EP0000092B1 - Method of preparing ascorbic acid and intermediates specially adapted for use therein - Google Patents

Method of preparing ascorbic acid and intermediates specially adapted for use therein Download PDF

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EP0000092B1
EP0000092B1 EP78300014A EP78300014A EP0000092B1 EP 0000092 B1 EP0000092 B1 EP 0000092B1 EP 78300014 A EP78300014 A EP 78300014A EP 78300014 A EP78300014 A EP 78300014A EP 0000092 B1 EP0000092 B1 EP 0000092B1
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lactone
carbon atoms
alkyl
hydroxyl
aldehyde
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EP0000092A1 (en
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Thomas Charles Crawford
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Pfizer Inc
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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
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a novel process for preparing ascorbic acid.
  • L-ascorbic acid, or Vitamin C is required in the human diet and is widely sold in tablet form and as an additive in various foodstuffs to meet this need and also as an antioxidant.
  • L-ascorbic acid is biosynthesised from D-glucose. The final step in this biosynthesis is the enzymatic conversion of L-gulono-1,4-lactone to L-ascorbic acid.
  • British Patent No. 763,055 discloses the conversion of L-gulono-1,4-lactone to L-ascorbic acid in about 40% yield by the use of an enzymatic oxidation system.
  • L - gulono - 1,4 - lactone Derivatives of L - gulono - 1,4 - lactone are known in the art.
  • Matsui et al have prepared 2,3:5,6 - di - O - isopropylidene - L - gulono - 1,4 - lactone, 3,5 - 0 - benzylidene - L - gulono - 1,4 - lactone, 2,6:3,5 - di - 0 - benzylidene - L - gulono - 1,4 - lactone (Yakugaku Zasshi 86, 110 (1966)), and 2,3,5,6 - -tetrabenzoyl -L -gulono -1,4 - lactone has been prepared by Kohn et al (J.A.C.S., 87, 5475 (1965)).
  • Chem., 1974, 38 (ii), 2189 - 90 described the reaction of D-glucuronolactone with acetone to form the 1,2 - 0 - isopolypylidene derivative, followed by oxidation, hydrolysis to remove the protecting group and sodium borohydride reduction to L-ascorbic acid.
  • the present invention provides a novel process for the preparation of ascorbic acid from a 1,4- lactone selected from gulono - 1,4 - lactone, glactono - 1,4 - lactone, idono - 1,4 - lactone and talono - 1,4 - lactone.
  • L-ascorbic acid is prepared from lactones of the L-series and D-ascorbic acid results from lactones of the D-series.
  • the lactone is first reacted with a hydroxyl-protecting reagent to form a hydroxyl-protected intermediate wherein one of the hydroxyl groups located at the 2- and 3- positions of the ring is protected while the other remains as a free hydroxyl group.
  • the free hydroxyl group at the 2- or 3- position of this protected intermediate is then oxidised to a keto group and the resulting compounds subjected to hydrolysis until substantial conversion to ascorbic acid has occurred.
  • this process may be effected by (a) contacting a 1,4-lactone , selected from gulano - 1,4 - lactone, galactono - 1,4 - lactone, idono - 1,4 - lactone and talono - 1,4 - lactone with about three equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone; (b) contacting the resulting intermediate having a free hydroxyl group at the 2- or 3- position with an oxidizing agent effective to convert said hydroxyl group to a keto group and (c) hydrolyzing the compound formed in step (b) until conversion to ascorbic acid is substantially complete.
  • a 1,4-lactone selected from gulano - 1,4 - lactone, galactono - 1,4 - lactone, idono - 1,4 - lactone and talono - 1,4 - lactone with about three equivalents of a hydroxyl-protecting reagent per mole of 1,
  • Preferred hydroxyl-protecting reagents for this process include trialkylsilyl halides and dialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms; alkanoic anhydrides of 3 to 8 carbon atoms; alkanoyl halides of 2 to 6 carbon atoms; aroyl halides wherein said aroyl is benzoyl, naphthoyl or mono-substituted benzoyl; wherein said substituents are alkyl or 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; dialkyl ketones, wherein each alkyl is of 1 to 6 carbon atoms; alkyl aldehydes of 2 to 8 carbon atoms; and triphenylmethyl halides.
