SK168298A3 - Enantiomer separation from chromane acid esters - Google Patents

Abstract

The invention relates to processes for the chromatographic separation of enantiomeric esters from 2-alkanoyl-chromane derivatives of the formula (I) in which Z is -(CH2)n1-(CHA)n2-(CH2)n3, where n1 = 0, 1, 2 or 3, n2 = 0 or 1, n3 = 0, 1, 2 or 3, with the proviso that n1 + n2 + n3 < 4, R<6>, R<7>, R<8> and R<9> are mutually independently H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl with 3 to 7 atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2NHAc or -CH2NHSO2CH3, where two neighbouring radicals may also be an alkylene chain with 3 or 4 C atoms, A is alkyl with 1 to 6 C atoms, Ac is alkanoyl with 1 to 10 C atoms or aroyl with 7 to 11 C atoms, Ph is unsubstituted or R<5>, 2, 3 or 4-pyridyl or phenoxy-substituted phenyl, R<5> is unsubstituted or 1-5 F, CF3 or wholly or partially fluorine-substituted A, A and/or OA-substituted phenyl, by means of chromatography on sorbents containing aromatic carbamate-substituted polysaccharides, e.g. cellulose, especially cellulose-tris(3,5 dimethyl phenyl carbamate), using eluents containing C1 to C5 alcohols. Suitable eluents are C1 to C5 alcohols, especially methanol and ethanol or their mixtures. Preferred eluents are C1 to C5 alcohols and C1 to C10 hydrocarbons, especially mixtures of hexane or heptane with 2-propanol.

Description

Method for resolution of enantiomers of chromanoic acid esters Technical field

The invention relates to a process for chromatographic separation of the enantiomers of the esters of the 2-alkanoylchroman derivatives of the general formula I, in particular by a continuous process.

BACKGROUND OF THE INVENTION

where it means

Z - (CH ₂ ) _{n 1} "CHA) _{n 2} - (CH ₂ ) _{n 3} where _n 1 is 0, 1, 2 or 3, n 20 is 0 or 1, n 3 0, 1, 2 or 3, provided that n 1 + n 2 + n3 <4

R ⁶ , R ⁷ , independently of one another H, A, OA, phenoxy, OH, F, Cl,

R ⁸ , R ⁹ . Br, J, CN, CF ₃ , NO ₂ , NH ₂ , NH ₂ , NA ₂ , Ac, Ph, C 3 -C 7 cycloalkyl, -CH ₂ NH ₂ , -CH ₂ NHA, -CH ₂ NA ₂ , -CH ₂ NHAc or -CH ₂ NHSO ₂ CH ₃ , wherein also two adjacent groups are optionally alkylene of 3 or 4 carbon atoms,

A (C1-C6) alkyl,

(C 1 -C 10) alkanoyl or (C 7 -C 11) aroyl group,

Ph is unsubstituted or R ⁵ , 2-, 3- or

4-pyridyl or phenoxy substituted phenyl; and

R ^{5 is} unsubstituted or substituted by 1 to 5 fluorine atoms or trifluoromethyl or completely or partially by fluorine atoms substituted by A, A and / or OA substituted phenyl.

The esters of 2-alkanoylchrománových compound of formula I, particularly esters, where the sum of nl + n2 + n3 is zero or 1 (where the meaning of 1, zs is preferably -CH ₂ -), are particularly important intermediates in the preparation of pharmaceutically active amino (thio) ether derivatives which are known, for example, from EP-A-0 707007. If these chromate derivatives are optically active, resolution of the enantiomers is necessary or desirable.

For certain chromate derivatives, methods for the preparation of enantiomerically pure chromate derivatives have been described (J. Heterocyclic Chem. 29, 1992, p. 431). However, these methods are not readily applicable to other similar compounds.

It is also known (J. Med. Chem. 38, 858-868, 1995) to resolve the enantiomers of certain benzopyranecarboxylic acid derivatives by chiral phase chromatography in connection with leukotriene B ₄ -receptor antagonists. It is also known (EP-A-0 448254) to separate enantiomers of chroman-2-carboxylates by saponification of enantiomeric esters by microbial lipase. This method is only applicable when the chromate ester is cleavable by lipase.

It is therefore an object of the invention to separate the enantiomers of the derivatized chromate esters without limiting the limited specificity of the substrate.

