JPH0499772A - Tocopherol-5,6-o-isopropylidene-l-ascorbic acid-2-dicarboxylic acid diester, production thereof and vitamin c vitamin e supplier composed of same diester - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula {R1 and R2 are H or CH3; R3 is CH2, 0, CO or [(CH2)p-CH=CH]q, etc., (p and q are 0-4); x and y are 0-10}. USE:Used as a vitamin C and vitamin E supplier. Also used for food as an anti- oxidizing agent, for drug such as anti-inflammatory or inhibition of platelet aggregation, etc., and further useful as raw material of cosmetic, etc., having whitening effect and senescence-inhibiting effect. PREPARATION:A dicarboxylic acid or anhydride of the acid is reacted with tocopherol in the presence of a base to obtain a tocopherol-acid dicarboxylic acid ester. Next, resultant ester is reacted with 5,6-O-isopropylidene-L-ascorbic acid in the presence of a base and a dehydrating agent at 0-50 deg.C to afford the compound expressed by the formula.

Description

[Detailed Description of the Invention] [Industrial Application Field] The sixth invention provides cosmetics, pharmaceuticals, foods, etc., which have improved fat solubility of vitamin C and water solubility of vitamin E, and have excellent storage stability. A new vitamin C/vitamin E derivative that can be applied to the skin, a method for producing the same, and a vitamin C/vitamin E supplement comprising the same.

[Conventional technology]

It has long been well known that various vitamins are essential nutrients for living organisms. Among them, monoascorbic acid (vitamin C) and tocopherol (vitamin E) both have a wide range of physiological and pharmacological effects, including antioxidant effects, and are therefore widely used in cosmetics, pharmaceuticals, foods, etc.

However, vitamin C is water-soluble and unstable to heat and light, and vitamin E is oil-soluble, so when used in cosmetics, for example, it lacks stability on the skin. The reality is that there are restrictions on how they can be used.

In recent years, tocopherol/tocotrienol-L-ascorbic acid-6-dicarboxylic acid diester has been developed as a product that complements the solubility of vitamins C and E (Japanese Patent Application Laid-open No. 187470 (1987)).

However, this is an unstable compound in which the hydroxyl group bonded to the carbon 2.3 position of ascorbic acid is susceptible to oxidation reactions, making it difficult to stably incorporate it into dosage forms such as creams and emulsions.

[Invention tries to solve it! ! Title]

Therefore, the object of the present invention is to improve the solubility of vitamins C9 and E, to be applicable to various dosage forms, and to maintain the activity of vitamins C and E even during storage.
The purpose of the present invention is to provide vitamin C and vitamin E derivatives.

[Means to solve problems]

The present invention provides the following: (11 below - tocopherol represented by Wuwei (1))
5,6-0-isopropylidene-ascorbic acid-
2-Dicarboxylic acid diester.

(In the formula, R6 and R1 are H or CHs Rs is CH
x, O, Co, ((CHz)p CH=CH).

CHN Hz, ((CHyo)-(CHCH5)-)t
, x and y are integers of O to 10, p and q.

(r, s, t represent integers of O to 4) (2) dicarboxylic acid or its anhydride and tocopherol are reacted in an organic solvent in the presence of a basic catalyst and optionally a dehydrating agent; , the produced tocopherol acidic dicarboxylic acid ester was converted into 5.60-isopropylidene-
A method for producing compound (1) according to claim (1), characterized in that the reaction is carried out with ascorbic acid in an organic solvent in the presence of a basic catalyst and a dehydrating agent.

(3) consisting of the compound (T) according to claim (1);
Vitamin C, vitamin E supplement.

It is.

Examples of the dicarboxylic acid or anhydride thereof used in the production of compound (I) in the present invention include nouric acid, malon f11. Succinic acid, curtaric acid, adipic acid, pimelic acid, sheric acid, azelaic acid, sebacin M, 1
．． 9-nonamethylene dicarboxylic acid, 1.10-decamethylene dicarboxylic acid, 1.11 undecamethylene dicarboxylic acid, 1.12-dodecamethylene dicarboxylic acid, 1.1
3-) Ridecamethylene dicarboxylic acid, 1.14-tetradecamethylene dicarboxylic acid, 1.15-pentadecamethylene dicarboxylic u, 1i6-hexadecamethylene dicarboxylic acid, 1.17-hebutadecamethylene dicarboxylic acid 1
．． 18-octadecamethylene dicarboxylic acid, diglycolic acid, acetone dicarboxylic acid, fumaric acid.

maleic acid, trans-2-butenedicarboxylic acid trans, trans-muconic acid, traumatic acid mucic acid, glutamic acid, aspartic acid, 3-methyladipic acid, 3-
Examples include, but are not limited to, methylglutaric acid, 2.3 dimethylsuccinic acid, and anhydrides thereof.

