DE102009032080A1 - Process for the separation of alcohol-ketone mixtures - Google Patents

Abstract

The invention relates to a process for the separation of a mixture with a first compound dissolved in a solvent, which comprises at least one keto group, and a second compound, which comprises a chiral carbon atom with a hydroxyl group, which is formed from the first compound by stereoselective reduction of the keto group , wherein the mixture is brought into contact with an inorganic adsorber material and at least part of the second compound is adsorbed on the inorganic adsorber material, and a mixture depleted in the second compound is separated from the inorganic adsorber material.

Description

The The invention relates to a method for separating a mixture with a first dissolved in a solvent A compound comprising at least one keto group, as well as a second compound having a chiral carbon atom with a Hydroxy group comprising by reduction of the keto group from the first connection has emerged.

chiral Hydroxy compounds are valuable synthesis building blocks for the production pharmaceutically active compounds. Leave chiral connections usually difficult to enantiomerically pure by classical chemical methods produce. If both enantiomers are formed in one synthesis step, they must subsequently undergo complex separation processes be separated using optically active auxiliaries. For the preparation of chiral compounds therefore biotechnological attempts Apply method, wherein the stereoselectivity enzymatic Reactions is used. It can both complete microorganisms be used as well as completely or partially purified isolated enzymes.

Different routes can be followed for the enzymatic synthesis of chiral alcohols. Examples of suitable enzymes are oxidoreductases, hydrolases, and Lyases. K. Goldberg, K. Schroer, S. Lütz and A. Liese, Appl. Microbiol. Biotechnol. (2007) 76: 237-248 give an overview of processes for the preparation of chiral alcohols using isolated enzymes.

Stereoselective syntheses can also be carried out using whole microorganisms, such as bacteria or fungi. In this reaction, the metabolism of the cells can be used for an internal regeneration of the cofactor. To give an overview of the use of complete cells to reduce ketones to chiral alcohols K. Goldberg, K. Schroer, S. Lütz and A. Liese in Appl. Microbiol. Biotechnol. (2007) 76: 249-255 ,

enzymes from the class of the Oxireduktasen catalyze redox reactions, the means reactions in which electrons are transferred to or from the substrate become. The group of the oxidoreductases include, among others the alcohol dehydrogenases (ADH), which are also called carbonyl reductases (CR). Alcohol dehydrogenases catalyze, for example the reduction of prochiral ketones to chiral alcohols.

The Most alcohol dehydrogenases are dependent on the redox cofactors β-1,4-nicotinamide adenine dinucleotide (NADH) or β-1,4-nicotinamide adenine dinucleotide phosphate (NADPH), which in the enzymatic reduction stoichiometric consumed. A stoichiometric use of this Cofactors is uneconomical because of the high prices. The enzymatic Reaction is therefore usually conducted so that the cofactor in a further enzyme-catalyzed reaction by oxidation of a Cosubstrats is regenerated. A cosubstrate is a compound, which is enzymatically oxidized as a reducing agent, wherein the case released electrons are transferred to NAD or NADP, which are regenerated to NADH or NADPH.

Around to use the enzymes used more efficiently in industrial processes to be able to reduce costs The enzymes are also recovered, so in another Reaction can be used.

In the EP 1 568 780 B1 describes a process for the enantioselective reduction of keto compounds by enzymes. The keto compound is first reduced to a secondary alcohol in an aqueous reaction medium which contains a reducing agent, alcohol dehydrogenase and coenzyme in addition to water. The reaction is carried out under reduced pressure so that volatile components can be removed from the reaction system. The aqueous phase is then extracted with a water-immiscible organic solvent such that the secondary alcohol formed transitions from the aqueous phase to the organic phase. The organic phase is separated and the aqueous phase reused and re-added for the next reaction cycle with keto compound and optionally reducing agent, enzyme and coenzyme.

Enzymatic reactions are equilibrium reactions, which means that a thermodynamic equilibrium sets in during the reaction. If whole cells are used for the reaction, the product may also be toxic to the cell. Thus, if the concentration of the product in the batch exceeds a certain value, the cells die. In both cases, therefore, the reaction comes to an end after an initial phase. In order to avoid a deactivation or a reduction of the synthesis activity, it is possible to remove the product in situ from the reaction mixture, so that the balance on the Page of the product. This can be done, for example, by continuously removing a gaseous product from the reaction mixture or continuously precipitating a product.

JT Vincenzi, MJ Zmijewski, MR Reinhard, BE Landen, WL Muth and PG Marler, Enzyme and Microbiol. Technology 20: 494-499, 1997 describe a stereoselective enzymatic reduction of a ketone, wherein the resulting alcohol is bound in situ to a polymeric resin and thus removed from the reaction equilibrium. The authors describe the reduction of 3,4-methylenedioxyphenylacetone to S-3,4-methylenedioxyphenylisopropanol by Zygosaccharomyces rouxii. Complete cells were used. The yield was more than 95% with an enantiomeric excess (ee) of more than 99.9% Since both the substrate and the product are toxic to the cells used, hydrophobic polymer resins are used which have been loaded with the substrate. The substrate bound to the solid polymer phase is in equilibrium with the aqueous phase in which the cells are provided. The small amount of substrate dissolved in the water phase is reduced by the cells to the corresponding optically active alcohol, which is then re-bound to the solid resin phase. In this way, a low constant concentration of the substrate or of the product in the water phase can be set, with overall very high yields of the desired product being obtained. A disadvantage of this method is that a relatively expensive resin is used for the separation of the product. This is particularly disadvantageous if the chiral alcohol is used for the synthesis of a product which is under great cost pressure, for example products for the agricultural industry or intermediates in the chemical industry. Furthermore, the resin used must be tailored to the particular reaction, so that a highly preferred adsorption of the alcohol and thus a high concentration of the remaining ketone is achieved in the reaction mixture.

Another way to reduce the cost of an enzymatically catalyzed reaction is to bind the enzyme to an adsorbent, which can be separated from the reaction mixture after the end of a reaction and used in a further approach. In the DE 10 2006 010 994 A1 describes a process for the enzymatic preparation of chiral alcohols, wherein the reaction mixture contains an adsorbent, which is associated with a Oxireduktase and which is separated from the reaction mixture after the end of the reaction. In the examples, diatomite is (Celite ^®) is used as an adsorbent for the enzyme. After filtration of the reaction mixture, the filter cake can be placed in a further batch and used there again for the catalysis of a reduction of a ketone to an optically active alcohol.

The described above, known from the prior art use relatively expensive components for the synthesis. Such Processes are therefore justified only if the optically active alcohols, which are obtained in the reaction, for the synthesis very expensive fabrics are used. Therefore, if chiral alcohols to be used for the production of products which are under a high cost pressure, are the described Procedure not suitable in itself.

