EP1463720A1 - Systemes et procedes de generation d'un acide ascorbique a couleur reduite - Google Patents

Systemes et procedes de generation d'un acide ascorbique a couleur reduite

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Publication number
EP1463720A1
EP1463720A1 EP02800980A EP02800980A EP1463720A1 EP 1463720 A1 EP1463720 A1 EP 1463720A1 EP 02800980 A EP02800980 A EP 02800980A EP 02800980 A EP02800980 A EP 02800980A EP 1463720 A1 EP1463720 A1 EP 1463720A1
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EP
European Patent Office
Prior art keywords
keto
gulonic acid
acid
ascorbic acid
gulonic
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Application number
EP02800980A
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German (de)
English (en)
Inventor
Joseph R. Zoeller
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Eastman Chemical Co
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Eastman Chemical Co
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Publication date
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Publication of EP1463720A1 publication Critical patent/EP1463720A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to methods and systems for producing L-ascorbic acid with reduced color. Specifically, the present invention relates to ascorbic acid with reduced color formed using palladium supported catalysts.
  • L- Ascorbic acid (vitamin C) is produced commercially by combined chemical and fermentation processes starting from glucose or sorbose.
  • a common intermediate generated in the commercial process is 2-keto-L-gulonic acid (KLG), or its protected form, diacetone-2- keto-L-gulonic acid.
  • KLG 2-keto-L-gulonic acid
  • the conversion of 2-keto-L-gulonic acid to L-ascorbic acid may be carried out by esterification with methanol, followed by cyclization using stoichiometric amounts of a base, in a methodology derived from the original Reichstein process (T.
  • diacetone- 2-keto-L-gulonic acid may be cyclized directly, with a loss of acetone followed by consecutive lactonization and enolization, to form ascorbic acid.
  • Direct cyclization of diacetone-2-keto-L-gulonic acid requires extensive purification for recovery of the acetone and other by-products generated.
  • An alternative means of producing ascorbic acid from 2-keto-L-gulonic acid involves an aqueous intramolecular cyclization process without the use of copious amounts of acid catalysts (T. Reichstein, Helv. Chim. Acta 17, 1934, pp. 311-328 and BP 428,815).
  • aqueous cyclization does not require the extensive purification steps associated with acid catalysis, non-acid catalyzed intramolecular cyclization is associated with relatively low yields.
  • 2-keto-L-gulonic acid may be heated in water saturated with carbon dioxide with a 50% yield after fractional crystallization (U.S. Patent No. 2,265,121).
  • 2- keto-L-gulonic acid or derivatives of 2-keto-L-gulonic acid may be heated to 130-140°C in water to generate ascorbic acid with yields approximating 50% (U.S. Patent No. 2,491,065).
  • a common problem encountered with conversion of 2-keto-L-gulonic acid to ascorbic acid in water or acidic solutions is the production of colored solutions from degradation products that are formed during the reaction. These degradation products generally include high molecular weight compounds that accumulate as a function of conversion. Thus, with increasing conversion, solutions tend to become increasingly colored and eventually form insoluble by-products.
  • methods to decolor ascorbic acid involve adsorption of the colored by-products using carbon or other solid supported agents. The use of large amounts of carbon or other solid decolorizing agents significantly hinders subsequent purification of the L-ascorbic acid product and ultimately, may become cost prohibitive.
  • the agents used for reducing the formation of color employ materials that are relatively inexpensive, non-toxic, and easy to handle.
  • the agent used contributes to catalysis of the reaction.
  • color reducing catalysts are useable in systems that allow for separation of the catalyst from the reaction components.
  • color reducing should allow for recycling of unused starting compounds and/or catalyst when the synthesis is taken only to partial conversion, as for example, to avoid excessive degradation of ascorbic acid product.
  • the present invention describes the synthesis of ascorbic acid with reduced color using palladium (Pd) as a heterogeneous catalyst.
  • the palladium catalyst may include an inert support such as, but not limited to, carbon or barium sulfate.
  • the catalyst of the present invention is active under aqueous conditions suitable for ascorbic acid synthesis.
  • the present invention comprises a method for reducing the amount of color formed when ascorbic acid is synthesized from 2-keto-gulonic acid or 2-keto-gulonic acid derivatives comprising conducting the synthesis in the presence of palladium.
  • the palladium at least in part reduces the fo ⁇ nation of colored byproducts in the reaction.
  • the present invention comprises ascorbic acid synthesized from 2- keto-gulonic acid or a 2-keto-gulonic acid derivative in the presence of palladium.
  • the present invention comprises a system for reducing the amount of color formed when ascorbic acid is synthesized from starting material comprising 2-keto-gulonic acid or a 2-keto-gulonic acid derivative comprising a reactor for conducting the synthesis in the presence of palladium.
  • an object of the present invention is to provide methods and systems for synthesizing ascorbic acid from 2-keto-gulonic acid or a 2-keto-gulonic acid derivative to produce ascorbic acid that has relatively low levels of discoloration. More specifically, the present invention provides for the use of palladium as both a heterogeneous catalyst and as an agent to reduce the formation of color.
  • the palladium catalysts of the present invention provide for efficient synthesis of ascorbic acid in aqueous or acid conditions.
  • the present invention may be used to prevent the formation of colored, high molecular weight byproducts and thus, improve the efficiency of the reaction and reduce purification costs.
  • the palladium catalysts of the present invention are easily removed from the ascorbic acid product.
  • the palladium catalysis of the present invention may be used in established reactor formats such as stirred tank reactors, fluidized beds, or fixed bed reactors.
