EP1372594A1

EP1372594A1 - Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same

Info

Publication number: EP1372594A1
Application number: EP01928230A
Authority: EP
Inventors: Ok Sob Lee; Duk Hee Kim; Yi Seop Jang; Seong Joon Moon; Yeong Cheol Shim; Young Ha Lee; Dong Soon Park; Han Kon Kim; Hak Hee Kang; Heung Soo Baek; Jae Sung Hwang
Original assignee: Amorepacific Corp
Current assignee: Amorepacific Corp
Priority date: 2001-03-09
Filing date: 2001-05-02
Publication date: 2004-01-02
Also published as: EP1372594A4; JP2004521936A; CN1492755A; WO2002083092A1; KR20020082500A; KR100376088B1

Abstract

There are provided a water-in stable kojic acid derivative represented by the following formula 1, a method for preparing the same and a skin-whitening cosmetic composition containing the same as an active ingredient:

Description

WATER-IN-STABLE KOJIC ACID DERIVATIVES AND METH^~0-D FOR

PREPARING THEREOF, AND WHITENING COSMETICS

COMPOSITION CONTAINING THE SAME

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a water-in-stable kojic acid derivative represented by the following formula 1 (I) and to a method for preparing the same, and to a skin-whitening cosmetic composition containing the same as an active ingredient: [Formula 1]

(I)

2. Description of Prior Art

Generally, kojic acid is a γ-pyrone compound isolated from Aspergillus and can chelate with metal ion such as copper ion, to inhibit the activity of tyrosinase, which is an enzyme, involved in the melanin biosynthesis. Therefore, kojic acid can block abnormal pigmentation of the skin. In detail, tyrosinase is an enzyme of catalyzing the formation of dopaquinone in a serial process of the melanin biosynthesis: tyrosine -» dopa - dopaquinone - dopachrome -> melanin, and kojic acid inhibits the activity of the tyrosinase by chelating copper ion in the active site of tyrosinase.

Based on this tyrosinase-inhibiting activity, kojic acid has been used extensively in topical compositions for preventing hyperpigmentation such as moles and freckles. For example, JP 56-18569B, JP 53-3538A and JP 62-59084B disclosed whitening cosmetic compositions containing kojic acid as an active ingredient. And, JP 54-92632A, JP 58-22152A and JP 60-9722A disclosed whitening cosmetic compositions containing kojic acid derivatives such as kojic mono- or di-fatty acid esters having good properties such as stability, feeling and solubility and improved tyrosinase-inhibiting activity. Further, JP 3-14508A, JP 4-145096A and JP 5-39298A proposed various kojic acid derivatives having a strong tyrosinase-inhibiting activity, such as kojic ethers, glucosylated kojic acids and amino-protected kojic amino acids.

However, in case of application to the cosmetics, kojic acid and its derivatives are easily oxidized, and therefore, have difficulties in long-term preservation. And, its potency and activity decreases in the process for preparing the cosmetics, which do not allow to obtain aimed effects.

Therefore, in order to improve the stability of kojic acid, many efforts have been made. As results, many derivatives, of which the active sites, i.e. 4-carbonyl and 5-hydroxy groups are protected and 2-hydroxy position is substituted, have been synthesized. These derivatives purposed to have tyrosinase-inhibiting activity and improved stability in water base. But, because 5-hydroxy group is protected, these derivatives still have a problem in stability such as discoloration. Under these circumstances, in order to solve the above problems of the kojic acid derivatives and to develop novel derivatives having improved water-instability, the present inventors have conducted extensive studies for kojic acid derivatives. As a result thereof, it was found that kojic acid derivative substituted, at 5-hydroxy position, with 3-aminopropane phosphoric acid in the form of phosphoric diester accomplished said purposes, wherein, the 3-aminopropane phosphoric acid itself is an active cosmetic material which has effects on fibroblast proliferation and collagen biosynthesis and good safety to the skin, so to be used extensively in skin aging-preventing cosmetics. SUMMARY OF THE INVENTION

Therefore, an object of the invention is to provide a novel kojic acid derivative or its salts represented by the following formula 1 (I): [Formula 1]

(I) Further, another object of the present invention is to provide a method for preparing said kojic acid derivative.

