Crystalline 2-o--d-glyukopiranozil-l-ascorbic acid and its preparation

 

(57) Abstract:

Usage: in medicine, food industry, cosmetics, etc. as an active derivative of vitamin C. the product Entity crystalline 2-0 - a-D-glyukopiranozil - L-ascorbic acid. Reagent 1: L-ascorbic acid. Reagent 2: a-glucosylceramide selected from the group consisting of maltooligosaccharide, the product of partial hydrolysis of starch, the starch is transformed into a liquid, gelatinous starch, soluble starch and their mixtures with a concentration of 0.5 to 30 times higher than that of L-ascorbic acid. Reagent 3: saccharide carrying an enzyme selected from the group consisting of cyclopentadienylmanganese (EU 2,4,1.19) and a-glucosidase, possibly in the presence of glucoamylase (EU 3.21.3) at pH 3-9, at a temperature of 20-80°C. reaction Conditions: crystallization from a saturated solution of 1.05 to 1.5) in the presence of the seed crystal in an amount of 0.1-10 wt. 2 S. and 2 C.p. f-crystals, 4 Il. table 1.

The invention relates to a method of obtaining a new crystalline 2-0--D-glyukopiranozil-L-ascorbic acid of General formula I

< / BR>
exhibiting enhanced stability during storage.

The purpose of the invention to realize stable during storage and nephroscope is only limited by the introduction of vitamin C as an important element of power, but is wider. In particular, due to its chemical structure and physiological activity of L-ascorbic acid suitable as podkalyvaesh agent, reducing agent, antioxidant, bleach and stabilizer in a variety of chemical reagents, food and beverages, pharmaceuticals in the prevention and treatment of diseases such as viral and bacterial diseases, malignant tumors. In addition, it is suitable as a reducing agent, UV absorbing agent and an inhibitor of melanin production in cosmetics, for example for cleaning and whitening the skin.

The main disadvantage of L-ascorbic acid is that it easily loses its physiological activity, because it has a direct reducing activity, poor stability and are highly prone to oxidation.

For stabilization of L-ascorbic acid were offered some sacharine derivatives. For example describes the biochemical synthesis of glucosides L-ascorbic acid (1, 2).

Described (3) organic chemical method of synthesis sharidny derivatives of L-ascorbic acid.

However, in all these derivatives of D-glucose linked in-position is benovoy acid.

The invention is directed to overcoming the shortcomings of conventional sharidny derivatives of L-ascorbic acid. More precisely investigated new sahariano derivative of L-ascorbic acid obtained by biochemical method using the transfer reaction of the saccharide.

As described in (4) new connection-glycosyl-L-ascorbic acid in particular 2-0--D-glyukopiranozil-L-ascorbic acid with no direct reducing activity, high stability, easily hydrolyzable in vivo, and has a satisfactorily high physiological activity.

It was also found that when L-ascorbic acid is absorbed from-glucosaminyl a saccharide, 2-0- <N>alpha<N>-D-glyukopiranozil-L-ascorbic acid is synthesized and then subjected to metabolism in vivo and this may be the perfect new sharedmem derivative of L-ascorbic acid from a security standpoint.

The powder obtained by concentration and spray aqueous solution 2-0- -D-glyukopiranozil-L-ascorbic acid, is amorphous and highly hygroscopic and has the disadvantage that readily absorbs moisture under normal conditions and this causes blurring and clumping.

Under the notes, in particular receive a satisfactory, low-friction powder with no significant hygroscopicity and caking in normal conditions.

The expression "L-ascorbic acid this invention relates to L-ascorbate, such as salts of alkali metals, alkaline earth metals and mixtures thereof, and is not limited to free L-ascorbic acid. Thus, if necessary, in response Zaharenko migration, you can use L-ascorbate, sodium L-ascorbate, calcium, and free L-ascorbic acid.

