Process for purifying L-ascorbyl 2-monophosphate

Details Process for purifying L-ascorbyl 2-monophosphate Process for purifying L-ascorbyl 2-monophosphate

2000-05-31

2001-09-11

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06288243

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns a process for purifying L-ascorbyl 2-monophosphate wherein this substance, in the form of its mono-alkali metal salt, is recovered from a mixture of its alkali metal and alkaline earth metal salts, salts of other phosphorylated forms of L-ascorbic acid, and various alkali metal and/or alkaline earth metal phosphates using a basic anion exchange resin.
BACKGROUND OF THE INVENTION
As is known, ascorbic acid (vitamin C) and its salts are used as additives for foodstuffs, animal feeds, and cosmetic products. Ascorbic acid itself is sensitive to heat and oxidation, as a result of which it has the undesirable tendency to readily decompose. Accordingly, it is unsuitable in this form in many applications, e.g. in cosmetic products, and interest has developed in producing derivatives of ascorbic acid which have increased stability and which can replace ascorbic acid in the same applications.
It is also well known that ascorbic acid phosphates (ascorbyl phosphates) represent protected forms of ascorbic acid which are less susceptible to thermal and oxidative degradation. The use of such ascorbic acid derivatives, which are substantially more stable than ascorbic acid itself, almost completely eliminates the problem of decomposition or degradation. Ascorbic acid, which is the biologically active moiety, is liberated from such derivatives in the host organism by the action of the enzyme phosphatase.
Two fundamentally different processes have hitherto been of significance for the phosphorylation of ascorbic acid, namely phosphorylation using phosphorus oxychloride (as described, for example, in U.S. Pat. Nos. 4,999,437 to Dobler, et al. (Dobler '437), 5,420,302 to Kaiser, et al. (Kaiser '302), and 4,179,445 to Seib, et al. (Seib '445)) and phosphorylation using polyphosphates, e.g. sodium trimetaphosphate (see, for example, U.S. Pat. Nos. 4,647,672 to Seib, et al. (Seib '672) and 5,110,950 to Seib, et al. (Seib '950), and European Patent Publication 866,069), an L-ascorbic acid salt being phosphorylated under basic conditions in both cases.
The first phosphorylation process set forth above yields ascorbyl 2-monophosphate as the main product, and as by-products mainly ascorbyl 3-phosphate, 2-pyrophosphate, and bis(ascorbyl)-2,2′-diphosphate (see C. H. Lee et al., Carbohydrate Res. 67, 127-138 (1978)). In the past, the reaction products have required complicated purification and could not be converted in a simple manner, e.g. by spray drying of the entire reaction mixture, into a commercially useable product.
The second process, i.e. phosphorylation using polyphosphates, yields in the case of Seib '672 and Seib '950, ascorbyl 2-polyphosphates as the primary products, for example ascorbyl 2-triphosphate when sodium trimetaphosphate is used, but also a certain proportion of ascorbyl 2-monophosphate. The ascorbyl 2-polyphosphates can be degraded to the monophosphate by an excess of base. The ratio of ascorbyl 2-monophosphate to ascorbyl 2-diphosphate and higher polyphosphates is influenced by the amount of base which is used and the other reaction conditions. A disadvantage of the processes described above is that a very large amount of phosphorylating agent, e.g. at least 1 mol of sodium trimetaphosphate per mol of ascorbic acid, is required. Moreover, when it is desired that the product contain relatively small amounts of ascorbyl polyphosphates and more ascorbyl 2-monophosphate, a large amount of base, e.g. calcium hydroxide, must be used. Accordingly, the product contains a large amount of inorganic phosphates; the content of ascorbic acid equivalents in a dried product amounts to a maximum of about 25 weight percent.
Another process for the phosphorylation of L-ascorbic acid using polyphosphates is disclosed in European Patent Publication No. 866,069. In this process, the L-ascorbyl 2-polyphosphate, which itself may be produced separately or in situ by phosphorylating an alkali metal or alkaline earth metal salt of L-ascorbic acid with a phosphorylating agent such as sodium trimetaphosphate, is reacted with the L-ascorbic acid salt in concentrated aqueous solution under alkaline conditions using such amounts of the L-ascorbic acid salt and alkaline earth metal hydroxide (used as the base) that the pH value of the reaction medium is maintained in the range of about 8 to 11. In this reaction, a stepwise transfer of phosphate groups from the polyphosphate to the L-ascorbic acid salt occurs until the L-ascorbic acid from both sources is mainly in the form of its 2-monophosphate salt. Although this process affords the L-ascorbyl phosphate salt with very high monophosphate content and thus a much higher content of ascorbic acid equivalents in the dried product than achieved with the previously developed processes, the product still inevitably contains some unreacted starting materials and by-products, in particular non-phosphorylated ascorbate, ascorbyl di- and higher phosphates (ascorbyl polyphosphates), and orthophosphate and pyrophosphate (inorganic phosphates).
The relative proportion of the desired ascorbyl monophosphate to the ascorbyl polyphosphates, non-phosphorylated ascorbate, inorganic phosphates, etc., resulting from the processes described above depends on the stoichiometric ratios in which the starting materials are employed and on the other reaction conditions, and is never completely satisfactory. The recovery of L-ascorbyl 2-monophosphate or its inorganic salts from mixtures thereof with the unreacted starting materials and the by-products, i.e. the purification of L-ascorbyl 2-monophosphate, is difficult, in particular because the components of such mixtures largely feature similar physical properties. For example, they are all practically insoluble in organic solvents. In water, however, the free acids and the sodium salts, for example, are readily soluble, whereas the calcium salts are sparingly soluble. Thus purification by crystallization is rendered impracticable.
L-ascorbyl 2-phosphate purification procedures also have been described previously. For example, Japanese Patent Publication (Kokai) 51293/1984 describes the purification of L-ascorbyl 2-phosphate using an activated charcoal column and an aqueous solution of phosphoric acid and ammonium hydroxide as the eluent, followed by passage of the eluate through a column of a strong cation exchange resin to remove ammonium ions followed by treatment with magnesium oxide to remove excess phosphoric acid as its magnesium salt. The resulting L-ascorbyl 2-phosphate in the pure magnesium salt form is purified again with activated charcoal and crystallized from methanol.
Another Japanese Patent Publication (Kokai) 106,494/1984 describes an ascorbyl phosphate purification process involving, as an alternative to activated charcoal, diatomaceous earth or acid clay, and a precipitation in an organic solvent. However, it is known that active charcoal and the aforementioned alternative media are suitable for removing colored substances, but not for removing the by-products of ascorbic acid phosphorylation. Shimbo, et al., U.S. Pat. No. 4,724,262 (Shimbo '262), in which both these Kokai are briefly reviewed, discloses further disadvantages of the processes described therein. The process of purifying L-ascorbyl 2-phosphate described in Shimbo '262 involves the use of a basic anion exchange resin as an adsorbent for, inter alia, the aforementioned desired component, which is subsequently eluted with an aqueous solution of a mineral acid or an inorganic salt. This process is disadvantageous, however, because the acid or salt solution for the elution saturates the anion exchange resin, which must subsequently be regenerated with a base, such as sodium hydroxide solution. This leads to unnecessary and ecologically undesirable salt solutions.
SUMMARY OF THE INVENTION
Before a mixture of alkali metal and alkaline earth metal salts of L-ascorbyl phosphates (mono- and polyphosphates) produced by the phosphorylation of ascorbic acid under ba

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