KR20030087446A - Novel chromane derivative and methods for preparation thereof, and skin external application composition containing thereof - Google Patents

Abstract

PURPOSE: Chroman derivatives, a preparation method thereof, and a dermatoiogics composition containing the same compounds are provided. The compounds have strong antioxidant activity and melanin formation inhibiting activity. CONSTITUTION: Chroman derivatives represented by the formulae 1 and 2 are provided, wherein R1, R2, R3 and R4 are the same or different, hydrogen, C1-C18 alkyl, alkoxy, alkenyl or alkynyl. A process for preparing the chroman derivatives of the formulae 1 and 2 comprises the steps of: (A) reacting thionyl chloride with kojic acid in an organic solvent to prepare nonyl chloride; (B) reacting trolox with hydroxide salt to prepare trolox salt; and (C) reacting the trolox salt with koji chloride in an organic solvent. A dermatoiogics composition contains the chroman derivatives of the formulae 1 and 2 in the amount of 0.001 to 20 wt.%.

Description

Novel chromane derivative and methods for preparation, and skin external application composition containing thereof

The present invention relates to a novel chromman derivative, a method for preparing the same, and a composition for external application for skin containing the same. More specifically, the present invention is prepared by combining the trolox having a strong antioxidant effect and kojic acid having the effect of inhibiting melanin production, to the following formulas 1 and 2 having a whitening effect according to the antioxidant effect and the inhibition of melanin production The present invention relates to a novel chromman derivative and a method for preparing the same, and an external composition for skin containing the same.

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.)

Human skin color is complexly determined by red blood cells, carotene and melanin in the blood. In particular, hyperpigmentation such as skin color differences, blemishes, and freckles is known to be caused by melanin.

Melanin is converted from tyrosine to dopa (DOPA) and dopaquinone by tyrosinase present in pigmented cells, and is produced through non-enzymatic oxidation reactions. Increased production, inflammatory reactions, or constant exposure to ultraviolet light increases production. Among them, ultraviolet rays cause blemishes, freckles, and skin roughness on the skin.

Blemishes and freckles stimulate the growth of melanocytes in melanocytes in the epidermal base layer after continuous UV irradiation, and these melanocyte growth factors increase melanin pigmentation and cause pigmentation. Causes pigmentation.

It has been found through many studies that active oxygen plays a large role as a skin barrier for UV rays. Hydrogen peroxide, the most stable form of active oxygen, is known to elevate the activity of tyrosinase in melanoma cells, and in the case of hydroxyl radicals, tyrosinase, the first synthetic step of melanin production. Tyrosine is known to play a role in promoting the hydroxylation of dopa and the oxidation of dopaquinone. Paying attention to the role of active oxygen, vitamin C and vitamin E are known as substances that exhibit whitening effect by eliminating active oxygen, but they are not stable and thus have many restrictions.

Trolox is a kind of water-soluble vitamin E derivative, which is known to have a powerful effect of protecting and preventing skin damage caused by ultraviolet rays. In particular, vitamin E is not effective in preventing the oxidation of vegetable oils, whereas trolox is an effective antioxidant because it is effective in both animal and vegetable oils, but despite its strong antioxidant effect, trolox is also active according to pH. And there has been a problem that the use is limited because there is a problem that the stability is changed. That is, trolox has a problem that the activity is unstable, such as the change in activity with the change of pH.

Therefore, the present inventors have solved the problem of trolox, which has been limited in use due to its instability and stability as described above, and has been studied to effectively use it, and as a result, it has a strong tyrosinase inhibitory effect to inhibit melanin production. By combining kojic acid having excellent effects with the trolox, it was possible to prepare a novel chromman derivative compound. In particular, the Trolox was ester-bonded to the 2-position hydroxymethyl group and 5-position hydroxy group moiety of kojic acid, respectively, to prepare two kinds of Chroman derivatives having different structures and activities. The present inventors have completed the present invention by finding that the novel chromman derivative compound prevents damage to the skin by free radicals and is excellent in skin whitening effect by inhibiting melanin production, and is a very stable substance.

