WO2011003607A2 - Procédé de séparation de mélanges alcool-cétone - Google Patents

Procédé de séparation de mélanges alcool-cétone Download PDF

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Publication number
WO2011003607A2
WO2011003607A2 PCT/EP2010/004155 EP2010004155W WO2011003607A2 WO 2011003607 A2 WO2011003607 A2 WO 2011003607A2 EP 2010004155 W EP2010004155 W EP 2010004155W WO 2011003607 A2 WO2011003607 A2 WO 2011003607A2
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Prior art keywords
adsorbent
compound
inorganic
mixture
reduction
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German (de)
English (en)
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WO2011003607A3 (fr
Inventor
Kirstin Suck
Ulrich Sohling
Friedrich Ruf
Andreas Liese
Katja Goldberg
Paul Bubenheim
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Sued Chemie AG
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Sued Chemie AG
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Priority to EP10731478A priority Critical patent/EP2451761A2/fr
Publication of WO2011003607A2 publication Critical patent/WO2011003607A2/fr
Publication of WO2011003607A3 publication Critical patent/WO2011003607A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/04—Preparation of oxygen-containing organic compounds containing a hydroxy group acyclic
    • C12P7/18—Preparation of oxygen-containing organic compounds containing a hydroxy group acyclic polyhydric
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/265—Adsorption chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/06—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04
    • B01J20/08—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04 comprising aluminium oxide or hydroxide; comprising bauxite
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/10—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate
    • B01J20/16—Alumino-silicates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment

Definitions

  • 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 having a hydroxy group which has arisen by reduction of the keto group from the first compound.
  • Chiral hydroxy compounds are valuable building blocks for the preparation of pharmaceutically active compounds. Chiral compounds are usually difficult to prepare enantiomerically pure by classical chemical methods. If, in a synthesis step, both enantiomers are formed, they must subsequently be subjected to complex separation processes
  • Suitable enzymes are oxidoreductases, hydrolases and lyases.
  • Redox reactions that is reactions in which electrons are transferred to or from the substrate.
  • Oxireduktases include, among others, the alcohol dehydrogenases (ADH), which are also referred to as carbonyl reductases (CR). Alcohol dehydrogenases, for example, catalyze the reduction of prochiral ketones to chiral alcohols.
  • ADH alcohol dehydrogenases
  • CR carbonyl reductases
  • a co-substrate is a compound which is oxidized enzymatically as a reducing agent, the released electrons being transferred to NAD or NADP, which are thereby regenerated to NADH or NADPH.
  • the enzymes can also be recovered so that they can be used in a further reaction.
  • EP 1 568 780 Bl a method for the
  • keto compound is first in an aqueous reaction medium, which in addition to water
  • Reducing agent alcohol dehydrogenase and coenzyme, reduced to a secondary alcohol.
  • 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 becomes
  • Enzymatic reactions are equilibrium reactions, that is, they occur during the course of the reaction
  • thermodynamic equilibrium 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 deactivation or reduction of the synthesis activity, it is possible to remove the product in situ from the reaction mixture, so that the equilibrium is shifted to the side of the product. This can be done for example by a gaseous
  • 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 on the
  • Reaction mixture is achieved.
  • 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.
  • DE 10 2006 010 994 Al a method for enzymatic
  • Oxireduktase is associated and which is separated from the reaction mixture after the end of the reaction.
  • Examples is used as an adsorbent for the enzyme diatomaceous earth (Celite ®). 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.
  • Celite ® diatomaceous earth
  • the invention therefore an object of the invention to provide a method for separating a mixture of a ketone and an obtained from the ketone by reduction optically active alcohol available, which can be carried out easily and inexpensively.
  • This object is achieved by a method having the features of patent claim 1.
  • Advantageous embodiments of the method are the subject of the dependent claims.
  • the invention was based on the observation that ketones are less strongly bound by inorganic adsorbents than alcohols. Inorganic adsorbents are generally inexpensive and available in large quantities. The process can therefore also be adapted very easily to industrial standards, without high cost pressure from the
  • Provision of the inorganic adsorbent is triggered.
  • the method is therefore particularly suitable for the provision of such optically active alcohols, which u. a. used as building blocks for the production of fine chemicals, for example for the chemical industry, where profit margins are limited by relatively high competitive pressure.