  • Ascorbic acid may also be prepared by (a) contacting a 1,4-lactone selected from gulono - 1,4 - lactone and idono - 1,4 - lactone in the presence of an acid catalyst having a pK a of less than about 2.5 with at least about two equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone, said reagent being selected from an alkyl aldehyde of 2 to 8 carbon atoms; an aryl aldehyde, an arylalkyl aldehyde and an arylalkenyl aldehyde, wherein said aryl is phenyl, mono-substituted or disubstituted phenyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of one to six carbon atoms, halo or nitro, and said alkyl and alkenyl are each of 2 to 4 carbon atoms; (b) contacting
  • Preferred hydroxyl-protecting reagents for effecting this process include acetaldehyde, isobutyraldehyde, benzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, 3,4-dichlorobenzaldehyde, o-methoxybenzaldehyde, o-chlorobenzaldehyde and cinnamaldehyde.
  • the present process for the preparation of ascorbic acid utilizes as starting material a 1,4-lactone selected from gulono-1,4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1,4-lactone.
  • 1,4-lactone selected from gulono-1,4-lactone, galactono-1,4-lactone, idono-1,4-lactone and talono-1,4-lactone.
  • L-ascorbic acid is derived from 1,4-lactones of the L-series
  • D-ascorbic acid is prepared from the D-enantiomers.
  • ascorbic acid gulono - 1,4 - lactone, galactono - 1,4 - lactone, idono - 1,4 - lactone and talono -1,4 - and to intermediates derived therefrom is meant to include compounds of both the L-series and the D-series.
  • L-gulono-1,4-lactone can be prepared by the hydrogenation of D-glucurono- lactone.
  • L-galactono-1,4-lactone may be prepared from pectin via D-galacturonic acid.
  • D - gulono - 1,4 - lactone can be prepared from D-xylose. See, for example, Chem. Pharm. Bull. 13, 173 (1965), Helv. Chim. Acta. 21, 3 (1938); Bull Chem. Soc. Japan 13, 272 (1938); J.A.C.S. 49, 478 (1928); Helv. Chim. Acta 18 482 (1938) and Organic Synthesis IV, 506 (1963).
  • Gulono - 1,4 - lactone is a preferred starting material.
  • the first step in the present process is the formation of a protected intermediate, having an unprotected hydroxyl group remaining at either, but not both, the 2- or 3- position of the lactone ring.
  • This may be effected in one embodiment of the invention by the reaction of the 1,4-lactone with about three equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone.
  • a hydroxyl-protecting reagent is considered to be any compound that will react with the hydroxyl groups of the lactone, replacing the hydrogen atom with a radical derived from the reagent, which radical can in subsequent steps be removed by hydrolysis to regenerate the hydroxyl groups.
  • hydroxyl-protecting reagent By an equivalent of hydroxyl-protecting reagent is meant the stoichiometric amount required to react with one hydroxyl group.
  • the hydroxyl-protecting reagent may be monofunctional, by which is meant that one molecule of reagent reacts with one hydroxyl group of the lactone. When such a reagent is used the hydroxyl groups at the 5- and 6- positions and one of the hydroxyl groups at the 2-or 3- position will be protected. Since only three equivalents are employed only one of the hydroxyl groups at the 2- and 3- positions will react and a free hydroxyl group will remain at the other position.
  • the protected intermediates formed by this reaction are of the formulae: wherein R is a monofunctional hydroxyl-protecting group, as defined herein; or mixtures thereof, and their enantiomers.
  • hydroxyl-protecting reagents including, but not limited to, trialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms; alkanoyl halides of 2 to 6 carbon atoms; aroyl halides, wherein aroyl is benzoyl, naphthoyl or mono-substituted benzoyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; alkanoic anhydrides of 3 to 8 carbon atoms; alkyl vinyl ethers, wherein said alkyl is of 1 to 6 carbon atoms; alkyl mono- or di-substituted vinyl ethers, wherein said substituents are alkyl of 1 to 6 carbon atoms or halo; and triphenylmethyl halides.
  • hydroxyl-protecting reagent is not critical and any compound which will allow formation of a protected intermediate which can be oxidized at the 2- or 3- position and the hydroxyl-protecting groups removed thereafter can be employed.
  • a preferred class of monofunctional hydroxyl-protecting reagents is trialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms. Of these, trimethylsilyl halides and t-butyl-dimethylsilyl halides are especially preferred.