Of the The invention was therefore based on the object, a method for separation a mixture of a ketone and one from the ketone by reduction to provide the obtained optically active alcohol, which is simple and inexpensive can be.

These The object is achieved by a method having the features of the patent claim 1 solved. Advantageous embodiments of the method are the subject of the dependent claims.

Of the The invention was based on the observation that ketones are less strong of inorganic adsorbents are bound as alcohols. inorganic Adsorbents are generally inexpensive and in large amount available. The procedure can therefore very easy to industrial standards be adjusted without a high cost pressure by providing of the inorganic adsorbent is triggered. The Method is therefore particularly suitable for the provision such optically active alcohols, which u. a. as building blocks for the production of fine chemicals for example for The chemical industry will be used where profit margins go through be limited to a relatively high competitive pressure.

According to the present invention, there is provided a method for separating a mixture with a first compound dissolved in a solvent comprising at least one keto group and a second compound comprising a chiral carbon atom having a hydroxy group formed by reducing the keto group from the first compound Provided, wherein the mixture is brought into contact with an inorganic adsorbent material and at least a part of the second compound on the anorgani Adsorber material is adsorbed, and a depleted in the second compound mixture is separated from the inorganic adsorber.

The inventive method is therefore suitable for the separation of mixtures, as typically in a Reduction of a prochiral keto compound to give an alcohol become. The reduction is carried out in solution, Therefore, both the starting material and the product in solution available. The reduction is preferably carried out in the manner that essentially only one of the enantiomers is formed. It is therefore not necessary, on the inorganic adsorber a To perform enantiomer separation. The information about the stereochemistry that occurs during reduction on Carbon atom of the keto group is set, so already during introduced the reduction of the keto group in the second compound. It is not significant at first, in what way the stereoselective reduction takes place. So it's also possible the reduction for example with a stereoselective catalyst in the course of a conventional hydrogenation, wherein the information about introduced the stereochemistry at the carbon atom of the keto group is, for example, by using asymmetric catalysts.

at the reduction remains the carbon skeleton of the first compound essentially obtained, so preferably first compound and second compound in their structure only at the carbon atom of Keto group of the first compound, which in an optically active Alcohol is differentiated. In the reduction the highest possible stereoselectivity is sought. Preferably, the mixture has an enantiomeric excess in favor of one of the two enantiomeric alcohols of more than 98%, preferably more than 99%, particularly preferably more than 99.5%.

The Mixture containing both the first compound, ie the ketone, as also contains the second compound, ie the optically active alcohol, is then contacted with an inorganic adsorber material. The inorganic adsorber material is thereby selected that it preferably has the highest possible adsorption in favor of the alcohol, that is the second compound. exemplary inorganic adsorbent materials are aluminum oxides, alumina hydrates, Bentonites, silica gels, silicates, such as aluminosilicates, magnesium silicates, Calcium silicates and hydrotalcites. The mixture will be with you for so long brought into contact with the inorganic adsorbent material, at least a proportion of the second compound on the inorganic adsorbent material is adsorbed and thus the mixture at the second compound is depleted. The second compound thus becomes out of the reaction removed so that in the case of an equilibrium reaction the equilibrium in favor of the product or, if the product is inhibitory or toxic to the catalyst, from the reaction mixture Will get removed.

The Method can be used in particular advantageous if in the reaction mixture no or at least only a small Concentration of molecules are included, which with the second compound around adsorption sites at the inorganic Adsorber material compete. Because water is a very polar solvent is and therefore very strong with that in the reduction of the keto group Alcohol formed around binding sites on the inorganic Adsorber material can compete, the inventive Method according to one embodiment preferably carried out in such a way that as a solvent an organic solvent is used. Especially preference is given to using organic solvents, which have no protonatable or deprotonatable groups. Preferably, the organic solvent is selected that it has a lower polarity than that in the Reduction of resulting alcohol. Especially preferred are solvents used, which have a relatively low polarity. Such solvents are characterized by a relative low boiling point at atmospheric pressure. Preference is given to organic Solvent used, which at atmospheric pressure a Boiling point of less than 90 ° C, preferably less than 80 ° C, more preferably less than 70 ° C exhibit. Suitable solvents are, for example Esters, such as ethyl acetate, ethers, such as methyl t-butyl ether, Alkanes, such as hexane or petroleum ether, or else aromatic hydrocarbons, like toluene.

According to a further preferred embodiment, the solvents used are those organic solvents which are substantially immiscible with water. As organic solvents which are substantially immiscible with water, preference is given to using those organic solvents which at 20 ° C. and normal pressure are less than 5% by weight, less than 2% by weight, particularly preferably less than 1% by weight .-%, in particular less than 0.5 wt .-% water. Thus, in this embodiment, if the mixture contains greater amounts of water, two phases are formed, with the reduction of the keto group to the chiral hydroxy group occurring substantially in the organic phase. In this way, the inventive method may also include the reaction of polar compounds as reactants, which dissolve only in the water phase. Without thinking of this theory To be bound, the inventors start from the idea that in this case the reaction takes place at interfaces between the organic phase and the water phase, wherein the product is essentially dissolved in the organic phase and is adsorbed thereon on the inorganic adsorber material.

As already explained above, in the inventive Method carried out the reduction of the keto group in the manner that essentially only one of the enantiomers is formed. Can do this For example, stereoselective catalysts can be used. According to one preferred embodiment is the reduction of the keto group to the hydroxy group bonded to a chiral carbon atom performed in such a way that the reduction under catalysis done by an enzyme. Enzymes have high regio- and stereoselectivity so that the reduction with a high enantiomeric excess in favor of an enantiomer. The Enzymes are preferably selected from the class of the oxidoreductases. The specific Oxireduktase is dependent selected from the substrate. The enzymes can both be used in isolated and possibly purified form as well in cells, so that the reduction of the keto group in the form of a fermentation is carried out. In itself subject to the inventive method no restrictions here. Unless the enzymes are in substance can be used, they are both in the form of more open-minded Cells are used as well as in purified form. In the latter Case it is both possible to dissolve the enzymes Use form as well as in a bound form, that is in a form in which the enzyme is bound to a solid matrix is. The skilled person can refer here to known techniques.

The enzymatic reduction by oxireductases generally requires the presence of a cofactor which, when reduced to stoichiometric Quantity is consumed. According to one embodiment Therefore, provided that the reduction of the keto group to that on a chiral carbon-bonded hydroxy group by the enzyme in Presence of a cofactor occurs. Cofactors are customary cofactors used. Exemplary cofactors are NADH and NADPH. It is however, it is also possible to use other known cofactors.