  • Figure 1 illustrates a schematic of a reaction system using palladium on carbon (Pd Carbon) for the conversion of 2-keto-L-gulonic acid to L-ascorbic acid in accordance with an embodiment of the present invention showing: 10 - starting material for reaction feedstock; 20 — conduit from feedstock tank into reaction vessel; 25 - conduit from reaction vessel to product tank; 30 - reaction vessel comprising coils containing Pd catalyst; 35 - heating zone; 40 - recirculating oil bath; 50 - pressure gauge; 55- entry port for reaction vessel; 60 - pump; 65 - exit port for reaction vessel; 70 - filter; 80 - feedstock tank; 90 - cooling coils; 95 - filter; 100 - ascorbic acid product; 110 - pressure gauge; 120 - back pressure regulator; 130 -product tank; and 135 - ascorbic acid product tank valve.
  • Pd Carbon palladium on carbon
  • Figure 2 illustrates a spectra for color reduction using palladium on carbon (Pd/Carbon) for the conversion of 2-keto-L-gulonic acid to L-ascorbic acid in accordance with an embodiment of the present invention.
  • the present invention relates to methods and systems for the synthesis of ascorbic acid with reduced color formation.
  • the method employs palladium catalysts for aqueous or acidic synthesis of ascorbic acid from 2-keto-gulonic acid or derivatives of 2-keto-gulonic acid.
  • the catalysts of the present invention work by decarbonylation of furfural intermediates that generate highly colored, high molecular weight compounds.
  • the use of palladium based catalysts reduces the amount of carbon and other decolorizing agents required for decolorization of the ascorbic acid product and thus, significantly simplifies purification of ascorbic acid from the reaction.
  • the present invention also describes systems for the synthesis of ascorbic acid having reduced color.
  • the systems of the present invention use inexpensive components and reagent systems and thus, can be scaled up for plant capacity as described herein.
  • the present invention comprises a method for reducing the amount of color in ascorbic acid synthesized from 2-keto-gulonic acid or 2-keto-gulonic acid derivatives comprising conducting the synthesis in the presence of palladium.
  • the palladium at least in part reduces the formation of colored byproducts. Also in an embodiment, the palladium at least in part catalyses the synthesis of ascorbic acid from 2-keto-gulonic acid or 2-keto-gulonic acid derivatives. Thus, the palladium may improve the overall efficiency of the synthesis of ascorbic acid from 2-keto- gulonic acid or 2-keto-gulonic acid derivatives.
  • the ascorbic acid comprises L-ascorbic acid synthesized from 2-keto-L- gulonic acid or a 2-keto-L-gulonic acid derivative.
  • the 2-keto-L-gulonic acid comprises an aqueous solution from a fermentation process for producing 2-keto-L- gulonic acid.
  • the 2-keto-L-gulonic acid comprises an aqueous solution of 2-keto-L-gulonic acid derived from the hydrolysis of the bisacetonide of 2-keto-L- gulonic acid or the esters of 2-keto-L-gulonic acid.
  • the 2-keto-gulonic acid derivative comprises a 2-keto-gulonic acid ester.
  • the synthesis of ascorbic acid is carried out in a solvent.
  • the solvent is moderately polar.
  • the solvent comprises water.
  • the solvent may comprise an alcohol.
  • the alcohol comprises the alkoxy moiety of a 2-keto-L-gulonic acid ester used as the 2-keto-gulonic acid derivative.
  • the palladium is supported on a particulate substrate. More preferably, the substrate comprises carbon or barium sulfate.
  • the catalyst comprises particles ranging in size from 1 ⁇ m to 5 cm. More preferably, the catalyst comprises particles ranging in size from 25 ⁇ m to 5 cm. More preferably, the catalyst comprises particles ranging in size from 100 ⁇ m to 2.5 cm. Even more preferably, the catalyst comprises particles ranging in size from 150 ⁇ m to 1.5 cm.
  • the amount of palladium which can be used is at least in part dependent on the size of the particles, with smaller particles allowing for a higher concentration of palladium in the reaction.
  • the palladium on the support may range from 0.1 to 10 weight percent palladium or in alternate embodiments, from 0.1 to 5 weight percent palladium or from 1 to 3 weight percent palladium.
  • the synthesis comprises heating the 2-keto-gulonic acid or 2-keto- gulonic acid derivative.
  • the step of heating may be done at a temperature of from about 25 to about 250°C. More preferably, the step of heating is at a temperature of from about 75 to about 200°C.
  • the step of heating is generally performed under an absolute pressure of from about 0.1 to about 100 arm (1.5-1460 psi) and more preferably, under an absolute pressure of from about 0.7 to about 17 atm (10-250 psi).
  • the synthesis of ascorbic acid from 2-keto-gulonic acid comprises an aqueous solution of 1 to 40 weight percent 2-keto-L-gulonic acid compound. More preferably, the synthesis comprises an aqueous solution of 5 to 30 weight percent 2-keto-L- gulonic acid compound. Even more preferably, the synthesis comprises an aqueous solution of 8 to 25 weight percent 2-keto-L-gulonic acid compound.
  • the conversion of 2-keto-L-gulonic acid substrate to L-ascorbic acid product preferably ranges from about 10 % to 90%. More preferably, the conversion of 2- keto-Lgulonic acid substrate to L-ascorbic acid product ranges from about 20% to 80 %. Even more preferably, the conversion of 2-keto-L-gulonic acid substrate to ascorbic acid product ranges from about 40% to 70%.
  • the conversion of 2-keto-gulonic acid to ascorbic acid is taken to only partial conversion to avoid excessive degradation of ascorbic acid product.
  • the method may also comprise the steps of: removing from the reactor a post-reaction solution comprising the unreacted 2-keto-gulonic acid compound and ascorbic acid; separating the ascorbic acid from unreacted 2-keto-gulonic acid compound in the post-reaction solution to form an ascorbic acid rich solution and a solution rich in the unreacted 2-keto-gulonic acid compound; and recycling the solution comprising unreacted 2-keto-gulonic acid compound to the reactor.
  • ascorbic acid rich solution refers to an aqueous solution of ascorbic acid in which the ratio of ascorbic acid to 2-keto-gulonic acid has been increased relative to the post-reaction solution.