  • alkanoic anhydrides of 3 to 8 carbon atoms; these are considered as monofunctional reagents for the purpose of this process, since the anhydride reacts dissociatively and each lactone hydroxyl reacted is esterified.
  • a preferred alkanoic anhydride is acetic anhydride.
  • Other preferred hydroxy-protecting reagents are alkanoyl halides of 2 to 6 carbon atoms; especially preferred are acetyl chloride and acetyl bromide.
  • a further preferred class of hydroxyl-protecting reagents is aroyl halides, wherein said aroyl is benzoyl, naphthoyl or mono-substituted benzoyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro.
  • aroyl chloride and benzoyl bromide are especially preferred.
  • a preferred triphenylmethyl halide is triphenylchloromethane.
  • difunctional hydroxyl-protecting reagents may be employed.
  • a difunctional hydroxyl-protecting reagent is meant a compound of one molecule of which can react with two hydroxyl groups of the lactone to form a bridged intermediate.
  • one mole of such a reagent provides two equivalents of hydroxyl-protecting reagent according to the definition used herein.
  • the difunctional hydroxyl-protecting reagents may be effective to form two types of intermediates, depending on the choice of reagent employed. Difunctional reagents react to form a 5,6-bridged intermediate.
  • difunctional hydroxyl-protecting reagents that can be employed in the formation of such an intermediate include, but are not limited to, dialkylsilyl halides, alkyl isocyanates, and alkyl haloformates, wherein each alkyl is of 1 to 6 carbon atoms; aryl isocyanates, wherein aryl is phenyl, monosubstituted or disubstituted phenyl, wherein the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro; and alkyl aldehydes of 2 to 8 carbon atoms.
  • Choice or reagent is not critical.
  • a difunctional hydroxy-protecting reagent When a difunctional hydroxy-protecting reagent is employed it is preferably used in the amount of about two equivalents in conjunction with one equivalent of a monofunctional hydroxyl-protecting reagent, which reacts with one of the hydroxyl groups at the 2- or 3-position of the lactone, to form an intermediate of the type: wherein R i is a difunctional hydroxyl-protecting group and R is a monofunctional hydroxyl-protecting group, as defined herein; or mixtures thereof, and their enantiomers.
  • a preferred class of difunctional hydroxyl-protecting reagents is dialkylsilyl halides, wherein each alkyl is of 1 to 6 carbon atoms.
  • Another class of preferred hydroxyl-protecting reagents is dialkyl ketones, wherein each alkyl is of 1 to 6 carbon atoms; especially preferred are acetone, methyl ethyl ketone and methyl isobutyl ketone.
  • a further class of preferred difunctional hydroxyl-protecting reagents is alkyl aldehydes of 2 to 8 carbon atoms; especially preferred compounds are acetaldehyde and propionaldehyde.
  • the alkyl aldehydes may be used directly or in the form of dialkyl acetals and reference to such aldehydes in the specification and claims hereof is intended to include such acetals.
  • Non-hydroxylic organic solvents include, but are not limited to, dimethyl formamide, pyridine and dimethyl sulfoxide. It is not necessary, however, that the starting lactone be fully soluble in the organic medium and the protected intermediate can be prepared in a heterogeneous system where the lactone is dispersed in an inert organic diluent.
  • the 1,4-lactone is contacted with the appropriate hydroxyl-protecting reagent at temperatures in the range of about -10°C to 150°C. Temperature is, however, not critical and usually the reaction can be most conveniently accomplished at room temperature.
  • the hydroxyl-protecting reagent may be added to the solution of the 1,4-lactone either dropwise or in one batch. In either case, the mixture should be adequately stirred throughout the period of reaction.
  • the time for complete reaction will, of course, vary with the temperature and concentration of reagents. In general, however, the reaction will be substantially complete in a period of about 30 minutes to about 15 hours.
  • the reaction may be advantageously conducted in the presence of a weak Lewis acid catalyst, such as cupric sulfate or ferric chloride.
  • a limited number of difunctional hydroxyl-protecting reagents have been found to form a 3,5- adduct of the type: wherein R 3 is a difunctional hydroxyl-protecting group derived from an alkyl aldehyde, aryl aldehyde, arylalkyl aldehyde or arylalkenyl aldehyde, as defined hereinafter; and the enantiomer thereof.