Essentially, enantiomers may be separated. on chiral sorbents. Those skilled in the art are aware of a large number of chiral sorbents, such as those based on cellulose derivatives, cyclodextrins, or poly (meth) acrylamide derivatives with an optically active side chain. Such chiral sorbents and their use are described, for example, in the patent literature (EP-A-0 147804, EP-A-0 155637, DE 36 19 303, DE 40 05 868 or DE 40 06 923).

It has been found that separation of the enantiomers of chroman-2-carboxylic acid esters, in particular of the chroman-2-carboxylic acid ethyl esters, into a series of conventional chiral sorbents is not possible. Silica gel-bound polymethacrylamide derivatives (DE 36 19 303, ChiraSpher, Merck, DE), silica gel-bound cyclodextrin derivatives (DE 40 06 923, ChiraDex ^R , Merck, DE), and dinitrobenzoylphenylglycine ( Baker). Likewise, the use of two cellulose-based sorbents does not allow separation: enantiomers cannot be separated either on cellulose triacetate (Merck, DE) or on tris (3,5-dimethylbenzoate) cellulose (adsorbed on silica gel, CHIRACEL ^R OJ, from Daicel, JP ). However, it has surprisingly been found that separation on a cellulose-based sorbent similar to CHIRACEL ^r OO in which the same aromatic substituent (3,5-dimethylphenyl) is bound by a carbamate bond instead of an ester bond. Separation into tris- (3,5-dimethylphenylcarbamate) cellulose (adsorbed onto silica gel, CHIRACEL OD, from Daicel, JP) is possible with good separation factors with alcohols or mixtures of alcohol and hydrocarbons as eluents such as column chromatography (continuous method) as well as simulated moving bed SMB chromatography. Similarly, sorbent separation is also possible, in which the (3,5-dimethylphenylcarbamate residue is bound to amylose (CHIRALPAK ^R AD, from Daicel, JP). Porous cellulose esters such as cellulose tribenzoate according to the European patent have also proved to be good sorbents. EP-0 316270.

C 1 -C 5 alcohols, in particular methanol and ethanol, or mixtures thereof, as well as mixtures of C 1 -C 5 alcohols and C 5 -C 10 hydrocarbons, in particular hexane or heptane mixtures, are particularly suitable as eluents. 2-propanol.

In FIG. 1 schematically illustrates a method of countercurrent chromatography based on simulated moving layer chromatography (SMB chromatography). Sorbent current, ie. The stationary phase is denoted 1. In the SMB method, only a physically difficult to implement sorbent stream is simulated by cyclically switching the multi-way valves that connect several connected columns to the circuit.

The experimental realization of the partitioning was performed on an SMB unit which operates according to the four-zone model explained below. According to the invention, SMB units can also be used which operate according to other models, for example according to the three-zone model. Suitable process variants are known to those skilled in the art from the literature.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention relates to a process for the separation of enantiomers of derivatized chroman esters of the general formula I, in particular chroman-2-carboxylic acid esters and in particular chroman-2-carboxylic acid ethyl ester, by chromatography on sorbents containing aromatic carbamate substituted polysaccharides, for example cellulose; 5-dimethylphenylcarbamate) cellulose using an eluent containing alcohols having 1 to 5 carbon atoms. Alcohols of 1 to 5 carbon atoms, in particular methanol and ethanol or mixtures thereof, are suitable as eluents. Preferred eluents are mixtures of C 1 -C 5 alcohols and C 5 -C 10 hydrocarbons, in particular mixtures of hexane or heptane with 2-propanol.

Derivatized chroman esters of the formula I as well as the preferred meanings of the individual symbols in the formula I are known from EP-A0 707007. Preferred compounds of the formula I are the chroman-2-carboxylic acid esters, especially the chroman-2-carboxylic acid ethyl ester. . In preferred derivatized chroman esters of formula I, R ^6, R ^7, R ⁸ and R ⁹ are H, the symbol Z n2 and n3 is zero; particularly preferred is the ethyl ester (A is ethyl).

