JPH0920790A - Ascorbic acid/alpha-hydroxy acid combination compound or its salt, and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the new subject compound which is a vitamin C derivative maintaining the active action and improved in stability by reacting an ascorbic acid derivative with the reaction product of a specific bis(dialkylamino)phosphine with a glycolic acid. SOLUTION: A new ascorbic acid-α-hydroxy acid combination compound (salt) of formula I [R3 , R4 are H, (CH2 )p CH3 (p is an integer of 0-20), ((CH2 )q -(CH2 CH3 )r )s (q, r, s are each an integer of 0-20), CH((CH2 )t -CH3 )n (t, n are each an integer of 0-20)]. The compound is useful as a vitamin C derivative maintaining the activity and improved in stability. The compound is obtained by reacting a compound of formula II (R<1> groups are each a secondary or tertiary alkyl, or are combined with each other to form the residue of a heterogeneous ring amine; R2 is a group which can be released by a reducing reaction, such as a benzyl group) with a compound of formula III (R2 is the same as R1 ) in the presence of a condensing agent, reacting the produced compound of formula IV with an ascorbic acid derivative in the presence of a condensing agent and subsequently removing the protecting agent 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 ascorbic acid / α-hydroxy acid conjugate applicable to cosmetics and pharmaceuticals having excellent storage stability of vitamin C, a method for producing the same, and use thereof.

[0002]

2. Description of the Related Art It has been well known that various vitamins are essential nutrients for the living body. Among them, L-ascorbic acid, which is vitamin C, 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. For example, when used as a cosmetic, it has been widely used as a whitening ingredient because it has an excellent melanin production inhibitory effect associated with the reducing action of dopaquinone and melanin pigment. However, vitamin C is unstable to heat and light, and it is difficult to exert the above effect for a long period of time. for that reason,
It has a property of lacking stability on the skin, and the fact is that its usage form is restricted.

On the other hand, α-hydroxy acid is a compound which is present in fruits and sugar cane, and has a cell activating effect that activates the metabolism of epidermal stratum corneum cells and arranges cell turnover, and enhances the proliferation of dermal fibroblasts. It has been widely used in recent cosmetics because it has the effect of improving wrinkles.
It is also used as a hair control agent for softening hard hair because it has a high effect of adjusting the binding of fiber proteins in the hair and enhancing the moisturizing state.

[0004]

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. The present compound contains vitamin C and α-in vivo.
It is enzymatically decomposed into hydroxy acid, and has pharmacologically both vitamin C action and α-hydroxy acid action,
Furthermore, since it is a compound that is well absorbed into the skin, it can be applied to cosmetics, pharmaceuticals, foods, and the like.

[0005]

In order to achieve the above object, various ascorbic acid / α-hydroxy acid bond derivatives were synthesized and the stability was tested. As a result, the following formula (I):

Embedded image It has been found that the novel ascorbic acid / α-hydroxy acid conjugate represented by the formula (3) has excellent stability and can be applied to cosmetics, pharmaceuticals, foods and the like.

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

Embedded image And a compound represented by the general formula (III):

Embedded image A compound represented by the formula (IV):

Embedded image A compound represented by the formula (IV) and a compound represented by the general formula (V):

Embedded image The compound represented by the formula (II) is reacted in the presence of a condensing agent and then oxidized to give general formula (VI):

Embedded image The compound of formula (VI) can be prepared by removing the R ₂ and R ₅ groups of the formula (VI) under reducing conditions.

Alternatively, the following formula (II):

Embedded image And a compound represented by the general formula (V):

[Chemical 21] The compound represented by the general formula (VII):

Embedded image A compound represented by the formula (VII) and a compound represented by the general formula (III):

Embedded image The compound represented by the formula (II) is reacted in the presence of a condensing agent and then oxidized to give general formula (VI):

Embedded image The compound of formula (VI) can be prepared by removing the R ₂ and R ₅ groups of the formula (VI) under reducing conditions.