According to one preferred embodiment is used as an enzyme for the stereoselective reduction of the ketone an alcohol dehydrogenase used. The alcohol dehydrogenase becomes dependent selected from the substrate. Suitable alcohol dehydrogenases are, for example, yeast alcoholdehydrogenase (YADH), alcoholdehydrogenase-A (ADH-A), Lactobacillus brevis alcoholdehydrogenase (LbADH), 6-hydroxyhexanoic acid dehydrogenase (HCADH) or the reductase carbonyl reductase from Rhodococcus erythropolis (RECR) or carbonyl reductase (CPCR) from Candida parapsilosis.

The Alcohol dehydrogenases are recovered by conventional methods. Preference is given to using those alcohol dehydrogenases which also in organic solvents, the reduction of the keto group a hydroxy group bonded to a chiral carbon atom catalyze.

As already explained above, the process according to the invention can also be carried out in the presence of a small amount of a water phase. This may be required, for example, to solve a very polar cofactor, such as NAD ⁺ or NADP ⁺ . After the oxidation, the cofactor, for example NADH or NADPH, may optionally pass into the organic phase and be used there in the enzymatically catalyzed reduction of the keto group. Since large amounts of water cause water molecules to compete for adsorption sites on the inorganic adsorber, it is provided according to a preferred embodiment of the method according to the invention that the cofactor is dissolved in a water phase and the water phase in addition to the organic solvent in a proportion of less than 1 wt .-%, based on the organic solvent, is contained in the mixture. In one embodiment, the water phase is contained in the mixture in a proportion of at least 0.1% by weight, based on the organic solvent. The proportion of the water phase is chosen according to an embodiment at least so large that the cofactor can be completely dissolved in the water phase.

As already explained above, the cofactor, for example only be dissolved in the reduced form in the water phase and return to the organic phase after its oxidation. But it may also be that the cofactor is reduced in both and in the oxidized form in the water phase and the enzyme-catalyzed reduction of the ketone at a limiting phase between organic phase and water phase takes place. In this embodiment the method according to the invention is preferred that the water phase in finely divided form in the organic Phase is dispersed.

The enzymes which are used in the enzymatic reduction of the first compound, ie the reduction of the keto group, usually require the presence of a cofactor which, during the enzyma The reaction is oxidized. These cofactors are consumed in stoichiometric amounts as explained above. Since they are very expensive, it is provided according to a preferred embodiment that the cofactor is regenerated during the reduction of the keto group, ie the cofactor is circulated between its oxidized and its reduced state.

The Regeneration of the cofactor can in itself after usual Procedures are performed. So can the regeneration done electrochemically. But it is also possible to carry out the regeneration chemically by mixing the mixture another reducing agent is added, for example, sodium dithionite. However, the regeneration of the cofactor is preferred as well enzyme-catalyzed performed. This can usual Systems are used. For example, formic acid or formates are oxidized by formate dehydrogenase to carbon dioxide become. Next, as a reducing agent, for example, glucose or glucose-6-phosphate are used, which by glucose dehydrogenase or glucose-6-phosphate dehydrogenase to the corresponding sugar acids be oxidized.

According to one Embodiment will also be the regeneration of the cofactor carried out by an alcohol dehydrogenase, wherein the Alcohol dehydrogenase for both the reduction of the ketone to the chiral alcohol as well as the oxidation of a so-called Alcohol can be used to the corresponding ketone. at this embodiment of the invention Process is therefore intended that the mixture as another Component contains a sacrificial alcohol for the regeneration of the cofactor. As the sacrificial alcohol are preferably lower secondary alcohols used, which preferably comprise 3 to 10 carbon atoms, especially preferred isopropanol or isobutanol. The victim alcohol can be used in excess. According to one Embodiment is the proportion of the sacrificial alcohol in the mixture less than 25 wt .-%, preferably less than 10 Wt .-%, particularly preferably less than 5 wt .-%, based on the organic solvent which is involved in the enzymatic Reduction does not participate. Preferably, the sacrificial alcohol is at least used in an amount in the mixture, which of the double stoichiometric amount, more preferably at least which corresponds to three times the stoichiometric amount is required for the regeneration of the cofactor.

According to one Embodiment is provided that the sacrificial alcohol lower molecular weight than the second compound. The molecular weight of the sacrificial alcohol is preferably less than 75%, more preferably less than 55% of the molecular weight the second connection.

As already explained above, the information about the stereochemistry at the chiral carbon atom, to which the hydroxy group is bonded, preferably during the reduction of the keto group introduced. It is then not necessary, a separation of enantiomers to carry out the resulting alcohol. According to one Embodiment is therefore intended that the inorganic Adsorbent is an achiral adsorbent. Under a achiral adsorbent is understood to mean an adsorbent in which both enantiomers adsorb essentially the same be so that by the adsorption no separation of the two possible Enantiomers take place. In the method according to the invention can therefore very cheap inorganic adsorbents be used, which is particularly for a technical Application is advantageous.

Prefers the process according to the invention becomes such performed that in the reduction of the keto group resulting alcohol is continuously removed from the reaction mixture becomes. For this purpose, the enzyme may, for example, from the solvent phase be separated. The solvent, which is the mixture contains first and second connection, is with the Inorganic adsorbent brought into contact, so that the second compound through the inorganic adsorbent at least partially removed from the solvent. This can be provided that the reaction mixture in which the enzymatic Reaction is carried out, for example, over a membrane is separated so that the enzyme from a part of the solvent is separated. The solvent is then contacted with the inorganic adsorbent, for example, the solvent over a Column is passed from the inorganic adsorbent was packed so that the solvent phase on the second compound is depleted. The solvent phase depleted in the second compound can then be returned to the reaction mixture become.

According to one Embodiment of the invention Method is provided that the reduction of the keto group to a hydroxy group bonded to a chiral carbon atom performed in the presence of the inorganic adsorbent becomes.

In this embodiment, therefore, the inorganic adsorbent to the reaction mixture to given. The amount of inorganic adsorbent is selected to be sufficiently high, so that a sufficiently large amount of the second compound can be adsorbed on the inorganic adsorbent to adjust the reduction of the keto group of the first compound in favor of the highest possible yield in favor of the second compound.

To the reaction, the reaction mixture can be separated very easily by adding the inorganic adsorbent, for example sediment and the solvent phase, which the enzyme and optionally also shares of the first compound contains, is decanted off. It is also possible the inorganic adsorbent after reduction of the Keto group by filtration from the solvent phase separate.

The inorganic adsorbents are preferably selected that the second connection increased adsorbed to the inorganic adsorbent.