It is therefore an object of the present invention to provide a method for stabilizing trolox.

Another object of the present invention is to provide a novel chroman derivative and a method for preparing the same, prepared by combining kojic acid and trolox.

Still another object of the present invention is to provide an external composition for skin containing the novel chromman derivative.

The present invention provides a chromate derivative represented by the following Chemical Formula 1 and Chemical Formula 2 and a method for preparing the same, which have antioxidant and melanin production inhibitory effects. The chroman derivative may be prepared by esterifying hydroxy groups of 2-position and 5-position of carboxylic acid and kojic acid of trolox. The chroman derivatives prepared above not only have the antioxidant effect of trolox and the melanin production inhibitory effect of kojic acid, but also are considerably more stable than natural trolox or kojic acid. That is, trolox alone or kojic acid alone is very unstable and difficult to store, but the chroman derivatives prepared by ester bonding them are more stable than expected. The chromamann derivative of the present invention is not only stable over the effects of conventional stabilizers, but also maintains the characteristics of each component such as trolox or kojic acid as it is.

Hereinafter, the present invention will be described in more detail.

The chemical formulas of the chroman derivative compounds 1 and 2 provided in the present invention are as follows.

[Formula 1]

.... (Compound 1)

[Formula 2]

.... (Compound 2)

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.)

Referring to the method for producing a chroman derivative provided in the present invention in detail.

Method for producing the Chromane derivative compound 1 provided by the present invention,

(A) reacting the chloride with kojic acid in an organic solvent to produce a cosyl chloride;

(B) reacting trolox with hydroxide salt in an organic solvent to prepare a trolox salt; And

(C) preparing a chroman derivative by reacting the trolox salt prepared in step (B) with an organic solvent with the cosyl chloride prepared in step (A);

Characterized by including.

The method for preparing the chroman derivative compound 1 provided in the present invention can be illustrated by the following Scheme 1.

Scheme 1

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.)

The preparation method of the chromaman derivative compound 1 of the present invention is described in detail.

Step (A). Reacting the chloride with kojic acid in an organic solvent to prepare a co-chloride [Formula III]

As the chloride, thionyl chloride, oxal chloride, phosphorus trichloride and phosphorus oxychloride can be used, but are not limited thereto. Preferably thionyl chloride is preferable.

Organic solvents include, but are not limited to, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetone, toluene, and benzene.

It is preferable to react the kojic acid and the chloride in an equivalent ratio of 1: 1 to 1: 1.3. Moreover, although reaction temperature can be 0 degreeC-80 degreeC, about 10-40 degreeC is preferable.

Step (B). Step of preparing Trolox salt [Formula IV] by reacting Trolox with hydroxide in an organic solvent

Sodium hydroxide and potassium hydroxide may be used as the hydroxide, but is not limited thereto.

The organic solvent may be ethanol, methanol, butanol and isopropyl alcohol, but is not limited thereto.

Step (C). Preparing a chroman derivative by reacting the trolox salt prepared in step (B) with an organic solvent with the co-chloro chloride prepared in step (A).

For example, the chemical formula of Chromane derivative compound 1 prepared by the above method is as follows.

6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid-5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester

That is, the Croman derivative compound 1 is prepared by esterification of trolox with a 2-position hydroxymethyl group moiety of kojic acid.

Method for producing a chroman derivative compound 2 provided by the present invention,

(A) reacting trolox with chloride in an organic solvent to produce an acid chloride; And

(B) reacting the acid chloride prepared in step (A) with kojic acid under an organic base to prepare a chroman derivative;

Characterized by including.

The preparation method of the chroman derivative compound (II) provided in the present invention can be illustrated by the following Scheme 2.

Scheme 2

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.)

The preparation method of the chromaman derivative compound 2 of the present invention will be described in detail.

Step (A). Reacting trolox with chloride in an organic solvent to produce an acid chloride

The chloride used for the preparation of the acid chloride may be thionyl chloride, oxal chloride, phosphorus trichloride, and phosphorus oxychloride, but is not limited thereto. Preferably thionyl chloride is preferable.

Chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, toluene and benzene may be used as the solvent, but are not limited thereto.

Preferably, the trolox and chloride are reacted in an equivalent ratio of 1: 1 to 1: 1.3. Moreover, although reaction temperature can be 0 degreeC-80 degreeC, 10-40 degreeC is preferable.

Step (B). Reacting an acid chloride with kojic acid under an organic base to prepare a chroman derivative

Triethylamine, pyridine and dimethyl aminopyridine may be used as the organic base, but are not limited thereto.

For example, the chemical formula of Chroman derivative compound 2 prepared by the above method is as follows.

6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid-5-hydroxy-4-oxo-4H-pyran-5-ylmethyl ester

That is, Chroman derivative compound 2 is prepared by esterification of trolox with a 5-position hydroxy site of kojic acid.

Chromane derivative compounds 1 and 2 of the present invention prepared by the above method may be contained as an active ingredient of the external preparation composition for skin. At this time, it may be added in an effective amount for the whitening action, specifically, it may be contained in an amount of 0.001 to 20.0% by weight relative to the total weight of the external preparation for skin, for example.

The formulation of the external preparation composition for skin containing the Chroman derivative compound provided in the present invention can be used as long as it can be prepared as an external preparation for skin, but it may be a softening lotion, nourishing cosmetic, massage cream, nourishing cream, pack, gel, essence, lipstick, makeup Widely applicable in formulations such as cup bases, foundations, lotions, ointments, creams, gels, patches or sprays.

The external preparation composition for skin provided in the present invention may be prepared by adding various compositions and contents according to its use and purpose as long as it is a component that can be added as the external preparation composition for skin in addition to the chromamann derivative compound.

Hereinafter, the method for preparing the chroman derivative compound according to the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Reference Example 1: Preparation of Cosyl Chloride

300 ml of chloroform was added to a 500 ml round flask, and 50 g of kojic acid was dissolved. To this were added 50.2 g of thionyl chloride at 25 ° C, and further stirred at the same temperature for 4 hours to dissolve. After completion of the reaction, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate, and then the organic layer was washed twice with dilute hydrochloric acid solution and three times with water, and the organic layer was separated and dried. Concentrated under reduced pressure and left overnight with petroleum ether. The resulting solid was filtered and dried to give 46.7 g (yield: 83%) of light brown coloryl chloride.

Reference Example 2: Preparation of Trolox Salts

10 g of trolox and 2.25 g of potassium hydroxide were added to a 500 ml round flask, and 100 ml of anhydrous ethanol was added, followed by stirring at 25 ° C. for 2 hours to dissolve. This was filtered and the resulting solid was dried to give 11 g of a white trolox salt (yield: 95%).

Preparation Example 1 Preparation of Chroman Derivative Compound 6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid-5-hydroxy-4-oxo-4H-pyran-2-ylmethyl ester

The sodium chloride (5.6 g) prepared in Reference Example 1 and the trolox salt (10 g) prepared in Reference Example 2 were dissolved in 150 ml of dimethylformamide, and then refluxed for 5 hours. After the reaction was completed, the reaction solution was filtered and concentrated, and 500 ml of chloroform was added thereto to dissolve the reaction mixture. This was washed twice with 0.1 N hydrochloric acid solution, dried over anhydrous manganese, filtered and concentrated and ethyl acetate was added and left overnight. The resulting solid was filtered and dried to obtain 7.8 g of Croman derivative (yield: 60%).

The properties and instrumental analysis data of the obtained Croman derivative compound are as follows.

a) Properties of the substance: pale yellow solid

b) TLC (ethyl acetate): R _f = 0.62

c) ¹ H-NMR spectrum (DMSO-d ₆ , δ): 9.23 (s, 1H), 8.04 (s, 1H), 7.59 (s, 1H), 6.38 (s, 1H), 5.02 (s, 2H) 2.71-2.35 (m, 3H), 2.19 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H), 1.99-1.83 (m, 1H), 1.62 (s, 3H).