A further object of the present invention is to provide a skin- whitening cosmetic composition which can inhibit melanin-formation and promote fibroblast-proliferation and collagen-biosynthesis, and has good safety to the skin and good stability in cosmetic base.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description of the present invention. A method for preparing the present kojic acid derivative may comprise the following steps of :

(A) reacting 3-amino-l-propanol with phosphorus oxychloride in an equivalent ratio of 1:1~1.3, in an organic solvent, in the presence of an organic base, at a temperature of 0-5 ^°C , for 1-2 hours, to form 2-chlorotetrahydro-2H- 1,3,2-oxazaphosphorin P-oxide ;

(B) reacting the 2-chlorotetrahydro-2H-l,3,2-oxazaphosphorin P-oxide of step (A) with kojic acid, in an organic solvent, in the presence of a base; (C) filtering the resultant of step (B), concentrating under reduced pressure, and then hydrolyzing with addition of an acidic solution, at a temperature of 5-100 ^°C, for 3-10 hours; and

(D) recrystallizing the product of step (C) with a polar organic solvent, to give kojic acid derivative.

And, said method of the present invention may comprise further step (E) of neutralizing the kojic acid derivative of step (D) with a neutralizer.

Said method of the present invention may be schematized by the following reaction scheme 1 :

[Reaction Scheme 1] (A)

(B) <">

(C)

(HI) (I)

As shown in the reaction scheme 1, the preparation method of the present kojic acid derivative will be described hereinafter in more detail.

Step (A) of reacting 3-amino-l-propanol with phosphorus oxychloride, in an organic solvent, in the presence of an organic base, at a temperature of 0-5 °C , for 1-2 hours, to form 2-chlorotetrahydro-2H-l,3.2-oxazaphosphorin P-oxide represented by said formula ( IO: In this step, it is preferable that the reaction between 3-amino-l-propanol and phosphorus oxychloride may be performed in an equivalent ratio of 1:1-1.3. In case that the ratio is lower than 1 : 1, the objective product may not be obtained. While, in case that the ratio is higher than 1:1.3, excessive by-products as well as the objective product may be obtained. Accordingly, in the preparation of 2-chlorotetrahydro-2H-l,3,2-oxazaphosphorin P-oxide by said method, an intermediate 1:1 complex of 3-amino-l-propanol and phosphorus oxychloride is produced 95% or more, and a by-product 2:1 complex of 3-amino-l-propanol and phosphorus oxychloride is produced 1-2% or less. However, the by-product may be removed by chromatography or recrystallization with toluene. Specially, two of three chlorine atoms of phosphorus oxychloride are replaced by functional hydroxyl and amino groups of 3-amino-l-propanol, to form cyclic 2-chlorotetrahydro-2H-l,3,2-oxazaphosphorin P-oxide. And, the third chlorine atom is inactivated at a low temperature of 5 ^°C or less and is not replaced. The reason is that the chlorine atom of 2-chlorotetrahydro- 2H- 1 ,3 ,2-oxazaphosphorin P-oxide is stable in an inert anhydrous solvent and not replaced easily by 3-amino-l-propanol. Therefore, the method can prevent the production of the 2:1 by-product of 3-amino-l-propanol and phosphorus oxychloride, by reacting 3-amino-l-propanol with phosphorus oxychloride in an equivalent ratio of 1:1-1.3, at a temperature of 0-5 ^°C for 1-2 hours. Especially, in the present invention, since the third chlorine atom of phosphorus oxychloride need not to be protected by ester groups or amide groups, the process can be simple.

An organic base employed in said step (A) may be pyridine, triethylamine, etc., and preferably be triethylamine. And, an organic solvent employed in said step (A) may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and ethyl ether, and preferably be chloroform.

Further, the reaction may be preferably performed at a temperature of 0-5 ^°C . If the temperature is higher than 5 ^°C, two equivalents or more of 3-amino-l-propanol are substituted to phosphorus oxychloride, resulting in excessive by-products. While, if the temperature is lower than 0^°C, the solubility of reactant may decrease, resulting that the reaction may proceed slowly and with difficulty. In this case, unreacted materials may increase, to reduce the yield.

