Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
  • C07H1/06—Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/02—Acyclic radicals
  • C07H7/027—Keto-aldonic acids

Definitions

• L-ascorbic acid (vitamin C, ascorbic acid, L-xylo-ascorbic acid, L-threo-hex-2-enolic acid- ⁇ -lactone) is usually made from 2-keto-L-gulonic acid (KGS), monoacetone-2-keto-L -gulonic acid or diacetone ketogulonic acid.
• KGS is obtained in a one- or multi-stage fermentative process, for example through the two-stage fermentation of sorbitol via sorbose with suitable, sometimes specially modified microorganisms.
• KGS or the diacetone-2-keto-L-gulonic acid obtained in the "Reichstein process” is lactonized directly or via intermediates such as esters, in particular methyl or butyl esters.
• Acids usually mineral acids, especially concentrated hydrochloric acid (acid Lactonization) or bases such as, for example, sodium hydroxide solution, NaHC0 3 , Na 2 C0 3 , alcoholates, etc. (alkaline lactonization) is also described, and the autocatalytic conversion of KGA to ascorbic acid is described KGS, from which the ascorbic acid must then be purified.
• ascorbic acid and KGS can be separated from one another from aqueous solution by crystallizing the KGS as Na-KGS. In a subsequent step, KGS must be released from Na-KGS.
• the process according to JP 31856 also provides crystalline ascorbic acid.
• the publication describes the acid-catalyzed lactonization of diacetone-2-keto-L-gulonic acid hydrate in a mixture of toluene, an alcohol and acetone as solvent.
• halogenated hydrocarbons are added as precipitation aids in order to achieve sufficient yields and ascorbic acid purities. This creates unwanted by-products, such as alkyl halides, which have to be disposed of at great expense.
• the sodium salt of ascorbic acid is first formed, which must be converted into free ACS in a further process step and is associated with an equimolar amount of NaCl or Na 2 S0 4 . After that, another crystallization step is usually necessary.
• DE 861 841 describes direct lactonization with partial conversion and ascorbic acid removal by selective crystallization and starting material recycling. Unreacted starting material is separated off by crystallization of the ascorbic acid. After crystallization, the starting material may only be present in the mother liquor in a low concentration, since otherwise the product will be contaminated. It is therefore necessary to operate on high sales.
• No. 1,904,619 describes a process for continuous KGS (derivative) lactonization with partial conversion in aqueous solution.
• the product is isolated by crystallization and recrystallization from methanol. All mother liquors must be combined, concentrated and transferred back to an aqueous solution.
• WO 98/08584 describes a process for the liquid / liquid extraction of acids from aqueous solutions with supercritical CO 2 . However, it is only used for the pure isolation of KGS or ascorbic acid from a fermentation broth. A selective separation of KGS and ACS from a more aqueous solution is not described. According to FR 1050832 and FR 1099614, impurities are extracted from aqueous solution by liquid / liquid extraction, and ascorbic acid is thus separated from sugars and crude ascorbic acid is purified.
• the educt or product is derivatized. So in particular
• Methyl or butyl esters of KGS are formed, which are soluble in alcohol as opposed to ascorbic acid.
• the separation processes described are very complex and not very efficient. Due to the high consumption of energy and the use of organic, largely toxic solvents, they are also ecologically questionable.
• ascorbic acid is characterized by special requirements in terms of purity and yield in all process stages: on the one hand to enable the use of the end product in human nutrition and on the other hand to reduce the production costs as much as possible.
• the object of the present invention is therefore to provide an advantageous process for selectively and economically separating 2-keto-L-gulonic acid from a mixture containing ascorbic acid and 2-keto-L-gulonic acid.
• the present invention consequently relates to a method for extracting 2-keto-L-gulonic acid (KGA) from a polar solvent, characterized in that the method comprises the following step:
• R1, R2, and / or R3 is in each case a saturated unbranched or branched alkyl radical with 6 to 14 carbon atoms independently of one another or simultaneously;
• GB 1,426,018 describes the extraction of i.a. Citric acid, lactic acid and oxalic acid from aqueous solutions by extraction.
