JPH07206840A - Ascorbic acid-hydroxycarboxylic acid combination product and method for producing the same - Google Patents

Abstract

PURPOSE:To provide a new combination product improved in the storage stability of vitamin C and capable of being apllied to cosmetics, medicines, foods, feeds, etc. CONSTITUTION:The combination product of formula I (R1, R2 are H, CH3, CO2H; R3 is CH2, O, CO, etc.; x, y are 0-10; p, r, q, r, s, t are 0-4). For example, 3-O-benzyl-2-O-benzyloxycarbonylmethyl-L-ascorbic acid. This combination product is obtained e.g. by reacting a compound of formula II (R4 is a group capable of being released by a reducing reaction; X is Cl, Br, I) with a compound of formula III in the presence of a basic catalyst in an organic solvent, and subsequently releasing the R4 group of the obtained compound of formula IV under a reducing condition.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel vitamin C-hydroxycarboxylic acid conjugate having excellent storage stability of vitamin C and applicable to cosmetics, pharmaceuticals, foods, feeds and the like, and a method for producing the same.

[0002]

2. Description of the Related Art It has been well known that various vitamins are essential nutrients for the living body. Of these, vitamin C, L-ascorbic acid, has a wide range of physiological and pharmacological actions including an antioxidant action, and is therefore widely used in cosmetics, pharmaceuticals, foods and the like. However, vitamin C is unstable to heat and light, and it is difficult to exert the above effect for a long period of time. Therefore, for example, when it is used as a cosmetic product, it has a property of lacking stability on the skin, and the actual condition is that its usage form is restricted.

[0003]

Therefore, an object of the present invention is to provide an extremely stable vitamin C derivative in which the activity of vitamin C is not lost by storage.

Since hydroxycarboxylic acids represented by glycolic acid have an anti-aging effect on the skin, they are compounds which have been actively used in cosmetics and the like in recent years. Since it is decomposed into a hydroxycarboxylic acid and pharmacologically has both a vitamin C action and a hydroxycarboxylic acid action at the same time, it can be applied to medicines, cosmetics, foods, and feeds.

[0005]

In order to achieve the above object, various vitamin C-hydroxycarboxylic acid bond derivatives were synthesized and their stability was tested. As a result, the following formula:

[Chemical 11] [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of H, R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
X, y is an integer of 0 to 10, p, q,
r, s, t represent the integer of 0-4. ] It was discovered that the novel vitamin C-hydroxycarboxylic acid conjugate represented by the formula has excellent stability and can be applied to pharmaceuticals, cosmetics, foods and feeds.

The compound represented by the formula (I) of the present invention has the following formula (II):

[Chemical 12] [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of R ₄ and R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
R ₄ represents a group capable of leaving by a reduction reaction, x and y are integers of 0 to 10, and p, q, r, s, and t are 0.
Is an integer of 4 and X represents chlorine, bromine or iodine. ] The compound represented by the following formula (III) or (IV):

[Chemical 13] [In the formula, R ₄ represents a group capable of leaving by a reduction reaction, and R ₅ represents a group capable of leaving by a hydrolysis reaction. ] With the compound represented by the following in an organic solvent in the presence of a basic catalyst,
The following formula (V) or (VI):

[Chemical 14] [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , x and y are as defined above. ] The compound of the formula (V)
Alternatively, it can be produced by removing the R ₄ group of the compound of (VI) under reducing conditions and the R ₅ group under acidic conditions.

The compound represented by the formula (VII) of the present invention is
Formula (II) below:

[Chemical 15] [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of R ₄ and R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
R ₄ represents a group capable of leaving by a reduction reaction, x and y are integers of 0 to 10, and p, q, r, s, and t are 0.
Is an integer of 4 and X represents chlorine, bromine or iodine. ] The compound represented by the following formula (VIII):

[Chemical 16] [In the formula, R ₅ represents a group capable of leaving by a hydrolysis reaction. ] With the compound represented by the following formula (IX) in an organic solvent in the presence of a basic catalyst:

[Chemical 17] [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , x and y are as defined above. ] The compound of the formula (IX)
The compound ( ₄₎ can be produced by eliminating the R ₄ group under reducing conditions and the R ₅ group under acidic conditions.

The haloester represented by the formula (II) can be produced, for example, as follows.

