WO2015004686A2

WO2015004686A2 - A process for purification of efavirenz and intermediates thereof using chromatographic methods

Info

Publication number: WO2015004686A2
Application number: PCT/IN2014/000463
Authority: WO
Inventors: Satyanarayana Chava; Venkata Lakshmi Narasimha Rao Dammalapati; Venkata Siva Ramakrishna Reddy KALLAM; Lakshmi Narayana Chennuru; Thirupathi CHOPPARI
Original assignee: Laurus Labs Private Limited
Priority date: 2013-07-11
Filing date: 2014-07-11
Publication date: 2015-01-15
Also published as: WO2015004686A3

Abstract

The present invention relates to a process for the enantiomeric enrichment of efavirenz using chromatographic methods such as simulated moving bed chromatography and/or batch elution chromatography method.

Description

"A PROCESS FOR PURIFICATION OF EFAVIRENZ AND INTERMEDIATES THEREOF USING CHROMATOGRAPHIC METHODS"

PRIORITY:

This application claims the benefit under Indian Provisional Application No. 3101/CHE/2013, filed July 11, 2013, the content of each of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a process for enantiomeric enrichment of Efavirenz and intermediates thereof using chromatographic methods without requiring cumbersome resolution agents to separate isomers.

BACKGROUND OF THE INVENTION

Efavirenz chemically known as (S)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1, 4-dihydro-2H-3,l-benzoxazin-2-one of Formula I, is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI).

H

Formula I

Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease of the immune system transmitted through blood especially by sexual contact or contaminated needles and is presumed to be caused by the human immunodeficiency virus (HIV), which is an RNA genetically unique retrovirus, having a gene not found to date in other retroviruses.

A number of compounds are effective in the treatment of the HIV which is the retrovirus that causes progressive destruction of the human immune system. Effective treatment through inhibition of HIV reverse transcriptase is known for non- nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase.

Efavirenz is efficacious against HIV reverse transcriptase resistance. Due to the importance of efavirenz, an economical and efficient process for its production needs to be developed. Efavirenz has one asymmetric center and exist as two optical isomers (S-enantiomer and R-enantiomer). The S-enantiomer of efavirenz is the active compound and is marketed under the brand name Sustiva™.

U.S. Patent No. 5,519,021 ("the '021 patent") discloses certain benzoxazinones including efavirenz, useful in the inhibition of HIV reverse transciptase (including its resistant varieties). The '021 patent further discloses a process for the preparation of efavirenz by cyclisation of racemic mixture of 2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol using Ι,Γ-carbonyldiimidazole as carbonyl delivering agent to give racemic efavirenz. Further, resolution of the racemic efavirenz is carried out using (-) camphanic acid chloride to yield optically pure Efavirenz. The process disclosed is schematically represented as follows:

Efavirenz (Racemic) Efavirenz (S-enantiomer)

U.S. Patent No. 5,633,405 ("the '405 patent") discloses an asymmetric process for preparing efavirenz by reacting trifluoromethyl ketone with cyclopropyl acetylene in presence of alkyl lithium base and a chiral moderator, followed by cyclization of the resulting chiral amino alcohol. The process disclosed is schematically represented as follows:

U.S. Patent No. 6,015,926 ("the '926 patent") discloses an asymmetric process for preparing efavirenz by reacting trifluoromethyl ketone with magnesium cyclopropyl acetylide in presence of dialkyl zinc, an alcohol and a chiral moderator, followed by cyclization of the resulting chiral amino alcohol. The process disclosed is schematically represented as follows:

U.S. Patent Application No. 2010/286408 (the "408 application") discloses an asymmetric process for preparing efavirenz by reacting trifluoromethyl ketone with magnesium cyclopropyl acetylide in presence of zinc salt, an alcohol and a chiral moderator, followed by cyclization of the resulting chiral amino alcohol.

The processes for preparation of efavirenz via separation of desired (S)-enantiomer using chiral mediated asymmetric synthetic processes described in the above literature have certain drawbacks as it involves: a) use of expensive chiral moderator compounds, b) harsh reaction conditions for example use of strong bases such as lithium alkyl c) use of explosive dialkyl zinc and/or d) reaction at very strict conditions (at -20°C).