One suitable inorganic adsorbent is, for example, silicon dioxide, which is preferably used in finely dispersed form.

In the process according to the invention, preference is given to using inorganic adsorbents which have an aluminum content, calculated as Al ₂ O _3, of more than 40% by weight. The aluminum may be contained in the inorganic adsorbent in the form of alumina. However, it is also possible that the inorganic adsorbent contains the aluminum in the form of, for example, a mixed oxide. In addition to aluminum, other metals may be included in the inorganic adsorbent, such as silicon. The alumina-containing inorganic adsorbent may be degraded from a natural source, so be a natural mineral. Preferably, however, synthetic compounds are used. These can be produced under controlled conditions and therefore lead to reproducible properties and results in the process according to the invention. The inorganic adsorbent preferably consists predominantly of an aluminum oxide-containing inorganic adsorbent. It is possible that the inorganic adsorbent in addition to the actual adsorbent, for example, contains a binder, which itself may also have no adsorption properties. Preferably, the inorganic adsorbent comprises more than 60 wt .-%, preferably more than 80 wt .-%, more preferably more than 90 wt .-% Al ₂ O ₃ . The difference to 100% could for example be formed in each case by a proportion of a binder, with which the inorganic adsorbent is bound, for example, to a particle. According to a particularly preferred embodiment, the inorganic adsorbent consists only of alumina.

The inorganic adsorbent used in the process according to the invention preferably has a very high specific surface area. Preferably, the inorganic adsorbent has a specific surface area of more than 100 m ² / g. According to a preferred embodiment, the inorganic adsorbent has a specific surface area in the range of 100 to 750 m ² / g, particularly preferably 120 to 700 m ² / g, particularly preferably 140 to 650 m ² / g. The specific surface area is determined by the BET method.

According to a further preferred embodiment, the inorganic adsorbent used in the process according to the invention has a high pore volume. According to a preferred embodiment, the inorganic adsorbent has a pore volume of more than 0.1 ml / g, more preferably a pore volume of more than 0.2 ml / g. The pore volume is calculated as the cumulative pore volume according to BJH ( IP Barret, LG Joiner, PP Haienda, J. Am. Chem. Soc. 73, 1991, 373 ) for pores with a diameter of 1.7 to 300 mm. In one embodiment, the inorganic adsorbent has a pore volume of less than 1.4 ml / g. According to another embodiment of the method, the pore volume of the inorganic adsorbent is less than 1.3 ml / g and in another embodiment less than 1.2 ml / g.

As the alumina-containing component, aluminum oxides, aluminum hydroxides, boehmite or aluminosilicates are preferably used. These compounds can be used in pure form or else in the form of mixtures of the compounds mentioned. As alumina, both α-, γ- and ε-Al ₂ O ₃ can be used. According to one embodiment, aluminum oxides are used as the inorganic adsorbent, with γ-Al ₂ O _{3 being} more preferred. The aluminas can be used in pure form or as a mixture of two or three of said phases. It is possible to use aluminum hydroxides of different composition, which may also have a different degree of dehydration or polymerization. Boehmite is AlOOH.

aluminas and their hydrates can be prepared, for example, by adding basic aluminate solutions by adding acid be neutralized. The precipitation of aluminum hydroxides or their hydrates can by the addition of crystallization nuclei get supported. It is also possible hydrated Aluminum hydroxides from acidic solutions of aluminum salts by adding bases or by combining basic solutions of aluminates with acidic solutions of aluminum salts precipitate. The separated from the aqueous phase hydrated aluminas can then be removed by annealing be converted into aluminum oxides.

A suitable method for producing hydrated aluminas, for example, in WO 01/02297 described.

The Aluminum oxides and their hydrates can also over be prepared a sol-gel process. This can, for example Aluminum alkoxides are hydrolyzed. The hydrolysis can be general performed in a temperature range of 30 to 150 ° C. become. The solid alumina hydrate is separated from the aqueous Alcohol phase separated. The resulting crystals can for example, be aged under hydrothermal conditions.

A suitable method is for example in WO 00/09445 described.

According to one Another preferred embodiment is the alumina-containing Component a synthetic aluminosilicate.

The aluminosilicates preferably have a silicon content, calculated as SiO ₂ , of less than 60% by weight, preferably less than 55% by weight, more preferably less than 50% by weight. According to one embodiment, the silicon content of the aluminosilicate, calculated as SiO ₂ , is more than 0.5% by weight, according to a further embodiment more than 0.75% by weight.

Aluminosilicates can be prepared, for example, by hydrolyzing organic aluminum compounds under acidic conditions and then aged together with silicic acid or silicic acid compounds under hydrothermal conditions. Suitable aluminum compounds are, for example, aluminum alcoholates, aluminum hydroxyalcoholates, aluminum acetylacetonates, aluminum alkyl chlorides or else aluminum carboxylates. A suitable method is for example in US 6,245,310 B1 described.

In order to obtain particularly pure aluminosilicates, it is also possible to use hydrolyzable organosilicon compounds instead of silica, the hydrolysis of the organosilicon compounds and of the hydrolyzable aluminum compounds being carried out together. Such a method is for example in the EP 0 931 017 B1 described.

Particular preference is given to using aluminosilicates which contain only SiO ₂ and Al ₂ O ₃ as constituents. The proportion of other metals, calculated as the most stable oxide, is preferably chosen to be less than 1% by weight.

The inorganic adsorbent can be in the form of a Powder be provided. The particle size of the powder is generally adjusted so that the inorganic Adsorbents without difficulty with a suitable method, such as filtration, within a suitable period of time can be separated from the reaction mixture.

Especially for an application of the inorganic adsorbent but in the form of a column packing are also higher Grain sizes suitable. For this purpose, the inorganic adsorbent preferably used in the form of granules. Especially for the preparation of column packs is preferred Granules used, which has a particle size of more than 0.1 mm. The granules preferably have a particle size in the range of 0.2 to 5 mm, particularly preferably 0.3 to 2 mm on. The grain size can be, for example set by sieving.

The Granules can be prepared by conventional methods, by, for example, the finely ground inorganic adsorbent with a granulating agent, such as water, applied and then in a conventional granulating in a mechanical produced fluidized bed is granulated. It can, however Other methods are used to produce the granules. Thus, the powdery inorganic adsorbent be formed for example by compaction to a granulate.

The Inorganic adsorbents can also be used as shaped bodies be prepared, for example, by extrusion of a plastic mass can be obtained. This will be off the alumina-containing component and optionally further components, such as a binder, by adding a liquid, preferably water, a paste made. This paste is then extruded and crushed the extrudate, for example by the extruded strand into short cylindrical pieces is cut, and then dried, the obtained shaped bodies. In addition to massive cylinders z. B. also hollow cylinder getting produced.

