JP3423430B2 - Ascorbic acid-kojic acid conjugate and method for producing the same - Google Patents

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-kojic acid conjugate applicable to cosmetics, pharmaceuticals, foods, feeds and the like having excellent storage stability of vitamin C 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. 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. 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.

On the other hand, kojic acid is a substance produced from carbohydrates by Aspergillus oryzae of koji, which absorbs ultraviolet rays well,
Further, since it inhibits the action of tyrosinase and suppresses the production of melanin to prevent spots and freckles, it is a substance effective in the cosmetic field as a skin whitening agent, and is also used in the food field as an anti-browning agent and a freshness-retaining agent. There is.
Further, since it shows a weak antibiotic action against Gram-positive / negative bacteria, it is used in the pharmaceutical field as an antibiotic modifier.

Therefore, an object of the present invention is to provide a compound that simultaneously has a vitamin C action and a kojic acid action pharmacologically, and this compound is applicable to pharmaceuticals, cosmetics, foods, feeds and the like. It is possible.

[0006]

In order to achieve the above object, various ascorbic acid-kojic acid bond derivatives were synthesized,
As a result of testing its stability, the following formula

[Chemical 6] It has been found that the novel ascorbic acid-kojic acid conjugate represented by the formula (1) has excellent stability and can be applied to pharmaceuticals, cosmetics, foods, feeds and the like.

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

[Chemical 7] [Wherein R ₁ is benzyl, methoxybenzyl, nitroben
Zil, cyanobenzyl, diphenylmethyl, triphenyl
Rumethyl, methoxyphenyldiphenylmethyl and dime
Selected from the group consisting of toxyphenylphenylmethyl
A group capable of leaving by a reduction reaction or methoxymethyl,
Tetrahydropyranyl, methoxytetrahydropyrani
, Tetrahydrofuranyl, ethoxyethyl, methylmeth
Toxyethyl, isopropoxyethyl and t-butyl?
Can be eliminated by a hydrolysis reaction selected from the group consisting of
In the group, X represents chlorine, bromine or iodine. ] And the following formula (III):

[Chemical 8] [In the formula, R ₂ is methylene, ethylidene, trichloroethyl
Den, isopropylidene, phenylethylidene, cyclo
Selected from the group consisting of pentylidene and cyclohexylidene.
A group capable of leaving by a selected hydrolysis reaction or a reducing reaction
Benzylidene group that can be eliminated by hydrolysis or hydrolysis
R ₁ is benzyl, methoxybenzyl, nitrobenzi
Reduction reaction selected from the group consisting of
Group that can be eliminated by reaction, methoxymethyl,
Doropyranyl, methoxytetrahydropyranyl, tetra
Hydrofuranyl, ethoxyethyl, methyl methoxyethyl
A group consisting of vinyl, isopropoxyethyl and t-butyl.
The groups that can be eliminated by a selected hydrolysis reaction.
You ] The compound represented by is reacted in the presence of a base catalyst,
The following formula (IV):

[Chemical 9] [Wherein R ₁ , R ₂ and X are as defined above. To give the compound represented by], R ₁ of the compound of the formula (IV) and
It can be produced by eliminating the R ₂ group under acidic conditions or reducing conditions.

The protected kojic acid represented by the formula (II) is
For example, it can be manufactured as follows.

[0009] Kojic acid and benzyl halide are reacted in an organic solvent in the presence of a base catalyst at 60 to 150 ° C for 12 to 24 hours to benzylate the hydroxy group at the 5-position.

The thus-obtained 5-position protected compound was added to triphenylphosphine in the presence of carbon tetrachloride at 60 to 77 ° C for 24 to 3
It can be produced by reacting for 6 hours.

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

[0012]

[Chemical 10] Suitable examples of the base catalyst used in the production of the compound (II) in the present invention include alkali metal salts such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

Examples of suitable benzyl halides used in the above reaction include, but are not limited to, benzyl bromide and benzyl chloride.