Among these, dicarboxylic anhydride has the advantage that there is no need to use a dehydrating agent when producing tocopherol acidic dicarboxylic acid ester, and among these, succinic anhydride and adipic anhydride are particularly preferred.

The 5,6-0-isopropylidene-ascorbic acid used in the present invention can be prepared, for example, as follows.

Ascorbic acid is reacted with acetyl chloride in an acetone solvent, suspended at room temperature, cooled in a refrigerator, and tp
It can be prepared by washing the collected crystals with chilled acetone and drying (Journal
of American Chemical 5oc
i-ety 1980. Vol, 102. &20,6
304-6311).

The organic solvent used in the present invention is preferably an inert solvent that does not react with raw materials, products, catalysts, etc. during the reaction process, such as pyridine, dimethylformamide,
Suitable examples include dimethyl sulfoxide, hexamethylphosphorustriamide, hexamethylphosphoramide, dioxane, and tetrahydrofuran, and chlorinated solvents such as methylene chloride, chloroform, and carbon tetrachloride.

Chlorofluorocarbons, fluorocarbons.

Ketones such as acetone and 2-butanone, and ethers such as diethyl ether and isopropyl ether can also be used.

The basic catalysts used in the present invention include pyridines such as pyridine and dimethylaminopyridine, aliphatic amines such as triethylamine, diethylamine, diisopropylamine, butylamine, and cyclohexylamine, aromatic amines such as aniline, and alkali metal carbonates. Among these salts, pyridine, dimethylaminopyridine, and triethylamine are particularly preferred, and by using these in appropriate combination, the reaction time can be shortened and the yield can be increased.

Pyridine is available! Although it is used both as a solvent and as a basic catalyst, the reaction time is shorter and the yield is better when used together with other basic catalysts or organic solvents than when used alone as both.

Preferred examples of the dehydrating agent used in the present invention include NN'-dicyclohexylcarbodiimide, paratoluenesulfonyl chloride, diethyltriphenylphosphonium azodicarboxylate salt, and thionyl chloride trifluoroacetic anhydride. Other known dehydrating agents can also be used.

Compound (1) of the present invention can be produced, for example, as follows.

Tocopherol and dicarboxylic acid (or its anhydride) are reacted in an organic solvent in the presence of a basic catalyst and a dehydrating agent (not necessary in the case of dicarboxylic anhydride) at about 10 to 150'C to form tocopherol acidic dicarboxylic acid ester. get.

Next, this tocopherol acidic dicarboxylic acid ester and 5
．． 6-〇-isopropylidene-L-ascorbic acid! The reaction is carried out in a solvent in the presence of a basic catalyst and a dehydrating agent at room temperature or about 0 to 50°C to produce tocopherol-5,6-0-isopropylidene-L-ascorbic acid diester.

The present invention will be explained in more detail with reference to Examples below.

〔Example〕

Example I DL-α-tocopherol 13.0 g, anhydrous amber #3.75 g, 4-dimethylaminopyridine 0.758
15mj of pyridine in the mixture! ,) diethylamine4.
5 ml was added and stirred at room temperature for 5 hours.

After confirming the disappearance of DL-α-tocopherol by TLC, 8.0 g of 5.6-〇-isopropylidene L-ascorbic acid and 7.6 g of N,N'-dicyclohexylcarbodiimide were added, and the mixture was further heated to room temperature. The mixture was stirred for 2.5 hours at a lower temperature.

After confirming the disappearance of DL-α-tocopherol acid succinate by TLC, the precipitate was removed by TFX separation. (This precipitate was 1,3-dicyclohexylurea.) The solvent of the solution was distilled off under reduced pressure, ethyl acetate and ice were added, and 5% hydrochloric acid was added twice.

This was followed by one wash with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. To the resulting red viscous oil, add n-hexane-ethyl acetate (1:1) 4
0mj! was added and completely melted, and then cooled with ice water to precipitate crystals. The crystals were separated, washed with a small amount of diethyl ether and dried, and white powder crystals of DL-α-tocopherol-5,6-0-isopropylidene-L-ascorbic acid-2-succinic acid diester14. 4
g (yield 66%) was obtained.

The physical properties of the obtained substance were as follows.

Elemental analysis: CazHhaO+.