  • Keto group originated from the first compound, to
  • the mixture is brought into contact with an inorganic adsorbent material and at least a part of the second compound to the inorganic
  • Adsorber material is adsorbed, and a depleted in the second compound mixture of the inorganic
  • Adsorber material is separated.
  • Carbon atom of the keto group is introduced, for example by using asymmetric catalysts.
  • the carbon skeleton of the first compound is substantially retained, so that the first compound and the second compound preferably differ in their structure only at the carbon atom of the keto group of the first compound which is converted into an optically active alcohol.
  • the highest possible stereoselectivity is sought.
  • the mixture preferably 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, and the second compound, ie the optically active alcohol, is then brought into contact with an inorganic adsorbent material.
  • Adsorber material is selected so that it preferably has the highest possible adsorptive power in favor of the alcohol, so the second compound.
  • inorganic adsorbent materials are aluminum oxides
  • Alumina hydrates such as aluminosilicates, magnesium silicates, calcium silicates and
  • Hydrotalcites The mixture is so long with the inorganic Adsorber material brought into contact that at least one
  • Adsorber material is adsorbed and thus the mixture is depleted in the second compound.
  • the second compound is thus removed from the reaction, so that in the case of an equilibrium reaction the equilibrium in favor of
  • Adsorber material can compete, the inventive method according to an embodiment is preferably carried out in such a way that as an organic solvent
  • Solvent is used. Particular preference is given to using organic solvents which have no protonatable or deprotonatable groups.
  • the organic solvent is selected so that it has a lower polarity than the alcohol resulting from the reduction.
  • Used solvents which have a relatively low polarity Such solvents are characterized by a relatively low boiling point at atmospheric pressure. Preference is given to using organic solvents which are added at
  • Normal pressure have a boiling point of less than 9O 0 C, preferably less than 80 0 C, particularly preferably less than 70 0 C.
  • 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 aromatic hydrocarbons, such as toluene.
  • the solvents used are those organic solvents which are substantially immiscible with water.
  • organic solvents which are substantially immiscible with water such organic ones are preferred
  • Used solvent which is less than 5 wt .-% at 20 0 C and atmospheric pressure, less than 2 wt .-%,
  • Embodiment the mixture contains larger amounts of water, therefore, two phases are formed, wherein the reduction of the keto group to the chiral hydroxy group takes place substantially in the organic phase.
  • the inventive method can also be the implementation of polar
  • Catalysts are used. According to a preferred embodiment
  • the reduction of the keto group to the hydroxy group bonded to a chiral carbon atom is carried out in such a manner that the reduction occurs under catalysis by an enzyme.
  • Enzymes have a high regio- as well
  • the enzymes are preferably selected from the class of the oxidoreductases.
  • Oxireduktase becomes dependent on the substrate
  • the enzymes can be used both in isolated and possibly purified form as well as in cells, so that the reduction of the keto group is carried out in the form of a fermentation. As such, the method according to the invention is not subject to any restrictions here. If the enzymes are used in substance, they can both in shape
  • bonded form that is, in a form in which the enzyme is bound to a solid matrix.
  • the skilled person can refer here to known techniques.
  • the enzymatic reduction by oxidoreductases generally requires the presence of a cofactor which is consumed in the reduction in stoichiometric amount. According to one embodiment it is therefore envisaged that the reduction of the keto group to the hydroxy group bound to a chiral carbon is effected by the enzyme in the presence of a cofactor.
  • Cofactors used are conventional cofactors. Exemplary cofactors are NADH and NADPH. However, it is also possible to use other known cofactors.
  • an alcohol dehydrogenase is used as the enzyme for the stereoselective reduction of the ketone.
  • the alcohol dehydrogenase is selected depending on the substrate. Suitable alcohol dehydrogenases are, for example, yeast alcoholdehydrogenase (YADH),
  • ADH-A alcoholdehydrogenase A
  • LbADH 6-hydroxyhexanoic acid dehydrogenase
  • HCADH 6-hydroxyhexanoic acid dehydrogenase
  • CPCR carbonyl reductase
  • the alcohol dehydrogenases are recovered by conventional methods. Preferably, such alcohol dehydrogenases are used, which also in organic solvents, the reduction of the keto group to a chiral
  • Water phase can be performed. This may be required, for example, to solve a very polar cofactor, such as NAD + or NADP + .