The phosphoramidite represented by the formula (II) can be prepared, for example, as follows. Phosphorus trihalide and 4 equivalents of secondary amine in organic solvent-1
It is produced by reacting at 0 to 70 ° C for 2 to 30 hours to obtain bisaminomonohalogenophosphine, and reacting this with an alcohol in an organic solvent in the presence of a base catalyst at -10 to 35 ° C for 2 to 10 hours. You can

That is, this can be shown by a reaction formula as follows.

[0010]

Embedded image Examples of the secondary amine used in the production of the compound (II) in the present invention include diisopropylamine and di-t-
Examples thereof include, but are not limited to, butylamine, morpholine, thiomorpholine, pyrrolidine, piperidine, 2,6-dimethylpyrrolidine, piperazine, trimethylsilyldiisopropylamine, trimethylsilyldiisopropylamine, trimethylsilyldi-t-butylamine, and the like.

The alcohol used in the above reaction may be any alcohol as long as it acts as a protective group for a hydroxyl group when a phosphate triester is formed and can be deprotected under reducing conditions. Alcohol, methoxybenzyl alcohol, nitrobenzyl alcohol,
Preferred examples include cyanobenzyl alcohol and the like.

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, for example, diethyl ether,
Tetrahydrofuran, benzene, toluene, xylene,
Hexane and the like are mentioned as suitable ones, but not limited thereto.

The α-hydroxy acid derivative represented by the formula (III) can be prepared, for example, as follows.

Α-hydroxy acid and benzyl halide in an organic solvent in the presence of a basic catalyst at 10 to 20 ° C.
Obtained by reacting for 12 hours.

Examples of the α-hydroxy acid used in the production of the compound (III) in the present invention include glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxycaproic acid and 2-hydroxylaurin. Examples thereof include acid, 2-hydroxymyristic acid, 2-hydroxypalmitic acid, 2-hydroxystearic acid, 2-hydroxybehenic acid, etc., but are not limited thereto.

Preferable examples of the benzyl halide used in the above reaction include benzyl chloride, benzyl bromide, benzyl iodide and the like.

The organic solvent used in the above reaction is preferably an inert solvent which does not react with the raw materials, products, catalysts and the like in the reaction step, and practically, water-soluble organic solvents such as tetrahydrofuran, dioxane and acetone are suitable. It is mentioned as a thing.

Suitable examples of the base catalyst used in the above reaction include amines such as triethylamine and pyridine, but are not limited thereto.

The ascorbic acid derivative represented by the formula (V) can be prepared, for example, as follows.

In the presence of a catalytic amount of p-toluenesulfonic acid, ascorbic acid and benzaldehyde dimethyl ether were added in a dimethylformamide solvent at 50 to 70 ° C. for 2 hours.
It is prepared by reacting for 10 hours and then reacting the obtained 5,6-O-benzylidene-L-ascorbic acid with a benzyl halide in a dimethylformamide solvent for 12 to 24 hours in the presence of potassium bicarbonate or potassium carbonate. be able to.

That is, this can be shown as a reaction formula as follows.

[0022]

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

Reacting the phosphoramidite represented by the formula (II) with the α-hydroxy acid derivative represented by the formula (III) in an organic solvent in the presence of a condensing agent at 0 to 30 ° C. for 0.5 to 5 hours. Get by.

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

Obtained by reacting the phosphoramidite represented by the formula (II) and the ascorbic acid derivative represented by the formula (V) in an organic solvent in the presence of a condensing agent at 0 to 30 ° C. for 0.5 to 5 hours. .

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

After reacting the phosphoramidite represented by the formula (IV) and the ascorbic acid derivative represented by the formula (V) in an organic solvent in the presence of a condensing agent at 0 to 30 ° C. for 0.5 to 5 hours, Then, add an oxidizer at -20 to 0 ° C, and add 1 to 5
Obtained by reacting for a time.