To The shaping can be the granules or the shaped bodies are still heat treated and, for example, by heating be sintered. As a result, the stability of the granules or the molded body can be increased. For the Heat treatment, the moldings or the Granules preferably at a temperature of more than 300 ° C, according to a further embodiment to a temperature of more than 400 ° C, and according to still a further embodiment to a temperature of heated more than 500 ° C. According to one embodiment the temperature is lower than 1200 ° C, according to a further temperature less than 1000 ° C chosen.

Around To obtain stable shaped bodies, is the heat treatment preferably for a period of at least 30 minutes, according to a another embodiment for a period of at least 60 minutes. According to one embodiment the duration of treatment is chosen to be less than 5 hours.

As already explained, the inorganic adsorbent be added directly to the reaction mixture, this according to a Embodiment moves, such as shaken becomes.

According to one Another embodiment is the inorganic adsorbent provided in the form of a column packing. The reaction mixture can then be passed through the column packing. The solvent depleted in the second compound can then according to one embodiment again be returned to the reaction mixture.

The Column packing, for example, in the form of a cartridge to be provided. In the practical implementation can the reaction mixture or the solvent, of which before the enzyme was separated, then through the cartridge be passed until the adsorption capacity of the cartridge exhausted contained inorganic adsorbent is. The cartridge can then easily replaced with a new cartridge become. The in the cartridge on the inorganic adsorbent adsorbed second compound can then be treated with a suitable eluent be eluted.

Becomes the inorganic adsorbent in the form of a column packing provided, the inorganic adsorbent in the form of larger Grains provided to an excessive Prevent pressure drop across the column packing.

at This embodiment therefore becomes the inorganic adsorbent preferably used in the form of granules having a particle diameter of more than 0.1 mm, particularly preferably a particle diameter in the range of 0.2 to 5 mm.

It may also be advantageous to the inorganic adsorbent to heat a higher temperature to physically bound To remove water. For this purpose, according to one embodiment the inorganic adsorbent at a temperature of more be heated as 600 ° C. According to one Embodiment, the temperature is less than 1000 ° C. selected. By such treatment, for example in the case of boehmite, the superficially bound first Water are removed and the hydrate converted into an oxide phase become.

The The invention will be further described by way of examples and by reference explained in more detail on the accompanying figures. The figures show in detail:

1 : a schematic representation of an apparatus for carrying out the method according to the invention;

2 Fig. 3 is a graph showing the concentration of 2,5-hexanedione and 2,5-hexanediol bound from adsorbent 3 solution in ethyl acetate;

3 FIG. 3: a diagram in which the concentration of 2,5-hexanedione and 2,5-hexanediol are indicated which is bound from a solution in ethyl acetate to adsorbent 5;

4 a chromatogram for a separation of 2,5-hexanedione and 2,5-hexanediol on adsorbent 5;

5 Figure 3 is a graph showing the concentration of 2,5-hexanediol in the supernatant upon adsorption of 2,5-hexanediol from a mixture of toluene and 10% vv- ¹ 2-propanol for various adsorbents;

6 Figure 3 is a graph showing the change in pH upon the addition of various adsorbents to various solvents;

7 Figure 3 is a graph showing the adsorption of NADH from an aqueous potassium phosphate buffer;

8th Figure 3 is a graph showing the adsorption of NADH from a mixture of a potassium phosphate aqueous buffer and isopropanol;

9 Figure 3 is a graph showing the change in concentration of 2,5-hexanedione and 2,5-hexanediol during an enzymatically catalyzed reduction, the reaction being conducted without the presence of an inorganic adsorbent;

10 Fig. 2 is a graph showing the change in the concentration of 2,5-hexanedione and 2,5-hexanediol during an enzymatically catalyzed reduction, the reaction being carried out in the presence of an inorganic adsorbent.

1 shows a structure in which the inventive method can be performed. In a reactor 1 is a reaction mixture 2 containing an organic solvent in which a first compound having a prochiral keto group is dissolved, and a second compound comprising a hydroxy group bonded to a chiral carbon atom and resulting from the first compound. Next contains the mixture 2 an alcohol dehydrogenase and a sacrificial alcohol, for example isopropanol. Next includes the mixture 2 a water phase in which a cofactor, for example NADP ⁺ , is dissolved. The mixture is passed through a stirrer 3 emotional. About a drain 4 will be the mix 2 from the reactor 1 taken and in a separator 5 with the help of a membrane 6 divided into a portion that contains the enzyme and that via a return line 7 back to the reactor 1 recycled, and a portion containing the organic solvent, but no enzyme, and that via a feed line 8th an adsorber cartridge 9 is supplied. The adsorber cartridge 9 is packed with an inorganic adsorbent material, for example, alumina, so that the second compound partially adsorbs to the inorganic adsorbent material and thus depleted of the organic solvent on the second compound. The organic solvent, which still contains a portion of the first compound, is then returned 10 back to the reactor 1 returned.

On top of that in the absorber cartridge 9 Being able to elute absorbed product is a feed 11 for an eluant and a drain 12 provided over which the loaded with the product eluent can be removed. This is the over the reactor 1 leading circuit of the solvent stopped and the absorber cartridge 9 rinsed with eluent, which via feed 11 fed and over expiration 12 is dissipated.

Determination of physical parameter

The physical properties of the inorganic adsorbent were determined by the following methods:

BET surface area / pore volume after BJH and BET:

The Surface and pore volume were combined with a fully automatic Nitrogen porosimeter Micromeritics type ASAP 2010 determined.

The sample is cooled in a high vacuum to the temperature of liquid nitrogen. Subsequently, nitrogen is continuously metered into the sample chambers. By recording the adsorbed amount of gas as a function of pressure, an adsorption isotherm is determined at constant temperature. In a pressure equalization, the analysis gas is gradually removed and a desorption isotherm is recorded.

To determine the specific surface area and the porosity according to the BET theory, the data according to DIN 66131 evaluated.

The pore volume is also determined from the measurement data using the BJH method ( IP Barret, LG Joiner, PP Haienda, J. Am. Chem. Soc. 73, 1991, 373 ). This procedure also takes into account effects of capillary condensation. Pore volumes of certain volume size ranges are determined by summing up incremental pore volumes obtained from the evaluation of the BJH adsorption isotherm. The total pore volume by BJH method refers to pores with a diameter of 1.7 to 300 nm.

Water content:

The water content of the products at 105 ° C is determined using the method DIN / ISO 787/2 determined.