Preparation Example 2 Preparation of Chroman Derivative Compound 6-Hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid-5-hydroxy-4-oxo-4H-pyran-5-ylmethyl ester

Thionyl chloride (5.7 g) and trolox (10 g) were dissolved in 150 ml of tetrahydrofuran and refluxed for 5 hours. This was added dropwise to a solution of koji acid (5.7 g) and triethylamine (5.3 g) in 50 ml of tetrahydrofuran and refluxed for 4 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and then dissolved in 200 ml of chloroform. It was washed twice with 0.1 N hydrochloric acid solution, dried over anhydrous forget-me-not, filtered and concentrated, and left overnight with ethyl acetate. The resulting solid was filtered and dried to obtain 8.7 g (yield: 58%) of Chromman derivatives.

The properties and instrumental analysis data of the obtained Croman derivative compound are as follows.

a) Properties of the substance: pale yellow solid

b) TLC (ethyl acetate): R _f = 0.53

c) ¹ H-NMR spectrum (DMSO-d ₆ , δ): 8.59 (s, 1H), 7.57 (s, 1H), 6.43 (s, 1H), 5.81 (t, 1H, J = 7.8Hz), 4.40 (d, 2H, J = 7.6 Hz), 2.82-2.43 (m, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H), 2.03-1.81 (m, 1H), 1.78 (s, 3 H).

<Test Example 1. Determination of melanin production inhibitory effect using the pigment cells of the rat>

Mel-Ab cells from C57BL / 6 mice were placed in Dulbecco's modified Eagle's media (DMEM) with 10% fetal placental serum, 100 nM 12- o -tetradecanoylphorbol-13-acetate, 1 nM cholera toxin. (cholera toxin) was added to the culture medium at 37 ° C. and 5% CO ₂ . The cultured Mel-Ab cells were detached with 0.25% trypsin-EDTA, and then cultured in a 24-well plate at a concentration of 10 ⁵ cells / well. From the second day after the cultivation, 10 ppm each of the kojic acid and the chroman derivatives prepared in Preparation Examples 1 and 2 were added thereto for 3 consecutive days.

After removing the culture solution and washing with PBS, the cultured cells were dissolved with 1N sodium hydroxide to measure the absorbance at OD _400nm , and the melanin production inhibition rate was calculated according to Equation 1 below and the results are shown in Table 1 below. Dooley's way).

Melanin production inhibition rate measurement result of tocopherol kojic acid derivative Test substance Melanin production inhibition rate (% control) Kojisan 25.0 Chromane derivative of Preparation Example 1 52.3 Chromane derivative of Preparation Example 2 35.5

As can be seen from the above table, the melanin production inhibition rate of the cultured cells treated with Chromane derivative of the present invention is higher than that of melanin production in the cultured cells treated with kojic acid, which is known to have an effect of inhibiting melanogenesis. It can be seen that it is higher. In particular, the Croman derivative of Preparation Example 1 prepared by binding trolox to 2-position of kojic acid was superior to that of Preparation Example 1 in melanin production.

<Test Example 2. Whitening effect test on human skin>

Twelve healthy men were attached with an opaque tape with a diameter of 1.5 cm in their upper arm and irradiated with UVB (1.5-2 times the minimum erythema of each subject) to induce skin blackening. .

After UV irradiation, 1% of each of the Chroman derivative compounds prepared in Preparation Examples 1 and 2 (solvent is 1,3-butylene glycol: ethanol = 7: 3) and 3% kojic acid (solvent is 1,3-butyl as a control) Lenglycol: ethanol = 7: 3) was applied to the irradiated site for 10 weeks. At this time, one place was left without anything applied. Skin color was measured by Chromameter CR2002 (Minolta, Japan) on a weekly basis. The whitening effect was evaluated by the degree of increase of the "L" value ("ΔL"), and the results are shown in Table 2.