Expressions: -glycosyl-L-ascorbic acid and 2-0--D-glyukopiranozil-L-ascorbic acid" in this invention means advanced, and svobodnaia form.

-glucosamine sugars that are suitable in this invention are those which allow sharedprinter the enzyme to convert L-ascorbic acid-glycosyl-L-ascorbic acid, where equimolar or more D-glucosamine residues associated with L-ascorbic acid.

The method according to the invention provide that the solution contains at least 1 wt. L-ascorbic acid and-glycosylceramide selected from the group consisting of maltol, actuarily starch and their mixtures with a concentration of 0.5 to 30 times higher than that of L-ascorbic acid, is subjected to the action sharedprinter enzyme selected from the group consisting of cyclobutanecarbonitrile (EC 2.4.1.19) and-glucosidase, possibly in the presence of glucoamylase (EC 3.21.3) at pH 3-9 at 20-80aboutWith, then isolate and purify the obtained 2-0- -D-glyukopiranozil-L-ascorbic acid, cook it a supersaturated solution with the degree of over-saturation of 1.05 to 1.5, and preferably crystallized in the presence of the seed crystal in an amount of 0.1-10 wt.

In the presented examples explained in detail the preparation and properties of crystalline 2-0--D-glyukopiranozil-L-ascorbic acid according to this invention.

P R I m e R 1. Obtaining crystalline 2-0--D-glyukopiranozil-L-ascorbic acid.

9 wt.h. dextrin (DE about 6) is dissolved in 15 wt.h. water when heated, and to the solution was added 3 wt.h. L-ascorbic acid under reducing conditions, and then 400 units/g dextrin cyclobutanecarbonitrile production Hayashibara Biochemical Laboratories Inc. Okaijama (Okayama) Japan and conducting the reaction for 24 h, while maintaining the solution at pH 5.5 and 60aboutC. the Reaction mixture is poured into LM Seisakusho Ltd. Kyoto, (Japan) and elute buffer 0.1 m KN2RHO4-N3RHO4(pH -2,0) at a rate of 0.5 ml/min, monitoring detector system UZ T-340" produced by Japan Spectroscopic Co. Ltd. Tokyo (Japan). In the L-ascorbic acid goes with a retention time of 9.5 min, and educated-D-glucosyl-L-ascorbic acid, D-maltose-L-ascorbic acid, D-maltotriose-L-ascorbic acid, D-maltotetraose-L-ascorbic acid, D-multipartemail-L-ascorbic acid, -D-maltogenase-L-Scola - binova acid and D-maltogenase-L-ascorbic acid and D-maltoheptaoside-L-ascorbic acid face with retention times respectively 11.2 min 15,7 min, 20,6 min 24,9 minutes of 28.1 min, 32,1 min and 38.6 minutes to About 60% L-ascorbic acid is transformed into glycosyl-L-ascorbic acid. Then the reaction mixture was filtered through an ultrafiltration membrane to remove the enzyme, adjusted to pH 5.0 and 55aboutC, add the glucoamylase (EC 3.2.1.3) in an amount of 10 units/g dextrin production Seikagaku Kojyo Ltd, Tokyo (Japan) are Riccio 24 h, Ehud-analysis shows that in the reaction mixture-D-maltose-L-ascorbic acid and higher-glycosyl-L-ascorbic acid hydrolyzed to 2-0--D-glyukopiranozil-L-ascorbinicum and filtered through activated charcoal and the filtrate is concentrated to approximately 50 wt.

The concentrate is subjected to column to chromatographicaliy "XT-1016 (Na+-form)", a strongly acidic cation-exchange resin production Tokyo Chemical Industries, Tokyo (Japan) in accordance with the method described in Japan patent N 23799/83 c minor modifications, elwira and allocating a fraction enriched 2-0- -D-glyukopiranozil-L-ascorbic acid of a purity of about 94% which is then purified by demineralization using cation exchange resin (H+-form), concentrated to about 80 wt. placed in a glass vessel and incubated for about 1 month when 20-35aboutC. the resulting crystallization. Some crystals are added to a fresh sample of the same purified and concentrated fraction enriched 2-0--D-glyukopiranozil-L-ascorbic acid and crystallized under weak stirring. The resulting crystalline mass is divided into mother liquor and crystals, which are washed, Obrucheva a small amount of the cooled clean water, dissolve in water, recrystallized. So, get a high-purity crystals with a purity of about 99.9% and above.