  • 2-keto-gulonic acid rich solution or “solution rich in 2-keto-gulonic acid compound” refers to an aqueous solution of
  • 2-keto-gulonic acid or derivatives thereof in which the ratio of 2-keto-gulonic acid compound to ascorbic acid product has been increased relative to the post-reaction solution.
  • derivatives of 2-keto-gulonic acid may comprise esters of 2-keto-gulonic acid, diacetone-2-keto-gulonic acid, and other derivatives of 2-keto-gulonic acid which may be cyclized to ascorbic acid.
  • the L isomer is preferred.
  • the palladium catalyst for reducing color is mixed with a second catalyst for increasing the conversion of starting 2-keto-gulonic acid or 2-keto-gulonic acid derivatives to ascorbic acid.
  • the reactor is a plug flow reactor.
  • the range of space velocities in the plug flow reactor is between 0.05 h "1 to 500 h "1 . More preferably, the range of space velocities is between 0.1 h "1 and 100 h "1 .
  • Other reactor designs, such as continuous stirred tank reactor, wherein the catalyst is maintained as a slurry, or a trickle bed reactor may also be used.
  • the present invention comprises ascorbic acid synthesized from 2- keto-gulonic acid or a 2-keto-gulonic acid derivative in the presence of palladium.
  • the ascorbic acid comprises reduced color compared to ascorbic acid synthesized from 2-keto-gulonic acid or a 2-keto-gulonic acid derivative in the absence of palladium.
  • the palladium at least in part reduces the formation of colored byproducts in the reaction.
  • the palladium at least in part catalyses the synthesis of ascorbic acid from 2-keto-gulonic acid or 2-keto-gulonic acid derivatives.
  • the ascorbic acid is L-ascorbic acid synthesized from 2-keto-L-gulonic acid or a 2-keto-L-gulonic acid derivative.
  • the 2-keto-gulonic acid comprises an aqueous stream from a fermentation process for producing 2-keto-L-gulonic acid.
  • the 2-keto-gulonic acid derivative comprises a 2-keto-L- gulonic acid ester.
  • the 2-keto-gulonic acid comprises the hydrolysis of the bisacetonide of 2-keto-L-gulonic acid.
  • the synthesis of ascorbic acid is carried out in a solvent. More preferably, the solvent is moderately polar. In an embodiment, the solvent comprises water.
  • the solvent may comprise an alcohol.
  • the alcohol comprises the alkoxy moiety of a 2-keto-L-gulonic acid ester used as the 2-keto-gulonic acid derivative.
  • the palladium is supported on a particulate substrate.
  • the substrate comprises barium sulfate or carbon.
  • the palladium comprises particles ranging in size from 1 ⁇ m to 5 cm, more preferably from 25 ⁇ m to 5 cm, more preferably, from 100 ⁇ m to 2.5 cm, and even more preferably, from 150 ⁇ m to 1.5 cm
  • the conversion of 2-keto-gulonic acid compounds to ascorbic acid is taken to only partial conversion to avoid excessive degradation of the ascorbic acid product. Even more preferably, the ascorbic acid product is separated from unreacted 2-keto-gulonic acid or a derivative thereof.
  • the synthesis is carried out in a plug flow reactor although other types of reactors such as stirred tank reactors, fluidized beds and trickle bed fixed bed reactors may be used.
  • the present invention provides methods for making ascorbic acid having reduced color.
  • a common problem encountered with conversion of 2-keto-L-gulonic acid to L-ascorbic acid in water or in the presence of acidic solutions is the production of colored solutions formed from degradation products. These degradation products generally comprise high molecular weight compounds that accumulate as a function of conversion. Thus, with increasing conversion, solutions tend to become increasingly colored and eventually form insoluble by-products.
  • methods to decolor ascorbic acid involve adsorption of the colored by-products using carbon or other solid supported agents.
  • the use of large amounts of carbon or other solid decolorizing agents can significantly increase cost.
  • the use of agents to remove color from the ascorbic acid product increases the need for substantial additions to the reactor to purify the absorbent from the L-ascorbic acid.
  • the present invention teaches the use of palladium catalysts to prevent color from being formed and thus, employs reagents and additional reactor units on a much smaller scale.
  • color bodies formed in aqueous or acid catalyzed synthesis of ascorbic acid from 2-keto-L-gulonic acid may result as a consequence of the decomposition of 2-keto-L-gulonic acid and ascorbic acid to furfural (2-furaldehyde) and subsequent polymerization.
  • furfural forming furan and either carbon monoxide or carbon dioxide
  • Palladium (Pd) catalysts allow for decarbonylation of furfural in the liquid phase at elevated temperatures and pressures.
  • a palladium catalyzed decarbonylation of furfural to furan utilized a barium sulfate supported palladium catalyst operating at the boiling point of furfural (162°C) (Eschinazi, H.E., Bull. Soc. Chim. Fr., 967-969 (1952)).
  • Palladium on alumina has also been shown to be efficient in promoting decarbonylation of furfural to furan, especially when promoted by alkali metals (U.S. Patent No. 3,007,941; E. L.
  • furfural intermediates are believed to be the end result of consecutive conversions of 2-keto-L-gulonic acid to L-ascorbic acid, and therefore, build up over the course of the reaction.
  • the reported turnover rates reported for undiluted furfural indicated that even the most active catalysts (e.g. palladium on carbon in the presence of potassium carbonate) (Jung, K.J., et al, 1988a) would be unable to degrade furfural intermediates at the rate they are formed during the conversion of 2-keto-L-gulonic acid to L-ascorbic acid.
  • the present invention describes the surprising result that palladium based catalysts reduce color bodies produced during the conversion of 2-keto-gulonic acid, or derivatives of 2-keto-gulonic acid, to ascorbic acid.