It can be obtained by reacting benzyl alcohol or benzyl halide with a halocarboxylic acid in an organic solvent in the presence of a basic catalyst or a dehydrating agent at -50 to 100 ° C. for 3 to 24 hours.

Examples of the halocarboxylic acid used for producing the compound (II) in the present invention include monochloroacetic acid, monobromoacetic acid, monoiodoacetic acid, chloropropionic acid, bromopropionic acid, iodopropionic acid, chlorobutyric acid, bromobutyric acid, iodobutyric acid. , Chlorosuccinic acid, bromosuccinic acid, iodosuccinic acid and the like, but are not limited thereto.

The organic solvent used in the above reaction is preferably an inert solvent which does not react with the raw material, the product and the catalyst in the reaction step, and examples thereof include pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphorustriamide and hexa. Methylphosphoramide, dioxane, tetrahydrofuran, acetone, 2-butanone, dimethoxyethane, diethyl ether, isopropyl ether, carbon tetrachloride, chloroform, methylene chloride and the like are mentioned as suitable ones, but practically, dioxane, acetone, methylene chloride. Is particularly preferable.

The basic catalyst used in the above reaction includes, but is not limited to, aliphatic and aromatic amines such as pyridine, dimethylaminopyridine and triethylamine.

As the dehydrating agent used in the above reaction, N, N'-dicyclohexylcarbodiimide, diethyl triphenylphosphonium azodicarboxylic acid salt, thionyl chloride, oxalyl chloride and the like can be mentioned as preferred ones, but paratoluenesulfonyl chloride, Other known dehydrating agents such as trifluoroacetic anhydride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and phosphorus tribromide can also be used.

The above compounds (V) and (VI) can be produced, for example, as follows.

The haloester represented by the formula (II) and the formula (II
I) or L-ascorbic acid represented by the formula (IV) 3,
It is obtained by reacting a 5,6-O-protected compound in an organic solvent in the presence of a basic catalyst at 10 to 150 ° C. for 5 to 50 hours.

The above compound (IX) can be produced, for example, as follows.

The haloester of formula (II) and the formula (VI
It is obtained by reacting the L-ascorbic acid 5,6-O-protected compound represented by II) in an organic solvent in the presence of a basic catalyst at 10 to 150 ° C. for 5 to 50 hours.

The compound (VIII) used in the present invention can be prepared, for example, as follows.

It can be prepared by reacting ascorbic acid in an acetone solvent at room temperature in the presence of a catalytic amount of anhydrous hydrogen chloride.

The compound (III) used in the present invention can be prepared, for example, as follows. 5,6-O-isopropylidene-L-ascorbic acid, prepared according to the above method, was combined with -benzyl halide in dimethylformamide solvent, potassium bicarbonate and 18-crown-.
It can be prepared by reacting in the presence of 6-ether.

The compound (IV) used in the present invention can be prepared, for example, as follows.

5,6-O-isopropylidene-L-ascorbic acid prepared according to the above method was mixed with a monohalogenated dimethyl ether in a dimethylformamide solvent.
It can be prepared by reacting in the presence of potassium carbonate.

That is, the reaction formula is as follows.

[0024]

[Chemical 18] [In the formula, X represents chlorine, bromine or iodine. The organic solvent used in the production of the compounds (V), (VI), and (IX) in the present invention is preferably an inert solvent which does not react with the raw material, the product, the catalyst and the like in the reaction step. Preferred examples include dimethylformamide, dimethyl sulfoxide, hexamethylphosphorus triamide, hexamethylphosphoramide, etc., but also ether solvents such as dioxane, tetrahydrofuran, dimethoxyethane, and ketones such as acetone and 2-butanone are used. it can.

Examples of the basic catalyst used in the above reaction include alkali carbonates such as sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, alkali hydroxides such as caustic soda and potassium hydroxide, 15-crown-5-ether and 18-crown. -6-ether, crown ethers such as cryptant [2,2,2], triethylamine, pyridine,
Aliphatic and aromatic amines such as dimethylaminopyridine can be mentioned, but potassium bicarbonate, 18-crown-6-ether and dimethylaminopyridine are particularly preferable, and the reaction time can be shortened by using these in an appropriate combination. It is possible to increase the yield.