  • These 3,5-adducts are formed with such aldehyde hydroxyl-protecting reagents in the presence of a strong acid catalyst having a pKa of less than about 2.5.
  • Such intermediates are only formed with gulono - 1,4 - lactone and idono - 1,4 - lactone, in which the stereochemistry of the 3- and 5-hydroxyl groups allows the formation of this bridged compound.
  • the hydroxyl-protecting reagents that have been found to form this type of intermediate are aryl aldehydes, arylalkyl aldehydes and arylalkenyl aldehydes, wherein aryl is phenyl, mono-substituted or disubstituted phenyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro, and alkyl and alkenyl are each of 2 to 4 carbon atoms; and alkyl aldehydes of 2 to 8 carbon atoms.
  • Preferred alkyl aldehydes are acetaldehyde and isobutyraldehyde.
  • Preferred aryl aldehydes include benzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, 3,4-dichlorobenzaldehyde, o-methoxybenzaldehyde and o-chlorobenzaldehyde.
  • Benzaldehyde is an especially preferred reagent.
  • Another especially preferred reagent is o-methoxybenzaldehyde.
  • a preferred arylalkenyl aldehyde is cinnamaldehyde.
  • Formation of the 3,5-protected intermediates described above and represented by formula IX is conducted in an organic solvent or diluent.
  • Suitable solvents are non-hydroxylic organic compounds such as dimethyl formamide, pyridine and dimethyl sulfoxide.
  • a particularly preferred process employs an excess of the aldehyde hydroxyl-protecting reagent as solvent of diluent. Since the intermediate is a 3,5-adduct, further reaction of the aldehyde with other hydroxyl groups of the same lactone ring does not occur. Thus, for example, the 1,4-lactone can be contacted with from about 3 to about 10 equivalents of the aldehyde hydroxyl-protecting reagent.
  • the formation of the 3,5-adduct requires the presence of a strong acid catalyst having a pKa of less than about 2.5, generally added in an amount between about 0.05 and about 1.5 moles per mole of 1,4-lactone.
  • Suitable acid catalysts include, but are not limited to, hydrochloric acid, sulfuric acid p-toluenesulfonic acid, sulfonic ion exchange resins and polyphosphoric acid. Temperatures between about -10°C and 150°C may be employed.
  • the reaction is usually conducted at about room temperature.
  • the hydroxyl protecting reagent may be added to the solution of the 1,4-lactone either dropwise or in one batch while stirring the reaction mixture.
  • the time for complete reaction will depend on the temperature and the concentration of the reagents. In general, however, the reaction will be substantially complete in a period of about 30 minutes to about 15 hours.
  • the 3,5-adducts of formula IX may also be formed from 5,6-adducts formed with alkyl aldehyde protecting groups by heating in the presence of a strong acid catalyst as described above.
  • the 3,5-adduct of formula IX can be used directly in the next step of the process i.e., the oxidation of the hydroxyl group to a keto group.
  • the free hydroxyl at the 2-position may be selectively oxidized in preference to the other free hydroxyl at the 6-position of the lactone.
  • the first step in the process may be effected by contacting a 1,4-lactone selected from gulonolactone and idono-lactone in the presence of an acid catalyst having a pKa of less than about 2.5 with at least about two equivalents of a hydroxyl-protecting reagent per mole of 1,4-lactone, said reagent being selected from an alkyl aldehyde of 2 to 8 carbon atoms; an aryl aldehyde, an arylalkyl aldehyde and an arylalkenyl aldehyde, wherein said aryl is phenyl, mono-substituted or disubstituted phenyl wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms halo or nitro, and said alkyl and alkenyl are each of 2 to 4 carbon atoms.
  • an acid catalyst having a pKa of less than about 2.5 with at
  • R is a monofunctional hydroxyl-protecting group and R 3 is a difunctional hydroxyl-protecting group derived from an alkyl aldehyde, an aryl aldehyde, an arylalkyl aldehyde or an arylalkenyl aldehyde, as defined above; and the enantiomer thereof.
  • a preferred monofunctional hydroxyl-protecting reagent for the formation of these intermediates is a triphenylmethyl halide, such triphenylchloromethane.
  • Intermediates of formula X are suitable for oxidation of the 2-hydroxyl group to a keto group in the same way as other 3,5-adducts, as described hereinafter.