  • the preferred substrate is 2-keto-L-gulonic acid
  • other derivatives of 2-keto-gulonic acid are known in the art to be suitable for the preparation of ascorbic acid, and more preferably, L-ascorbic acid.
  • Such derivatives of 2- keto-gulonic acid include, but are not limited to, esters of 2-keto-L-gulonic acid, such as 2- keto-L-guIonic acid methyl ester, 2-keto-L-gulonic acid ethyl ester, and the like.
  • Another preferred substrate is the bisacetonide of 2-keto-L-gulonic acid.
  • palladium catalysts are used, they are placed on an inert support.
  • the choice of support is an important component of catalyst design.
  • Other common supports, including silica and alkaline earth silicates, can render the catalyst ineffective for furfural decomposition.
  • the support comprises a carbon support.
  • the support comprises a barium sulfate support.
  • the preferred catalyst would be selected from the group of catalysts consisting of palladium supported on any of a variety of carbon based supports, with palladium on barium sulfate being less preferred.
  • the carbon supported palladium catalysts that are preferred for this process may be generated by any of a variety of methods well known to any practitioner of the art, such as impregnation by evaporation of a solution of a palladium compound in the presence of a carbon support. Further, the desired palladium catalysts are commercially available from a variety of sources with a wide range of palladium content, a variety of particle sizes, and a wide variety of carbon sources.
  • composition of the preferred catalyst such as palladium content, carbon type, and particle size, are not entirely determined by chemical behavior, but in large part, are constrained by the preferred reactor configuration.
  • the preferred reaction mode is to operate this reaction as a plug flow reactor.
  • larger particles are generally preferred since they have the lowest pressure drop and are least likely to become plugged during operation.
  • other particle sizes might be preferred.
  • finer particles would be preferred since finer particles facilitate dispersion throughout the reactor. Therefore, although any particle size may be used, the normal range would be between 1 ⁇ m to 5 cm more preferably, from 25 ⁇ m to 5 cm, with particle sizes of 100 ⁇ m to 2.5 cm, and 150 ⁇ m to 1.5 cm being particularly preferred.
  • the normal range of palladium content from commercial and laboratory sources of palladium supported on the support (t.e. carbon) is 0.1-10 weight percent (wt %) palladium, where wt % palladium is grams palladium per 100 g support.
  • catalysts containing the highest levels of palladium would be the preferred catalysts
  • catalysts containing high levels of palladium are normally achieved with powdered (t.e. very small particle size) supports.
  • the preferred reactor modes for ascorbic acid synthesis require catalysts that have relatively larger particle sizes. Supporting palladium on larger sized particles sizes generally limits the achievable range of palladium content.
  • the preferred particle sizes suitable for a plug-flow reactor range generally leads to a palladium content of from 0.1-5 wt % palladium, with 0.5-3 wt % palladium being typical. Therefore, consistent with the preferred catalyst size, the preferred range would be 0.1-10 wt % palladium, more preferably 0.1 -5 wt % palladium, with the most preferred being
  • Any source of carbon may be used for a support in this process.
  • Typical sources of commercial carbon supports span the range of carbon containing materials, including wood, bone, egg shell, coal, and polymers. Consistent with the preferred plug flow reactor mode of operation, the carbon supports would be selected from the carbons with particle size ranges between 1 ⁇ m to 5 cm, and more preferably, from 25 ⁇ m to 5 cm, with particle sizes of 100 ⁇ m to 2.5 cm, and 150 ⁇ m to 1.5 cm being particularly preferred.
  • Commercial sources of carbon with these characteristics are available, and further, commercial sources of palladium supported on carbon meeting these criteria are also available.
  • the commercial catalysts meeting these criteria are granular or are pellets generated by extruding finer carbon particles into pellets after the addition of binders and/or the application of pressure.
  • the catalyst may be the only catalytic material present in the reactor, or may be physically mixed with other catalytic components.
  • the reactor comprises a mixture of the palladium catalyst and a second catalyst which may be used to accelerate the conversion of 2-keto-L-gulonic acid to L-ascorbic acid while still maintaining the function of the palladium on carbon in reducing color.
  • the second catalyst may be a homogeneous catalyst, such as hydrochloric acid, or a heterogeneous catalyst, such as
  • the palladium catalyst comprises a soluble source of alkali metal or alkaline earth elements.
  • the source of the 2-keto-gulonic acid is unimportant in the process.
  • Alternative processes for producing 2-keto-L-gulonic acid from glucose S. Anderson, et al., Science, 230, 144-149 (1985)) or sorbose (Y. Saito, Biotechnol Bioeng., 58, 309-315, 1998) continue to be developed.
  • the starting 2-keto-L-gulonic acid is obtained by fermentation of sorbose or glucose.
  • an initial purification of this filtrate to remove solids using techniques such as electro dialysis, ion exchange, or crystallization is undertaken, but is not a precondition for the operation of the invention.
  • the 2-keto-L-gulonic acid compound may comprise the hydrolysis products of bisacetonide of 2-keto-L-gulonic acid or the esters of 2-keto-L-gulonic acid. Regardless of the source of 2-keto-L-gulonic acid compound, it is preferred that the concentration of 2-keto-L-gulonic acid is about 1 to 40 percent, more preferably about 5 to 30 weight percent, and even more preferably, 8 to 25 weight percent.
  • the reactions are normally carried out in a solvent.
  • the choice of solvent may be chosen from a wide variety of organic solvents or even water and is only limited by the solubility of the 2-keto-L-gulonic acid and its derivatives and the L-ascorbic acid product in the solvent. Since the 2-keto-L-gulonic acid and its derivatives have limited solubility in non- polar solvents, the preferred solvents would be at least moderately polar.
  • the synthesis of ascorbic acid from 2-keto-L-gulonic acid may utilize an aqueous solvent.
  • the solvent is water.
  • the solvent comprises the alcohol corresponding to the alkoxy moiety of the 2-keto-L-gulonic acid ester.