Alternatively, the phosphoramidite represented by the formula (VII) and the α-hydroxy acid derivative represented by the formula (III) are mixed in an organic solvent in the presence of a condensing agent at 0 to 30 ° C. for 0.5.
After reacting for -5 hours, an oxidizing agent is subsequently added at -20 to 0 ° C, and the mixture is reacted for 1-5 hours.

As the organic solvent used in the production of the compounds (IV), (VI) and (VII) in the present invention, an inert solvent which does not react with the starting materials, products, catalysts and the like in the reaction step is preferable and practically used. Preferred examples include, but are not limited to, dichloromethane, acetonitrile, and the like.

Suitable condensation catalysts used in the above reaction include, but are not limited to, 1H-tetrazole and diisopropylammonium tetrazolide.

Examples of the oxidizing agent used in the production of the compound (VI) in the present invention include hydrogen peroxide, t-butyl hydroperoxide, m-chloroperbenzoic acid, peroxides such as dibenzoyl peroxide, iodine and sulfur. However, the present invention is not limited to these.

The compound (I) of the present invention is prepared by dissolving the compound (VI) in an organic solvent and supporting it on activated carbon in accordance with a conventional method for the protective group of the conjugate represented by the formula (VI). It is produced by desorbing under reducing conditions such as by catalytic hydrogenation under the conditions.

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

[0034]

[Reference example]

[Reference Example 1] Method for producing bis (diisopropylamino) chlorophosphine 80 g of phosphorus trichloride was dissolved in 100 ml of n-hexane and cooled to 0 ° C in an ice bath. To this, 325 ml of diisopropylamine dissolved in 1 liter of n-hexane was added dropwise over 2 hours. Then, the temperature was slowly raised to room temperature, and the mixture was further stirred under reflux with boiling for 30 hours.

After cooling, the crystallized diisopropylamine hydrochloride was filtered off and washed with n-hexane. The filtrate was distilled under reduced pressure to obtain 85 g (yield 55%) of white crystals of bis (diisopropylamino) chlorophosphine.

The physical properties of the obtained substance were as follows.

Melting point: 98 to 100 ° C. Boiling point: 95 to 100 ° C./0.1 mmHg ¹ H-NMR (CDCl ₃ , δ): 1.28 (dd, 24H,-(CH ₃ ) ₂ ,
J = 7.0Hz), 2.8 to 4.5 (m, 4H, N-CH-, J = 7.0Hz) ³¹ p-NMR (CDCl ₃ , δ): 140.8 MS: (i-Pr ₂ n) ₂ PCl ⁺ (18 ), (i-Pr ₂ N) ₂ P ⁺ (41), i-Pr ₂ N
PCl ⁺ (100), i-Pr ₂ NPH ⁺ (76), i-PrNP ⁺ (82), i-PrNPHCl ⁺
(46) [Reference Example 2] Method for producing benzyloxybis (diisopropylamino) phosphine (II) Bis (diisopropylamino) chlorophosphine 3.0
g was dissolved in 30 ml of diethyl ether and cooled to -10 ° C. A solution prepared by diluting 1.0 g of benzyl alcohol and 1.1 g of triethylamine with 5 ml of diethyl ether was added dropwise over 5 minutes so that the temperature did not exceed 0 ° C. Then, the temperature was slowly raised, and the mixture was further stirred at room temperature for 2 hours.

The crystallized triethylamine hydrochloride was filtered off and washed with n-hexane cooled to 0 ° C. When the filtrate was distilled under reduced pressure, 3.4 g of a transparent oily product of benzyloxybis (diisopropylamino) phosphine (yield 100
%) Obtained.

The physical properties of the obtained substance were as follows.