The compound (I) of the present invention is prepared, for example, according to a conventional method for the 5,6-O-protecting group of the L-ascorbic acid-hydroxycarboxylic acid ester conjugate represented by the formula (V). ) Is dissolved in an organic solvent and concentrated hydrochloric acid is added to eliminate it under acidic conditions, and then the 3-O-protecting group and the ester protecting group are subjected to a conventional method, for example, palladium dissolved in an organic solvent and supported on activated carbon. It is produced by desorbing under reducing conditions such as catalytic hydrogenation in the presence of a catalyst.

Alternatively, 3,5 of the L-ascorbic acid-hydroxycarboxylic acid ester conjugate represented by the formula (VI)
A 6-O-protecting group is prepared according to a conventional method, for example, compound (VI)
Is dissolved in an organic solvent and is removed under acidic conditions by adding concentrated hydrochloric acid, and then the 3-O-protecting group and the ester protecting group are subjected to a conventional method, for example, a palladium catalyst dissolved in an organic solvent and supported on activated carbon. It is produced by desorbing under reducing conditions such as catalytic hydrogenation in the presence.

In the compound (VII) of the present invention, the 5,6-O-protecting group of the L-ascorbic acid-hydroxycarboxylic acid ester conjugate represented by the formula (VIII) is prepared by a conventional method,
For example, it is produced by dissolving the compound (V) in an organic solvent and removing it under acidic conditions by adding concentrated hydrochloric acid.

The present invention will be described in more detail below with reference to Reference Examples and Examples.

[0030]

[Reference Example] Production Method of Compounds (II), (VIII), (III), and (IV) (Reference Example 1) Production Method of Bromoacetic Acid Benzyl Ester 10.8 g of benzyl alcohol and monobromoacetic acid 1
3.8 g was dissolved in 50 ml dioxane, and 1.3 g of 4-dimethylaminopyridine was added to make a uniform solution. N, N'-dicyclohexylcarbodiimide 20.6
g was added, and the mixture was stirred at room temperature for 7 hours.

The resulting crystals of 1,3-dicyclohexylurea were filtered off and the filtrate was concentrated. The residue was dissolved in ether and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 27.9 g of an orange liquid.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixed liquid of n-hexane / ethyl acetate (100: 1) to obtain 19.0 g of bromoacetic acid benzyl ester as a transparent liquid (yield 84%). Was obtained.

The physical properties of the obtained substance were as follows.

The boiling point: 166~170 ℃ / 22mmHg IR: 1825cm -1 1 H-NMR (CDCl 3, δ): 3.8 (s, 2H, O
_{-CH 2 -Ph), 5.1 (s} , 2H, Br-CH 2 -C
O), 7.3 (s, 5H , O-C 6 H 5) ( suspended adding acetone 900ml in Reference Example 2) of 5, 6-O-isopropylidene--L- ascorbate preparation L- ascorbic acid 200g It was a liquid. Add 10 parts of hydrogen chloride saturated acetone solution.
0 ml was added, and the mixture was stirred at room temperature for 5 hours. Crystals began to precipitate as the reaction proceeded. The crystals are filtered and n-
After washing with hexane / acetone (7: 4), 200 g of pale yellow crystals were obtained. Furthermore, this is acetone 2.5
When recrystallized from liter, 185 g of white cotton-like crystals of 5,6-O-isopropylidene-L-ascorbic acid were obtained.
(Yield 75%) was obtained.

The physical properties of the obtained substance were as follows.

[0036] mp: 208 to 210 ° C. ^{(decomposition) IR: 1667,1757cm -1 1 H-} NMR (CDCl 3, δ): 1.4 (s, 6H-C
_{H 3), 3.0~4.0 (bs,} 2H, -OH), 4.
1 (m, 3H, O- CH 2 -CH-O), 4.5 (d, 1
H, O-CH-C = C, J = 2Hz) (Reference Example 3) Method for producing 3-O-benzyl-5,6-O-isopropylidene-L-ascorbic acid 5,6-O-isopropylidene-L-ascorbic acid 2
1.6 g was dissolved in 50 ml dimethylformamide and 10.2 g potassium bicarbonate and 1.5 g 18-crown-6-ether were added. 17.1 g of benzyl bromide
Was added and the mixture was stirred at room temperature for 45 hours.

After the reaction was completed, 100 m of ethyl acetate was added to the reaction solution.
1 was added, and the mixture was washed 3 times with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from benzene to give 3-O
25.3 g (yield 83%) of white powder crystals of -benzyl-5,6-O-isopropylidene-L-ascorbic acid.
Was obtained.

The physical properties of the obtained substance were as follows.