Examples of the aldehyde used in the above reaction include, but are not limited to, benzaldehyde, 4-methoxybenzaldehyde, 2,4-dimexibenzaldehyde, 4-dimethylaminobenzaldehyde and 2-nitrobenzaldehyde. is not.

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, dimethylformamide, dimethylsulfoxide, hexamethylphosphorustriamide, hexamethylphosphoric acid. Lamide, dimethylimidazolidinone, methanol, ethanol, propanol and the like are mentioned as preferable ones, but methanol is particularly preferable in practical use.

The compound (III) used in the present invention is
For example, it can be prepared as follows.

Ascorbic acid is reacted at room temperature in the presence of acetone in the presence of a catalytic amount of anhydrous hydrogen chloride or acetyl chloride.

The resulting 5,6-O-isopropylidene-
It can be prepared by reacting L-ascorbic acid with a benzyl halide or a monohalogenated dimethyl ether in a dimethylformamide solvent in the presence of potassium bicarbonate or potassium carbonate.

That is, the reaction formula is as follows.

[0020]

[Chemical 11] [In the formula, X represents chlorine, bromine or iodine, and R represents a benzyl group or a methoxymethyl group. The compound (IV) used in the present invention can be produced, for example, as follows.

The kojic acid derivative represented by the formula (II) and the ascorbic acid derivative represented by the formula (III) in an organic solvent in the presence of a base catalyst at 20 to 50 ° C. for 1 to 50 hours, preferably 12 to 24 hours. Obtained by reacting.

The organic solvent used in the production of the compound (IV) 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, for example, pyridine, dimethylformamide, dimethylsulfoxide, Hexamethylphosphorus triamide, hexamethylphosphoramide and the like are mentioned as preferable ones.
Ether-based solvents such as dioxane, tetrahydrofuran and dimethoxyethane, and ketones such as acetone and 2-butanone can also be used.

As the basic catalyst used in the above reaction, alkali carbonates such as potassium carbonate and sodium carbonate, alkali hydroxides such as caustic soda and caustic potash, 15-
Examples include crown ethers such as clauraun-5-ether, 18-crown-6-ether, cryptant [2,2,2], and aliphatic and aromatic amines such as triethylamine and dimethylaminopyridine, but potassium carbonate is particularly preferable. , 18-crown-6-ether and dimethylaminopyridine are preferable, and by using these in an appropriate combination, the reaction time can be shortened and the yield can be increased.

In the compound (I) of the present invention, the 5,6-O-protecting group on the ascorbic acid side of the conjugate represented by the formula (IV) is subjected to a conventional method, for example, the compound (IV) is used as an organic solvent. Dissolve it and remove it under acidic conditions by adding concentrated hydrochloric acid, etc., and then, according to a conventional method, the 3-O-protecting group and the protecting group on the kojic acid side, for example, by dissolving in an organic solvent and supporting a palladium catalyst on activated carbon. It is produced by desorbing under reducing conditions such as by catalytic hydrogenation under the conditions.

Alternatively, according to a conventional method, the 3,5,6-O-protecting group on the ascorbic acid side of the conjugate represented by the formula (IV) is dissolved, for example, by dissolving the compound (IV) in an organic solvent and adding concentrated hydrochloric acid. It is desorbed under acidic conditions by adding, and then the protecting group on the kojic acid side is subjected to a conventional method, for example, by catalytic hydrogenation in the presence of a palladium catalyst dissolved in an organic solvent and supported on activated carbon, under reducing conditions. It is manufactured by desorbing with.

Alternatively, the 3,5,6-O-protecting group on the ascorbic acid side and the protecting group on the kojic acid side of the conjugate represented by the formula (IV) are prepared according to a conventional method, for example, compound (IV).
Is dissolved in an organic solvent, and concentrated hydrochloric acid is added to remove it under acidic conditions.

Alternatively, the 3,5,6-O-protecting group on the ascorbic acid side and the protecting group on the kojic acid side of the conjugate represented by the formula (IV) are prepared according to a conventional method, for example, compound (IV).
Is dissolved in an organic solvent and subjected to catalytic hydrogenation in the presence of a palladium catalyst supported on activated carbon to remove the compound under reducing conditions.