• EP 828725 discloses a process for extracting ascorbic acid from an aqueous solution with the addition of an acid with a water-immiscible composition, which (a) comprises at least one secondary or tertiary alkylamine in which the total number of carbon atoms is at least 20, contains as the primary extractant and (b) a polar extraction enhancer compound (“enhancer”).
• enhancer a polar extraction enhancer compound
• KGS can now be extracted selectively from a polar solvent by providing the method according to the invention.
• KGA can be selectively and economically separated from ascorbic acid by the inventive method described herein. So far it has not been shown that the two similar organic acids ascorbic acid and KGS can be selectively separated from one another by liquid-liquid extraction.
• KGA is advantageously extracted from a polar solvent which contains ascorbic acid and KGA.
• extraction means according to the invention that the substances contained therein, in particular ascorbic acid or KGA, are transferred from a solid or liquid sample with non-polar to polar solvents or solvent mixtures into the respective extractant or extractant mixture Extracting agent is also understood below to mean a mixture of different solvents, as long as the mixture has the properties described for the extracting agent, in particular can serve as an extracting agent for ascorbic acid or KGA.
• the extraction is a “liquid-liquid extraction”.
• a “liquid-liquid extraction” is understood to mean an extraction of a substance dissolved in a liquid solvent by means of a second liquid solvent.
• the extraction conditions e.g. the extractant or the temperature can be chosen so that a specific substance is extracted essentially or preferably or not.
• polar solvents are aqueous solutions, including water, or polar aprotic or protic organic solvents, e.g. alkyl alcohols with an alkyl radical having 1 to 4 carbon atoms, e.g. Methanol, ethanol, 1-propanol, 2-propanol or butanol or e.g. Acetone, acetonitrile or dimethyl sulfoxide or mixtures thereof.
• polar aprotic or protic organic solvents e.g. alkyl alcohols with an alkyl radical having 1 to 4 carbon atoms, e.g. Methanol, ethanol, 1-propanol, 2-propanol or butanol or e.g. Acetone, acetonitrile or dimethyl sulfoxide or mixtures thereof.
• aqueous solution is understood to mean water or an aqueous solution, including, for example, deionized, demineralized, distilled or bidistilled water.
• aqueous solution can be dissolved or mixed in the aqueous solution.
• the solvent preferably contains a KGA portion as described below.
• the KGS portion and the acorbic acid portion are as described below.
• extract 1 is understood to mean a solvent or solvent mixture which is not miscible with the solvent and which has a miscibility gap with the solvent.
• the extractant 1 preferably contains essentially the tertiary Am according to the invention in the formula
• R1, R2, and / or R3 is in each case a saturated unbranched or branched alkyl radical with 6 to 14 carbon atoms independently of one another or simultaneously, in particular R1, R2, and / or R3 can be - (CH 2 ) n -CH 3 with in each case n is 6 to 14 or consist of a mixture of the amines according to the invention and the organic polar diluent.
• the extractant preferably consists only of the amines mentioned or a mixture thereof and the organic polar diluent.
• an alkyl radical having 8 to 12 carbon atoms is particularly preferred, so in particular n is preferably 8 to 12.
• R1 is R2 is R3. Consequently, in a very particularly preferred embodiment, the process according to the invention relates to extraction with an extraction agent which contains tri-n-octylamine and / or tri-n-decylamine.
• the term “diluent” also includes the polar, in particular protic, enhancers disclosed in EP 828725, in particular alkanols, ketones, aldehydes, esters and ethers.
• the polar organic diluent contained in the extractant preferably consists of a saturated branched or unbranched Alkyl alcohol having 4 to 14 carbon atoms, preferably the diluent is a saturated branched or unbranched alkyl alcohol having 8 to 12 carbon atoms, most preferably it is i- or n-decanol, or a mixture thereof.
• the extractant 1 thus preferably consists of tri-n-octylamine and tri-n-decylamine, in particular in a ratio of 1: 0 to 0: 1, preferably in a ratio of 30:60 to 60:30, and the diluent, in particular decanol.
• amine mixtures are commercially available under the trade name Hostarex.