Various processes have been reported for purification of 2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol (amino alcohol) for enrichment of isomers, for example U.S. Patent Application No. 2012/264933 discloses purification of amino alcohol using aromatic hydrocarbon solvent.

Despite all prior advances, available methods for separating desired enantiomer for the preparation of efavirenz remain labor intensive, time consuming and environmentally unfavorable. Thus, there remains a need for a simple and scalable process for the separation of enantiomers of efavirenz that would avoid the aforementioned difficulties.

The present invention provides a process for separating the enantiomers of efavirenz and its intermediates thereof using chromatographic methods, particularly using simulated moving bed chromatography and/or batch elution chromatography methods such as Preparative chiral column chromatography (Preparative HPLC), Flash chromatography and the like, without requiring cumbersome resolution agents. The process of the present invention can be practiced on industrial scale, and also can be carried out without sacrifice of overall yield.

Simulated Moving Bed (SMB) chromatography is a large scale industrial chromatography purification system, which involves a separation tower divided into a number of individual separation beds. These beds are connected in series, and the outlet at the bottom most bed is connected to a pump that returned flow in a continuous loop to the upper most bed. The inlet apparatus for each bed has a port connected to a downward flowing conduit. The conduits terminate in fittings attached to a rotary valve designed to control both ingress and egress of liquids into or from the inlets to each individual bed. The system is called Simulated Moving Bed (SMB) chromatography because the beds appear to be moving in a direction countercurrent to the direction of flow. There are hundreds, if not thousands of adsorbents which have been used for simulated moving bed systems, some of which include resins, zeolites, alumina, and silica. Simulated Moving Bed (SMB) technology represents a variation on the principles of high performance liquid chromatography. SMB can be used to separate particles and/or chemical compounds that would be difficult or impossible to separate by any other means. Furthermore, SMB technology in combination of Varicol™ represents a continuous process which provides a significant economic and efficiency advantages in manufacturing operations compared to other separation methods including crystallization and other chromatographic separations.

Batch elution chromatography methods commonly referred to as stepwise chromatographic separations, which include Preparative HPLC, Flash chromatography and the like. Preparative HPLC and Flash chromatography are used to purify sufficient quantities of a mixture of components by separating the each individual component for further use, rather than analysis (and is thus a form of purification).

It is the objective of the invention to replace the current chemical purification steps of resolution of the racemic compounds, crystallization and isolation with a chromatographic purification process employing simulated moving bed technology and/or batch elution chromatography methods.

SUMMARY OF THE INVENTION Surprisingly, a process for the enantiomeric enrichment of (R) and (S) enantiomeric mixtures of Efavirenz to pure (S)-enantiomer of Efavirenz is carried out by chromatographic techniques such as simulated moving bed chromatography (SMB technology in combination of Varicol™) and/or batch elution chromatography methods without employing chemical separation steps. The chromatographic methods of the present invention replace the batch process of a series of chemical purification steps, with chromatographic separation process to produce a high yield of acceptable pharmaceutical grade Efavirenz. Further advantages include, less handling loss than batch processing methods as described in the art. The term "enantiomeric enrichment" is to be understood in the context of the invention in that a starting mixture, which contains the two enantiomers of efavirenz, (S)- and (R)-efavirenz, is separated in such a manner that after the separation the enantiomers are present in higher optical purity than before separation. The present invention encompasses a process for purification of crude efavirenz and intermediates thereof from its isomerically impure compound with high product yield and quality, wherein the purification comprise use of chromatographic purification techniques, particularly use of simulated moving bed chromatography and/or batch elution chromatography methods, without requiring cumbersome resolution agents to separate isomers, thereby process more convenient and economical, particularly on commercial scale.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a process for enantiomeric enrichment of efavirenz, comprising the steps of:

a) subjecting enantiomeric mixtures of Efavirenz to chromatography, and b) separating the (S)-enantiomer enriched Efavirenz.