Whitening Effect of Tocopherol Kojic Acid Derivatives on Human Skin Test substance Skin color brightness degree (ΔL) Solvent 0.50 ± 0.15 Kojisan 0.99 ± 0.11 Chromane derivative of Preparation Example 1 0.58 ± 0.21 Chromane derivative of Preparation Example 2 1.71 ± 0.25

Test Example 3: Antioxidant Effect Test of Chromman Derivative

100 uM DPPH (1,1-diphenyl-2-picrylhydrazyl) radical solution was dissolved in 99% ethanol to prepare a DPPH reaction solution. The Croman derivatives of Preparation Examples 1 and 2 at appropriate concentrations were dissolved in distilled water, and 10 µl of this sample was mixed with 190 µl of the prepared DPPH reaction solution to prepare a test solution. In addition, the control was prepared by mixing trolox in the DPPH reaction solution. After sufficiently reacting the test solution and the control at 37 ° C. for 30 minutes, the absorbance was measured at _{515 nm} to measure the loss of DPPH radicals. The results are shown in Table 3 below.

Antioxidant Effect Test Results of Chromman Derivatives Test substance Antioxidant Effect (IC ₅₀ ) Trolox 30.84 Chromane derivative of Preparation Example 1 38.26 Chromane derivative of Preparation Example 2 30.98

As can be seen from the above table indicated by the concentration (IC ₅₀ ) of the compound scavenging DPPH radicals, the antioxidant effect of the Chroman derivative compound (II) of the present invention is similar to Trolox, in particular Chromann derivative compound It can be seen that the antioxidant effect of (I) is very superior to trolox.

Test Example 4: Test of Stability Effect of Chromman Derivative

2 g of each of Chroman derivative compounds and Trolox, which are the compounds of Preparation Example 1, were dissolved in 50 ml of ethanol and 50 ml of water having pH conditions of Table 4, and then stored in a 50 ° C. thermostat for 3 weeks, and then the presence or absence of coloring The change over time was observed according to the following evaluation criteria, and the results are shown in Table 4 below.

1 week 2 weeks 3 weeks Preparation Example 1 Trolox Preparation Example 1 Trolox Preparation Example 1 Trolox pH 2.6 - + - + + ++ pH 3 - + - + + ++ pH 4 - - - + - ++ pH 5 - - - + - ++ pH 6 - - - + - ++ pH 7 - + + ++ + +++ pH 8 - + + ++ + +++ [Note] Evaluation Criteria-: Colorless or light yellow +: Coloring Small + +: Coloring + +: Coloring

Formulation Example: Formulation of External Skin Composition Containing Chromman Derivative

Formulation examples of the external preparation composition for skin to which the Croman derivative compounds prepared in Preparation Examples 1 and 2 are added are shown in Tables 4 to 8 below.

Nourishing Cosmetic (Milk Skin Lotion) 1. Purified water To 100 2. Glycerin 8.0 3. Butylene Glycol 4.0 4. Hyaluronic Acid Extract 5.0 5. Beta Glucan 7.0 6. Carbomer 0.1 7. Preparation Example 1 0.5 8. Caprylic Capric Triglycerides 8.0 9. Squalane 5.0 10. Cetearyl Glucoside 1.5 11.Sorbitan Stearate 0.4 12. Cetearyl Alcohol 1.0 13. Preservative Quantity 14. Incense Quantity 15. Pigment Quantity 16. Triethanolamine 0.1

Massage cream 1. Purified water To 100 2. Glycerin 8.0 3. Butylene Glycol 4.0 4. Liquid paraffin 45.0 5. Beta Glucan 7.0 6. Carbomer 0.1 7. Preparation Example 1 10.0 8. Caprylic Capric Triglycerides 3.0 9. Beeswax 4.0 10. Cetearyl Glucoside 1.5 11.Sesqui oleic acid sorbitan 0.9 12. Vaseline 3.0 13. Preservative Quantity 14. Incense Quantity 15. Pigment Quantity 16. Paraffin 1.5

pack 1. Purified water To 100 2. Glycerin 4.0 3. Polyvinyl Alcohol 15.0 4. Hyaluronic Acid Extract 5.0 5. Beta Glucan 7.0 6. Allantoin 0.1 7. Preparation Example 2 5.0 8. Nonyl Phenyl Ether 0.4 9. Polysorbate 60 1.2 13. Preservative Quantity 14. Incense Quantity 15. Pigment Quantity 16. Ethanol 6.0