[0039] ^{mp: 105~106 ℃ IR: 1695,1764cm -1 1} H-NMR (CDCl 3, δ): 1.4 (s, 6H, -
CH3), 3.3 (s, 1H, -OH), 4.1 (m,
_{3H, O-CH 2 -CH-} O), 4.5 (d, 1H, O
-CH-C = C, J = 2 Hz), 5.5 (s, 2H, P
_{h-CH 2 -O), 7.2} (s, 5H, -C 6 H 5) (Reference Example 4) 3-O-methoxymethyl-5,6-O-
Method for producing isopropylidene-L-ascorbic acid 8.4 g of 5,6-O-isopropylidene-L-ascorbic acid was dissolved in 40 ml of dimethylformamide, and 6.4 g of potassium carbonate was added and ice-cooled. Chloromethyl ether 3.6 dissolved in 5 ml tetrahydrofuran
g was added dropwise over 40 minutes, and the mixture was further stirred at room temperature for 3 hours.

After the reaction was completed, 100 m of ethyl acetate was added to the reaction solution.
1 was added, and the mixture was washed 3 times with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from benzene to give 3-O
-Methoxymethyl-5,6-O-isopropylidene-L
-6.6 g of white powder crystals of ascorbic acid (yield 66
%) Obtained.

The physical properties of the obtained substance were as follows.

[0042] ^{mp: 93~94 ℃ IR: 1695,1764cm -1 1} H-NMR (CDCl 3, δ): 1.4 (S, 6H -
_{CH 3), 3.3 (s,} 1H, -OH), 3.5 (s,
_{3H, CH 3 -O), 4.1} (m, 3H, O-CH 2 -C
H-O), 4.5 (d, 1H, O-CH-C = C, J =
2Hz), 5.5 (s, 2H , O-CH 2 -O)

[0043]

【Example】

(Example 1) Method for producing compound (V) 3-O-benzyl-5,6-O-isopropylidene-L
-Ascorbic acid 10.0 g, bromoacetic acid benzyl ester 7.0 g and 18-crown-6-ether 0.
After dissolving 8 g in 15 ml of dimethylformamide, 3.6 g of potassium hydrogen carbonate was added, and the mixture was stirred at room temperature for 22 hours.

The potassium chloride formed was filtered off, 500 ml of benzene was added, and the mixture was washed 5 times with water and once with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 14 g of a yellow viscous liquid.

This was purified by subjecting it to silica gel column chromatography, eluting with a mixture of n-hexane / ethyl acetate (10: 1) to give 3-O-benzyl-
2-O-benzyloxycarbonylmethyl-5,6-O
10.8 g (yield 78%) of a transparent oily substance of isopropylidene-L-ascorbic acid was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.4
_{(S, 6H -CH 3),} 4.1 (m, 3H, O-CH 2
-CH-O), 4.5 (d, 1H, O-CH-C = C,
J = 2Hz), 4.8 (s , 2H, O-CH 2 -C
O), 5.2 (s, 2H , Ph-CH 2 -OCO),
5.6 (s, 2H, Ph- CH 2 -O-C = C), 7.
_{3 (s, 5H, -C 6} H 5) ( Example 2) Preparation 3-O-methoxymethyl--5,6-O-isopropylidene -L- ascorbate 2.6g of compound (VI), benzyl bromoacetate After dissolving 2.3 g of the ester and 0.3 g of 18-crown-6-ether in 10 ml of dimethylformamide, 1.0 g of potassium hydrogencarbonate was added and the mixture was allowed to stand at room temperature for 24 hours.
Stir for hours.

After the potassium chloride produced was filtered off, 500 ml of benzene was added, and the mixture was washed 5 times with water and once with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3 g of a yellow viscous liquid.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (10: 1) to give 3-O-methoxymethyl-2-O-benzyloxycarbonylmethyl-5. ，
2.9 g (yield 71%) of a transparent oily substance of 6-O-isopropylidene-L-ascorbic acid was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.4
_{(S, 6H -CH 3),} 3.5 (s, 3H, CH 3 -
O), 4.1 (m, 3H , O-CH 2 -CH-O),
4.5 (d, 1H, O-CH-C = C, J = 2Hz),
4.8 (s, 2H, O- CH 2 -CO), 5.2 (s,
_{2H, Ph-CH 2 -OCO)} , 5.5 (s, 2H, O
_{-CH 2 -O), 5.6 (s} , 2H, Ph-CH 2 -O-
C = C), 7.3 (s , 5H, -C 6 H 5) ( Example 3) Preparation 3-O-benzyl--2-O-benzyloxycarbonyl-methyl compounds (I) -5,6-O -8.7 g of isopropylidene-L-ascorbic acid was dissolved in 50 ml of tetrahydrofuran, 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours.

