrichum candidum Lipase, Pseudomonas aroginosa Lipase, Aspergillus niger Lipase. Pseudomonas cepacia Lipase, Pseudomonas fluorescens Lipase, Candida rugosa Lipase, Rhizopus delemar Lipase, Rhizopus oryzae Lipase, Penicillium camembertii Lipase, Mucor javanicus Lipase, Penicillium roqueforti Lipase, Candida antarctica lipase B (CAL-B), lyophilized microbial, Lipase, Thermomyces sp. Lipase, Alcallglnes sp., Chromobacterium viscosum Lipase, Candida utilis Lipase, Rhizopus niveus Lipase, Pseudomonas sp., Lipoprotein Lipase, Tfiermomuces ianuginosus Lipase, Rtiizomucor miehei Lipase, Wheat Germ Lipase, Rfiizopus arrfiizus Lipase, Pancreatic Lipase 250, Novozyme-435 and the like

The acylating agents that can be used in the present invention are selected from vinyl acetate and Isopropenyl acetate and the like.

The suitable organic solvents that can be used in the present invention are selected from chlorinated solvents such as chloroform, dichloromethane, dichloroethane, trlchloroethane and the like, hydrocarbons such as propane, butane, pentane n-hexane, n-heptane and the like, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone and the like or mixtures thereof.

The reaction temperature for the process of the present invention is in the range selected from 30 to 60° C.

The advantage of the present invention is that the enzyme used in the present invention can be reused thus makes the invention cost effective.
Experimental Example

To a suspension of rac-Licarbazepine (1 gram, 3.94mM) in dry chloroform (40 ml), was added vinyl acetate/isopropenyl acetate (4ml/10ml). To the reaction mixture was added Candida antarctica lipase A (0.5 g) and the resulting mixture was shaken at 55 °C and 200 rpm. The course of the reaction was followed by HPLC till conversion was around 45%. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent gradient 4-5% MeOH/dichloroform) to give esNcarbazepine acetate for ee 95 to 98% and (R)-ticarbazepine for ee 70 to 80 %.

We claim

1. An enzymatic process for the preparation of Eslicarbazepine acetate
comprising the steps of:

a) Suspending rec-Licabazepine in solvent,

b) adding acylating reagent and an enzyme

c) removing the solvent and

d) isolating Eslicarbazepine acetate.

2. An enzymatic process for the preparation of Eslicarbazepine acetate
comprising the steps of:

a) dissolving rec-Licabazepine in solvent,

b) adding acylating reagent and an enzyme

c) removing the solvent and

d) isolating Eslicarbazepine acetate.

3. The process according to claim 1or 2, wherein the solvent is selected from chlorinated solvents selected from chloroform, dichloromethane, dichloroethane, trichloroethane, hydrocarbons selected from propane, butane, pentane n-hexane, n-heptane , ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone or a mixture thereof.

4. The process according to claim 1 or 2, wherein the acylating reagent is selected from vinyl acetate or isopropenyi acetate.

5. The process according to claim 1or 2, wherein the enzyme is selected from Lipozymes, Porcine Pancreatic Lipase, Candida antarctica lipase A (CAL-A), lyophilized Candida lipolytica Lipase, Geotrichum candidum Lipase, Pseudomonas aroginosa Lipase, Aspergillus niger Lipase, Pseudomonas cepacia Lipase, Pseudomonas fluorescens Lipase, Candida rugosa Lipase, Rhizopus delemar Lipase, Rhizopus oryzae Lipase, Penicillium camembertii Lipase, Mucor javanicus Lipase, Penicilllum roqueforti Lipase, Candida antarctica lipase B (CAL-B), lyophilized microbial, Lipase, Thermomyces sp. Lipase, Alcaligines sp., Chromobacterium viscosum Lipase, Candida utilis Lipase, Rhizopus niveus Lipase, Pseudomonas sp., Lipoprotein Lipase, Thermomuces lanuginosus Lipase, Rhizomucor miehei Lipase, Wheat Germ Lipase, Rhizopus arrhizus Lipase, Pancreatic Lipase 250, Novozyme-435.

6. The process according to claim 1or 2, wherein the enzyme is selected from Candida antarctica lipase A.

7. The process according to claim 1 or 2, wherein the solvent is removed using techniques such as distillation under reduced pressure.

8. The process according to claim 1 or 2, wherein the reaction temperature is In the range selected from 30 to 60°C,

9. The process according to claim 1 or 2, wherein the isolated Eslicarbazepine acetate is purified by using chromatography techniques.

10. The process according to claim for 2, wherein Eslicarbazeplne acetate having enantiomer excess purity of more than 95 %.