  • the solvent is methanol. In another embodiment, the solvent is ethanol.
  • polar comprises molecules which have entities in which the electrons within the molecule are disproportionately distributed, resulting in a net partial negative charge and a net partial positive charge at opposing ends of the molecule.
  • polar solvents include solvents such as water, alcohols, sulfoxide and sulfones (e.g. sulfolane), amides (dimethyl formamide, dimethyl acetamide), and nitriles.
  • Moderately polar solvents comprise ketones, esters, and the like.
  • the operating pressure is dependent upon the temperature employed. Preferably, the reaction is operated over a temperature range from 25-250°C. More preferably, the reaction is operated between 75-200°C.
  • the vapor pressure of the water would be 25 arm (370 psi) but below 100°C it would be less than one atm (14.6 psi). Therefore, the reaction may be operated over a very wide range of pressures, with pressures ranging from 0.1-100 atm all being practicable. However, consistent with the preferred temperature range of 75-200°C, the preferred operating pressure would be in the range of 0.7- 17 atm (10-250 psi) absolute pressure.
  • reaction and product be operated and stored under a non-oxidizing (oxygen depleted) atmosphere.
  • Anaerobic storage/reaction conditions are generally accomplished by using carbon dioxide, nitrogen, argon, among other gases, often under slightly elevated pressures.
  • the present invention also provides reactors and production systems for employing palladium as a means to reduce the color of ascorbic acid.
  • the present invention comprises a system for reducing the amount of color in ascorbic acid synthesized from starting material comprising 2-keto-gulonic acid or a 2-keto-gulonic acid derivative comprising a reactor for conducting the synthesis in the presence of palladium.
  • the system comprises a reaction vessel comprising a solid palladium catalyst; at least one port in the reaction vessel to provide a means to transfer the starting material into the reaction vessel and to remove the ascorbic acid product of the synthesis from the reaction vessel; a means to heat the reaction vessel; and a means to control to the pressure in the reaction vessel.
  • the palladium reduces the formation of colored byproducts in the reaction.
  • the palladium at least in part catalyses the synthesis of ascorbic acid from 2-keto-gulonic acid or 2-keto-gulonic acid derivatives.
  • the palladium may improve the overall efficiency of the synthesis of ascorbic acid from 2-keto- gulonic acid or 2-keto-gulonic acid derivatives, as for example by removing colored intermediates that inhibit the reaction or the performance of the reactor system.
  • the ascorbic acid comprises L-ascorbic acid synthesized from 2-keto-L- gulonic acid or a 2-keto-L-gulonic acid derivative.
  • the 2-keto-gulonic acid comprises an aqueous solution from a fermentation process for producing 2-keto-L- gulonic acid.
  • the 2-keto-gulonic acid comprises an aqueous solution of 2-keto-L-gulonic acid derived from the hydrolysis of the bisacetonide of 2-keto-L-gulonic acid or the esters of 2-keto-L-gulonic acid.
  • the 2-keto-gulonic acid derivative comprises a 2-keto-L-gulonic acid ester.
  • the system includes a fermentation device to generate 2-keto-gulonic acid or a derivative thereof from a sugar. More preferably, the system further comprises a means to purify the 2-keto-L-gulonic acid isolated from the fermentation device for use in synthesis of ascorbic acid.
  • the system includes a means to isolate unreacted 2-keto-gulonic acid starting material from the ascorbic acid product.
  • the means to isolate unreacted 2-keto-gulonic acid starting material from the ascorbic acid product comprises a device for recycling the unreacted starting material back into the reaction vessel.
  • the recycling means comprises a continuous separation of ascorbic acid product from unreacted 2-keto-gulonic acid starting material to form an ascorbic acid rich solution and a solution rich in 2-keto-gulonic acid compound that is recycled back into the reaction vessel.
  • the synthesis of L-ascorbic acid is carried out in a solvent.
  • the solvent is moderately polar.
  • the solvent comprises water.
  • the solvent may comprise an alcohol.
  • the alcohol comprises the alkoxy moiety of a 2-keto-L-gulonic acid ester used as the 2-keto-gulonic acid derivative.
  • the reaction vessel comprises a plug flow reactor.
  • the range of space velocities in the plug flow reactor is preferably between 0.05 h "1 to 500 h "1 . More preferably, the range of space velocities in the plug flow reactor is between 0.1 h "1 and 100 h "1 .
  • the palladium is supported on a particulate substrate.
  • the substrate comprises carbon or barium sulfate.
  • the palladium comprises particles ranging in size from 1 ⁇ m to 5 cm.
  • the palladium preferably comprises particles ranging in size from 25 ⁇ m to 5 cm, more preferably, from 100 ⁇ m to 2.5 cm, and even more preferably, from 150 ⁇ m to 1.5 cm.
  • the reaction is generally carried out at elevated temperatures and pressures, although the pressure is dependent upon the temperature employed. Thus, at higher temperatures the vapor pressure is generally about 25 atm, but below 100°C, the pressure is less than 1 atm.
  • the reaction vessel is preferably heated to a temperature ranging between 25°C and 250°C during at least a part of the synthesis, and even more preferably, the reaction vessel is heated to a temperature ranging between 75°C and 200°C during at least a part of the synthesis.
  • the reaction vessel is maintained under an absolute pressure of from 0.1 atm to about 100 atm during at least a part of the synthesis, and even more preferably, the reaction vessel is maintained under an absolute pressure of from 0.7 atm to about 17 atm during at least a part of the synthesis.
  • the systems of the present invention comprise continuous as well as batch reactor formats. Although a preferred method of conducting this reaction is in a plug flow reactor, other reactor configurations are still useful and may be employed in the operation of this invention.
  • a plug flow reactor is particularly suited for the methods of the invention as it presents a reactor format which allows for removal of the L-ascorbic acid within a kinetic time frame such that product degradation is minimized.
  • the reactants are pushed through a reactor packed with the palladium/carbon catalyst.