  • 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
  • the water phase is in a proportion of at least 0.1 wt .-%, based on the organic solvent
  • Water phase is chosen according to an embodiment at least so large that the cofactor can be completely dissolved in the water phase.
  • the cofactor can be dissolved, for example, only in the reduced form in the water phase and, after its oxidation, back into the organic phase pass. But it may also be that the cofactor in both the reduced and the oxidized form in the
  • Water phase is included and the enzyme-catalyzed reduction of the ketone takes place at a boundary phase between the organic phase and the water phase.
  • Water phase is dispersed in finely divided form in the organic phase.
  • 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 is oxidized during the enzymatic reaction.
  • Cofactors are consumed in stoichiometric amounts as discussed 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 cycled between its oxidized and its reduced state.
  • the regeneration of the cofactor can be carried out by conventional methods.
  • the regeneration can be done electrochemically.
  • formic acid or formates may be through
  • Formate dehydrogenase are oxidized to carbon dioxide. Next can be used as a reducing agent, for example, glucose or glucose-6-phosphate, which by
  • Glucose dehydrogenase or glucose-6-phosphate dehydrogenase are oxidized to the corresponding sugar acids.
  • the regeneration of the cofactor is also by an alcohol dehydrogenase
  • the alcohol dehydrogenase can be used both for the reduction of the ketone to the chiral alcohol and for the oxidation of a so-called sacrificial alcohol to the corresponding ketone.
  • the mixture as a further constituent of a sacrificial alcohol for
  • Regeneration of the cofactor contains.
  • lower secondary alcohols are preferably used, which preferably comprise 3 to 10 carbon atoms, more preferably isopropanol or isobutanol.
  • the alcohol used can be used in excess. According to one
  • the proportion of the sacrificial alcohol in the mixture is less than 25 wt .-%, preferably less than 10 wt. ⁇ %, particularly preferably less than 5 wt .-%, based on the organic solvent, which does not participate in the enzymatic reduction.
  • the sacrificial alcohol is used at least in an amount in the mixture which corresponds to twice the stoichiometric amount, particularly preferably at least three times the stoichiometric amount required for the regeneration of the cofactor.
  • Sacrificial alcohol has a lower molecular weight than the second compound.
  • the molecular weight of the sacrificial alcohol is less than 75%, more preferably less than 55%, of the molecular weight of the second compound.
  • the inorganic adsorbent is an achiral adsorbent. Under an achiral adsorbent is a
  • Adsorbent understood in which both enantiomers are adsorbed substantially the same, so that by the
  • the process according to the invention is preferably carried out in such a way that the alcohol formed during the reduction of the keto group is continuously removed from the reaction mixture.
  • the enzyme can be separated, for example, from the solvent phase.
  • the reaction mixture in which the enzymatic reaction is carried out for example via a membrane
  • Solvent is separated.
  • the solvent is then contacted with the inorganic adsorbent by passing the solvent through, for example, a column packed from the inorganic adsorbent so that the solvent phase on the second compound is depleted.
  • the depleted in the second compound solvent phase can then be returned to the reaction mixture.
  • Adsorbent added to the reaction mixture.
  • the amount of inorganic adsorbent is chosen to be sufficiently high, so that a sufficiently large amount of the second
  • Compound can be adsorbed on the inorganic adsorbent to the reduction of the keto group of the first
  • the reaction mixture can be separated very easily by allowing the inorganic adsorbent to sediment, for example, and the
  • Solvent phase which contains the enzyme and optionally also portions of the first compound is decanted off.
  • the inorganic adsorbent is preferably so
  • Adsorbent is adsorbed.
  • a suitable inorganic adsorbent is
  • silica which is preferably used in finely dispersed form.
  • 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. But it is also possible the inorganic adsorbent contains the aluminum in the form of, for example, a mixed oxide.
  • Aluminum may contain other metals in the inorganic adsorbent, such as silicon.
