Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-17
2002-05-14
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S315000, C549S316000
Reexamination Certificate
active
06388098
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing conveniently an ascorbic acid-2-monophosphate salt, particularly an L-ascorbic acid-2-monophosphate (hereinafter sometimes abbreviated to “AsMP”) salt in a high yield, by hydrolyzing an ascorbic acid-2-polyphosphate or a salt thereof, particularly an L-ascorbic acid-2-polyphosphate (hereinafter sometimes abbreviated to “AsPP”) or a salt thereof, as the starting material in the presence of magnesium ion.
BACKGROUND OF THE INVENTION
L-Ascorbic acid (vitamin C) is known to have various physiological and pharmacological actions, and particularly by virtue of its effect of preventing melamine pigmentation, L-ascorbic acid has been used in whitening cosmetics. However, L-ascorbic acid is unstable to oxygen or heat, therefore, L-ascorbic acid derivatives stable against oxygen or heat have been heretofore formed by converting the hydroxyl group at the 2-position into a phosphate.
A salt, particularly a magnesium salt of L-ascorbic acid-2-monophosphate (hereinafter the “magnesium L-ascorbic acid-2-monophosphate” is sometimes abbreviated to “APM”) is being used as a stabilized vitamin C derivative. APM exhibits excellent stability in cosmetic materials and scarcely decomposes. Furthermore, APM is easily absorbed through the skin and by the action of phosphatase present inside the human body, L-ascorbic acid is liberated to bring about various physiological actions such as prevention of melamine pigmentation.
High-purity AsMP salts are useful as a stabilized derivative of L-ascorbic acid and can be used in cosmetics, medical products, food additives, feed and other various industrial fields.
For monophosphorylating L-ascorbic acid, three methods described below are known. A first method comprises monophosphorylating L-ascorbic acid using phosphorus oxychloride as the phosphorylating agent and this method is described, for example, in JP-B-45-30328 (the term “JP-B” as used herein means an “examined Japanese patent publication”), JP-B-52-18191, JP-B-59-4438 and JP-A-2-27969 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”) and the like. The second method comprises transposing the phosphoric acid group of a phosphoric acid donor (e.g., adenosine triphosphate, pyrophosphoric acid and the like) to L-ascorbic acid using an enzyme and this method is described, for example, in JP-A-2-283283. The third method comprises reacting a soluble salt of metaphosphoric acid used as a phosphorylating agent with L-ascorbic acid and drying the aqueous solution to obtain AsMP salt and this method is described, for example, in JP-A-5-155893.
The first method above is most frequently used and according to
Carbohydrate. Res
., 67, 127-138 (1978), L-ascorbic acid-2-monophosphate is obtained as a main product in the form of tricyclohexylamine salt in a yield of 86%. The by-products are L-ascorbic acid-3-monophosphate, L-ascorbic acid-2-diphosphate (hereinafter sometimes abbreviated to “AsDP”) and 2,2′-bis(L-ascorbic acid)phosphate. For the purification thereof, a complicated step such as ion exchange chromatography is necessary. L-ascorbic acid has four hydroxyl groups active in the reaction with phosphorus oxychloride and phosphorus oxychloride has three active sites, therefore, many by-products are produced. Furthermore, chloride ion generated from phosphorus oxychloride after the reaction is 3 molar times the phosphorus oxychloride used and this requires purification by electrodialysis and the like.
The second method is advantageous from the viewpoint that generation of by-products is prevented but still has the defect that the productivity is low. According to JP-A-2-283283, AsMP is produced using an enzyme fixed to an ion exchange resin and using diphosphoric acid (pyrophosphoric acid) as a phosphoric acid donor. However, the yield of AsMP of 34% is very low. Also, the amount of AsMP produced is as low as 1.7% in terms of the concentration in the reaction solution and large scale reaction equipment is necessary. Furthermore, in order to obtain high-purity AsMP salt, purification through many steps such as removal of a large amount of water and recovery of unreacted L-ascorbic acid is required.
The third method is a method of drying L-ascorbic acid-2-triphosphate (hereinafter sometimes abbreviated to “AsTP”) in an aqueous solution and thereby stepwise hydrolyzing the phosphate bonded to produce AsMP. According to JP-A-5-155893, AsMP is produced by preparing an aqueous solution of AsTP from a soluble salt of metaphosphoric acid and L-ascorbic acid, adjusting the pH thereof to about 5.5 to 6.5 and performing drying at a temperature of from 120 to 180° C. As known from the pH of aqueous solution, this stepwise hydrolysis reaction of phosphate is acid hydrolysis reaction. Therefore, although it is set forth therein that sodium and calcium are advantageous as the cation present in the aqueous solution, the alkali property of the cation has no relation to the acid hydrolysis, since the pH of the aqueous solution is acidic.
Furthermore, the product AsMP obtained by this production method has extremely low purity and the yield is also low. As seen from the composition of the product obtained by this method described in the Examples, the AsMP purity is 61% and the yield based on AsTP is 66%. In addition, much L-ascorbic acid, AsDP and AsTP are present as by-products. The presence of L-ascorbic acid shows that the acid hydrolysis reaction of AsTP extended to L-ascorbic acid over AsMP.
This means that it is useless to phosphorylate the hydroxyl group at the 2-position of L-ascorbic acid so as to improve lack of stability of L-ascorbic acid to oxygen or heat. Furthermore, the L-ascorbic acid present in the product decomposes due to oxygen or heat causing coloration or produce oxalic acid which is a skin irritant. The product cannot be used in cosmetics and the like as it is. Therefore, the impurities must be purified by a complicated method such as ion exchange chromatography. For these reasons, this production method of AsMP by the drying of AsTP aqueous solution is not an industrial attractive.
As described above, AsMP salt is useful as a stabilized derivative of L-ascorbic acid, nevertheless, the production methods thereof are complicated and disadvantageous in industry. Under these circumstances, a simplified preparation process is demanded therefor.
SUMMARY OF THE INVENTION
As a result of extensive studies to eliminate the above-described defects, the present inventors have found that high-purity AsMP salt can be conveniently prepared in a high yield by hydrolyzing, preferably under heating AsPP, or a salt thereof at a pH of 7 or more as a starting material in the presence of magnesium ion. The present invention has been accomplished based on this finding of a new process.
The present invention provides the following embodiments for preparing an ascorbic acid-2-monophosphate salt:
(1) a process for preparing an ascorbic acid-2-monophosphate salt, comprising hydrolyzing an ascorbic acid-2-polyphosphate or a salt thereof in the presence of magnesium ion at a pH of 7 or more;
(2) the process as described in (1) above, comprising hydrolyzing a reaction product of an ascorbic acid and a polyphosphoric acid or a salt thereof in the presence of magnesium ion at a pH of 7 or more;
(3) the process as described in (1) above, comprising eating a mixture comprising:
(A) an ascorbic acid-2-polyphosphate or a salt thereof,
(B) water,
(C) a magnesium compound capable of supplying magnesium ion in water, and
(D) a base necessary for maintaining a pH of 7 or more;
(4) the process as described in (3) above, wherein the
ascorbic acid-2-polyphosphate or a salt thereof (A) is one or more selected from the group consisting of an L-ascorbic acid-2-triphosphate and a salt thereof, an L-ascorbic acid-2-diphosphate and a salt thereof, and a mixture thereof;
(5) the process as described in (3) above, wherein the magnesium compound (C) is one or more selected from the group consisting of magnesium chloride, magnesiu
Kobayashi Yuji
Ohmori Kazuhiro
Soda Tomokazu
Showa Denko Kabushiki Kaisha
Trinh Ba K.
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