The C 1 -C 5 alcohols mentioned are methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; methanol or ethanol are preferred. A mixture of these alcohols may also be used in the process of the invention. Particularly preferred as eluents are mixtures of the abovementioned C 1 -C 5 alcohols and C 5 -C 10 linear, branched or cyclic hydrocarbons, which mixtures may contain more than one alcohol as defined above and more than one hydrocarbon characterized as above. Examples of C 5 -C 10 linear, branched or cyclic hydrocarbons include n-pentane, isopentane, n-hexane, isohexane, cyclohexane, n-heptane, isoheptane, o-octane and isooctane. In the alcohol-hydrocarbon mixtures, the hydrocarbon content is preferably 70 to 99% by volume, in particular 85 to 95% by volume.

The separation process according to the invention can be carried out in a known continuous manner. It is preferred to divide by a continuous SMB method, which will be explained in more detail in FIG. First

A prerequisite for the separation of enantiomers on a preparative scale is a good separation if possible (separation of baselines with a high selectivity factor a). Since only conventional partition chromatography is used in conventional flash chromatography at some point in the separation, in which the material to be separated is on its column path, high-performance column separations (high number of theoretical plates) are required. Overall, in conventional column splitting, in particular, performance with respect to time and volume is not very high; accordingly, the cost of such a method is considerable. In a continuous process, for example in SMB chromatography, a significantly improved performance with respect to time and volume is achieved. SMB chromatography is a continuous countercurrent system in which the mobile and stationary phases are conducted in the opposite direction (Chirality 5, p. 267, 1993). Thus, unlike the continuous method, the separation of the entire stationary phase is utilized at each time point, thereby greatly increasing the selectivity of the separation system. Compared to intermittent chromatography, considerably fewer theoretical plates are required for SMB chromatography.

Due to the countercurrent principle, SMB chromatography is ideally suited for the separation of two-fold mixtures of enantiomers (for example both enantiomers of the racemate).

The continuous process SMB process, shown schematically in FIG. 1 permits the setting of a time-stationary state in which the eluent 2 as well as the solution of the two-component mixture (feed 5) can be continuously introduced into the system and also the two separate components (raffinate 6 and extract 5) can be continuously removed from the system. The supply and removal of the fabric streams is carried out by means of four pumps (not shown). The main stream of eluent 2 is circulated through another pump (recirculation pump (not shown)). Since, therefore, the system must introduce only a small amount of fresh eluent (eluent _{injection-new} = raffinate + extract), the solvent consumption per unit product in the SMB significantly lower than in the case of an intermittent chromatography. The column layer of the stationary phase is divided between the SMBs in four zones (one absorption and desorption zone for both split components), defined as follows with respect to inlet and outlet points: zone I between eluent line and extract line, zone II between line extract zone and feed line, zone III between feed line and raffinate line, zone IV between raffinate line and eluent line.

In the case of separation of a two-component mixture, conditions, i.e. flow rates, can now be found in zones I to IV, in which the weaker refined component with the mobile phase and the stronger refined component with the stationary phase are moving. The separated components can then be collected in pure form with the extract stream or the raffinate stream.

It is technically only very difficult to realize the actual movement of the stationary phase 1. Therefore, this movement of the stationary phase is simulated. For this purpose, the total column layer is divided into cyclically arranged individual columns. The total number of columns is several times the number 4 because the system, as mentioned above, has four chromatographic zones. Between each column there are four two-way valves, which provide a connection to the four supply and discharge lines. Thus, on the basis of these valves, each point between the columns can perform any function (supply of eluent, feed or raffinate, or extract extraction). At any given time, the position of the four inlet and outlet lines defines four chromatographic zones. Since the position of the four lines is further switched by one column unit in the direction of movement of the liquid means after a defined time, this corresponds to the movement of the column layers in the opposite direction. Thus, by further assigning the injection points in defined periods of time, each individual column proceeds sequentially to all four zones until the inlet and outlet lines return to their original position and thus the cycle is closed.

When several cycles have taken place, a stationary state is set which allows, at a suitable choice of flow rates in the system and at the appropriate times for switching on the valves, to collect the separated products in pure form as the extract stream and the raffinate stream.

Without further elaboration, it is believed that one skilled in the art can make the most of the above description.

The preferred embodiments are for the purpose of illustration only and are not intended to limit the method of the invention in any way.

A complete listing of all earlier and later filed patent applications, patents and publications, and the corresponding patent application DE 196 23 755.6, filed June 14, 1996, are set forth above.