Step (B) of reacting 2-chlorotetrahvdro-2H-l,3,2-oxazaphosphorin P-oxide of step (A) with ko ic acid, in an organic solvent, in the presence of a base:

A base employed in this step (B) may be an organic base such pyridine and triethylamine, as described in above step (A); or an inorganic base such as sodium, sodium hydroxide, potassium hydroxide, etc. Preferably, it may be potassium hydroxide.

And, an organic solvent employed in said step (B) may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and ethyl ether; or a polar solvent such as methanol, ethanol and propanol. Preferably, it may be methanol.

Step (C of filtering the resultant of step (B , concentrating under reduced pressure, and then hydrolyzing with addition of an acidic solution, at a temperature of 5-100 ^°C , for 3-10 hours:

In this step, the residue obtained by filtering the resultant of step (B) and then concentrating the filtrate under reduced pressure may be hydrolyzed in the presence of an acidic catalyst such as strong cation exchange resin (Amberlite 15), hydrochloric acid and sulfuric acid as a conventional hydrolysis. After addition of an acidic solution, in case of stirring the compound obtained in above step (B) at a temperature of 5-100 ^°C, the P-N bond can be hydrolyzed. Therefore, after filtration and then concentration, hydrolysis may be preferably performed with addition of an acidic solution, at a temperature of 5-100 °C and more preferably of 40 ^°C , for about 5 hours. pH of the acidic solution may be in a range of 1-5 and preferably of 2-4.

Step (D) of recrystallizing the product of step (O with a polar organic solvent, to give kojic acid derivative, kojic 3-aminopropanol phosphoric acid diester:

A polar organic solvent employed for recrystallization in this step may be, but not limited thereto, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile or dioxane.

Said method may comprise further step (E) of neutralizing the kojic acid derivative obtained in said step (D) to form a salt thereof. The form of salt obtained by neutralization may be salt by alkali metal such as sodium and potassium; salt by alkaline earth metal such as calcium and magnesium; or salt by ammonia or amine such as triethanolamine. A neutralizer employed in this step (E) may be alkali metal salt such as sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide; alkaline earth metal salt such as calcium hydroxide; metal oxide such as calcium oxide and magnesium oxide; basic amino acid such as lysine, arginine and histidine; ammonia or amine such as triethanolamine; cationic polymer such as polyquaternium-4, -6, -7, -10, -11 and -16; and cationic surfactant such as lauryldimethylbenzyl ammonium chloride and stearyldimethylbenzyl ammonium chloride. But, it may not be limited thereto.

The obtained kojic 3-aminopropanol phosphoric acid diester (hereinafter, "Kojyl-APPA") or its salt may be incorporated into a skin-whitening cosmetic composition in an amount of 0.01-10% by weight and preferably of 0.02-4.0% by weight based on the total weight of composition. If the amount is less than 0.01wt%, it may be difficult to obtain aimed effect. While, if the amount is more than 10wt%, there may be no benefit in increase of effect or in stability of formulation.

The skin-whitening cosmetic composition of the present invention may be formulated, but not limited thereto, into skin softners, astringents, nutrient toilet water, nutrient creams, massage creams, essences, eye creams, eye essences, cleansing creams, cleansing foams, cleansing water, packs, powders, body lotions, body creams, body essences and the like. And, the composition may further incorporate other ingredients depending on the formulation or the final purposes thereof.

PREFERRED EMBODIMENT OF THE INVENTION

The present invention will be described in more detail by way of the following examples, which should not be considered to limit the scope of the present invention.

<Preparation Example> Preparation of 2-chlorotetrahvdro-2H-l,3,2-oxaza phosphorin P-oxide

34.1m#(0.36mol) of phosphorus oxychloride was dissolved in 400m# of dichloromethane and then cooled to a temperature of 0-5 ^°C in an ice bath. In another reactor, 30m£(0.39mol) of 3-amino-l-propanol and 102m£(0.73--.ol) of triethylamine were diluted with 200m# of dichloromethane and then gradually added to the above solution for 2 hours. After the addition, the resulting mixture was filtered to remove triethylammonium chloride. The filtrate was washed with lOOm of distilled water, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. Thereto was toluene added to give crystals. And then, the product was dried under vacuum, to give 53g of 2-chlorotetrahydro- 2H-l,3,2-oxazaphosphorin P-oxide as white powder. Melting Point : 79-82 ^°C IR(CHC1₃, cm^-1) : 3254, 1477, 1274, 1092, 1036, 996 1H-NMR(CDC1₃) : δ(ppm) : 1.7(m, 1H), l.l(m, 1H), 3.3(m, 2H), 4.4(m, 2H), 4.9(br, 1H)