  • the alumina-containing inorganic adsorbent may be degraded from a natural source, so a
  • Adsorbent is preferably predominantly of an alumina-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 comprises
  • Adsorbent more than 60 wt .-%, preferably more than
  • the difference to 100% could be formed, for example, each by a proportion of a binder, with which the inorganic adsorbent, for example, to a
  • the inorganic adsorbent consists only of alumina.
  • the inorganic adsorbent used in the process according to the invention preferably has a very high
  • the inorganic adsorbent has a specific surface area of more than 100 m 2 / g.
  • 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.
  • Adsorbent 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 determined to be cumulative pore volume according to BJH (I.P. Barret, L.J. Joiner, P.P. Haienda, J. Am. Chem. Soc., 73, 1991, 373) for pores having a diameter of 1.7 to 300 mm.
  • the inorganic adsorbent has a pore volume of less than 1.4 ml / g.
  • the pore volume of the inorganic adsorbent is less than 1.3 ml / g and in another embodiment less than 1.2 ml / g.
  • alumina-containing component As the alumina-containing component are preferred
  • Boehmite is AlOOH.
  • aluminas and their hydrates can be prepared by neutralizing basic aluminate solutions by the addition of acid. The precipitation of
  • Aluminum hydroxides or their hydrates can be supported by the addition of nuclei. It is also possible hydrated aluminum hydroxides from acidic solutions of aluminum salts by the addition of bases or by
  • aqueous phase separated hydrated aluminas can then be converted to aluminas by annealing.
  • Aluminum oxides are described, for example, in WO 01/02297
  • the aluminas and their hydrates can also have a
  • Sol-gel process can be produced.
  • aluminum alkoxides can be hydrolyzed for this purpose.
  • the hydrolysis can generally in a temperature range of 30 to 150 0 C.
  • the solid alumina hydrate is separated from the aqueous alcohol phase. The obtained
  • crystals can be aged under hydrothermal conditions.
  • the alumina-containing component is a synthetic
  • 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. on.
  • 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 together with silica or
  • Silica compounds are aged under hydrothermal conditions. Suitable aluminum compounds are
  • Aluminum alkyl chlorides or aluminum carboxylates are described for example in US 6,245,310 Bl.
  • hydrolyzable ones can also be used instead of silica
  • Organosilicon compounds are used, wherein the
  • hydrolyzable aluminum compounds is carried out together. Such a method is described for example in EP 0 931 017 Bl.
  • the inorganic adsorbent may be provided, for example, in the form of a powder.
  • the particle size of the powder is generally adjusted so that the
  • Inorganic adsorbents without difficulty with a suitable method, such as filtration, can be separated from the reaction mixture within a suitable period of time.
  • a suitable method such as filtration
  • adsorbents in the form of a column pack are also suitable for larger particle sizes.
  • the inorganic adsorbent is preferably in the form of granules
  • Saulenpackungen is preferably used a granule having a grain size of more than 0.1 mm.
  • the granules have a grain size in the range of 0.2 to 5 mm, particularly preferably 0.3 to 2 mm.
  • the grain size can be adjusted, for example, by sieving.
  • the granules can be prepared by conventional methods, such as the finely ground inorganic
  • Adsorbent with a granulating agent for example, water, applied and then in a conventional
  • Fluidized bed is granulated.
  • other methods can be used to prepare the granules.
  • the inorganic adsorbent can also be provided as a shaped article, which can be obtained, for example, by extrusion of a plastic mass.
  • a shaped article which can be obtained, for example, by extrusion of a plastic mass.
  • the moldings or the granules are preferably at a temperature of more than 300 0 C, according to another
  • Embodiment heated to a temperature of more than 400 0 C, and according to yet another embodiment to a temperature of more than 500 0 C.
  • the temperature is less than 1200 0 C, chosen according to another temperature lower than 1000 0 C.
  • the heat treatment is preferred for a duration of at least 30 minutes, according to a further embodiment for a duration of at least 60
  • the inorganic adsorbent can be added directly to the reaction mixture, wherein according to one embodiment it is agitated, for example shaken. According to a further embodiment, the inorganic
  • Adsorbent provided in the form of a column packing.
  • the reaction mixture can then be passed through the column packing.
  • Solvent may then be recycled back to the reaction batch in one embodiment.