• the preferred ratio of amine to diluent depends on the particular components. Preferably the ratio is 20:80 to 80:20.
• a particularly preferred ratio of tri-n-octylamine / tri-n-decylamine to isodecanol is 40/60.
• amine tri-n-octylamine / tri-n-decylamine 50:50 and amine to isodecanol: 40:60.
• an economical separation of KGS from a mixture of ascorbic acid and KGS can be achieved if the ratio of the distribution coefficients under normal conditions for KGS to ascorbic acid is at least 1.5: 1, preferably 4: 1, more preferably 7: 1 or more, the Distribution coefficient of course depends on the temperature.
• the distribution coefficient can be determined using methods familiar to those skilled in the art, e.g. after a one-step extraction with subsequent HPLC analysis and iodometric titration.
• the extraction according to the invention can be carried out as described in the documents cited herein or as described in the examples, e.g. using a countercurrent extraction column or a multi-stage mixer-decanter cascade (mixer-settle ⁇ .
• the extractant 1 and the mixture of ascorbic acid and KGA in the solvent are preferably used in the process according to the invention in a ratio of 0.5: 1 to 3: 1, a ratio of 2: 1 to 1: 1 is particularly preferred is a 1: 1 ratio.
• an aqueous solution or a branched or unbranched C 1 -C 4 -alkyl alcohol is used as the solvent in the process according to the invention.
• Water or an aqueous solution is preferably used.
• aqueous solutions as defined herein includes both water and buffers, fermentation solutions, salt solutions and other solutions which contain substances, for example to influence the pH, the sterility of the solution or the stability of the substances.
• the solvent can also a fermentation broth or the supernatant of a decanted, filtered or otherwise purified fermentation broth.
• the product discharge from the preceding lactonization reaction can be concentrated, as described below, for example. will.
• the solution is advantageously cooled and then the KGA is extracted.
• the concentration is advantageously carried out by evaporation at elevated temperature and reduced pressure, for example as described herein.
• water or an aqueous solution e.g. a fermentation broth, e.g. with the KGS and ascorbic acid proportions described below, and 1 tri-n-octylamine / tri-n-decylamine / iDecanol in the ratio 20:20:60 as extractant.
• the extraction of step (a) preferably takes place at a temperature between 10 ° C. and 60 ° C.
• a temperature between 15 ° C. and 30 ° C. is particularly preferred.
• the person skilled in the art will weigh the extraction efficiency against the use of cooling energy to achieve the respective extraction temperatures and the solubility of the starting materials at the respective extraction temperatures.
• a temperature can be preferred which can be achieved for cooling or heating without additional energy supply (ambient temperature).
• the process step according to the invention is most preferably carried out at 30 ° C. to 60 ° C., preferably at 40 ° C. ,
• the method according to the invention comprises the following further step:
• “Full or partial back-extraction” is understood according to the invention to mean that KGAs are back-extracted essentially, preferably at least 30% by weight to 100% by weight, into the extracting agent 2. 50% by weight are preferred, 75% by weight are more preferred .-% or more.
• the concentration of KGA in extraction medium 2 before the back extraction is lower than in extraction medium 1, i.e. the proportion is preferably 10% by weight, more preferably 5% by weight or 1% by weight or less, most preferably 0.1 or less% by weight.
• the extractant 2 is a polar solvent as described above, preferably it is water or an aqueous solution or a branched or unbranched d to C 4 alkyl alcohol.
• the extraction agent 2 and the solvent consist essentially of the same solvent components.
• Essentially consisting of the same solvent components means here that the two agents do not differ essentially in their solvent components, for example 30% or less, more preferred are 10%, even more preferred are 5% difference or an identical composition.
• one agent may consist essentially of an aqueous solution with a small proportion of an alkyl alcohol, while the other agent consists only of an aqueous solution, In a preferred embodiment the two agents are identical in terms of their solvent components and proportions.
• the extractant 2 is preferably also polar.
• the solvent and extractant 2 are particularly preferably water or aqueous solutions.