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

[0029]

[Reference example]

[Reference Example 1] Method for producing 5,6-O-isopropylidene-L-ascorbic acid Acetone 900 ml was added to 200 g of L-ascorbic acid to give a suspension. 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.

[0031] mp: 208 to 210 ° C. ^{(decomposition) IR: 1667,1757cm -1 1 H-} NMR (CDCl 3, δ): 1.4 (s, 6H,
_{-CH 3), 3.0~4.0 (bs,} 2H, -OH),
4.1 (m, 3H, O- CH 2 -CH-O), 4.5
(D, 1H, O-CH -C = C, J = 2Hz) [α] _{^{20 D: + 25 ° (C}} = 1, water) Preparation 5, 6-O-isopropylidene of Reference Example 2 Compound (III) Ridene-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 isopropyl ether to give 15.5 g of white powder crystals of 3-O-benzyl-5,6-O-isopropylidene-L-ascorbic acid.
(Yield 51%) was obtained.

The physical properties of the obtained substance were as follows.

[0034] ^{mp: 105~106 ℃ IR: 1695,1764cm -1 1} H-NMR (CDCl 3, δ): 1.4 (s, 6H,
_{-CH 3), 3.3 (s,} 1H, -OH), 4.1
(M, 3H, O-CH 2 -CH-O), 4.5 (d, 1
H, O-CH-C = C, J = 2 Hz), 5.5 (s, 2
_{H, O-CH 2 -Ph)} , 7.2 (s, 5H, -C 6 H
₅ ) [α] ²⁰ _D : + 22 ° (C = 1, methanol) [Reference Example 3] Preparation of compound (III) 5,6-O-isopropylidene-L-ascorbic acid 8.4 g was dissolved in dimethylformamide 40 ml. Then, 6.4 g of potassium carbonate was added and the mixture was 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 completion of the reaction, 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. Recrystallization of the residue from benzene gave 5,6
-O-isopropylidene-3-O-methoxymethyl-L
-6.6 g of white powder crystals of ascorbic acid (yield 66
%) Obtained.

The physical properties of the obtained substance were as follows.

[0037] ^{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-C
_{H 2 -CH-O), 4.5} (d, 1H, O-CH-C =
C, J = 2Hz), 5.5 (s, 2H, O-CH 2 -
O) [Reference Example 4] Method for producing 5-benzyloxy-2-hydroxymethyl-γ-pyrone 20 ml of an aqueous solution of 8.3 g of sodium hydroxide was added to 220 ml of a methanol solution of 27.2 g of kojic acid, and then benzyl chloride 26. 5 g was added, and the mixture was stirred under boiling reflux for 12 hours.

After the solvent was distilled off under reduced pressure, the residue was washed with ice water 25
The mixture was added to 0 ml and stirred for 30 minutes. The crystallized orange crystals were separated by filtration, washed with ether and then dried to obtain 38.8 g (yield 87%) of white crystals of 5-benzyloxy-2-hydroxymethyl-γ-pyrone.

The physical properties of the obtained substance were as follows.

Melting point: 132-133 ° C. ¹ H-NMR (DMSO-d6, δ): 4.26 (s,
_{2H, C = C-CH 2} -O), 4.94 (s, 2H, O
_{-CH 2 -Ph), 5.3~5.9 (t} , 1H, O
H), 6.31 (s, 1H, CO-CH = C), 7.3
_{8 (s, 5H, -C 6} H 5), 8.12 (s, 1H, O
-CH = C) [Reference Example 5] Method for producing compound (II) 5-benzyloxy-2-hydroxymethyl-γ-pyrone 37.5 g and triphenylphosphine 42.3 g
Suspended in 1 liter of carbon tetrachloride and heated under boiling reflux for 24 hours.
Stir for hours.

After the solvent was distilled off under reduced pressure, the residue was recrystallized from methylene chloride and washed with ether to give 23.5 g of white powdery crystals of 2-chloromethyl-5-benzyloxy-γ-pyrone (yield: Rate 58%) was obtained.