<Example 1> Preparation of kojic 3-aminopropanol phosphoric acid diester (Koiyl-APPA) 10G of kojic acid was dissolved in 80m^. of methanol. 4.3 G of potassium hydroxide was dissolved in 20ml of methanol and then gradually added to the above solution. After stirring at room temperature for 30 minutes, thereto was gradually added 11.2g(l.leq) of 2-chlorotetrahydro-2H-l,3,2-oxaza phosphorin P-oxide. After the addition, the mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated under reduced pressure and then stood at a temperature of 0-5 ^°C overnight. The formed solid was filtered and dried under vacuum, to give [2-(hydroxymethyl)-4-oxo-4H- pyran- 5-yloxy]-l,3,2-oxazaphosphorin P-oxide as white powder.

The obtained solid was dissolved in 30ml of aqueous solution with pH4, and then stirred in a thermostat of 40 °C for 5 hours. After the stirring, to the reaction mixture was added 150m# of isopropanol and then filtered to recover crystals. The crystals were dried under vacuum, to give 16g of kojic 3-aminopropanol phosphoric acid diester (Kojyl-APPA) as pale yellow powder. Melting Point : 118-128 ^°C (decomposed) IR(KBr, cm^-1) : 3446, 3322, 2904, 1658, 1616, 1250, 1090, 863

1H-NMR(D₂0) : δ(ppm) : 2.05(m, 2H), 3.15(t, 2H), 4.12(m, 2H), 4.54(m, 2H), 6.64(s, 1H), 8.27(s, 1H)

<Example 2> Preparation of sodium salt of kojic 3-aminopropanol phosphoric acid diester

1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added 5% sodium carbonate, adjusting to pH7. The obtained solution was freeze dried, to give sodium salt of kojic 3-aminopropanol phosphoric acid diester as white powder. <Example 3> Preparation of potassium salt of kojic 3-aminopropanol phosphoric acid diester

1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added 5% potassium carbonate, adjusting to pH7. The obtained solution was freeze dried, to give potassium salt of kojic 3-aminopropanol phosphoric acid diester as white powder.

<Example 4> Preparation of calcium salt of kojic 3-aminopropanol phosphoric acid diester 1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added calcium hydroxide, adjusting to pH7. The obtained solution was freeze dried, to give calcium salt of kojic 3-aminopropanol phosphoric acid diester as white powder.

<Example 5> Preparation of magnesium salt of kojic 3-aminopropanol phosphoric acid diester

1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added magnesium oxide, adjusting to pH7.

The obtained solution was freeze dried, to give magnesium salt of kojic 3-aminopropanol phosphoric acid diester as white powder.

<Example 6> Preparation of triethanolamine salt of kojic 3-aminopropanol phosphoric acid diester

1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added 5% triethanolamine, adjusting to pH7. The obtained solution was freeze dried, to give triethanolamine salt of kojic 3-aminopropanol phosphoric acid diester as white powder.

Experimental example 1> Stability of Kojyl-APPA in an aqueous base The water-in-stability of Kojyl-APPA was compared with that of kojic acid.

Each 2g of Kojyl-APPA obtained in Example 1 and kojic acid was dissolved in 100m£ of serial aqueous solutions adjusted to pH2~pH8, and then preserved in a thermostat of 50 ^°C for 3 weeks. During the preservation, instability such as discoloration was observed with the lapse of time and evaluated according to the following scoring system :

- : Colorless or pale yellow + : A little discoloration

++ : Some discoloration +++ : Severe discoloration

The results are shown in Table 1.

[Table 1] Discoloration

As shown in Table 1, no discoloration or precipitation was observed, indicating that the present compound is very stable in aqueous base and has high purity.

Experimental example 2> Stability of Kojyl-APPA

The stability of Kojyl-APPA in diluted solution was compared with that of kojic acid.