  • the protected intermediates formed in the first step of the process as described above may be used directly in the next step of the present process without further purification. If desired, however, the protected intermediates may be isolated and purified by recrystallisation or other means known in the art. Preferably, before use in the next step excess solvent is removed.
  • the second step in the present process is the oxidation of the unprotected hydroxyl group, located at the 2- or 3- position of the protected lactone, to keto.
  • This may be effected by methods known in the art for the oxidation of secondary alcohols to ketones.
  • choice of oxidizing agents will be affected by the protecting groups employed and the type of intermediate formed in the first step of the process. For example, oxidation of the 3,5-protected intermediates and others having a free hydroxyl group at the 2-position of the lactone may conveniently be effected with manganese dioxide.
  • the hydroxyl group at the 2-position is oxidized preferentially by such use of manganese dioxide.
  • Any of the intermediates formed in the first step of the process may be oxidized via a sulf q xonium salt, formed from a mixture of dimethyl sulfoxide and, for example, acetic anhydride or trifluoroacetic anhydride, or from a mixture of dimethylsulfide and N-chlorsuccinimide, in the presence of a base, such as triethylamine.
  • Oxidation may also be effected catalytically using either pure oxygen or an oxygen-containing gas.
  • a suitable catalyst is platinum. Oxidation may also be effected elctro- chemically.
  • the oxidation is conducted in an organic solvent, which may be the same as that used in the first step of the process in forming the protected intermediate. However, other solvents may be used and in general, any organic solvent inert to oxidation conditions can be employed. Examples of suitable solvents include, but are not limited to, dimethyl formamide, pyridine, dimethyl sulfoxide, dichloromethane and acetone. It is not necessary that the intermediate be fully soluble in the organic medium. Temperatures suitable for the oxidation reaction will vary according to the type of oxidation employed.
  • the oxidation may be conducted at about -60°C to 100°C depending on the method used to generate the initial sulfonium salt.
  • the reaction is preferably conducted at about 0°C to 50°C.
  • Oxidation by manganese dioxide is conducted at about -10°C to about 75°C, preferably about 0°C to room temperature.
  • Catalytic oxidation using platinum and oxygen may be conducted at about room temperature to about 100°C, preferably about 50°C to about 75°C.
  • the oxidized intermediate should be separated from any excess oxidizing agent, for example, by filtration of solid catalyst residues or by extraction or recrystallisation of the product.
  • the oxidized intermediate can be isolated and purified by means known in the art; however, this is not necessary.
  • the oxidized intermediates may exist in the keto, enol or hydrated forms depending on the protecting groups employed.
  • the 3,5- protected intermediates are generally isolated as the hydrated or keto form.
  • oxidized intermediates formed as described above are novel compounds. Particularly useful and preferred intermediates are those of the formula: and the hydrated form thereof,
  • R 3 is a hydroxyl-protecting group derived from an alkyl aldehyde of 2 to 8 carbon atoms; an aryl aldehyde, an arylalkyl aldehyde or an arylalkenyl aldehyde, wherein said aryl is phenyl, mono- substituted or di-substituted phenyl, wherein said substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo or nitro, and said alkyl and alkenyl are each of 2 to 4 carbon atoms.
  • the final step in the present process is the removal of the hydroxyl-protecting groups by hydrolysis and subsequent rearrangement to yield ascorbic acid.
  • Hydrolysis may generally be effected under said acid conditions. Suitable acids for effecting removal of the hydroxyl-protecting groups include hydrochloric acid, sulfuric acid, acetic acid and other lower alkyl carboxylic acids and sulfonic ion exchange resins. Hydroylsis may be conducted in aqueous organic co-solvent mixtures, with methanol and other lower alkyl alcohols being suitable solvents. Another preferred hydrolysis medium is aqueous acetic acid. With some hydroxyl-protecting groups hydrolysis may also be effected under basic conditions, for example, where ester intermediates are employed.
  • Suitable bases include sodium carbonate, sodium hydroxide and similar salts.
  • the ascorbic acid is then obtained in the form of the sodium or other metal salt and can be converted to the free acid by treatment with a dilute acid, such as hydrochloric acid, or by ion exchange.
  • a dilute acid such as hydrochloric acid, or by ion exchange.