In a second embodiment, the present invention provides a process for enantiomeric enrichment of efavirenz, comprising the steps of:

wherein the chromatography is simulated moving bed chromatography or batch elution chromatography method such as Preparative column chromatography or Flash chromatography.

In a third embodiment, the present invention provides a process for enantiomeric enrichment of efavirenz, comprising the steps of:

a) subjecting a mixture of (S) and (R) enantiomers of Efavirenz to chromatography, and

b) separating the (S)-enantiomer enriched Efavirenz. In a fourth embodiment, the present invention provides a process for (S) enantiomer enriched efavirenz, comprising the steps of:

a) subjecting a mixture of (S) and (R) enantiomers of Efavirenz to simulated moving bed chromatography, and

b) separating the (S)-enantiomer enriched Efavirenz.

In a fifth embodiment, the present invention provides a process for enantiomeric enrichment of efavirenz, comprising the steps of:

a) subjecting a mixture of (S) and (R) enantiomers of Efavirenz to simulated moving bed chromatography employing a chiral stationary phase, and b) separating the (S)-enantiomer enriched Efavirenz.

wherein the chiral stationary phase contain a derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates or optically active network polymers.

In a sixth embodiment, the present invention provides a process for enantiomeric enrichment of Efavirenz, comprising the steps of:

a) subjecting a mixture of (S) and (R) enantiomers of Efavirenz to Preparative column chromatography, and b) separating the (S)-enantiomer enriched Efavirenz.

In a seventh embodiment, the present invention provides a process for enantiomeric enrichment of efavirenz, comprising the steps of:

a) subjecting a mixture of (S) and (R) enantiomers of Efavirenz to Flash chromatography, and

b) separating the (S)-enantiomer enriched Efavirenz.

For the process according to the invention, there is preferably employed a starting mixture which contains the enantiomers in a range of about 99.7:0.3 to about 0.3:99.7 and preferably about 95:5 to about 5:95. More preferably, the starting mixture contains 97:3 of S & R enantiomers of efavirenz.

Efavirenz can advantageously be obtained according to any known process, for example US 5,519,021. It has surprisingly been found that the enantiomeric separation according to the invention can also be carried out in the presence of by-products, if any formed during the formation of racemic efavirenz.

In simulated moving bed (SMB) chromatography, in general a stream of liquid moving in one direction and optionally circulating is produced in an SMB unit by means of two or more segments connected to one another, each segment having at least one column filled with a chiral stationary phase and being provided in the flow direction at least with a liquid inlet and a liquid outlet and each segment having at least one inlet, via which a feed stream or an eluting agent can be fed to the optionally circulating stream of liquid, and furthermore having at least one outlet, via which solutions of the more weakly adsorbing compound (raffinate) or solutions of the more strongly adsorbing compound (extract) can be removed from the optionally circulating stream of liquid.

During operation of the SMB unit, the inlets and outlets are periodically, but not necessarily simultaneously, connected further in the direction of the flow of liquid, for example, via valves such as, for example, individual valves, multiway valves, valve blocks, flaps or rotation valves, such that apparently a countercurrent movement of the stream of liquid and stationary phase results. In certain cases, it can be advantageous to connect the individual segments of the abovementioned device one after the other, not in an endless sequence (closed circulation), but in a series of individual segments having an inlet at the beginning of the segment series and an outlet at the end of the segment series. In this case, an open circulation is referred to. Here, a part flow or the entire flow of the fluid, which is obtained via the outlet of the segment series, can be recirculated to the inlet of the segment series directly or after suitable treatment. Advantageous treatment methods are, for example, intermediate storage, testing, distillation, removal of components by means of membrane processes, mixing, temperature-controlling and others. In an embodiment of the invention, the operation of an SMB unit as a closed circulation (with a circulating stream of liquid) is preferred.

In another embodiment of the invention, it is advantageous to employ a column number from 4 to 24, preferably 5 to 12 and more preferably 6 to 10.

Suitable chiral stationary phases are in particular those which contain the derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates or optically active network polymers and which are optionally and preferably applied to a support material.

Suitable support materials are, for example, inorganic or organic support materials. For use in the process according to the invention, inorganic support materials are preferred.