P R I m m e R 2. Physico-chemical properties of crystalline 2-0--D-glyukopiranozil-L-ascorbic acid.

the Ozil-L-ascorbic acid.

Below are the properties of crystals.

Found, C is 42.6; H are 5.36

C12H18O11< / BR>
Calculated C 42,4; H lower than the 5.37; N < 0,01.

Molecular mass.

ID mass spectrometric analysis on "M-80", mass spectrometer production Hitachi Ltd, Tokyo, Japan, shows (M+N)+peak at 339 (mol.m. for formulas WITH12H18ABOUT11equal 338).

Melting point 158,5-159,5aboutC.

The heat of dissolution: endothermic (to 27.2 kcal/g).

Specific optical rotation: []D20+189,6o(water, pH 1,98; []D20+246,3o(water, pH 7,10).

Range of UV absorption: recorded at 50 μm solution. The spectrum at pH 2.0, shown in Fig.1, and at pH 7.0 in Fig.2.

(max) 238 nm, = 0,93 x 104(pH 2.0);

(max) 260 nm, = 1.50 x 104(pH 7.0).

IR absorption spectrum: shot in the KBr tablet IR spectrum of the crystals shown in Fig.3, and amorphous compounds (control) Fig.4.

Solubility, 125 g of the crystals are dissolved in 100 g of water at 25aboutC.

Solubility in solvents. Easily soluble in water, 0.1 G. of NaOH and 0.1 G. of acetic acid; soluble in methanol and ethanol; insoluble in ether, benzene, chloroform and ethylacetate.

Analysis of methylation. The crystals was identified in the method described in Pao-Wen. Zu and other Journal of Agricultural Food and Chemistry, vol 32, pp. 21-28 (1984), where L ascorbic acid was identified in the diazomethane with the formation of mainly 3-0-methyl-L-ascorbic acid. Subsequent hydrolysis leads to the formation of 3-0-methyl-L-ascorbic acid and D-glucose as the main product.

P R I m e R 3. The stability of the crystalline 2-0--D-glyukopiranozil-ascorbic acid in solution.

2-0--D-glucosyl-L-ascorbic acid compared to 6-0-a-D-glucosyl-L-ascorbic acid and L-ascorbic acid stability in aqueous solution. Namely, each sample was adjusted to a concentration of 70 μm and up to pH 7.0 or 2.0, placed in a cuvette and measure the absorbance at 260 nm (pH 7.0) or at 245 nm (pH 2.0), keeping the temperature 45aboutC. retention (%) expect the Il-L-ascorbic acid and L-ascorbic acid, crystal 2-0--D-glyukopiranozil-L-Scola - binova acid has an extremely high stability in aqueous solution.

P R I m e R 4. Acute toxicity.

The sample crystal 2-0--D-glyukopiranozil-L-ascorbic acid obtained by example 1 was orally administered to mice aged 7 weeks for tests on acute toxicity. In the mouse did not die in the introduction to 5 g of the sample, a higher dose is difficult to test.

This confirms that the sample has a very low toxicity.

The following examples a and b illustrate the crystalline 2-0--D-glyukopiranozil-L-ascorbic acid and its use.

P R I m e R a-1. Crystal 2-0- -D-glyukopiranozil-L-ascorbic acid.