Melting point: 14-15 ° C. ¹ H-NMR (CDCl ₃ , δ): 1.15 (d, 24H,-(CH ₃ ) ₂ ,
J = 7.0Hz), 2.9 to 4.1 (m, 4H, N-CH-, J = 7.0Hz), 4.67 (d, 2
H, Ph-CH ₂ -O, J = 7.0Hz), 7.30 (s, 5H, -C ₆ H ₅ ) ³¹ P-NMR (CH ₂ Cl ₂ , δ): 123.3 [Reference Example 3] Glycolic acid benzyl ester Preparation of 1.52 g of glycolic acid and 3.42 g of benzyl bromide
Was dissolved in 60 ml of acetone and stirred at room temperature for 3 hours.

After the solvent was distilled off under reduced pressure, ethyl acetate was added and the mixture was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (5: 1) to obtain 2.5 g of a clear oily product of benzyl glycolate (yield 75%). ) Got it.

The physical properties of the obtained substance were as follows.

Boiling point: 134-136 ° C./14 mmHg ¹ H-NMR (CDCl ₃ , δ): 2.8-3.2 (s, 1H, -O
H), 4.15 (s, 2H , O-CH 2 -C = O), 5.17 (s, 2H, O-CH 2, Ph), 7.30
_{(s, 5H, -C 6 H} 5) [ Reference Example 4] 5,6-O- benzylidene -L- ascorbate Preparation L- ascorbic acid 20.0g and benzaldehyde dimethyl ether 20.0g of dimethyl formamide 6
It was dissolved in 0 ml, and p-toluenesulfonic acid monohydrate 0.
2 g were added. The reaction temperature was kept at 60 ° C., and the resulting methanol was distilled off under reduced pressure, followed by stirring for 5 hours.

After distilling off the solvent under reduced pressure, 100 ml of isopropyl ether was added to the reaction solution, which was washed with water and saturated saline. After drying the organic layer over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was recrystallized from isopropyl ether to give 15.5 g of white powder crystals of 5,6-O-benzylidene-L-ascorbic acid (yield 52
%) Obtained.

The physical properties of the obtained substance were as follows.

Melting point: 162-164 ° C. ¹ H-NMR (CDCl ₃ , δ): 3.26 (s, 2H, -OH), 4.06
(m, 2H, J _6a5 = 6.72Hz, J _6b5 = 8.54Hz, J _6a6b = 24.3Hz), 4.34
(ddd, 1H, J ₅₄ = 3.66Hz, J _56a = 6.72Hz, J _56b = 9.96Hz), 4.66
(d, 1H, J ₄₅ = 3.66Hz), 5.80 (s, 1H, O-CH-Ph), 7.20 (s, 5H, -C
₆ H ₅ ) [Reference Example 5] Method for producing 3-O-benzyl-5,6-O-benzylidene-L-ascorbic acid (V) 5,6-O-benzylidene-L-ascorbic acid 2.6
g was dissolved in 20 ml of dimethylformamide, and 1.0 g of potassium bicarbonate was added. 1.7 g of benzyl bromide
Was added, and the mixture was stirred at room temperature for 22 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 sodium sulfate, and the solvent was evaporated under reduced pressure. Recrystallization of the residue from ether gave 3-O-
1.1 g (yield 31%) of white powder crystals of benzyl-5,6-O-benzylidene-L-ascorbic acid were obtained.

The physical properties of the obtained substance were as follows.

Melting point: 112-115 ° C. ¹ H-NMR (CDCl ₃ , δ): 3.26 (s, 1H, -OH), 4.06
(m, 2H, J _6a5 = 6.72Hz, J _6b5 = 8.54Hz, J _6a6b = 24.3Hz), 4.34
(ddd, 1H, J ₅₄ = 3.66Hz, J _56a = 6.72Hz, J _56b = 9.96Hz), 4.66
(d, 1H, J ₄₅ = 3.66Hz), 5.45 (s, 2H, O-CH ₂ -Ph), 5.78 (s, 1H, O
-CH-Ph), 7.20 (s, 10H, -C ₆ H ₅ )

[0051]

【Example】

[Example 1] Method for producing benzyloxybenzyloxycarbonylmethoxydiisopropylaminophosphine (IV) Glycolic acid benzyl ester 2.28 g and 1H-
0.54 g of tetrazole was weighed out, sufficiently replaced with nitrogen, and then dissolved in 20 ml of dry methylene chloride. To this, 2.2 ml of benzyloxybis (diisopropylamino) phosphine was added, and the mixture was stirred at room temperature for 4 hours.

Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

This was subjected to silica gel column chromatography, and n-hexane / triethylamine (25: 1) was used.
When purified by eluting with a mixed solution of 3.7 g of a clear oily product of benzyloxybenzyloxycarbonylmethoxydiisopropylaminophosphine (yield 98
%) Obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.20 (dd,
12H,-(CH ₃ ) ₂ , J = 7.0Hz), 3.3 to 4.0 (m, 2H, N-CH-), 4.27 (d, 2
H, PO-CH ₂ -CO, J = 11.0Hz), 4.74 (d, 2H, PO-CH ₂ -Ph, J = 9.0H
z), 5.17 (s, 2H , CO-CH 2 -Ph), 7.29 (s, 10H, -C 6 H 5) [ Example 2] 3-O-benzyl -5,6-O-benzylidene-2- O- (glycolic acid benzyl ester-2
-O-benzyl phosphate) -L-Ascorbic acid (VI) production method 6-O-benzyloxybenzyloxycarbonyl methoxydiisopropylaminophosphine 2.62 g, 1H
-0.60 g tetrazole and 3-O-benzyl-
5,6-O-benzylidene-L-ascorbic acid 2.3
0 g was weighed and sufficiently replaced with nitrogen. After dissolving in 30 ml of dry methylene chloride, the mixture was stirred at room temperature for 2 hours.

After the reaction solution was cooled to 0 ° C. in an ice bath, 2.32 g of m-chloroperbenzoic acid was added. The ice bath was removed and stirring was continued for 1 hour.

Ethyl acetate was added to the reaction mixture, and the mixture was washed with 10% aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography, eluting with a mixture of n-hexane / ethyl acetate (2: 1) to give 3-O-benzyl-
3.54 g (yield 81%) of a transparent oily substance of 5,6-O-benzylidene-2-O- (glycolic acid benzyl ester-2-O-benzyl phosphate) -L-ascorbic acid was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 3.89 (m, 2
H, ascorbic acid 6th position), 4.2 to 4.3 (m, 3H, ascorbic acid 5th position, PO-CH ₂ -CO), 4.55 (m, 1H, ascorbic acid 4th position),
4.76 (m, 2H, PO-CH ₂ -Ph), 5.0 ~ 5.5 (m, 4H, O-CH ₂ -Ph, CO-CH
₂ -Ph), 5.50 (t, 2H, Ph-CH ₂ -O, ascorbic acid 3rd position), 5.73
(d, 1H, O-CH -Ph, J = 7.OHz), 7.2~7.5 (s, 2OH, -C 6 H 5) [ Example 3] 3-O-benzyl--2-O-benzyloxy-diisopropyl Production of aminophosphine-5,6-O-benzylidene-L-ascorbic acid (VII) 3-O-benzyl-5,6-O-benzylidene-L-ascorbic acid 2.28 g and 1H-tetrazole 0.2.
After weighing 50 g and performing sufficient nitrogen substitution, it was dissolved in 20 ml of dry methylene chloride. To this, 2.2 ml of benzyloxybis (diisopropylamino) phosphine was added, and the mixture was stirred at room temperature for 2 hours.