Organic support materials are, for example, polymers such as polystyrenes, polyacrylic acid derivatives or their copolymers.

Inorganic support materials are, for example, silicon compounds such as silica, silica gels and silicic acids, silicates such as zeolites, aluminium compounds such as alumina, aluminium oxides, aluminates, titanium compounds such as titanium dioxides and titanates, magnesium compounds such as magnesia, riglasses, kaolin or apatites such as, in particular, hydroxyapatite. Some of the support materials mentioned can occur in various modifications, which are likewise included.

Silica gels are particularly preferred as support materials.

The particles of the support material advantageously have an average diameter (based on the particle size) of 5μπι to 500mm, preferably ΙΟμπι to 100 μπι, more preferably 20 μπι.

Preferred derivatives of polysaccharides are those which are derived from natural or synthetic glucans, mannans, galactans, fructans, xylans or chitosans.

Preferably, derivatives of those polysaccharides are employed, which are derived from polysaccharides which have a regular mode of bonding in the chain. These are, for example, p-l,3-glucans such as in particular curdlan and schizophyllan, P-l,4-glucans such as in particular cellulose, β-Ι,ό-glucans such as in particular pustulan, β-1,2- glucans such as in particular crown gall polysaccharides, a-l,3-glucans, a-l,4-glucans such as in particular amylose and amylopectin or starches, a-l,6-glucans such as in particular dextrans and cyclodextrans, a a-l,6-mannans, P-l,4-mannans, β-1,4- galactans, P-l,2-fructans such as in particular inulin, P-2,6-fructans such as in particular levan, -l,3-xylans, -l,4-xylans, P-l,4-chitosans, a-l,4-N-acetylchitosans such as in particular chitin. More preferably, derivatives of those polysaccharides are employed which are derived from cellulose, chitin and amylose.

The average degree of polymerization of the polysaccharide (number average) can, for example, be and preferably is 5 to 500 monosaccharide units but in principle is not restricted upwardly.

The stationary chiral phases of the invention those are preferred which have derivatives of polysaccharides including the preferred ranges mentioned and are applied to silica gel. Such chiral phases are commercially available* for example, under the name CHI ALPAK® (IA, IB, IC, ID, IE, IF, AD, AS, AY, AZ)™ or CHIRALCEL® (OA, OB, OC, OD,OF, OG, OJ,OK,OX, OZ)™ from Daicel.

Preferably, chiral stationary phases used herein are those are which contain:

The starting mixture employed for the separation of enantiomers, which contains the mixtures of (S)- and (R)-enantiomers of efavirenz, is supplied to the circulating stream of liquid dissolved in a solvent as a "feed stream". The proportion of the starting mixture in the feed stream can be, for example, 1 to 35 mass%, preferably 5 to 30 mass % and more preferably 15 to 30 mass %.

Suitable solvents includes but are not limited to aliphatic hydrocarbons having C_6-12 carbon atoms such as methyl-cyclohexane, cyclohexane, n-hexane and n-heptane, ethers such as tetrahydrofuran, aliphatic alcohols having C_1-6 carbon atoms such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, benzonitrile and benzyl nitriles or mixtures of such solvents; preferably methanol, isopropanol, acetonitrile; more preferably methanol.

An eluting agent is furthermore supplied to the optionally circulating stream of liquid. The eluting agent is more advantageously an organic solvent, the above mentioned details including the preferred ranges applying in the same way. Preferably, the same solvents are employed for the feed stream and the eluting agent.

The pressure during the addition of the feed stream and of the eluting agent can be, for example, 0.5 bar to 100 bar, 1 bar to 60 bar being preferred. The temperature during the enantiomeric enrichment can be, for example, 0 to 80°C, preferably 10 to 60°C, more preferably 25 to 50°C.

The raffinate and the extract can then be removed from the SMB unit, these fractions in each case containing an enriched enantiomer of efavirenz and isolating the enriched enantiomers by conventional methods such as removal of the solvent, for example by evaporation.

In the manner according to the invention, the enantiomer of the raffinate, preferably, S- enantiomer of efavirenz can be obtained, for example, with purities of about 99.8% or more.