9 wt. h-cyclodextrin was dissolved in 20 wt.h. water when heated, and to the solution was added 3 wt. ch. L-ascorbic acid under reducing conditions, and maintaining the solution at pH 5.5 and 65aboutTo add 100 units/g-cyclodextrin cyclobutanecarbonitrile production Hayashibara Biochemical Laboratories, Inc. Okayama (Japan) and conducting the reaction for 40 hours ghud-Anal of the reaction mixture shows that about 50% L-ascorbic acid is transformed into glycosyl-L-a is segosa enzyme, adjusted to pH 4.5 and 55aboutWith add 50 units/g-cyclodextrin of glucoamylase and conduct the reaction 24 h ghud-analysis of the reaction mixture shows that-maltose-L-ascorbic acid and higher-glycosyl-L-ascorbic acid hydrolyzed to 2-0--D-glyukopiranozil-L-ascorbic acid.

Then the reaction mixture is heated to inactivate the remaining enzyme, discolor and filtered with activated charcoal and the filtrate applied to a column of cation exchange resin (H+-form) for demineralization, then applied on a column of anion exchange resin (HE--form) for adsorption of anions. Then the column is washed with water and put 0.5 N Hl for elution and the eluate gel chromatographic "HW-40 production Tosoh Corp. Tokyo (Japan) with the release fraction enriched 2-0--L-glyukopiranozil-L-ascorbic acid, which is then concentrated under vacuum to approximately 73 wt. placed in a crystallizer, added with 1 wt. the seed crystals 2-0--D-glyukopiranozil- -ascorbic acid, adjusted to the 40aboutWith gradually cooled to 25aboutWith over 12 days, accelerating crystallization careful mixing and placed in a basket centrifuge to separate the molasses. The rest is glyukopiranozil-L-ascorbic acid with a purity of about 99% and a yield of about 35 wt. in the calculation of the original L-Sarbinowo acid.

Although the product is a little different so square and the specific optical rotation of the crystals obtained in example 1, however, other properties are almost the same.

The product is practically non-hygroscopic, easy to use, has no direct reducing activity, and has a satisfactorily high stability and physiological activity. Therefore, the product can be successfully used as an agent to improve the taste, podkalyvali agent, stabilizer, agent quality improvement, an antioxidant, a physiologically-active agent, UV absorbing agent, a pharmaceutical agent and a chemical for food, beverages, medicines for relevant diseases, cosmetics and chemical reagent, as well as the agent for the enrichment of vitamin C.

P R I m e R a-2. Crystal 2-0- -D-glucopyranosyl-L-ascorbic acid.

30 wt.h. dextrin (DE about 6) is dissolved in 40 wt.h. water when heated, and to the solution was added 7 wt.h. L-ascorbic acid under reducing conditions, and maintaining the solution at a pH of 5.6 and 60aboutTo add 250 units/g dextrin tsiklodekstringlyukanotransferazy and conducting the reaction for 40 hours According to Ehud analysis of the reaction mixture, analogue 1.

Then the reaction mixture is filtered through an ultra-filter for udaleniya enzyme, adjusted to pH 5.0 and 50aboutTo add 100 units/g dextrin of glucoamylase and conducting the reaction for 6 hours Ehud Analysis of the reaction mixture shows that-D-maltose-L-ascorbic acid and higher-glycosyl-L-ascorbic acid into a 2-0--D-glyukopiranozil-L-ascorbic acid.

Then the reaction mixture is heated to inactivate the remaining enzyme and filtered, after which the filtrate is concentrated and chromatographic on a column of "Dowex 50WX4 (CA++-form) with a strongly acidic cation exchange resin of Dow Chemical Co. Midland, Michigan, USA, by method of example 1 with minor modifications. Elyuirovaniya enriched 2-0--D-glyukopiranozil-L-ascorbic acid fraction is distilled demineralization on cation exchange resin (H+-form), concentrated under vacuum to approximately 77 wt. placed in a crystallizer, added with 2 wt. the seed crystal is brought to 45aboutC and gradually cooled to 28aboutWith in 2 days, accelerating the crystallization of weak mixing. The resulting mass is divided analogously to example 1 and get crystal 2-0--D-glyukopiranozil-L-ascorbic acid cistaro a-1 the product is practically non-hygroscopic, easy to handle, has no direct reducing activity, and has a satisfactorily high stability and physiological activity. Therefore, the product can be successfully used as improves the taste of the agent, podkalyvali agent, water-holding agent, stabilizer, improves the quality of the agent, UV absorbing agent, a pharmaceutical agent and a chemical for food, beverages, medicines for relevant diseases and cosmetics, and as an agent for the enrichment of vitamin C.