  • a second catalyst which enhances the conversion of 2-keto-L-gulonic acid compounds to L-ascorbic acid may be included as well.
  • the reaction moves through the reactor as a singular mix, or "plug" such that the concentration of L-ascorbic acid at the end of the flow is increased and the concentration of 2-keto-L-gulonic acid derivative is decreased relative to the concentrations of L-ascorbic acid and 2-keto-L-gulonic acid derivative earlier in the flow.
  • an important parameter of the reaction is the space velocity, wherein space velocity is defined as the volumetric rate of addition of the solution/volume of the reactor.
  • the space velocity required for the reaction is a function of the desired conversion and selectivity, as well as the temperature of the reaction.
  • the space velocity may vary over a wide range, in a preferred embodiment, it is most likely to be determined empirically.
  • the range of space velocities is between 0.05 h " to 500 h "1 . More preferably, the range of space velocities is between 0.1 h "1 and 100 h "1 .
  • the conversion of the 2-keto-L-gulonic acid compound to L-ascorbic acid is preferably taken to only partial conversion to avoid excessive degradation of L-ascorbic acid product.
  • separation of the solid acid catalyst from the aqueous solution of 2-keto-L-gulonic acid compound and L-ascorbic acid utilizes simple procedures known to those in the art.
  • the L-ascorbic acid is isolated, and the unreacted 2-keto-L-gulonic acid compound is recycled back to the reactor.
  • This separation improves overall reaction efficiency by providing for unreacted 2-keto-L-gulonic acid to be recycled back to the reactor, while minimizing decomposition of product L-ascorbic acid, thereby enhancing the overall yield of ascorbic acid.
  • Operation of a reaction system with partial conversion of 2- keto-L-gulonic acid and a recycle step dramatically improves the overall yield to ascorbic acid.
  • Ascorbic acid is unstable for long periods of time under the reaction conditions (e.g. P.P. Regna and B.P. Caldwell, J. Am. Chem. Soc, 66, pp. 246-250, 1944), and undergoes secondary decomposition reactions.
  • Ascorbic acid yields in a single pass process are limited by this subsequent reaction of ascorbic acid in the reactor, and the behavior follows a typical consecutive order process. Therefore, there is an optimum for single pass reactor productivity and pushing toward high conversions may be deleterious, since conditions that lead to high conversion promote decomposition of the product.
  • the unreacted 2-keto-L-gulonic acid compound may be recovered and recycled to the reactor.
  • the recycled 2-keto-L- gulonic acid compound may be purified and/or concentrated prior to being recycled to the reactor.
  • the presence of a subsequent product separation units, purification units, and recycle loops would be expected and are encompassed within the scope of this invention.
  • exemplary product separation techniques for the subsequent separation and purification of L-ascorbic acid from keto-L-gulonic acid include fractional crystallization, electro-dialysis membrane separation, chromatographic methods, and the like.
  • crystallization may be inefficient for recovering ascorbic acid directly from a process stream containing large amounts of 2-keto-L-gulonic acid, unless combined with other separation techniques (see e.g., U.S. Patent No. 5,817,238).
  • Electro-dialysis membranes operated with anion exchange resins may be used to separate ascorbic acid from 2-keto-L-gulonic acid as the two components have differing pKa's (EP 0 554 090 and U.S. Patent Nos. 4,767,870 and 6,004,455). Once separated, the 2- keto-L-gulonic acid may be recycled back to the conversion step and the ascorbic acid may be recovered.
  • a variety of chromatographic methods are capable of separating 2-keto-L- gulonic acid and ascorbic acid.
  • U.S. Patent No. 5,817,238 describes a process for recovery of ascorbic acid from a filtrate solution obtained in the crystallization of ascorbic acid.
  • the ascorbic acid may be adsorbed onto a resin, and then desorbed using a neutral solvent in which the concentration of the ascorbic acid in the eluent is at least as concentrated as the ascorbic acid in the aqueous feed stream (WO 97/13761).
  • a neutral solvent in which the concentration of the ascorbic acid in the eluent is at least as concentrated as the ascorbic acid in the aqueous feed stream (WO 97/13761).
  • SMB simulated moving bed
  • feedstock comprising the 2-keto-gulonic acid substrate (10) is pumped (60) from the feedstock tank (80) via a conduit (20) into a reaction vessel (30).
  • the pressure is controlled throughout the system using multiple pressure regulators (e.g. 50, 110) and back pressure regulators (150) as needed.
  • the feedstock is filtered (70) prior to being pumped into the reaction vessel (30).
  • the reaction vessel (30) is packed with palladium catalyst.
  • the reaction vessel (30) may comprise coils packed with solid palladium.
  • the present invention contemplates any reactor format that allows the 2- keto-gulonic acid substrate to contact solid palladium under conditions suitable for aqueous or acidic catalysis of the 2-keto-gulonic acid substrate to ascorbic acid.
  • the reaction vessel comprises at least one port (55) to provide transfer of the starting material into the reaction vessel.
  • the reaction vessel (30) also includes a second port (65) to remove the ascorbic acid product of the synthesis from the reaction vessel.
  • the system preferably comprises a means to heat the reaction vessel, such as heaters or a recirculating oil bath (40) which produces a heated zone (35), since the formation of ascorbic acid is generally under conditions of elevated temperature and reduced pressure.
  • the reaction vessel ports (55, 65) comprise leads that extend out of the heated zone.
  • the ascorbic acid product exits the reaction vessel (30) via at least one exit port (65) to be transferred via a conduit (25) to a product tank (130).
  • the system may include a means for cooling (90) the reaction product, as well as filters (95) or other means to purify the product.
  • the 2-keto-gulonic acid substrate may be generated by fermentation of a sugar.
  • the fermentation system (not depicted in figure 1) may feed directly into the reactor, or may feed into a storage system such as the feedstock tank (80).