• the solvent and extractant 2 consist of solutions in which essentially the same substances are contained apart from the proportion of ascorbic acid and KGA.
• Constants consisting essentially the same substances except for the proportion of ascorbic acid and KGA means that both agents are essentially identical in the proportion of dissolved and undissolved constituents apart from ascorbic acid and KGA and differ only slightly, 30% are preferred, even more preferably 5% or less of the components other than KGS or ascorbic acid are different.
• the extraction temperature T T for the extraction of the KGA from the solvent containing a mixture of ascorbic acid and KGA is 5 ° C to 100 ° C lower than the back extraction temperature T 2 for the back extraction of the KGA from the extractant 1 with the extractant 2.
• a difference of 15 ° C. to 70 ° C. is preferred, more preferably 20 ° C. to 40 ° C.
• the temperature of the extraction is 10 ° C to 30 ° C and the back extraction temperature is 20 ° C to 80 ° C.
• the combination is preferred tion of ambient temperature or room temperature, here a temperature of 15 ° C to 30 ° C is understood for the extraction, with a temperature of 40 ° C to 60 ° C for the back extraction.
• the method according to the invention also comprises the following step:
• step (c) Returning the extractant 1 from which the KGA was back-extracted in step (b) to the extraction in step (a).
• the extractant is preferably discharged partially or completely before the recycling and reuse as the extractant in step (a), worked up and only then returned. Impurities are removed by the discharge.
• the extraction agent can be cleaned e.g. by distillation, micro- or nanofiltration or adsorption (e.g. on activated carbon).
• the proportion of discharged material essentially depends on the purity of solvent 1 and the proportion of back-extracted product of value, i.e. from KGS in the extractant 1 after back extraction. If the extractant contains only a small proportion of valuable product and a high proportion of impurities after the back extraction with extractant 2, a large proportion of contaminated extractant 1 can be discharged. If only partial extraction is carried out in the back extraction, there is still a high proportion of the product of value in the extraction medium 1 and the person skilled in the art will routinely weigh up the loss due to discharge against the degree of contamination.
• the method according to the invention for extracting the KGA preferably comprises the following further step:
• step (d) Returning the extraction agent 2 loaded with KGS from the back extraction according to step (b) to a process for producing ascorbic acid from KGS.
• the KGA-laden solvent is advantageously returned to a lactonization step and converted there to ascorbic acid.
• the product discharge of the lactonization can then be subjected to the steps of the method according to the invention described here or the steps of another method known to the person skilled in the art to obtain the ascorbic acid.
• the method according to the invention comprises the following further step: (e) concentrating the extractant 2 loaded with the KGS before returning to step (d); and optionally the step
• “Concentration” is understood here to mean that the volume of the sample is concentrated and the concentration of KGA or ascorbic acid after concentration is higher than in the starting solution, but without precipitating out. Thus 10% by volume or more of the solvent can The ascorbic acid is preferably drawn off or evaporated to the solubility limit of the loaded extractant 2. In a preferred embodiment, just enough solvent is evaporated that steady states can occur in the continuous system with recirculation. understood a "concentration”.
• Concentration can take place, for example, by heating, in particular under reduced pressure, for example a circulation evaporator, thin-film evaporator, etc. Samples can also be restricted by dialysis. The concentration should be done gently, preferably at -20 ° C to 100 ° C depending on the reaction time, pressure and solvent. Concentration at 30 ° C. to 90 ° C. is preferred, particularly preferably at 30 ° C. to 50 ° C. It is advantageous to carry out the narrowing under reduced pressure. Depending on the solvent or solvent mixture, the concentration can be carried out at normal pressure (1013 mbar) to 10 mbar. In the case of aqueous solutions, the concentration is preferably at 500 mbar to 10 mbar. After evaporation, the solution can be cooled, e.g. to the ambient temperature or the temperature of the following process step, e.g. by means of heat exchangers.
• the concentration is advantageously carried out by evaporating off the solvent at 30 ° C. to 50 ° C. and a pressure of 50 to 80 mbar. Possibly. After the concentration, the solution can be cooled and only then fed to the lactonization reactor.