Each of Kojyl-APPA obtained in Example 1 and- kojic acid was dissolved in hydrion buffer solution of pH7, adjusting to a concentration of 50μM, and then preserved in a thermostat of 50 °C . During the preservation, UN absorbance at 254nm was measured, to evaluate the stabilities of the test samples as residual ratio(%). The results are shown in Table 2.

[Table 2]

In general, the stability of compound rapidly drops in diluted solution such as kojic acid, which was decomposed within 1 hour in aqueous solution. But, as shown in Table 2, the compound of Example 1 is very stable in neutral aqueous solution.

(Preparation Method)

Aqueous phase(materials 15-19) and oily phase(materials 1-14) were heated to be dissolved, respectively. Two mixtures were admixed under stirring, and then cooled to room temperature, to produce cosmetics.

<Example 8 and Comparative Examples 6-10> Skin softners

(Preparation Method) Material 1 was added to material 8 and heated. Thereto were added the other aqueous materials 2-12 and mixed with ethanol parts(materials 13-15), to produce cosmetics. <Example 9> O/W emulsion

(Preparation Method)

Oily phase(materials 1-6) was heated to be dissolved and materials 7 and 8 were added and dispersed with homo-mixer. In this cosmetics, pigment mixture of meterial 8 were prepared by mixing 70.0wt% of titanium dioxide, 20.0wt% of ferric oxide and 10.0wt% of talc and pulverizing twice. Then, aqueous phase(materials 9-11) was heated to be dissolved and then added to said oily phase. After stirring, thereto were added materials 12 and 13 and then emulsified. The emulsion was cooled, to produce cosmetics.

Experimental example 3> Proliferation of fibroblast

The skin obtained from new epidermal tissue was treated with Type 1 collagenase to remove epidermis. The obtained fibroblast was cultured on Dulbecco's modified Eagle's media (DMEM). Amount of fibroblast was measured by way of MTT method. The result indicates that Kojyl-APPA of Example 1 shows an effective fibroblast-proliferation at a concentration as low as 30mM. Experimental example 4> Safety of Kojyl-APPA to the living body

In order to evaluate the safety of the cosmetic composition containing

Kojyl-APPA to the living body, toxicity and irritation of Kojyl-APPA to the body were examined through the following experiments. The results indicate that Kojyl-APPA of Example 1 is a safe material without toxicity and irritation as a cosmetic ingredient.

C4-1) Primary skin irritation test

Test was performed for twelve (12) of New Zealand White male rabbits whose backs were depilated before 24 hours of the application of the test sample. And, 1.0ml of Kojyl-APPA of Example 1 was diluted with physiological saline to give 50% of test sample. Test sample(0.5m^ per site) was applied to two sites (2.5cmx2.5cm) of the right back which of one is intact skin and the other is abraded skin. As a control, two sites (2.5cmx2.5cm) of the left back were treated with 1.0ml of physiological saline. Each tested site was covered with gauze, which was fixed using a non-irritative tape. 24 Hours later, the tested sites were washed with physiological saline.

24 Hours or 72 hours later, erythema and edema were observed. The test was performed according to Notification No. 96-8 of Korea Food & Drug Administration, "Standard guide for toxicity test of foods and drugs". As a result, no skin abnormality (general symptoms or change of weight) was observed. And, a little abnormality such as erythema and edema was observed in the abraded site applied with test sample, so to be calculated 0.396 of Draize's PII(Primary Irritation Index), indicating that test sample is a safe material without irritation.

(4-2) Human patch test

Test was performed for twenty-six(26) of healthy females and four(4) of healthy males aging average 25.4 years according to CTFA Guideline(The Cosmetic, Toiletry and Fragrance Association. Inc. Washington, D.C., 20023, 1991). The back of the subjected was washed with 70% of ethanol and dried, and then, applied with a fϊnn chamber containing 20βl of 10% of Kojyl-APPA in patch base. The finn chamber was fixed to the tested site using a micropore tape. 24 Hours later, the tape and the chamber were removed, and the tested site was marked with marking pen. After 24 hours or 48 hours, skin responses of the tested sites were observed and skin irritation was evaluated according to ICDRG(International Contact Dermatitis Research Group)'s criterion. As a result, primary irritative response was hardly observed. As shown in Table 3, average response was 0.00.