In the manner according to the invention, the enantiomer of the extract, preferably, R- enantiomer of efavirenz can be obtained, for example, with purities of about 99.8% or more.

The yields, based on the maximally obtainable amount of the enantiomers of efavirenz, in particular S-enantiomer, can be 80% or more, preferably 90% or more and more preferably 95% or more. If for a subsequent step only one enantiomer is of interest, it is advantageous to racemize the undesired enantiomer and fed it again to the SMB chromatography. In a further embodiment, the undesired enantiomer such as (R)-enantiomer may be converted in to a mixture of (S)- and (R)-enantiomers by conventional methods and fed it again to the SMB chromatography for enantiomer enrichment.

In another embodiment, the present invention provides a process for purification of efavirenz, comprising subjecting a mixture of (S) and (R) enantiomers of Efavirenz to batch elution chromatography, and separating the (S)-enantiomer enriched Efavirenz.

The batch elution chromatography includes, but is not limited to preparative chiral column chromatography method such as normal phase or reverse phase chromatography; or Flash chromatography. In a further embodiment of the present invention provides any ratio of (S) and (R) enantiomeric mixtures of efavirenz may be purified by normal phase preparative chiral column chromatography method. The normal phase preparative chiral column chromatography method can be performed using preparative chiral column and an eluent. The normal phase preparative chiral chromatography column may be selected by any chiral columns known in the art, for example, preferably chiral columns as described just as above for SMB chromatography can be used. Flow rate of the mobile phase may be selected from about 50 ml to 250ml per minute, preferably about 100 ml to 200 ml per minute, more preferably about 50 ml per minute. Conditions for the normal phase preparative chiral column chromatography are known to the person skilled in the art.

The eluent for normal phase preparative chiral column chromatography is selected from the group comprising aliphatic alcohols having C_1-6 carbon atoms such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, benzonitrile and benzyl nitriles or mixtures of such solvents; preferably methanol, isopropanol, acetonitrile; more preferably methanol.

In a further embodiment of the present invention provides any ratio of (S) and (R) enantiomeric mixtures of efavirenz may be purified by reverse phase preparative chiral column chromatography method. The reverse phase preparative chiral column chromatography method can be performed using reverse phase column chromatography and an eluent. The reverse phase preparative chiral chromatography column may be selected by any chiral columns known in the art, for example, preferably chiral columns as described just as above for SMB chromatography can be used. Conditions for the reverse phase preparative chromatography are known to the person skilled in the art.

The eluent for reverse phase preparative chiral column chromatography is selected from aliphatic alcohols having C_1-6 carbon atoms such as methanol, ethanol and isopropanol or mixture of such alcohol; nitriles such as acetonitrile, benzonitrile and benzyl nitriles or mixtures of such solvents and water; preferably a mixture of alcohol and water or a mixture of nitrile and water. In a further embodiment of the present invention provides any ratio of (S) and (R) enantiomeric mixtures of efavirenz may be purified by Flash chromatography method. The Flash chromatography method can be performed using Reveleris flash chromatography system and an eluent comprising an alcohol, a nitrile solvent, water and mixtures thereof. The eluent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, propionitrile, water and mixtures thereof. The Flash chromatography column may be selected from any column known in the art suitable for flash chromatography, for example, preferably chiral columns as described just as above for SMB chromatography can be used. Flow rate of the eluent may be selected from any flow rate that is efavirenz and its isomers are separable. Conditions for the flash chromatography are known to the person skilled in the art.

Efavirenz recovered using the process of batch elution chromatography of the invention has chiral purity of about 99.8% or more.

The present invention provides efavirenz, obtained by the above purification process, as analyzed optical purity using high performance liquid chromatography ("HPLC") with the conditions described below:

Column and Packing CHIRALPAK AS-H (250x4.6) mm, 5μ

Column Temperature 25°C

Mobile phase n-hexane/ethanol/diethyl amine 98/2/0.2 v/v/v

Flow rate 1 ml/min

Detection UV 252 nm

Injection volume 20μ1

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

Example 1: Purification of efavirenz using SMB/Varicol method.