After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 5 g of a brown viscous liquid.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (3: 1) to give 3-O-benzyl-2.
5.1 g (yield 64%) of white powder crystals of -O-benzyloxycarbonylmethyl-L-ascorbic acid were obtained.

The physical properties of the obtained substance were as follows.

Melting point: 93 to 95 ° C. ¹ H-NMR (CDC
l ₃ , δ): 2.2 (bs, 2H OH), 3.8
(M, 3H, O-CH 2 -CH-O), 4.6 (bs,
1H, O-CH-C = C), 4.7 (s, 2H, O-C
_{H 2 -CO), 5.2 (s} , 2H, Ph-CH 2 -OC
O), 5.6 (s, 2H , Ph-CH 2 -O-C =
C), 7.3 (s, 5H , -C 6 H 5) After the above 3-O-benzyl--2-O-benzyloxycarbonyl-methyl -L- ascorbate 10.9g was dissolved in tetrahydrofuran 50 ml, 5 % Palladium-
1.1 g of carbon was added. After replacing the inside of the reactor with hydrogen,
The mixture was stirred at room temperature for 5 hours.

After the Pd / C catalyst was filtered off, the solvent was distilled off under reduced pressure. The obtained white viscous crystal was recrystallized from acetonitrile to obtain 4.2 g of white powder crystal (yield 68%).

The physical properties of the obtained substance were as follows.

Melting point: 163-165 ° C. ¹ H-NMR (C
_{DCl 3, δ): 3.4 (} m, 1H, O-C-CH-
O), 4.0 (dd, 1H, OH), 4.1 (d, 2)
H, OH), 4.4 (s, 1H, O-CH-C = C),
4.6 (s, 2H, O- CH 2 -CO), 4.7 (d
_{d, 2H, O-CH 2} -C), 11.1 (bs, 1H,
CO ₂ H) ¹³ C-NMR (CDCl ₃ , δ): 62.78, 6
3.41, 64.91, 73.05, 117.4
5, 155.77, 166.45, 168.27 (Example 4) Method for producing compound (IX) 5,6-O-isopropylidene-L-ascorbic acid 1
After 9.6 g and bromoacetic acid benzyl ester 20.8 g were dissolved in dimethylformamide 40 ml, potassium hydrogencarbonate 9.3 g was added, and the mixture was stirred at room temperature for 24 hours.

The potassium chloride formed was filtered off, 500 ml of benzene was added, and the mixture was washed 5 times with water and once with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 20 g of a yellow viscous liquid.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (5: 1) to give 3-O-benzyloxycarbonylmethyl-5,6-O-isopropylidene. −
26.0 g of a transparent oily substance of L-ascorbic acid (yield 7
9%) was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.4
_{(S, 6H -CH 3),} 3.5 (bs, 1H, O
H), 4.1 (m, 3H , O-CH 2 -CH-O),
4.5 (d, 1H, O-CH-C = C, J = 2Hz),
4.8 (s, 2H, O- CH 2 -CO), 5.2 (s,
_{2H, Ph-CH 2 -OCO)} , 7.3 (s, 5H, -
C ₆ H ₅₎ (Example 5) Preparation 3-O-benzyloxycarbonyl-methyl compound (VII) -5,6-O
-Isopropylidene-L-ascorbic acid (26.0 g) was dissolved in tetrahydrofuran (100 ml), and concentrated hydrochloric acid (1) was added.
0 ml was added and the mixture was stirred at room temperature for 5 hours.

After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a brown viscous liquid.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (1: 1) to give white powdery crystals of 3-O-benzyloxycarbonylmethyl-L-ascorbic acid. Was obtained in an amount of 8.5 g (yield 29%).