Loss on ignition:

In a annealed weighed porcelain crucible with lid will Approximately 1 g of dried sample weighed to the nearest 0.1 mg and for 2 h annealed at 1000 ° C in a muffle furnace. After that will the crucible in the desiccator cooled and balanced.

Determination of bulk density

One at the 1000 ml mark truncated graduated cylinder is weighed. Then the sample to be examined is determined by means of a powder funnel so filled in the measuring cylinder in a train that above the completion of the measuring cylinder a cone of material formed. The pour cone is made with the help of a ruler, that passed over the opening of the measuring cylinder is stripped off and the filled measuring cylinder again weighed. The difference corresponds to the bulk density.

Used inorganic adsorbent materials:

In the following examples, a number of synthetic alumina compounds were used. As a first group of commercially available aluminosilicates were tested, which are available under the designations 40 ^® Siral 5, Siral 30 ^{®, ®} Siral. Furthermore, a boehmite was tested, which is sold under the name Pural ^® SCC 150. As a further adsorbent aluminas were used, which are offered under the name Puralox ^® . These adsorbents were purchased from Sasol Germany GmbH, Ankelmannsplatz 1, 20537 Hamburg, DE. Finally, aluminum oxides were used, as they are commonly used for chromatographic separation processes (manufacturer Macherey-Nagel, Düren, DE). As a comparative material, a commercially available silica gel for column chromatography was tested, which was obtained from Sigma-Aaldrich. Silica gel Merck type 9385, 230-400 mesh, 60 Å pore diameter, EC: 231-545-4.

The following designations are used below for the inorganic adsorber materials investigated: Table 1: Adsorber materials used Adsorbent 1 Siral 5 ^® (Sasol, Hamburg, DE) Adsorbent 2 Siral ^® 30 (Sasol, Hamburg, DE) Adsorbent 3 Siral ^® 40 (Sasol, Hamburg, DE) Adsorbent 4 Pural ^® SB (Sasol, Hamburg, Germany) Adsorbent 5 Puralox® ^® KR-160 (Sasol, Hamburg, Germany) Adsorbent 6 Pural SCC ^® 150 (Sasol, Hamburg, DE) Adsorbent 7 Puralox ^® SCCa-150/230 (Sasol, Hamburg, DE) Adsorbent 8 Alumina neutral (Macherey-Nagel, Düren, DE) Adsorbent 9 Aluminum oxide basic (Macherey-Nagel, Düren, DE) Adsorbent 10 Silica gel (Sigma-Aldrich)

The Properties of the adsorbents are summarized in Table 2.

Example 1: Adsorption of 2,5-hexanedione and 2,5-hexanediol on inorganic adsorbents when used different solvents

It was the adsorption of a mixture of 2,5-hexanedione and 2,5-hexanediol, each solved in different solvents was examined on the adsorbent 3 and the adsorbent 5.

• a) destilliertes Wasser
• b) Gemisch aus 18% vv^–1 2-Propanol und KP_I-Puffer 100 mM, pH 7,0
• c) Ethylacetat
• d) Toluol

The following solvents were tested:

• a) distilled water
• b) Mixture of 18% vv ^-1 2-propanol and KP _I buffer 100 mM, pH 7.0
• c) ethyl acetate
• d) toluene

General procedure:

Out The solvents to be examined in each case one Solution prepared containing a concentration of 50 mM 2,5-hexanedione or 50 mM 2,5-hexanediol.

Each 15 ml of the solution were at room temperature (20 ° C) offset with a defined amount of the adsorbent. The addition of the Adsorbent was either once or in several portions at a certain time interval. After addition of the adsorbent The suspension was stirred at 150 rpm on a rotary shaker incubated at room temperature. After a certain time has elapsed a sample was taken, the adsorbent separated by centrifugation and the supernatant analytically by gas chromatography or in the spectrophotometer at 340 nm (on examination of the cofactor NADH). When measured in the gas chromatograph was the Sample amount 70-100 μL.

The respectively used experimental conditions and the results are in the following tables.

a) Adsorption from water

The investigation was carried out according to the general rule given above. A solution containing 50 mmol of 2,5-hexanediol but no 2,5-hexanedione was used. At the beginning of the experiment, 3.0 g of adsorbent were added once. After sampling, the reaction mixture was further incubated at room temperature. The measured concentrations are summarized in Table 3. Table 3: Supernatant concentrations measured on adsorption of 2,5-hexanediol from water Time (min) 2,5-hexanediol (mM) Adsorbent 3 Adsorbent 5 20 52.88 53.34 150 51.84 53.57 270 48.44 49.05

b) Adsorption from KP _i buffer / isopropanol

The investigation was carried out according to the general rule given above. A solution containing 50 mmol of 2,5-hexanediol but no 2,4-hexanedione was used. At the beginning of the experiment, 3.0 g of adsorbent was added. After 20 h, an additional 0.5 g of adsorbent was added. The results are summarized in Table 4. Table 4: Adsorption of 2,5-hexanediol from KP _i buffer / isopropanol Time (min) 2,5-hexanediol (mM) Adsorbent 3 Adsorbent 5 20 50.71 50.74 1200 47,70 48.36 1475 50.11 52.22

Also from a Kp _i buffer, no significant adsorption of 2,5-hexanediol to the adsorbents investigated.

c) Adsorption from ethyl acetate

The Examination was carried out according to the above general Regulation carried out. In a first series of experiments became a stock solution with 51.45 mM 2,5-hexanedione and 48.65 mM 2,5-hexanediol, in a second series of experiments with 50.68 mM 2,5-hexanedione and 53.85 mM 2,5-hexanediol. At the beginning of the experiment 0.5 g of adsorbent was added to the solution. In the distance of Each additional 0.5 g of the adsorbent was added for 30 minutes.