A continuously operating simulated moving bed chromatography unit from Novasep, France, was employed. Characteristic components of the unit are 8 axial flow columns having a device for the dynamic axial compression of the stationery phase.

Feedstream: The feed solution of racemic efavirenz (97:3 of S:R isomer ratio) was prepared by dissolved 1140 gms of racemic efavirenz in 6 litres of methanol.

The following conditions are established for SMB chromatography:

Eluting agent 13.38 ml/min (100% methanol)

Feedstream I.67 ml/min (100% methanol)

Raffmate 4.01 ml/min of S-enantiomer in methanol

Extract I I .02 ml/min of R-enantiomer in methanol

Cycle time 99 sec

Temperature 30° C.

Pressure 35 bar

Chiral stationary phase CHIRALPAK AS-V, 20 μιη

S-efavirenz chiral purity 99.9% by HPLC.

Productivity 25 Kg feed/Kg CSP/day.

Example 2: Purification of efavirenz using SMB/Varicol method.

Feed concentration (40 gms crude efavirenz mixture (96.4:3.6 of S:R isomer ratio) /200 liter of solution.

The following conditions are established for SMB chromatography:

Eluting agent 396.9 ml/min (100% methanol)

Feed stream 38 ml/min (100% methanol)

Raffinate 87.8 ml/min of S-enantiomer in methanol

Extract 347.1 ml/min of R-enantiomer in methanol

Cycle time 1.4 min

Temperature 30°C.

Chiral stationary phase CHIRALPAK AS-V, 20 μηι

S-efavirenz chiral purity 99.91% by HPLC.

Productivity 18.55 Kg feed/Kg CSP/day.

Example 3: Purification of efavirenz using SMB/Varicol method.

Feed concentration: 11 kg crude efavirenz mixture in 55 liter of methanol. The following conditions are established for SMB chromatography:

Eluting agent 365-470 ml/min (methanol)

Feed stream . 35-45 ml/ min (methanol)

Raffinate 82-105 ml/min of S-enantiomer in methanol

Extract 318-410 ml/min of R-enantiomer in methanol

Cycle time 24 hours

Temperature 25-35°C,

Chiral stationary phase CHIRALPAK AS-V, 20 urn

S-efavirenz chiral purity 99.9% by HPLC.

Raffinate (120 Litres) from collection receiver was taken in to another reactor and distilled out methanol completely to obtain pure S-enantiomer of efavirenz.

Example 4: Purification of efavirenz using Preparative HPLC.

Input 5 g of Efavirenz with an enantiomer ratio of 97:3

Preparative HPLC system YMC K-Prep lOO

Preparative column 250 x 20 mm CHIRALPAK AS-H, 5 μπι

Mobile Phase 100% Methanol

Flow Rate 20 mL/min

Wavelength 300 nm

Sample Preparation 200 -250 mg /mL

Inj Volume 5-15 mL

Run Time 20 min

Column Temp 30°C

10 mL of sample solution was injected on to the preparative HPLC and recorded up to 20 minutes. The Efavirenz and its enantiomer were eluted at 4-5 min and 10-15 min respectively. Efavirenz peak collection was done from 3 to 6 minutes. CHIRALPAK AD-H (250 x 4.6), 5μπι column was used to monitor the purity of collected fractions. Collected fractions of Efavirenz and its enantiomer were concentrated on rotary evaporator to obtain residue.

Yield : 4.6 g. i.e >90% recovery

Chiral Purity of Efavirenz : >99.95%

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM:

Claim 1 : A process for enantiomeric enrichment of efavirenz, comprising the steps of:

Claim 2: The process according to claim 1, characterized in that, for the enantiomeric enrichment, a starting mixture is employed which contains the enantiomers in the range of about 99.7:0.3 to about 0.3:99.7. Claim 3: The process according to claim 2, characterized in that, for the enantiomeric enrichment, a starting mixture is employed which contains the enantiomers in the range of about 97:3 to about 3:97.

Claim 4: The. process according to claim 1, characterized in that the chromatography is simulated moving bed chromatography. Claim 5: The process according to claim 4, characterized in that the SMB unit has a column number of 4 to 24.