Melting point; 114-115°C [R; 3460.2955.1751 cmUV;
'maw 21 ]-1 nm C-NMR (solvent
DMSOdi) δ (ppm); 1 1.4.1 1.7.
1 2.5.1 9.5, 2 0.020, 4.22.
3.22.4.23.6.23.824, 1.24.4
．． 25.4.25.5.25.927, 4.2 B,
7.29.0.30.4.30.9°32, 1.33.
3.36.7.36.8.37.0°38, 9.65.
0.73.9.74.4.74.9109, 1.117
．． 4.118.6 12 +, 8.124.9.126.4140, 6.
148.8.152.0゜170, 1.170.7.1
73.0 Examples 2 to 6 10.6 g of Ascorbic acid and 4.8 g of 5.6-0-isopropylidene-L ascorbic acid were dissolved in an organic solvent, and a basic catalyst and a dehydrating agent (N, N' -Dicyclohexylcarbodiimide) 4.16 g was added, and the mixture was stirred at room temperature.

After removing the precipitate that had formed, the solvent was distilled off from the solution. Then, ethyl acetate and ice were added, and the mixture was washed twice with 5% hydrochloric acid and once with water. Hereinafter, in the same manner as in Example 1, white powder crystals of DL-α tocopherol-5,6-0-isopropylidene L-ascorbic acid-2-succinic acid diester were obtained.

Organic solvent and basic catalyst used, stirring time DL-α-
Tocopherol acid coacid succinate Example - DL-α-tocopherol-5,6 was prepared in the same manner as in Example 2, except that DL-α-tocopherol acid adipate was used in place of α-tocopherol acid succinate. -0-isopropylidene-L-ascorbic acid-2-adipic acid diester (yield 69%)
I got it.

Next, the physiological activity of vitamin C/vitamin E supplementation 1 of the present invention will be explained with reference to examples.

Example 8. Comparative Examples 1 to 3 Tocopherol-5, a vitamin C and vitamin E supplement consisting of tocopherol-5,6-○-isopropylidene-monoscorbic acid-2-succinic acid diester of the present invention
,6-0-isoprohylidene L-ascorbic acid-6-
Test samples of succinic acid diester vitamin E (purified product) and vitamin C (purified product) were stored in a constant temperature bath at 45°C for one month.

A total of 20 guinea pigs, 10 each male and 10 N, weighing around 200 g were made into one group, and the test sample in the amount shown in Table 2 was added to the vitamin-deficient feed to each group once a day. 1
The test was given for 6 days, and the growth status (increase/decrease in average body weight (g)) of the guinea pigs in each group was examined.

As a control example, vitamin E2 immediately after purification, 5 m
g and vitamin C1, Omg were added to the vitamin-deficient feed.

As is clear from the results in Table 2, the tocopherol-5,6-0-isopropylidene-ascorbic acid-2-succinic acid diester of the present invention exhibits physiological activity comparable to that of the vitamin C/vitamin E mixture. Moreover, it was found that the activity was almost the same as that of the vitamin E/vitamin C mixture immediately after purification even when stored for a relatively long period of time, indicating that it has high stability.

〔Effect of the invention〕

The tocopherol-5,6-0-isopropylidene-monoscorbic acid-2-dicarboxylic acid diester of the present invention is useful as a vitamin C/vitamin E supplement.

Since the reducing properties of vitamin E and vitamin C act synergistically, they can be applied to foods as antioxidants. Furthermore, since it has the ability to scavenge free radicals, it suppresses the production of lipid peroxide, and has anti-inflammatory and platelet aggregation suppressing effects, so it can also be applied to medicines. Furthermore, it has high anti-tyrosinase activity, whitening effect,
Because it has anti-aging effects, it is also useful as a raw material for cosmetics.

Furthermore, the compound of the present invention has the highly reactive 2-position hydroxyl group esterified, making it less susceptible to oxidative decomposition and increasing the water solubility of vitamin E.
Alternatively, it is possible to stably incorporate vitamin EIII into various dosage forms such as creams and emulsions, in which it has been difficult to incorporate vitamin EIII.

Claims (3)

[Claims] (1) Tocopherol-5,6-O-isopropylidene-L-ascorbic acid-2-dicarboxylic acid diester represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) (In the formula, R_1 and R_2 are H or CH_3, R_3 is C
H_2O, CO, ((CH_2)_p-CH=CH)_
q, CHNH_2, ((CH_2)_r-(CHCH_
3)_s)_t, x and y are integers of 0 to 10, and p, q, r, s, and t are integers of 0 to 4. ) (2) Dicarboxylic acid or its anhydride and tocopherol are reacted in an organic solvent in the presence of a basic catalyst and optionally a dehydrating agent, and the generated tocopherol acidic dicarboxylic ester is 5,6-O- Isopropylidene-L
- A method for producing compound (I) according to claim (1), which comprises reacting it with ascorbic acid in an organic solvent in the presence of a basic catalyst and a dehydrating agent. (3) A vitamin C and vitamin E supplement comprising the compound (I) according to claim (1).