• the vapors of the concentration consist essentially of extractant 2 and can therefore advantageously be used again as extractant 2 in step (b).
• the method includes the following further step:
• Various process steps for obtaining the ascorbic acid from polar solvents are known to the person skilled in the art. For example, Evaporation, cooling or displacement crystallizations or various drying processes, e.g. Spray drying for carboxylic acids, especially also for ascorbic acid.
• Evaporation, cooling or displacement crystallizations or various drying processes e.g. Spray drying for carboxylic acids, especially also for ascorbic acid.
• spray drying for carboxylic acids, especially also for ascorbic acid.
• insoluble salts or derivatives can also be formed, which then precipitate out in the solvent.
• the ascorbic acid is preferably isolated by evaporation, cooling or displacement crystallization.
• the method according to the invention can contain at least one of the following further steps before step (j):
• the washing can take place in the upper part of the extraction column in which the extraction can be carried out.
• the concentration takes place as described above.
• the concentration is carried out up an evaporation of the solvent at 30 ° C to 50 ° C and at reduced pressure, advantageously a temperature of 40 C C and a pressure of 50 to 100 mbar.
• step (j) Since the mother liquor remaining in step (j) during the crystallization of the ascorbic acid can still contain ascorbic acid, in a preferred embodiment the process according to the invention also contains one of the following further steps:
• KGS could also be separated from a mixture of ascorbic acid, KGS, monoacetone-2-keto-L-gulonic acid and / or diacetone ketogulonic acid.
• the present invention also relates to a process for the preparation of ascorbic acid from 2-keto-L-gulonic acid, which comprises the following steps:
• Lactonization preferably partial lactonization of 2-keto-L-gulonic acid
• Extracting the KGA from the ascorbic acid / KGA mixture according to the method described herein and iii. Isolate the ascorbic acid from the solvent loaded with the ascorbic acid.
• the mixture of KGA and ascorbic acid can be prepared by methods known to those skilled in the art, e.g. by a method for lactonizing KGS described herein.
• the mixture is preferably produced by direct partial lactonization, in particular by autocatalytic lactonization, from KGA to ascorbic acid.
• partial lactonization means an incomplete conversion of the starting material to ascorbic acid.
• An embodiment with a KGS partial conversion of 20% by weight to 40% by weight is particularly preferred.
• the lactonization reaction (i) can be carried out by methods as described in the prior art since 1933, as long as a mixture of the starting material, preferably KGA, and ascorbic acid in a polar solvent, preferably in an aqueous solution, in particular water, is obtained. Due to the lack of separation processes, the literature generally describes full conversions of KGS to ascorbic acid or, if only partial implementation, combines the separation with the derivatization of KGS to an ester and subsequent crystallization of the ascorbic acid as described above. Lactonization processes are described in the above-mentioned prior art and the documents cited therein, which are hereby expressly included in the disclosure content of this description.
• Ascorbic acid is usually produced from 2-keto-L-gulonic acid, monoacetone-2-keto-L-gulonic acid or diacetone ketogulonic acid.
• Other starting materials e.g. L-Gulon- ⁇ -lactone and the sodium salt of the ⁇ -alkyl-KGS-pyranoside have also been described.
• Direct lactonizations are usually acid-catalyzed, preferably with hydrochloric acid as a gas or with aqueous hydrochloric acid and have long been known in the art.
• alkaline catalyzed processes the reaction rate of lactonization is higher, which leads to higher space-time yields in the apparatus.
• alkali metal salts of weak acids eg NaHC0 3 or sodium acetate
• Na 2 C0 3 or sodium methylate in alcohols are used as basic catalysts.
• the sodium salt of ascorbic acid is initially formed, which must be converted into the free ascorbic acid in a further process step.
• a method for producing free ascorbic acid is described in US 5,041,563.
• the catalyst has to be separated off.
• the acid can decompose the product.
• an ascorbic acid salt is first produced, which must be converted into the free ascorbic acid.
• the process according to the invention can now be used to carry out a direct acidic or alkaline-catalyzed or an auto-catalyzed partial lactonization, for example via an acidic ion exchanger (for example Bayer Lewatit) or, preferably, by means of a fixed bed catalysis.