The invention is illustrated by the following non-limiting examples. The examples describe various enantiomer resolution variants of the invention using chroman-2-carboxylic acid ethyl ester. When mixtures of eluents are mentioned, the data are in volume (volume: volume) relationship.

Overview of pictures

In FIG. 1 schematically shows the above-described countercurrent chromatography method based on simulated moving layer chromatography (SMB chromatography)

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Separation of enantiomers of chroman-2-carboxylic acid ethyl ester into CHIRALCEI R OD (methanol is used as eluent)

Experimental conditions:

column: CHIRALCEL ^r OD (Daicel: column size

Eluent: methanol flow rate: 0.8 ml / min

UV at 220 nm detection:

Result: the first enantiomer elutes after 5.35 minutes, the second after 6.73 minutes (a = 1.95)

Example 2

Separation of the enantiomers of chroman-2-carboxylic acid ethyl ester into CHIRALCEL ^R OD (hexane / 2-propanol, 90:10 by volume)

Experimental conditions as in Example 1, but eluting with hexane / 2-propanol, 90:10 by volume.

Result: the first enantiomer eluted at 8.19 minutes, the second at 43.63 minutes (a = 9.26).

Example 3

Separation of the enantiomers of chroman-2-carboxylic acid ethyl ester into CHIRALCEL ^R OD (another eluent)

However, the test conditions as in Example 1, but as eluent, are used (a) ethanol and (b) heptane / 2-propanol (90:10 by volume).

The results:

eluent retention time 1. enantiomer retention time 2. enantiomer and (a) ethanol 5.17 min 7.27 min 2.65 (b) heptane / 9.27 min 44.32 min 7.53

2-propanol

Example 4

Separation of chroman-2-carboxylic acid ethyl ester enantiomers into CHIRALPAK ^r AD (ethanol is used as eluent)

Experimental conditions:

column: CHIRALPAK ^R AD (Daicel: column size

250x4 mm) eluent: flow rate detection: result:

ethanol

0.8 ml / min

UV at 220 nm the first enantiomer elutes after 5.19 minutes, the second after 6.29 minutes (a = 2.01)

Example 5

Separation of chroman-2-carboxylic acid ethyl ester enantiomers into CHIRALPAK ^R AD (methanol is used as eluent)

However, the experimental conditions of Example 4, but eluting with methanol. . , i ·

Result: the first enantiomer eluted after 5.27 minutes, the second after 7.08 minutes (a = 2.55).

Example 6

Separation of enantiomers of chroman-2-carboxylic acid ethyl ester on porous cellulose tribenzoate

Experimental conditions:

column i: porous layer forming cellulose tribenzoate (column size: 3 columns each 125x4 mm) eluent: methanol flow rate: 0.5 ml / min detection: UV at 220 nm result: first enantiomer eluting after 17.5 minutes , second after 23.1 minutes (a = 1.53)

Example 7

Separation of enantiomers of chroman-2-carboxylic acid ethyl ester into CHIRALCEL ^R OD (preparative column separation by continuous method)

Experimental conditions:

column: CHIRALCEL ^R OD (grain size: 20 μπι) column size: 250x50 nm flow rate: 45 ml / min eluent: heptane / 2-propanol (90:10, v / v)

An amount of 1 ml of chroman-2-carboxylic acid ester (racemic pure substance) still separates the baselines, i.e. the purity of the separated enantiomers is greater than 99.5%.

Example 8

Separation of the enantiomers of chroman-2-carboxylic acid ethyl ester into CHIRALCEL ^r OD (preparative separation by continuous SMB method)

SMB system: Licosep ^R 12-26 (Separex) fitted with 8 columns

Superformance ^R (Merck; 26 mm ID) stationary phase: CHIRALCEL ^R OD (grain size: 20 µπι) i column layer length: 100 mm) 1 I eluent: heptane / 2-propanol (90:10) temperature: 25 ° C Injection concentration: 10 g / 1 Flow rate: 5 ml / min Recycling flow rate: 50 ml / min

With these parameters, an offset of 200 g of racemate per 24 hours is achieved and the purity of the racemate and the extract is 99%.