Ethyl acetate was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate / triethylamine (50: 2: 1) to give 3-O-benzyl-2-O-benzyloxydiisopropyl. 3.73 g (yield 98%) of a transparent oily substance of aminophosphine-5,6-O-benzylidene-L-ascorbic acid was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.20 (dd,
12H,-(CH ₃ ) ₂ , J = 6.90Hz), 3.2 to 3.8 (m, 2H, N-CH-), 3.89 (m,
2H, J _6a5 = 6.71Hz, J _6b5 = 8.64Hz J _6ab = 24.30Hz), 4.22 (ddd, 1
H, J ₅₄ = 3.66Hz, J _56a = 6.72Hz, J _56b = 8.96Hz), 4.65 (d, 1H, J
₄₅ = 3.66Hz), 5.02 (d, 2H, Ph-CH ₂ -OP, J = 9.0Hz), 5.50 (s, 2
H, Ph-CH ₂ -O), 5.81 (d, 1H, Ph-CH-O, J = 7.0Hz), 7.28 (t, 15H,
-C ₆ H ₅₎ [Example 4] Synthesis 3-O-benzyl--2-O-benzyloxy-diisopropylamino phosphine compound (VI) -5,6-O- isopropylidene -L- ascorbate 3.73 g, 0.68 g of 1H-tetrazole and benzyl ester of glycolic acid 1.1
1 g was weighed and sufficiently replaced with nitrogen. After dissolving in 20 ml of dry methylene chloride, the mixture was stirred at room temperature for 2.5 hours.

After the reaction solution was cooled to 0 ° C. in an ice bath, 2.32 g of m-chloroperbenzoic acid was added. The ice bath was removed and stirring was continued for 1 hour.

Ethyl acetate was added to the reaction mixture, and the mixture was washed with a 10% aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography, eluting with a mixture of n-hexane / ethyl acetate (2: 1) to give 3-O-benzyl-
3.16 g (yield 75%) of a transparent oily substance of 5,6-O-benzylidene-2-O- (glycolic acid benzyl ester-2-O-benzyl phosphate) -L-ascorbic acid was obtained.

The physical properties of the obtained substance were the same as in Example 2.

[Example 5] 2-O- (glycolic acid-
2-O-phosphoric acid) -L-ascorbic acid (I) -sodium salt preparation method 3-O-benzyl-5,6-O-benzylidene-2-O
After dissolving 1.63 g of-(glycolic acid benzyl ester-2-O-benzyl phosphate) -L-ascorbic acid in 100 ml of methanol, 5% palladium / carbon 0.8
g was added. After replacing the inside of the reactor with hydrogen, perform 3 at room temperature.
Stirred for 0 hours.

After the Pd / C catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol, passed through a column packed with cation exchange resin DIAION SK1B-Na type (manufactured by Mitsubishi Kasei), and eluted with pure water. The water was distilled off under reduced pressure to give 0.79 g of the title compound as an orange crystal (yield 8
6%: 3Na salt) was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (D ₂ O, δ): 3.85 (t, 2H, J
₆₅ = 6.41Hz, 6th ascorbic acid), 4.29 (m, 1H, J ₅₄ = 3.36H
z, J ₅₆ = 6.41Hz, 5th ascorbic acid), 4.42 (dd, 1H, J ₄₅ = 3.
36Hz, 4th ascorbic acid), 4.84 (m, 2H, glycolic acid 2
Position) ¹³ C-NMR (D ₂ O, δ): 62.63 (ascorbic acid 6
Position), 63.04 (2nd position of glycolic acid), 64.08 (5 of ascorbic acid)
Position), 76.80 (4th position of ascorbic acid), 118.63 (2nd position of ascorbic acid), 172.30 (3rd position of ascorbic acid), 174.04 (1st position of ascorbic acid), 174.09 (1st position of glycolic acid) ³¹ P-NMR (D ₂ O) , Δ): -1.11 [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% ethanol aqueous solution to prepare 1% concentration,
After the solution was stored at 50 ° C. for 14 days and exposed to light for 14 days, the residual rate was determined from the absorbance of the UV spectrum of the sample. Table 1 shows the results.

[0074]

[Table 1]

[0075]

[Application example] Whitening effect test example The skin lotion having the formulation shown in Table 2 was continuously applied to the faces of 20 panelists (girls) twice a day for 2 months, and the whitening effect was examined. The effect was judged by the panelist as "effective", "somewhat effective" or "ineffective". As a comparative example, a compound containing ascorbic acid instead of the compound was used. Table 3 shows the results.