The physical properties of the obtained substance were as follows.

Melting point: 115-116 ° C. ¹ H-NMR (CDCl ₃ , δ): 4.27 (s, 2)
_{H, C = C-CH 2} -O), 5.06 (s, 2H, O-
_{CH 2 -Ph), 6.45 (s} , 1H, CO-CH =
C), 7.34 (s, 5H , -C 6 H 5), 7.54
(S, 1H, O-CH = C)

[0044]

【Example】

Example 1 Synthesis of compound (IV) 2-chloromethyl-5-benzyloxy-γ-pyrone 1
After dissolving 3.1 g and 9.8 g of 3-O-benzyl-5,6-O-isopropylidene-L-ascorbic acid in dimethylformamide, 4.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 16 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 brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a yellow oil.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixed solution of n-hexane / ethyl acetate (3: 2) to give 3-O-benzyl-2.
-O- (2'-oxymethyl-5'-benzyloxy-
γ-pyrone) -5,6-O-isopropylidene-L-ascorbic acid (16.4 g, yield 99%) as a transparent oily substance.
Was obtained.

The physical properties of the obtained substance were as follows.

¹ H-NMR (CDCl ₃ , δ): 1.3
7 (s, 6H,> C (CH 3) 2), 3.7~4.1
( _M , 2H, J _6a5 = 6.7Hz, J _6b5 = 8.64H
z, J _6a6b = 24.3 Hz, 4.22 (ddd, 1)
H, J ₅₄ = 3.66 Hz, J _{56 a} = 6.72 Hz, J
_{56b = 8.96Hz), 4.55 (d} , 1H, J 45 =
3.66Hz), 4.81 (s, 2H , C = C-CH 2
-O), 5.02 (s, 2H , O-CH 2 -Ph),
5.39 (s, 2H, O- CH 2 -Ph), 6.40
(S, 1H, CO-CH = C), 7.33 (s, 5H,
_{-C 6 H 5), 7.47 (} s, 1H, O-CH = C) Example 2 Preparation 3-O-benzyl--2-O- (2'- oxymethyl compound (I) -
After dissolving 16.4 g of 5'-benzyloxy-γ-pyrone) -5,6-isopropylidene-L-ascorbic acid in 50 ml of tetrahydrofuran, 5 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour.

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 18 g of white crystals.

This was purified by subjecting it to silica gel column chromatography and eluting with a mixture of n-hexane / ethyl acetate (1: 4) to give 3-O-benzyl-2.
-O- (2'-oxymethyl-5'-benzyloxy-
1 white powder crystal of γ-pyrone) -L-ascorbic acid
5.0 g (yield 99%) was obtained.

The physical properties of the obtained substance were as follows.

Melting point: 150 to 152 ° C. ¹ H-NMR (CDCl ₃ , δ): 3.7 to 4.1
(T, 2H, J ₆₅ = 6.71 Hz), 4.22 (dd
d, 1H, J ₅₄ = 3.66Hz, J ₅₆ = 6.72H
z), 4.55 (d, 1H, J ₄₅ = 3.66 Hz),
4.81 (s, 2H, C = C-CH 2 -O), 5.02
(S, 2H, O-CH 2 -Ph), 5.39 (s, 2
_{H, O-CH 2 -Ph)} , 6.40 (s, 1H, CO-
CH = C), 7.33 (s , 5H, -C 6 H 5), 7.
47 (s, 1H, O-CH = C) 11.5 g of the above 3-O-benzyl-2-O- (2'-oxymethyl-5'-benzyloxy-γ-pyrone) -L-ascorbic acid After dissolving in 100 ml of methanol, 2.2 g of 5% palladium-carbon was added. After replacing the inside of the reactor with hydrogen, the mixture was stirred at room temperature for 24 hours.

After the Pd / C catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was dissolved in water and washed with ethyl acetate.
The aqueous layer was concentrated under reduced pressure and recrystallized from methanol to give 2-
6.5 g of white powder crystals of O- (2'-oxymethyl-5'-hydroxy-γ-pyrone) -L-ascorbic acid were obtained.
(Yield 90%) was obtained.