The concentrations determined are shown in Tables 5a and 5b. Table 5a: Adsorption of 2,5-hexanediol / 2,5-hexanedione from ethyl acetate; 51.45 mM 2,5-hexanedione and 48.65 mM 2,5-hexanediol Adsorbent 3 Adsorbent 5 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] Hexanedione [mM] Hexanediol [mM] 30 0.5 49,30 36.74 50.69 37.34 60 1.0 47.68 29,75 50.32 28.40 90 1.5 46,65 25.50 50,53 21,90 120 2.0 49.88 20.86 46.64 25.40 1419 2.0 50.32 18.31 50.32 18.31 Table 5a (continued) Adsorbent 8 Adsorbent 9 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] Hexanedione [mM] Hexanediol [mM] 30 0.5 50.68 38.66 51.23 39.34 60 1.0 50.58 29.48 50.47 29.24 90 1.5 49.51 20.52 49.27 20.57 120 2.0 51.72 14.06 50.58 20.94 1419 2.0 51.06 18.15 50.64 18.62 Table 5b: Adsorption of 2,5-hexanediol / 2,5-hexanedione from ethyl acetate; 50.68 mM 2,5-hexanedione and 53.85 mM 2,5-hexanediol Adsorbent 4 Adsorbent 6 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] Hexanedione [mM] Hexanediol [mM] 30 0.5 50.65 41,80 50.19 45.53 60 1.0 49.28 30.36 48.09 34.91 90 1.5 48.56 24.35 48.38 31.06 120 2.0 48.96 21.68 49.13 27.14 180 2.0 48,99 16.97 48.38 22.83 300 2.0 47.11 17.56 49.21 22.93 Table 5b (continued) Adsorbent 7 Adsorbent 8 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] Hexanedione [mM] Hexanediol [mM] 30 0.5 50,35 44.32 50.39 45,04 60 1.0 49.10 29.93 49.85 34,60 90 1.5 49.04 23.36 49,40 28.37 120 2.0 48.84 17.52 49.29 22.63 180 2.0 49.42 12.33 50.02 17.50 300 2.0 51.46 13.18 51.67 17.55 Table 5b (continued) Adsorbent 9 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] 30 0.5 50.06 45.14 60 1.0 49.63 34.24 90 1.5 49.61 27.57 120 2.0 49.52 20.78 180 2.0 50.64 15.88 300 2.0 51.24 15.70 Table 5c: Adsorption of 2,5-hexanediol / 2,5-hexanedione from ethyl acetate; 51.23 mM 2,5-hexanedione and 48.67 mM 2,5-hexanediol Adsorbent 10 Time [min] Carrier [g] Hexanedione [mM] Hexanediol [mM] 30 0.5 48.89 32.94 60 1.0 47.63 31.84 90 1.5 46.14 29.03 120 2.0 46.96 28.54 150 2.0 45,26 26,86

In contrast to the aqueous or aqueous / organic medium, when using ethyl acetate as the solvent, the diol was preferably adsorbed. This can be shown for both boehmite, boehmite SiO ₂ mixed phases, γ-Al ₂ O ₃ , as well as for the amorphous Al-oxides.

By way of example, the adsorption capacities for two of the carriers under the experimental conditions mentioned are graphically in the 2 and 3 shown.

Example 2: Use of the Adsorbent 5 in a chromatography column

2,5-hexanedione and 2,5-hexanediol in a concentration of 50 mM were dissolved in ethyl acetate and applied to a column packed with 4.1 g of adsorbent 5 and equilibrated with ethyl acetate (length 24 cm, diameter: 0.7 cm). given. The mixture was then eluted with ethyl acetate as eluent. The 2,5-hexanedione was first eluted from the column and thereby completely separated from the 2,5-hexanediol. The chromatogram with the elution peak for 2,5-hexanedione is in 4 shown. The eluent for the 2,5-hexanediol is methanol or acetonitrile.

Example 3: Adsorption tests from toluene

A solution of 50 mM 2,5-hexanediol in toluene was prepared and added to 15 ml of this solution 0.5 g of the adsorbent to be examined. Subsequently, the suspension was incubated at 150 rpm on a rotary shaker at room temperature. After 30 minutes, the adsorbent was separated by centrifugation at 4 ° C for 5 minutes. From the clear supernatant, 100 μL was transferred to a sample jar. The remainder of the supernatant was added to 0.5 g of fresh adsorbent and incubated at the above conditions for an additional 30 minutes. The adsorbent was again separated by centrifugation and the supernatant was measured by gas chromatography. In the further course of the experiment, an additional 0.5 g of the adsorbent was added every 30 minutes and the suspension was incubated for a further 30 minutes at room temperature. This process was repeated two more times, wherein before the addition of the adsorbent in each case the concentration of 2,5-hexanediol in the supernatant was determined in the manner described above. The experimental data and the concentrations determined are shown in Table 6. The decrease in the concentration of 2,5-hexanediol in the supernatant is also in 5 graphically reproduced.

With several of the adsorbents could be used at a rate of 2.0 g Concentration of 2,5-hexanediol in the supernatant of 50.00 mM be reduced to 10.21 mM.

Example 4: Adsorption of the Cofactor NADH

Around the suitability of the adsorbents for an enzymatic process for a conversion of ketones to chiral alcohols below Use of the enzyme ADH-'A 'from Rhodococcus ruber DSM 44541 to test was the adsorption of the cofactor used in this system NADH examined.

In order to investigate the influence of the adsorbents on the pH of the solutions, initially 3 g of adsorbent 3 or 1.5 g of adsorbent 5 were added to 15 ml each of potassium phosphate buffer (100 mM) or distilled water. The suspensions were agitated at room temperature at 150 rpm for 60 minutes on a reaction shaker. The adsorbent was separated by centrifugation and the pH of the clear supernatant was determined with a glass electrode. Subsequently, the adsorbent was slurried in fresh suspending agent and incubated again at the above conditions for 60 minutes. This procedure was repeated several times. The values determined in the treatment with water are given in Table 7 and the values determined in the case of treatment with potassium phosphate buffer in Table 8. Table 7: Change in pH by rinsing the adsorbents with distilled water Minute Ads. 3 Ads. 4 Ads. 5 Ads. 6 Ads. 7 Ads. 8th Ads. 9 60 3.60 6.99 8.29 4.58 8.31 6.74 10.10 120 3.78 7.47 8.56 5.03 8.73 7.48 10.54 180 3.79 7.05 8.04 4.56 7.41 7.71 10.24 Table 8: Change in the pH by flushing the adsorbents with enzyme buffer (KP _i buffer) Minute Ads. 3 Ads. 4 Ads. 5 Ads. 6 Ads. 7 Ads. 8th Ads. 9 60 6.29 8.58 9.55 7.36 8.80 7.95 8.58 120 6.94 8.29 8.78 7.34 8.67 7.97 8.02 180 7.00 7.50 7.84 7.17 7.90 7.60 7.50

The determined pH values are exemplary for the adsorbents 3 and 5 in 6 graphically reproduced.

For the measurement of the adsorption of NADH to the adsorbent 3 or the adsorbent 5, 20 ml of the reaction mixture indicated in Table 9 were added to 4 g of adsorbent and the suspension was incubated at 150 rpm on a rotary shaker at room temperature. Samples were taken at regular intervals, the support separated by centrifugation and the supernatant measured photometrically at 340 nm. The determined concentrations are graphically in the 7 (Approach 1) and 8th (Approach 2). Table 9: Composition of reaction mixtures to study the adsorption of NADH on various adsorbents Approach 1 Approach 2 20 mL 0.1 M KP _i buffer pH 7.0 16.4 mL 0.1 M KP _i buffer pH 7.0 3.6 mL of 2-propanol 14.2 mg NADH 14.2 mg NADH

Like the ones in the 9 and 10 As shown in the data presented, the cofactor is not adsorbed by the adsorbents in significant quantities.