Comparative example

Separation of the enantiomers of chroman-2-carboxylic acid ethyl ester into cellulose triacetate

Experimental conditions: column: cellulose triacetate (Merck: column size 250x10 mm) eluent: flow rate: detection: methanol 1.8 ml / min UV at 220 nm the result: both enantiomers elute undivided after 15.6 minutes (a = 0.00) Comparative Example

Separation of enantiomers of chroman-2-carboxylic acid ethyl ester into tris (3,5-dimethylbenzoate) cellulose (using methanol as eluent)

Experimental conditions: column: Tris (3,5-dimethylbenzoate) cellulose adsorbed on silica gel (CHIRALCEL ^R OJ: Daicel: 250x4 mm column size) eluent: methanol

flow rate: 0.8 ml / min

detection: UV at 220 nm the result: both enantiomers elute undivided after 11.5 minutes (a = 0.00) Comparative Example C

Separation of the enantiomers of chroman-2-carboxylic acid ethyl ester on tris (3,5-dimethylbenzoate) cellulose (using ethanol as eluent)

The test conditions were the same as in Comparative Example B, but ethanol was used as the eluent.

Result: the enantiomers eluted after 10.8 optionally

11.1 minutes (a = 1.04), but the elution peaks almost completely overlap.

Industrial usability

Industrial process for the resolution of enantiomers of a 2-alkanoylchrománových derivatives chromatography sorbent comprising aromatic carbamates substituted polysaccharides, using an eluent containing C ₁ _ ₅ alcohols, particularly methanol and ethanol, or mixtures thereof. Preferred eluents are a mixture of C ₁ _ ₅ alcohols and C ₁ _ _Q1 hydrocarbons, particularly hexane or n-heptane: 2-propanol.

Claims (9)

PATENT TOOLS A process for the resolution of enantiomers of esters of 2-alkanoylchroman derivatives of the general formula I wherein: Z (CH ₂ ) _{n 1} -CHA _{n 2} - (CH ₂ ) _{n 3} where _n 1 is 0, 1, 2 or 3, n 20 is 0 or 1, n 3 is 0,1, 2 or 3, provided that n 1 + n 2 + n3 <4 R ⁶ , R ⁷ independently of one another H, A, OA, phenoxy, OH, F, Cl, R ⁸ , R ⁹ Br, J, CN, CF ₃ , NO ₂ , NH ₂ , NHA, NA ₂ , Ac, Ph, C 3 -C 7 cycloalkyl, -CH ₂ NH ₂ , -CH ₂ NHA, -CH ₂ NA ₂ , -CH ₂ NHAc or -CH ₂ NHSO ₂ CH ₃ , wherein also two adjacent groups are optionally C 3 or C 4 alkylene chains, A (C1-C6) alkyl, (C 1 -C 10) alkanoyl or (C 7 -C 11) aroyl group, Ph is unsubstituted or R ⁵ , 2-, 3- or 4-pyridyl or phenoxy substituted phenyl; and R ^{5 is} unsubstituted or substituted by 1 to 5 fluorine atoms or trifluoromethyl or fully or partially fluorine atoms substituted by A, A and / or OA substituted phenyl. characterized in that the separation is carried out on a sorbent containing aromatic carbamate-substituted polysaccharides and using an eluting agent containing a C 1 -C 5 -alkoxy. The method of claim 1, wherein the sobrent comprises a cellulose derivative as a substituted polysaccharide. A process according to claim 1 or 2, wherein the enantiomers are separated, wherein in formula I, R ⁶ , R ⁷ , R ⁸ and R ⁹ are each hydrogen and Z is n 1, n 2 and n 3 zero and other symbols are as defined in claim 1. A process according to claim 3, characterized in that the enantiomers are separated, wherein in formula I, A represents an ethyl group and n 2 and n 3 are zero and the other symbols have the meaning given in claim 3. A process according to any one of claims 1 to 4 wherein the sorbent comprises cellulose tris (3,5-dimethylphenylcarbamate). '' A process according to any one of claims 1 to 5, characterized in that an alcohol having 1 to 5 carbon atoms is used as the eluent. A process according to any one of claims 1 to 5, wherein the eluent is a mixture containing 16 C 1 -C 5 alcohol and C 5 -C 10 hydrocarbon. Method according to one of Claims 1 to 7, characterized in that the method is carried out continuously. Method according to claims 1 to 7, characterized in that the method is carried out continuously by the SMB method.