The physical properties of the obtained substance were as follows.

Melting point: 222-224 ° C. (decomposition) ¹ H-NMR (DMSO-d6, δ): 3.45 (t,
2H, J ₆₅ = 6.71 Hz), 3.80 (ddd, 1
H, J ₅₄ = 3.66 Hz, J ₅₆ = 6.72 Hz), 4.
83 (s, 3H, C = C-CH 2 -O, C = C-CH-
O (4th position), 6.60 (s, 1H, CO-CH =
C), 8.08 (s, 1H, O-CH = C), 9.0
9.4 (s, 1H, CH) ¹³ C-NMR (DMSO-d6, δ): 61.81 (6
Position), 68.46 (5th position, O—CH ₂ —C = C), 7
4.85 (4th place), 112.58 (3'th place), 119.
21 (2nd), 139.84 (6 '), 146.03
(5 '), 160.40 (3rd), 162.58
(2'th place), 169.24 (1st place), 173.83
(4'-position) [Example 3] The storage 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%,
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. The results are shown in Table 1.

[0057]

[Table 1] [Application Example] Whitening Effect Test Example A lotion having the formulation shown in Table 2 was continuously applied to the faces of 20 panelists (girls) twice a day for 2 months to examine the whitening effect. The effect was judged by the panelist as "valid", "somewhat valid" or "ineffective". As a comparative example, a compound containing ascorbic acid instead of the compound was used. The results are shown in Table 3.

[0058]

[Table 2]

[Table 3] [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. As the sample, the ascorbic acid-kojic acid conjugate of Example 2 was used. 10 g of normal feed with 10% added
When the life or death was judged 72 hours after oral administration of kg,
It showed no acute lethal toxicity. Further, the observation was continued for one week thereafter, but no difference from the normal animal group was observed.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A23L 1/302 A23L 1/302 (72) Inventor Hiroshi Watanabe 3 Bunkyo-cho, Matsuyama-shi, Ehime Ehime University Faculty of Engineering (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 407/12 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. An ascorbic acid-kojic acid conjugate represented by the following formula (I): 2. The following formula (I): A method for producing a compound represented by the general formula (I
I): [Wherein R ₁ is selected from the group consisting of benzyl, methoxybenzyl, nitrobenzyl, cyanobenzyl, diphenylmethyl, triphenylmethyl, methoxyphenyldiphenylmethyl and dimethylphenylphenylmethyl.
A group capable of leaving by a reduction reaction or methoxymethyl,
Tetrahydropyranyl, methoxy tetrahydropyranyl, tetrahydrofuranyl, ethoxyethyl, methyl methoxyethyl, isopropoxyethyl or ethyl and t- butyl
X represents chlorine, bromine or iodine, which is a group which can be eliminated by a hydrolysis reaction selected from the group consisting of: ] And a compound represented by the general formula (III): [Wherein R ₂ is selected from the group consisting of methylene, ethylidene, trichloroethylidene, isopropylidene, phenylethylidene, cyclopentylidene and cyclohexylidene.
Group or by hydrolysis reactions-option which leaves, changing the benzylidene group which leaves by the original reaction or hydrolysis reaction, R ₁ is benzyl, methoxybenzyl, reduction reaction selected from the group consisting of nitrobenzyl and cyanobenzyl Or a group consisting of methoxymethyl, tetrahydropyranyl, methoxytetrahydropyranyl, tetrahydrofuranyl, ethoxyethyl, methylmethoxyethyl, isopropoxyethyl and t-butyl .
Represents a group that can be removed by a hydrolysis reaction selected from ] The compound represented by is reacted in the presence of a base catalyst,
Formula (IV) below: [Wherein R ₁ , R ₂ and X are as defined above. ] The compound represented by these is obtained, and the R ₁ and R ₂ groups of the compound of the formula (IV) are eliminated under acidic conditions or reducing conditions.