• Lactonization is preferably carried out at low temperatures lead to a slight derivatization or decomposition of the ascorbic acid formed, particularly preferably below 60 ° C., for example by means of bio- or enzyme catalysis or in acid catalysis.
• step (i) for the lactonization of 2-keto-L-gulonic acid thus takes place autocatalytically and partially in the process according to the invention. Lactonizations in most processes are carried out with complete conversion of the respective educt.
• An advantage of the autocatalytic reaction is that neither catalysts nor other auxiliaries are required and must be removed from the reaction discharge.
• An economical use of the autocatalytic lactonization has so far failed due to the fact that complete conversion is not efficient and takes place in low yields.
• KGS can be lactonized in aqueous solutions by the action of an elevated temperature (T> 25 ° C, T ⁇ 200 ° C). Temperatures of 40 to 180 ° C. are preferred. A very short reaction time in the reactor can advantageously be achieved in this way. If a solution of KGS in water is heated to 80-150 ° C and the residence time in the reactor is kept between 1 and 30min, KGS conversions of 25-30% ascorbic acid selectivities can be obtained by 90% in solution. Partial conversion with educt recycling has so far only been described in the case of KGS esters.
• the initial concentration of KGA in water preferably does not exceed 30%.
• the present invention also relates to a process for the preparation and recovery of ascorbic acid, step (i) for lactonizing the 2-keto-L-gulonic acid being carried out autocatalytically under partial conversion under the following conditions:
• a KGA initial mass fraction of 10 to 15% by weight, a reactor temperature of 110 ° C. to 150 ° C. with a residence time of 3 to 5 minutes and a conversion of KGA of 20 to 25% by weight are particularly preferred.
• Suitable reactors for lactonization are, for example, tube bundles, plate heat exchangers, spiral tube reactors or propulsion jet reactors.
• reaction discharge from the lactonization reaction is concentrated in order to achieve a steady-state operating state in accordance with the concentration steps described above.
• the ascorbic acid or KGA can then be separated off in step (a) from the reaction effluent, which is preferably cooled to ambient temperature or from 20 ° C. to 25 ° C.
• the reaction discharge after the concentration preferably has a KGA content of 5 to 30% by weight, 8 to 25% by weight is particularly preferred, and an ascorbic acid content of 3 to 20% by weight, 5 to 10 is particularly preferred wt .-%. Consequently, the KGA-containing solvent of step (a) also has a KGA content of 5 to 30% by weight, 8 to 25% by weight being particularly preferred.
• the solvent of step (a) has a KGA content of 5 to 30% by weight, particularly preferably 8 to 25% by weight, and an ascorbic acid content of 3 to 20% by weight, particularly 5 to 10% by weight are preferred.
• the solvent loaded with ascorbic acid is preferably concentrated and the ascorbic acid is crystallized from the solvent.
• the condensed vapors of the various evaporation steps largely remain in the process in the process according to the invention and are used there as solvents, as was described for the different process steps above.
• the evaporation of the respective solvents is particularly preferably operated via the respective operating pressure such that energy can be transferred from the vapor condenser of a first evaporation to the evaporator of a second evaporation.
• the individual steps of the method described herein can be carried out continuously or discontinuously.
• the preferred embodiment is the continuous execution of the steps.
• the process according to the invention for the production of ascorbic acid or for the production of ascorbic acid contains all steps (a) to (g) and / or (i) to (iii) and / or (aa) to (cc) described herein.
• ascorbic acid and / or KGS is obtained without salt accumulation.
• the present invention is illustrated by the following example, which is not intended to be limiting in any way.
• a distribution coefficient (quotient of the concentration of the absorbing / releasing phase) of 1.1 kg / kg was measured for ascorbic acid and 6.6 kg / kg for KGS. Accordingly, the ratio of the distribution coefficients, i.e. H. the selectivity equal to 6. With regard to the back extraction of the KGA from the extractant 1, it was found that the distribution coefficient of the KGA at 80 ° C. is reduced to 0.18 under otherwise comparable conditions.

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