[0076]

[Table 2]

[Table 3]

[0077]

[Toxicity test] The toxicity test of the compound of the present invention was conducted as follows.

That is, an acute toxicity test by oral administration was carried out using 1 group of 10 mice each having a body weight of 15 to 20 g. The sample was the ascorbic acid-glycolic acid phosphate conjugate of Examples 5 and 6, and 10 g / kg of an ordinary sample was orally administered at 10 g / kg to determine the life or death 72 hours later. It showed no toxicity. Further, the observation was continued for one week thereafter, but no difference from the normal animal group was observed.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Yu Watanabe 3 Bunkyo-cho, Matsuyama City, Ehime Prefecture Ehime University Faculty of Engineering

Claims (3)

[Claims] 1. An ascorbic acid / α-hydroxy acid conjugate represented by the following formula (I) or a salt thereof: [Wherein R ₃ and R ₄ are each independently H, (CH ₂ ) _p C
_{H 3, ((CH 2)} q - (CHCH 3) r) s, CH ((CH
_{2) t} -CH ₃₎ represents one of _{u, p, q, r,} s,
t and u represent the integer of 0-20. ] 2. The following formula (I): A method for producing a compound represented by the general formula (II): [Wherein R ₁ represents a secondary or tertiary alkyl group or a residue in which both are combined to form a heterocyclic amine, and R ₂ is eliminated by a reduction reaction of benzyl, methoxybenzyl, nitrobenzyl, cyanobenzyl, etc. Represents a group to be obtained. ] And a compound represented by the general formula (III): [Wherein R ₂ is a group capable of leaving by a reduction reaction such as benzyl, methoxybenzyl, nitrobenzyl, cyanobenzyl, R ₃ and R ₄ are each independently H, (CH ₂ ) _p CH ₃ ,
_{((CH 2) q - (} CHCH 3) r) s, CH ((CH 2) t
Represents either _{-CH 3) u, p, q} , r, s, t, u
Represents an integer of 0 to 20. ] The compound represented by the general formula (IV): [Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above. ] The compound of the formula (IV) and the compound of the general formula (V): [Wherein R ₂ is a group capable of leaving by a reduction reaction such as benzyl, methoxybenzyl, nitrobenzyl and cyanobenzyl, and R ₅ is a group capable of leaving by a reduction reaction such as benzyl, methoxybenzyl, nitrobenzyl, cyanobenzyl and benzylidene. Represents a group that can be released. ] The compound represented by the formula is reacted in the presence of a condensing agent and then oxidized to give a compound represented by the general formula (VI): [In the formula, R ₂ , R ₃ , R ₄ and R ₅ are as defined above. To give the compound represented by], said process consisting in obtaining the compounds of formula (I) By R ₂ and R ₅ groups desorbed under reducing conditions a compound of the formula (VI). 3. The following formula (I): [In the formula, R ₃ and R ₄ are as defined above. ] A method for producing a compound represented by the following general formula (II): [In the formula, R ₁ and R ₂ are as defined above. ] And a compound represented by the general formula (V): [In the formula, R ₂ and R ₅ are as defined above. ] The compound represented by the general formula (VII): is reacted in the presence of a condensing agent. [Wherein R ₁ , R ₂ and R _{5 are as} defined above. ] The compound of the formula (VII) and the compound of the general formula (III): [In the formula, R ₂ , R ₃ and R ₄ are as defined above. ] The compound represented by the following is reacted in the presence of a condensing agent and then oxidized,
General formula (VI): [In the formula, R ₂ , R ₃ , R ₄ and R ₅ are as defined above. ]
The above-mentioned production method, which comprises obtaining a compound of formula (VI) and removing the R ₂ and R ₅ groups of the compound of formula (VI) under reducing conditions to obtain a compound of formula (I).