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 3.5
(T, 3H OH), 4.1 (m, 3H, O-CH 2 -
CH-O), 4.5 (d, 1H, O-CH-C = C, J
= 2Hz), 4.8 (s, 2H, O-CH 2 -CO),
5.2 (s, 2H, Ph- CH 2 -OCO), 7.3
_{(S, 5H, -C 6 H} 5) above 3-O-benzyloxycarbonyl-methyl -L-
After dissolving 8.5 g of ascorbic acid in 100 ml of ethyl acetate, 0.8 g of 5% palladium-carbon was added. After replacing the inside of the reactor with hydrogen, the mixture was stirred at room temperature for 4 hours.

After the Pd / C catalyst was filtered off, the solvent was distilled off under reduced pressure. The white viscous crystals obtained were recrystallized from ethyl acetate to obtain 4.8 g of white powder crystals (yield 78%).

The physical properties of the obtained substance were as follows.

Melting point: 142-144 ° C. ¹ H-NMR (CDCl ₃ , δ): 3.5 (m, 2H, O
_{-CH 2 -C), 3.7 (dd} , 1H, O-C-CH-
O), 4.9 (m, 4H, O-CH-C = C, O-CH
_2- CO, OH), 9.0 (bs, 1H, CO ₂ H) ¹³ C-NMR (CDCl ₃ , δ): 61.70, 6
6.68, 68.78, 74.64, 120.1
4, 149.56, 169.83, 170.18 (Example 6) The stability of the compound of the present invention was evaluated as follows.

That is, various ascorbic acid derivatives were dissolved in 50% aqueous ethanol solution to adjust the concentration to 1%, and the residual ratio was determined from the absorbance of the UV spectrum of the sample which was stored at 50 ° C. for 14 days and exposed to light for 14 days. I asked. The results are shown in the table below.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area A61K 31/375 ADK // A23L 1/302

Claims (4)

[Claims] 1. An ascorbic acid-hydroxycarboxylic acid conjugate represented by the following formula (I). [Chemical 1] [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of H, R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
X, y is an integer of 0 to 10, p, q,
r, s, t represent the integer of 0-4. ] 2. The following formula (I): [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of H, R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
X, y is an integer of 0 to 10, p, q,
r, s, t represent the integer of 0-4. ] A method for producing a compound represented by the following formula (II): [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
R _{4 is} any of R ₄ , and R ₃ is CH ₂ , O, CO, CO ₂ , S, S
_{2, SO, SO 2, (} (CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
R ₄ represents a group capable of leaving by a reduction reaction, x and y are integers of 0 to 10, and p, q, r, s, and t are 0.
Is an integer of 4 and X represents chlorine, bromine or iodine. ] And a compound represented by the following formula (III) or (IV) [In the formula, R ₄ represents a group capable of leaving by a reduction reaction, and R ₅ represents a group capable of leaving by a hydrolysis reaction. ] With the compound represented by the following in an organic solvent in the presence of a basic catalyst,
The following formula (V) or (VI) [Wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , x and y are as defined above. To give the compound represented by, the R ₄ group of a compound of the formula (V) or (VI) under reducing conditions, R ₅
A process as described above, which comprises removing the group under acidic conditions to obtain a compound of formula (I). 3. An ascorbic acid-hydroxycarboxylic acid conjugate represented by the following formula (VII). [Chemical 6] [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of H, R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
X, y is an integer of 0 to 10, p, q,
r, s, t represent the integer of 0-4. ] 4. The following formula (VII): [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of H, R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
X, y is an integer of 0 to 10, p, q,
r, s, t represent the integer of 0-4. ] A method for producing a compound represented by the following formula (II): [Wherein R ₁ and R ₂ are each independently H, CH ₃ and CO ₂
Any one of R ₄ and R ₃ is CH ₂ , O, CO, CO ₂ , S,
_{S 2, SO, SO 2,} ((CH 2) p -CH = CH) q,
_{((CH 2) p -C (} CH 3) = CH) q, ((CH 2) r -
(CHCH _{3) s) t} and _{CH - ((CH 2) p} -CH 3) q
R ₄ represents a group capable of leaving by a reduction reaction, x and y are integers of 0 to 10, and p, q, r, s, and t are 0.
Is an integer of 4 and X represents chlorine, bromine or iodine. ] And a compound represented by the following formula (VIII): [In the formula, R ₅ represents a group capable of leaving by a hydrolysis reaction. ] The compound represented by the following formula (IX): [Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , x and y are as defined above. ] The compound of the formula (IX)
The above-mentioned production method, which comprises obtaining the compound of the formula (VII) by eliminating the R ₄ group of the compound of 1) under a reducing condition and the R ₅ group thereof under an acidic condition.