  • the column packing may be provided, for example, in the form of a cartridge.
  • the reaction mixture or the solvent from which the enzyme was previously separated then be passed through the cartridge until the adsorption capacity of the in the
  • Cartridge contained inorganic adsorbent is exhausted.
  • the cartridge can then be easily replaced with a new cartridge.
  • inorganic adsorbent adsorbed second compound can then be eluted with a suitable eluent. If the inorganic adsorbent in the form of a
  • Adsorbent preferably used in the form of granules having a particle diameter of more than 0.1 mm
  • the inorganic adsorbent can be heated to a temperature of more than 600 0 C.
  • the temperature is chosen lower than 1000 0 C.
  • Fig. 1 a schematic representation of an apparatus for
  • Fig. 2 is a graph showing the concentration of 2,5-hexanedione and 2,5-hexanediol bound from a solution in ethyl acetate to adsorbent 3
  • Fig. 3 is a graph showing the concentration of 2,5-hexanedione and 2,5-hexanediol bound from a solution in ethyl acetate to adsorbent 5;
  • Fig. 4 a diagram in which the concentration of 2,5-hexanedione and 2, 5-hexanediol is indicated, which consists of a solution in heptane / 10% 2-propanol
  • Adsorbent 3 is bound
  • FIG. 5 shows a chromatogram for a separation of 2,5-hexanedione and 2,5-hexanediol on adsorbent 5; Is a diagram in which the concentration of 2,5 hexanediol in the supernatant in the adsorption of 2,5-hexanediol from a mixture of toluene and 10% vv "1 2-propanol for various adsorbents shown, Figure 7: Fig. 6.
  • Figure 3 is a graph showing the adsorption of NADH from an aqueous potassium phosphate buffer;
  • Fig. 1 shows a structure in which the method according to the invention can be carried out.
  • a reaction mixture 2 containing an organic solvent in which a first compound comprising a prochiral keto group is dissolved, and a second compound comprising a hydroxy group bonded to a chiral carbon atom and those of the first Compound has emerged.
  • the mixture contains 2 a
  • Alcohol dehydrogenase and a sacrificial alcohol for example isopropanol.
  • the mixture 2 comprises a water phase in which a cofactor, for example NADP + , is dissolved.
  • the mixture is agitated by a stirrer 3.
  • a drain 4 Via a drain 4, the mixture 2 is removed from the reactor 1 and in a separator 5 by means of a membrane 6 in a proportion
  • Return line 7 is returned to the reactor 1, and a proportion containing the organic solvent, but no enzyme, and via a feed line 8 a
  • Adsorberkartusche 9 is supplied.
  • the adsorber cartridge 9 is packed with an inorganic adsorbent material,
  • alumina so that the second compound is partially adsorbed on the inorganic adsorbent material and thus the organic solvent is depleted in the second compound.
  • the organic solvent which still contains a portion of the first compound is then returned via return line 10 back to the reactor 1.
  • an eluent feed 11 and a drain 12 are provided, via which the feed with the
  • Adsorbent were prepared by the following methods
  • Micromeritics type ASAP 2010 determined.
  • the sample is cooled in a high vacuum to the temperature of liquid nitrogen. Subsequently, it becomes continuous
  • Nitrogen dosed into the sample chambers By detecting the adsorbed amount of gas as a function of pressure, an adsorption isotherm is determined at a constant temperature. In a pressure equalization, the analysis gas is gradually
  • the pore volume is also determined from the measurement data using the BJH method (IP Barret, LG Joiner, PP
  • 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.
  • the water content of the products at 105 0 C is determined using the method DIN / ISO-787/2.
  • a graduated cylinder cut off at the 1000 ml mark is weighed. Then, the sample to be examined is filled by means of a Pulvertrichters so in a train in the measuring cylinder that above the conclusion of the
  • Measuring cylinder forms a Schüttkegel.