Example 5: Execution of a enzymatically catalyzed reduction of 2,5-hexanedione in the presence of adsorbents

To investigate the influence of adsorbents on the enzymatic reduction of 2.5 hexane dione was a supported alcohol dehydrogenase ADH-'A 'is used, wherein as a carrier for the enzyme porous glass particles TRISOPERL ^® (VitraBio, Steinach, D) were used. The immobilization of the ADH-'A 'on the glass particles is described in Goldberg, K .; Krueger, A .; Meinhardt, T .; Kroutil, W .; Mautner, B. & Liese, A. (2008), Novel immobilization routes for the covalent binding of anhydrogen dehydrogenase from Rhodococcus ruber DSM 44541 ', Tetrahedron: Asymmetry 19 (10), 1171-1173 ,

The cofactor was used as the stock solution, but 14.2 mg NADH were dissolved in 200 μL KPi buffer. The reaction medium (toluene) was saturated with KP _i buffer, for 30 ml of toluene with 10 mL of KP _i buffer (100 mM, pH 7.0) were mixed, and the toluene removed and used in the experiment.

First, the supported enzyme was mixed with 100 μL NADH stock solution. Next, 8.8 mL of toluene (saturated with buffer) and 1 mL of 2-propanol (10% vv- ¹ ) were added. The reaction was started by adding 97 μL hexanedione (80 mM). The sample was incubated at 30 ° C and 150 rpm on the rotary shaker.

For the determination of the concentration of 2,5-hexanedione and 2,5-hexanediol were the reaction mixture at certain intervals each 50 μL sample taken. The sample was filled with 50 μL Toluene diluted and measured by gas chromatography.

In a first series of experiments, the conversion of the reaction was investigated without addition of adsorbent. Under these conditions, the enzyme was intact and the concentration of 2,5-hexanedione decreased with increasing reaction time, while 2,5-hexanediol formed. The concentration of 2,5-hexanedione or 2,5-hexanediol is in 9 graphically represented as a function of time.

In a second series of reactions, the experiment was repeated, but in addition 3 g of adsorbent 5 were added. The decrease in the diketone concentration in the supernatant over time also indicates a functioning enzymatic conversion, the concentration of 2,5-hexanediol in the supernatant was lower. It can be assumed that the enzymatic product is bound to the adsorbent 5. The concentration of 2,5-hexanedione or 2,5-hexanediol is in 12 graphically represented as a function of time.

LIST OF REFERENCE NUMBERS

1

reactor

2

reaction

3

stirrer

4

outflow

5

separator

6

membrane

7

return

8th

supply

9

adsorption

10

return

11

Intake eluent

12

procedure eluent

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• EP 1568780 B1 [0008]
• - DE 102006010994 A1 [0011]
• WO 01/02297 [0044]
• WO 00/09445 [0046]
• - US 6245310 B1 [0049]
• - EP 0931017 B1 [0050]

Cited non-patent literature

• - Lyases. K. Goldberg, K. Schroer, S. Lütz and A. Liese, Appl. Microbiol. Biotechnol. (2007) 76: 237-248 [0003]
• K. Goldberg, K. Schroer, S. Lütz and A. Liese in Appl. Microbiol. Biotechnol. (2007) 76: 249-255 [0004]
• - JT Vincenzi, MJ Zmijewski, MR Reinhard, BE Landen, WL Muth and PG Marler, Enzyme and Microbiol. Technology 20: 494-499, 1997 [0010]
• - IP Barret, LG Joiner, PP Haienda, J. Am. Chem. Soc. 73, 1991, 373 [0041]
• - DIN 66131 [0080]
• - IP Barret, LG Joiner, PP Haienda, J. Am. Chem. Soc. 73, 1991, 373 [0081]
• - DIN / ISO-787/2 [0082]
• Goldberg, K .; Krueger, A .; Meinhardt, T .; Kroutil, W .; Mautner, B. & Liese, A. (2008), 'Novel immobilization routes for the covalent binding of an alcohol dehydrogenase from Rhodococcus ruber DSM 44541', Tetrahedron: Asymmetry 19 (10), 1171-1173 [0108]

Claims (16)

Process for separating a mixture with a dissolved in a solvent first compound, which at least one keto group, and a second compound, which comprises a chiral carbon atom having a hydroxy group, by stereoselective reduction of the keto group from the first Compound is formed, the mixture with an inorganic Adsorber material is brought into contact and at least a part of the second compound adsorbed on the inorganic adsorbent material and a mixture depleted in the second compound is separated from the inorganic adsorbent material. The method of claim 1, wherein the solvent an organic solvent. The method of claim 2, wherein the organic solvent is substantially immiscible with water. Method according to one of claims 1 to 3, wherein the reduction of the keto group to that at a chiral carbon atom bonded hydroxy group is carried out under catalysis by an enzyme. The method of claim 4, wherein the reduction of Keto group to the attached to a chiral carbon hydroxy group by the enzyme in the presence of a cofactor. A method according to claim 4 or 5, wherein the enzyme an alcohol dehydrogenase. The method of claim 6, wherein the cofactor is in a water phase is dissolved and the water phase next to the organic solvent in a proportion of less as 1 wt .-%, based on the organic solvent contained in the mixture. A method according to claim 6 or 7, wherein the mixture contains a sacrificial alcohol for the regeneration of the cofactor. The method of claim 8, wherein the sacrificial alcohol has a lower molecular weight than the second compound. Method according to one of the preceding claims, wherein the inorganic adsorbent is an achiral adsorbent is. Method according to one of the preceding claims, wherein the reduction of the keto group to one at a chiral carbon atom bonded hydroxy group in the presence of the inorganic adsorbent is carried out. Method according to one of the preceding claims, wherein the inorganic adsorbent has an aluminum content, calculated as Al ₂ O ₃ of more than 40 wt .-%. A method according to any one of the preceding claims, wherein the inorganic adsorbent has a specific surface area greater than 100 m ² / g. Method according to one of the preceding claims, wherein the inorganic adsorbent material has a pore volume of more than 0.2 ml / g, determined as cumulative pore volume after BJH for pores with a diameter of 1.7 to 300 nm. Method according to one of the preceding claims, wherein the inorganic adsorbent material is an aluminum silicate. Method according to one of the preceding claims, wherein after the separation of the depleted at the second compound Mix the second adsorbed on the inorganic adsorber Compound is desorbed from the inorganic adsorber.

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