P R I m e R a-3. Crystal 2-0- -D-glyukopiranozil-L-ascorbic acid.

Analogously to example a-2 cyclopentadecanone-transferase and glucoamylase enter into reaction with obtaining a reaction mixture containing 2-0--D-glyukopiranozil-L-ascorbic acid, which is then heated to inactivate enzymes, provide and filtered with activated carbon. The resulting filtrate demineralized cation exchange resin (H+-form) and chromatographic on a column of strongly acidic cation-exchange resin (H+-form) by the method of example 1 with a slight modification and elute. Allocate a fraction enriched 2-0--D-glyukopiranozil-L-ascorbic acid, concentrate out sitein, transfer to a tray and crystallized and utverjdayut 3 days at 25aboutC. the contents are Then removed from the pallet served in dispersing a spray and dried, yielding crystalline 2-0--D-glyukopiranozil-L-ascorbic acid-purity of about 95% with a yield of about 70 wt. from the source-ascorbic acid.

Similar to the product in example a-1 the product is practically non-hygroscopic, easily handled, has no direct reducing activity, and has a satisfactorily high stability and physiological activity. Therefore, the product can be successfully used as improves the taste of the agent, podkalyvali agent, stabilizer, agent quality improvement, an antioxidant, a physiologically-active agent, UV absorbing agent, a pharmaceutical agent and a chemical for food, beverages, medicines for relevant diseases, cosmetics and as a chemical reagent, and as agent for the enrichment of vitamin C.

P R I m e R a-4. Crystal 2-0- -L-glyukopiranozil-L-ascorbic acid.

Enriched 2-0--D-glyukopiranozil-L-ascorbic acid fraction obtained in example a-3, concentrate to about 80 wt. placed in the mold, add about 2 wt. patrocinio mass with a crystallinity of about 35% is sprayed through a nozzle with a diameter of 1.5 mm, provided in the upper part of the pillar of spraying high-pressure pump 150 kg/cm2.

At the same time the air temperature is 85aboutWith miss top of the column in the direction of the mesh conveyor for collecting the sprayed product, located at the bottom of the column; the conveyor gradually displays the resulting crystalline powder from the column for about 30 min while passing air at a temperature of 40aboutWith overhand over the net.

Then the crystalline powder is placed in a column of aging and incubated for 10 h for crystallization and dehydration. Thus obtained crystal 2-0--D-glyukopiranozil-L-ascorbic acid of a purity of about 95% with a yield of about 70 wt. from the original L-ascorbic acid.

Similar to the product in example a-1, the products are practically hygroscopic, easily processed, free from direct reducing activity, and have satisfactorily high stability and physiological activity. Therefore, the product can be used successfully as improves the taste of the agent, acidifying agent, stabilizer, agent quality improvement, an antioxidant, a physiologically-active agent, UV absorbing agent, a pharmaceutical agent and a chemical drug of choice From.

P R I m e R A-5. Crystal 2-0- -D-glyukopiranozil-L-ascorbic acid.

P R I m e R A-5 (1). Getting-glucosidase.

Mucor Javanicus IFO 4570 seeded and cultured for 44 h at 30aboutWith aeration and stirring at 500 wt.h. culture medium containing water and 4.0 wt./about. maltose, 0.1 wt./about. monobasic potassium phosphate, 0.1 wt. /about. ammonium nitrate, of 0.05 wt./about. the magnesium sulfate of 0.05 wt./about. potassium chloride, 0.2 wt./about. polypeptide and 1 wt./about. calcium carbonate, sterilized by heating and added to sterile water before planting. After completion of the cultivation of mycelium isolated and immobilized in the usual way.