  • temperatures are not critical, generally temperatures in the range of about 35°C to 100°C being suitable with temperatures of about 50°C to 75°C being preferred.
  • the lactone ring may be opened to form methyl 2-ketogulonate or 2-ketogulonic acid.
  • the methyl 2- ketogulonate or 2-ketogulonic acid may be isolated and purified.
  • the ascorbic acid produced can be purified by means known in the art, for example by recrystallisation from methanol, methanol-water or other suitable solvents or solvent mixtures.
  • the faster moving component was shown to be 2,5,6 - tri - O - t - butyldimethylsilyl - L - gulono - 1,4 - lactone by n.m.r. decoupling experments.
  • An analytically pure sample was prepared by preparative gas chromatography on 10% SE 30 on A/W DMCS Chromosorb G: i.r. (neat) 3550, 1800 cm 1 ; n.m.r.
  • the slower moving component was shown to be 3,5,6 - Tri - O - t - butyldimethylsilyl - L - gulono - 1,4 - lactone by n.m.r. decoupling experiments.
  • An analytically pure sample was prepared by preparative gas chromatography on 10% SE 30 on A/W DMCS Chromosorb G: i.r. (neat) 3400, 1790 cm -1 ; n.m.r. (DMSO-d 6 ) ⁇ H 0.10 (m, 18), 0.93 (m, 27), 3.50-4.67 (m, 6), 6.03 (d, I, -OH1.
  • This compound was also prepared by the above procedure but employing one equivalent of concentrated hydrochloric acid as the acid catalyst.
  • lodine titration of 0.222 g of this material showed the yield of ascorbic acid to be 70%. Recrystallisation of the remaining solid from methanol-ethyl acetate afforded 0.550 g of ascorbic acid in the first crop, 1.399 g in the second crop, and 0.247 in the third crop for a total of 2.196 g (12.5 mmol, 59%).
  • This material was identical with authentic ascorbic acid by t.l.c., g.l.p.c., i.r. and n.m.r., m.p. 184-5° (authentic 185-6°): i.r.
  • the column was initially eluted with water to elute non-acidic impurities and then with 0.5 N hydrochloric acid to elute the L-ascorbic acid. After removing the water, the resulting solid was triturated with chloroform-ethanol and recrystallised from methanol. The i.r. and n.m.r. spectra of this material were identical with authentic ascorbic acid.
  • the product may be converted to ascorbic acid by hydrolysis by the procedure of Example '5.
  • 3,5 - 0 - (2 - Methylpropylidene) - L - xylo - hexulosono - 1,4 - lactone hydrate was also prepared as follows. To a mixture of 30 ml of dioxane and 4 ml of water was added 0.60 g (2.59 mmol) of 3,5 - O - (2 - methylpropylidene) - L - gulono - 1,4 - lactone followed by 0.64 g of prereduced platinum oxide. The reaction mixture was heated to 70° and oxygen was bubbled through the solution. After one hour most of the starting material was gone, the catalyst was removed by filtration, and the solution concentrated in vacuo. T.l.c. and n.m.r. confirmed the presence of 3,5 - 0 - (2 - methyl- proylidine) - L - xylo - hexulosono - 1,4 - lactone.
  • the product may be converted to L-ascrobic acid by the procedure of Example 5.
  • This product may be converted to L-ascorbic acid by the procedure of Example 5.
  • This product may be converted to L-ascorbic acid by the procedure of Example 5.
  • 5,6 - 0 - isopropylidene - L - galactono - 1,4 - lactone can be prepared by the following procedure: To 5 ml of dry dimethylformamide was added 2.10 g (11.8 mmol) of L - galactono - 1,4 - lactone, 1.0 g (11.8 mmol) of ethyl isopropenyl ether and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at 0° for one hour and at room temperature for 18 hours.
  • the material obtained from the above chromatography was greater than 95% one isomer.
  • the n.m.r. data suggests that it is 5,6 - 0 - isopropylidene - 3 - 0 - acetyl - L - galactono - 1,4 - lactone.
  • the above crude mixture of acetates was converted to ascorbic acid as follows: To 25 ml of dry dichloromethane was added 1.69 ml (12 mmol) of trifluoroacetic anhydride. After cooling to less than -50°, 0.85 ml (12 mmol) of dimethylsulfoxide was added. The resulting heterogeneous solution was stirred at -50° or below for 30 minutes. Then 15 ml of dichloromethane containing 1.49 g (6.0 mmol) of the mixture of acetates was added. The resulting solution was stirred at less than -50° for 40 minutes at which time 1.2 ml of triethylamine was added.