Ointment 1. Purified water To 100 2. Glycerin 8.0 3. Butylene Glycol 4.0 4. Liquid paraffin 15.0 5. Beta Glucan 7.0 6. Carbomer 0.1 7. Preparation Example 2 0.1 8. Caprylic Capric Triglycerides 3.0 9. Squalane 1.0 10. Cetearyl Glucoside 1.5 11.Sorbitan Stearate 0.4 12. Cetearyl Alcohol 1.0 13. Preservative Quantity 14. Incense Quantity 15. Pigment Quantity 16. Beeswax 4.0

oil Total amount 100.0 1. Squalane 5.0 2. Macadamia Nut Oil 5.0 3. Jojoba Oil 1.0 4. Crude colostrum 0.5 5. Wild Rose Seed Extract 20.0 6. Preparation Example 1 0.01 7. Carlylic Capric Triglycerides 30.0 8. Liquid paraffin Remaining amount 9. Incense Quantity

As described above, the present invention is prepared by combining the carboxylic acid of the trotolox having a strong antioxidant effect and kojic acid having an effect of inhibiting melanin production, and thus the whitening effect of the antioxidant and melanin production is excellent. There is an excellent effect of providing Chromman derivative compounds. In addition, the present invention is a method for producing a novel Chroman derivative as described above, the structure and properties of each other by esterification of trolox to the 2-position of the hydroxymethyl group site and 5-position of the hydroxy group site of kojic acid, respectively Since there is an excellent effect of providing a method for producing another Chroman derivative, it is a very useful invention in the cosmetic manufacturing industry that can be widely used in external preparations for skin.

Claims (9)

Novel croman derivative compounds characterized in that the trolox and kojic acid are combined, and the carboxyl group and the hydroxyl group of kojic acid are produced by ester bonding. According to claim 1, wherein the Croman derivative compound is a novel Croman derivative compound, characterized in that represented by the formula (1) and 2. [Formula 1] [Formula 2] (Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.) The novel Chroma derivative compound according to claim 2, wherein R ₁ , R ₂ , R ₃ and R ₄ are all methyl groups. (A) reacting thionyl chloride with kojic acid in an organic solvent to produce a cosyl chloride; (B) reacting trolox with hydroxide salt in an organic solvent to prepare a trolox salt; And (C) preparing a chroman derivative by reacting the trolox salt prepared in step (B) with an organic solvent with the cosyl chloride prepared in step (A); Method for preparing a chroman derivative, which is represented by the following Scheme 1, characterized in that it comprises a. Scheme 1 (Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.) (A) reacting trolox with chloride in an organic solvent to produce an acid chloride; And (B) a method of preparing a chroman derivative, which is represented by the following Reaction Scheme 2, comprising the step of reacting the acid chloride prepared in step (A) with kojic acid under an organic base to prepare a chroman derivative. Scheme 2 (Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different hydrogen, C ₁ to C ₁₈ alkyl, alkoxy, alkenyl or alkynyl groups.) The method according to claim 4 or 5, wherein R ₁ , R ₂ , R ₃ and R ₄ are methyl groups. The external preparation composition for skin according to any one of claims 1 to 3, which is contained in an amount of 0.001 to 20% by weight based on the total weight of the external preparation composition for skin. A composition for external application for skin, characterized in that it comprises Chromman derivative compound prepared by the method according to any one of claims 4 to 6 in an amount of 0.001 to 20% by weight based on the total weight of the external composition for skin. A method of stabilizing trolox and kojic acid by combining trolox with kojic acid, but esterifying the carboxyl group of trolox and the hydroxyl group of kojic acid.