P R I m e R A-5 (2). Obtaining crystalline 2-0--D-glyukopiranozil-L-ascorbic acid.

40 wt.h. "SunmalT" crystalline maltose production Hayashibara Co., Ltd, Okayama (Japan), dissolved in 70 wt.h. water when heated, and to the solution was added 10 wt. ch. L-ascorbic acid under reducing conditions, and then 10 units/g maltose-immobilized-glucosidase obtained in example A-5 (1) and carry out the reaction for 3 h at pH 5.5 and 50 ° C without light.

One-glucosidase is defined as the amount of enzyme that liberates 1 micromoles of glucose at 37aboutWith over 1 mi the mixed solution of 250 μl of 4 wt./about. maltose and 750 μl of 0.1 M acetate buffer (pH 6.0) containing 1.35mm EDUC and conduct the reaction in a mixture of 30 min at 37aboutC, incubated in boiling water for 3 min to the suspension and centrifuged. Then take 20 ál of the supernatant, add to it 1 ml of Glucos B TEST" coloring reagent for glucoseoxidase way, the production of Wako Pure Chemical Industries, Ltd. Osaka, Japan, incubated 20 min at 37aboutWith the development of colouring and analyze the absorption at 505 nm.

Then the reaction mixture is filtered to highlight immobilized-glucosidase, which is re-used in another experience. The filtrate discolor activated carbon and chromatographic on a column of strongly acidic cation-exchange resin as in example a-2 with the release fraction enriched 2-0--D-glyukopiranozil-L-ascorbic acid, which is then purified by cation exchange resin as in example a-3, concentrated under vacuum to approximately 90 wt. placed in the mold, add the seed crystals, kristallisera and utverjdayut in the pan, served in dispersing pulverizator, dried, yielding crystalline 2-0--D-glyukopiranozil-L-ascorbic acid of a purity of about 88% with a yield of about 20 wt. from the original L-ascorbinogen, easily handled, has no direct reducing activity, and has a satisfactorily high stability and physiological activity. Thus the product can be used as an agent for improving taste, podkalyvali agent, stabilizer, agent quality improvement, an antioxidant, a physiologically-active agent, UV absorbing agent, a pharmaceutical agent and a chemical for food, beverages, medicines for relevant diseases and cosmetics, and also as agent for the enrichment of vitamin C.

1. Crystalline 2-O - a-D-glyukopiranozil-L-ascorbic acid of General formula

< / BR>
where n 0 6 integer.

2. Acid on p. 1 that detects when the x-ray diffraction analysis of the powder of the following main diffraction angles (2):10,3; 14,8o; 16,2o; 18,4oand 24.5o.

3. A method of obtaining a crystalline 2-O- -D-glyukopiranozil-L-ascorbic acid of General formula

< / BR>
where n is an integer,

characterized in that a solution containing at least 1 wt. L-ascorbic acid and-glucosylceramide selected from the group consisting of maltooligosaccharide, the product of partial hydrolysis of starch, liquefied, studiobandera.it action sharedprinter enzyme, selected from the group consisting of cyclobutanecarbonitrile (EC 2.4.1.19) and a-glucosidase, possibly in the presence of glucoamylase (EU 3.21 3) pH 3 9 20 80oWith, then isolate and purify the obtained 2-O - a-D-glyukopiranozil-L-ascorbic acid, cook it a supersaturated solution with the degree of over-saturation of 1.05 to 1.5 and crystallized, and the reaction ends at 80 for 3 hours

4. The method according to p. 3, characterized in that the crystallization is carried out in the presence of the seed crystal in an amount of 0.1 to 10.0 wt.

 

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