  • L-ascorbic acid may be prepared by the procedures of Examples 1 and 2 but employing each of L - galacto - 1,4 - lactone, L - talono - 1,4 - lactone and L - idono - 1,4 - lactone as starting materials.
  • D - ascorbic acid may be prepared by the procedures of Examples 1 and 2 but employing each of D - gulono - 1,4 - lactone, D - galacto - 1,4 - lactone, D - talono - 1,4 - lactone and D - idono - 1,4 - lactone as starting materials.
  • D-ascorbic acid may be prepared by the procedure of Example 5 but employing each of D-gulono - 1,4 - lactone and D - idono - 1,4 - lactone as starting materials.
  • This material may be converted to ascorbic acid using the hydrolysis conditions described in Example 5.
  • This product may be converted to L-ascorbic acid by the procedure of Example 5.

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EP78300014A 1977-06-03 1978-06-02 Method of preparing ascorbic acid and intermediates specially adapted for use therein Expired EP0000092B1 (en)

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US05/803,020 US4111958A (en) 1977-06-03 1977-06-03 Ascorbic acid synthesis
US803020 1977-06-03

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JP (2) JPS5845432B2 (ja)
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US4232168A (en) * 1977-06-13 1980-11-04 Pfizer Inc. Preparation of ascorbic acid intermediates
US4283340A (en) * 1977-06-13 1981-08-11 Pfizer Inc. Ascorbic acid intermediates
US4421924A (en) * 1980-05-05 1983-12-20 Pfizer Inc. Ascorbic acid intermediates and their preparation
WO1982000642A1 (en) * 1980-08-14 1982-03-04 A Welebir Nitrosourea derivatives having antitumor activity
US4423236A (en) * 1980-08-14 1983-12-27 National Foundation For Cancer Research, Inc. 5,6,-0-Isoalkylidene ascorbic acid derivatives
US4552888A (en) * 1982-01-15 1985-11-12 Eli Lilly And Company Ascorbic acid ethers in angiogene
DK36784A (da) * 1983-02-25 1984-08-26 Hoffmann La Roche Fremgangsmaade til fremstilling af chirale aldehyder
US4931558A (en) * 1983-09-21 1990-06-05 Eli Lilly And Company Processes for preparing intermediates of picenadol
JPS61192907U (ja) * 1985-05-24 1986-12-01
JPS6244712U (ja) * 1985-09-09 1987-03-18
JPS63114705U (ja) * 1987-01-20 1988-07-23
US4845246A (en) * 1987-06-15 1989-07-04 Takeda Chemical Industries, Ltd. Ascorbic acid ester
US5569875A (en) * 1992-03-16 1996-10-29 Legend Products Corporation Methods of making explosive compositions, and the resulting products
US5442079A (en) * 1993-05-10 1995-08-15 Virginia Polytechnic Institute And State University Method for preparing erythruronolactone
FR2761991B1 (fr) * 1997-04-11 1999-06-25 Ceca Sa 5-6,o alkylidenes gluconolactones-1(4) et derives, procedes de preparation et utilisations
ATE295843T1 (de) * 2000-12-22 2005-06-15 Eastman Chem Co Kontinuierliches verfahren zur herstellung von l- ascorbinsäure
DE10231890B4 (de) * 2002-07-12 2004-07-01 Basf Ag Verfahren zur Abtrennung von Ascorbinsäure aus einem polaren, Ascorbinsäure und 2-Keto-L-gulonsäure enthaltenden Lösungsmittel
CN104428876A (zh) * 2012-07-20 2015-03-18 富士胶片株式会社 蚀刻方法以及使用该方法制造半导体基板产品和半导体器件的方法

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JPS55149286A (en) 1980-11-20
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US4111958A (en) 1978-09-05
IE781103L (en) 1978-12-03
DK248178A (da) 1978-12-04
JPS5719117B2 (ja) 1982-04-20
IE47102B1 (en) 1983-12-28
DE2860636D1 (en) 1981-08-06
IT7824178A0 (it) 1978-06-02
JPS543058A (en) 1979-01-11

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