Claim 6: The process according to claim 4, characterized in that, for the enantiomeric enrichment, columns are employed which, as a chiral stationary phase, contain derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates, or optically active network polymers, which are optionally applied to a support material.

Claim 7: The process according to claim 6, characterized in that the chiral stationary phases are selected from the group comprising Amylose tris (3,5- dimethylphenylcarbamate), Cellulose tris (3,5-dimethyl phenylcarbamate), Cellulose tris (3,5-dichloro phenylcarbamate), Amylose tris (3-chlorophenylcarbamate), Amylose tris (3,5-dichlorophenylcarbamate), Amylose tris (3-chloro-4-methylphenylcarbamate), Amylose tris (3,5-dimethyl phenylcarbamate), Amylose tris [(S)-a- methylbenzylcarbamate], Amylose tris [5-chloro-2-methylphenylcarbamate], Amylose tris (3-chloro-4-methylphenylcarbamate), Cellulose tris (3,5-dimethyl phenylcarbamate), Cellulose tris (4-methylbenzoate), Cellulose tris (4-chloro-3- methylphenyl carbamate), Cellulose tris (3-chloro-4-methylphenylcarbamate), and are applied to Silica gel.

Claim 8: The process according to claim 4, characterized in that the solvents employed^' are aliphatic hydrocarbons, having C6-12 carbon atoms, ethrs, aliphatic alcohols, nitriles or mixture thereof.

Claim 9: The process according to claim 8, characterized in that the solvent employed are selected from the group comprising cyclohexane, methyl cyclohexane, n- hexane, n-heptane, tetrhydrofuran, methanol, ethanol, isopropanol, acetonitrile, benzonitrile, benzyl nitrile and mixtures thereof.

Claim 10: The process according to claim 4, characterized in that the pressure during the feed of the feed stream and the eluting agent is 0.5 bar to 100 bar.

Claim 11: The process according to claim 10, characterized in that the pressure during the feed of the feed stream and the eluting agent is 1 bar to 60 bar. Claim 12: The process according to claim 4, characterized in that the temperature during the enantiomeric enrichment is 0 to 80°C.

Claim 13: The process according to claim 12, characterized in that the temperature during the enantiomeric enrichment is 10 to 60°C.

Claim 14: The process according to claim 4, characterized in that the enriched, undesired enantiomer is racemized.

Claim 15: The process according to claim 14, characterized in that the enriched undesired enantiomer is racemized and fed again to the SMB.

Claim 16: The process according to claim 1, characterized in that the chromatography is Preparative column chromatography. Claim 17: The process according to claim 16, characterized in that, for the enantiomeric enrichment, columns are employed which, as a chiral stationary phase, contain derivatives of polysaccharides, optically active poly (acryl) amides, chiral polyacrylates, or optically active network polymers.

Claim 18: The process according to claim 17, characterized in that the chiral stationary phases are selected from the group comprising Amylose tris (3,5- dimethylphenylcarbamate), Cellulose tris (3,5-dimethyl phenylcarbamate), Cellulose tris (3,5-dichloro phenylcarbamate), Amylose tris (3-chlorophenylcarbamate), Amylose tris (3,5-dichlorophenylcarbamate), Amylose tris (3-chloro-4-methylphenylcarbamate), Amylose tris (3,5-dimethyl phenylcarbamate), Amylose tris [(S)-a- methylbenzylcarbamate], Amylose tris [5-chloro-2-methylphenylcarbamate], Amylose tris (3-chloro-4-methylphenylcarbamate), Cellulose tris (3,5-dimethyl phenylcarbamate), Cellulose tris (4-methylbenzoate), Cellulose tris (4-chloro-3- methylphenyl carbamate), Cellulose tris (3-chloro-4-methylphenylcarbamate).

Claim 19: The process according to claim 16, characterized in that the eluent employed are selected from the group comprising methanol, ethanol, isopropanol, acetonitrile, benzonitrile, benzyl nitrile and mixtures thereof.

Claim 20: The process according to claim 19, characterized in that the eluent is methanol.

Claim 21 : The process according to claim 16, characterized in that the chromatography is carried out according to example 4.