  • the reaction may be taken to partial completion, with recycling of the unreacted 2-keto-gulonic acid starting material to avoid excessive degradation of L-ascorbic acid product.
  • the ascorbic acid product (100) may be treated by one of the separation techniques described herein to separate unreacted 2-keto-gulonic acid from the ascorbic acid product, with recycling of the 2-keto-gulonic acid back to the reactor (or a prereactor storage tank) and further purification of the ascorbic acid product.
  • KLG 2-keto-L-gulonic acid
  • AsA ascorbic acid
  • Palladium chloride (0.532 g, 3 mmol) was dissolved in a mixture of 25 mL concentrated ammonia and 60 mL of distilled water. The solution was then added to 12 X 40 mesh (1.70 mm-0.425 mm) activated carbon granules (50.0 g) having a BET surface area in excess of 800 m /g and contained in an evaporating dish. The mixture was heated on the steam bath with continuous stirring until it became free flowing and then transferred to a quartz tube measuring 106 cm long by 25 mm outer diameter. The quartz tube containing the mixture was placed in a three-element electric tube furnace so that the mixture was located in the approximate center of the 61 cm long heated zone of the furnace.
  • Nitrogen was continuously passed through the catalyst bed at a rate of 100 standard cubic centimeters per minute, and the tube was heated from ambient temperature to 300°C over a 2 hour period, held at 300°C for 2 hours, and then allowed to cool back to ambient temperature.
  • the catalyst prepared in this manner contained 1.28 % Pd and had a density of 0.57 g per mL.
  • a solution of 2-keto-L-gulonic acid was obtained by fermentation of glucose using genetically modified Pantoea citrea followed by partial purification via microfiltration and electro dialysis. Subsequent removal of a portion of the water and crystallization provides the monohydrate of 2-keto-L-gulonic acid as a purified crystalline material.
  • an aqueous solution of crystallized 2-keto-L-gulonic acid was prepared by dissolving 110 g of the crystalline 2-keto-L-gulonic acid monohydrate obtained above in 890 mL of water.
  • the resultant solution contained 10.41 wt % 2-keto-L-gulonic acid and 0.05 wt % L-ascorbic acid by high pressure liquid chromatography (HPLC) analysis. This solution was used as feedstock throughout this experiment.
  • the feed system to the reactor consisted of a reservoir of aqueous 2-keto-L-gulonic acid, whose preparation and composition was described above, and was connected to a high pressure liquid chromatography (HPLC) pump using high pressure Teflon ® tubing (0.318 cm (l/8 th in) outer diameter (OD) and 0.16 cm (l/16 th in) inner diameter (ID)). All Teflon ® tubing used in this experiment was of the same dimensions unless otherwise stated, and where applicable, used PFTE fittings for connections.
  • the outlet of the HPLC pump was connected via high pressure Teflon ® tubing to a pressure relief valve set at 50 pounds per square inch (psi) followed by a pressure gauge (both constructed of 316 Stainless Steel) assembled in series using appropriate PFA reducing unions to connect the assembly to the HPLC pump.
  • psi pounds per square inch
  • a pressure gauge both constructed of 316 Stainless Steel
  • the outlet of the feed system was attached to the inlet of the reactor using high pressure Teflon ® tubing and appropriate Teflon ® PFA reducing unions.
  • the reactor should not be operated at >3.5 atm gauge pressure (51 psig) at temperatures of 150°C, since the fittings are not rated to handle reaction conditions exceeding these parameters. For safety, it is recommended that the upper temperature limit with this reactor be 140°C and the pressure be maintained at less than 3.5 atm.
  • the reactor was immersed in a circulating oil bath with the outlet of the reactor attached to a 75 cm length of high pressure Teflon ® tubing using appropriate PFA reducing unions.
  • the length of high pressure Teflon ® tubing was placed in a room temperature water bath and the outlet connected to a pressure gauge (316 Stainless Steel) using high pressure Teflon ® PFA tubing having a wall thickness of 0.16 cm (1/16 l in) and appropriate PFA reducing unions.
  • the pressure gauge was then attached to a backpressure regulator (316 Stainless Steel), which was used to maintain the pressure in the reactor above the vapor pressure of the solvent (water).
  • the outlet of the backpressure regulator was attached to a length of high pressure Teflon ® tubing using appropriate PFA reducing unions which led into a receiving vessel (round bottom flask).
  • a nitrogen atmosphere was maintained by placing a gas inlet with a septum on top of a round bottom flask and piercing the septum with the high pressure Teflon ® tubing and attaching the gas inlet to a nitrogen source.
  • the size of the round bottom flask required varied based on the flow rate and length of time between samples. Generally, a 50 mL or a 100 mL flask was adequate.
  • the temperature of the oil bath containing the reactor was raised to 145°C and the HPLC pump started at a flow rate of 0.50 mL/min, using the solution of 2-keto-L-gulonic acid prepared above. Samples were removed periodically and analyzed by HPLC as described below.
  • the reactor reached steady state in about 9 lrrs of operation. In this context, steady state refers to a condition of consistent chemical analysis and consistent color.
  • 10 samples were removed over a period of about 11 hrs. The samples were analyzed by High Pressure Liquid Chromatography using an
  • the mobile phase consisted of a solution of 10.55 g mono basic potassium phosphate, 3.4 g tetrabutylammonium phosphate, and 2.59 mL concentrated phosphoric acid diluted to 1000 mL in a volumetric flask with distilled water.
  • the analytical sample was prepared by diluting 125 ⁇ L of the liquid sample from the reactor to 50 mL with water using a volumetric flask.
  • a 5 ⁇ L sample was added to the column and eluted using a flow rate of 1.0 mL/min. Quantification was accomplished by comparison with the response for a range of standard solutions prepared by dissolving recrystallized 2-keto-L-gulonic acid and L-ascorbic acid in water at various concentrations. The standard solutions were prepared fresh and measured daily.