  • the pouring cone is made with the help of a ruler, which over the opening of the
  • Measuring cylinder is guided, stripped and the filled
  • 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, DE)
  • Adsorbent 5 Puralox ® KR-160 (Sasol, Hamburg, DE)
  • Adsorbent 6 Pural SCC ® 150 (Sasol, Hamburg, DE)
  • Adsorbent 8 aluminum oxide neutral (Macherey-Nagel, Düren,
  • Adsorbent 9 aluminum oxide basic (Macherey-Nagel, Düren,
  • Adsorbent 10 silica gel (Sigma-Aldrich)
  • the suspension was at 150 rpm on a
  • Rotationsschuttier incubated at room temperature. After a certain time, a sample was taken, the
  • Table 5a Adsorption of 2,5-hexanediol / 2,5-hexanedione
  • the diol was preferably adsorbed. This can be for both boehmite,
  • Boehmit / SiO 2 mixed phases, ⁇ -Al 2 O 3 , as well as for the amorphous Al oxides are shown.
  • a stamen solution was prepared containing 70 mM 2,5-hexanedione and 50 mM 2, 5-hexanediol in heptane / 10% 2-propanol. From this stock solution was added by adding
  • adsorbent 3 In glass vials 200 mg of adsorbent 3 were weighed in each case and mixed with 1 ml of the respective mixture from the dilution series. The samples were then incubated for 60 minutes on the rotary shaker (150 rpm) at room temperature. Subsequently, a sample was taken from each sample vessel, the adsorbent by centrifugation at 13,000 rpm / 1 min.
  • Example 3 Use of the Adsorbent 5 in a
  • Adsorbent 5 packed and equilibrated with ethyl acetate column (length 24 cm, diameter: 0.7 cm) was added. 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 shown in FIG. 5
  • the eluent for the 2,5-hexanediol is methanol or acetonitrile.
  • the concentration of 2, 5-hexanediol in the supernatant of 50.00 mM could be reduced to as much as 10.21 mM when using 2.0 g.
  • adsorbents 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 incubated at room temperature at 150 rpm for 60 minutes
  • Reaction detractor moves.
  • the adsorbent was through
  • Example 6 Carrying out an enzymatically catalyzed
  • ADH 'A' used, as carrier for the enzyme porous glass particles TRISOPERL ® (VitraBio, Steinach, D) were used.
  • the immobilization of the ADH- 1 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 alcohol 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 ⁇ L KPi buffer.
  • the reaction medium (toluene) was saturated with KPi buffer, for 30 mL toluene were mixed with 10 mL KPi buffer (100 mM, pH 7.0), the toluene phase was removed and used in the experiment.
  • the supported enzyme was diluted with 100 ⁇ L NADH
  • the reaction was started by adding 97 ⁇ L hexanedione (80 mM). The sample was incubated at 30 ° C. and 150 rpm on the rotary shaker.
  • Enzyme reaction was initially introduced as starting material 80 mM 2, 5-hexanedione and converted to the product 2, 5-hexanediol.
  • Reaction temperature was 30 0 C, stirred only the upper (organic) toluene phase with a Clipfish stirrer at 100 rpm.
  • the organic phase was measured in the GC. After the detection of a high

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Abstract

L'invention concerne un procédé de séparation d'un mélange contenant un premier composé, dissous dans un solvant et présentant au moins un groupe céto, et un deuxième composé, comportant un atome de carbone chiral avec un groupe hydroxy formé par réduction stéréosélective du groupe céto du premier composé, le mélange étant mis en contact avec un matériau adsorbant inorganique, au moins une partie du deuxième composé étant adsorbé sur le matériau adsorbant inorganique, et un mélange appauvri en deuxième composé étant séparé du matériau adsorbant inorganique.
PCT/EP2010/004155 2009-07-07 2010-07-07 Procédé de séparation de mélanges alcool-cétone Ceased WO2011003607A2 (fr)

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DE200910032080 DE102009032080A1 (de) 2009-07-07 2009-07-07 Verfahren zur Auftrennung von Alkohol-Keton-Gemischen

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WO2014159508A1 (fr) * 2013-03-14 2014-10-02 Honeywell International Inc. Oximation d'un sous-produit de mélange cyclohexanone/cyclohexanol

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159508A1 (fr) * 2013-03-14 2014-10-02 Honeywell International Inc. Oximation d'un sous-produit de mélange cyclohexanone/cyclohexanol
US9382195B2 (en) 2013-03-14 2016-07-05 Honeywell International Inc. Oximation of KA oil by-product

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