  • the average concentration of the effluent from the reactor was 4.39% 2-keto-L- gulonic acid and 3.85% L-ascorbic acid. This represents a 58% conversion of 2-keto-L- gulonic acid with a selectivity to L-ascorbic acid of 71%.
  • a visible spectrum of the effluent is shown in Figure 2 (black line).
  • Example 3 Comparative Example Example 2 was repeated except that, rather than using a palladium catalyst, the reactor was packed with the 12 X 40 mesh (1.70 mm-0.425 mm) activated carbon granules without any palladium added. These granules were identical (from the same container) used to generate the palladium/carbon mix.
  • the average concentration of the effluent from the reactor was 3.75% 2-keto-L- gulonic acid and 3.89% L-ascorbic acid. This represents a 64% conversion of 2-keto-L- gulonic acid with a selectivity to L-ascorbic acid of 65%.
  • a visible spectrum was recorded at steady state and compared with the spectrum obtained in Example 1 ( Figure 2; white line).
  • Example 4 Pilot Plant Studies This experiment was designed to test whether the system of the present invention could be scaled-up to generate production quantities of L-ascorbic acid. In addition, the experiment was designed to examine the stability of the catalyst when the system was operated for extended time periods (days and weeks).
  • Solutions of 2-keto-L-gulonic acid were prepared by fermentation of glucose using genetically modified Pantoea citrea followed by partial purification via microfiltration and electro dialysis as described for Example 2.
  • the aqueous solutions obtained by this method contain 2-keto-L-gulonic acid and traces of L-ascorbic acid as determined by HPLC analysis. Two separate batches were obtained for this experiment and operated under two different conditions. The analysis of the feedstock is specified below for each stage of the experiment.
  • the reactor was constructed from a 123 inch (310 cm) length of 3/8 inch (1 cm) OD Titanium tubing with a 1/16 th inch (1.6 mm) wall thickness that was twisted into coils of 9 inches (23 cm) and that included leads positioned about 12 inches (30 cm) as measured from the center of the coil that connected the reaction vessel to the rest of the system.
  • the reactor was connected at the front (input) end to a high pressure pump which pumped the feedstock through the reactor and at the back end to a collection system.
  • the collection system included: a cooling section of jacketed tubing about one foot in length and of the same diameter, thickness, and material of construction used for the reactor; a cloth filter; a back pressure regulator; and a product collection vessel that was periodically drained and sampled.
  • the relative positioning of the components of the cooling system is shown in Figure 1.
  • the coils comprising the palladium catalyst were placed in a heated circulating oil bath.
  • the oil bath was heated to 170°C and the back pressure regulator was set at a setting of ca. 900-1000 kPa at the exit to the reactor. This setting was chosen as being sufficient to raise the pressure at the outlet of the reactor above the boiling of the aqueous reaction solvent (water) (i.e. greater than 791 kPa).
  • the feedstock for this experiment (11.04% 2-keto-L-gulonic acid and 0.26% L-ascorbic acid) was pumped through the reactor at a rate of 14 mL/min and the reactor allowed to equilibrate for ca. 5 days before sampling began.
  • the reactor was operated at 170°C, with a flow rate of 14 mL/min for 8 days.
  • Samples were collected and analyzed for ascorbic acid product and 2-keto-L- gulonic acid starting material by HPLC over the course of the experiment. Sampling was performed several times a day until the reactor reached steady state at about 5 days. At this point, sampling was performed once or twice daily. The average conversion to L- ascorbic acid was 55% with an average selectivity of 78%. Over the course of the experiment, the average color, as measured at 450 nm in a 10% dilution in water, was 0.52 absorbance units. There was little variation in any of the above measurements over the course of the 8 day run.

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Abstract

La présente invention concerne la synthèse d'un acide ascorbique à couleur réduite. Le procédé décrit dans cette invention utilise des catalyseurs de palladium pour la synthèse d'un acide ascorbique à partir de l'acide 2-céto-gulonique ou de dérivés de l'acide 2-céto-gulonique. Ledit catalyseur de palladium peut comporter un support inerte, entres autres, tel que le carbone ou le sulfate de baryum. Contrairement à d'autres catalyseurs du palladium, le catalyseur de cette invention est actif dans des conditions aqueuses appropriées à la synthèse de l'acide ascorbique. Ladite invention concerne aussi des systèmes de conversion de l'acide 2-céto-gulonique ou de dérivés correspondants en acide ascorbique en présence d'un catalyseur de palladium solide et en acide ascorbique de couleur réduite élaboré à l'aide des procédés de cette invention.
EP02800980A 2001-10-09 2002-10-09 Systemes et procedes de generation d'un acide ascorbique a couleur reduite Withdrawn EP1463720A1 (fr)

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US32788401P 2001-10-09 2001-10-09
US327884P 2001-10-09
PCT/US2002/032259 WO2003031427A1 (fr) 2001-10-09 2002-10-09 Systemes et procedes de generation d'un acide ascorbique a couleur reduite

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JPS5594394A (en) * 1979-01-11 1980-07-17 Asahi Chem Ind Co Ltd Preparation of lactone
DK307386A (da) * 1985-07-05 1987-01-06 Takeda Chemical Industries Ltd Fremgangsmaade til rensning af l-ascorbinsyre
DE3621781A1 (de) * 1985-07-05 1987-01-15 Takeda Chemical Industries Ltd Verfahren zur reinigung von l-ascorbinsaeure
DE3819045C2 (de) * 1987-06-08 1997-06-19 Takeda Chemical Industries Ltd Herstellung von L-Ascorbinsäure
FR2648136B1 (fr) * 1989-06-12 1994-06-17 Rhone Poulenc Sante Procede de preparation de l'acide ascorbique
DE19919203A1 (de) * 1999-04-28 2000-11-02 Basf Ag Verfahren zur Herstellung von L-Ascorbinsäure

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