[Table 3]

Experimental example 5> Safety to the skin In order to evaluate safety of whitening cosmetic compositions containing

Kojyl-APPA onto the skin, the conventional patch test was performed for compositions of Examples 7-8 and Comparative Examples 1-10, and skin irritation was estimated according to the following scoring system :

+++ : Extremely severe irritation, estimated to be inadequate as a cosmetic

++ : Severe irritation, estimated to be better not to use as a cosmetic

+ : A little irritation, estimated to be carefully used as a cosmetic

+ : Little irritation

- : No irritation, estimated to be adequate for the sensitive skin

= : No irritation in repeat application [Table 4]

As shown in Table 4, the compositions containing Kojyl-APPA are no irritative to the skin.

Experimental example 6> Skin- whitening effect

In order to evaluate skin-whitening effect of cosmetic compositions containing Kojyl-APPA, the following experiment was performed for compositions of Examples 7-8 and Comparative Examples 1-10.

To lower parts of both the arms of ten(lθ) healthy volunteers were applied patches having four(4) holes of 1.5cm diameter and then, at a distance of 10cm therefrom, UV-ray irradiated using TL20W/12UN lamp(Philips) and TL20W/09UV lamp (Philips), in 1.5 MED once a day, for 2 days. Then, the subjected were divided into two groups, A and B. To A group was applied each of the creams prepared in Example 7 and Comparative Examples 1-5 and to B group was applied each of the skin softners prepared in Example 8 and Comparative Examples 6-10, two times a day for 6 weeks. The skin-whitening effect was observed with naked eyes and evaluated: No effect, Effective, and Significant effect. The results are shown in Table 5.

[Table 5]

As shown in Table 5, the whitening effect of the compositions containing

Kojyl-APPA (Examples 7 and 8) is similar to that of the compositions containing kojyl dipalmitate (Comp. Examples 4 and 9) which is conventional whitening material, while it is slightly less than that of the compositions containing kojic acid (Comp. Examples 2 and 7).

Experimental example 7> Stability of Kojyl-APPA in cosmetic base

In order to evaluate stability of Kojyl-APPA in cosmetic base, stability with the lapse of time was observed for compositions of Example 8 containing Kojyl-APPA and of Comp. Example 9 containing kojyl dipalmitate which has been known to have good stability. Each of composition was preserved in thermostats of 5 ^°C, 25 ^°C and 45 ^°C and then discoloration and precipitation were observed with the lapse of time, to be evaluated : 0 - No, 1 - Little, 2 - A little, 3 - Some and 4 - Severe. The results are shown in Table 6.

[Table 6]

As shown in Table 6, the composition containing Kojyl-APPA of Ex. 8 did not cause precipitation or discoloration at 5 ^°C and 25 °C and caused only discoloration of pale yellow with naked eye at 45 ^°C . It indicates that the compound of the present invention has improved stability, in comparison with kojyl dipalmitate.

As above described, the kojic acid derivative of the present invention, kojic 3-aminopropanol phosphoric acid diester or its salt is very stable in aqueous base and has high purity, to be applied to aqueous cosmetics. And, it can be decomposed to kojic acid having an activity of inhibiting melanin-formation and 3-aminopropanol phosphoric acid having effects on fibroblast-proliferation and collagen-biosynthesis and good safety to the skin. Accordingly, water-in-stable kojic acid derivative of the present invention can be used extensively in skin- whitening and skin aging-preventing cosmetics.

Although preferred embodiments of the present invention have been described in detail hereinabove, it should be clearly understood that many variations of the basic inventive concepts herein taught which may appear to those skilled in the art will still fall within the spirit and scope of the present invention as defined in the appended claims.

Claims

1. Kojic acid derivative represented by the following formula 1 ( 1 ) : [Formula 1]

2. A method for preparing said kojic acid derivative according to Claim 1, which comprises steps of :

(A) reacting 3-amino-l-propanol with phosphorus oxychloride in an equivalent ratio of 1:1-1.3, in an organic solvent, in the presence of an organic base, at a temperature of 0-5 ^°C , for 1-2 hours, to form 2-chlorotetrahydro-2H- 1,3,2-oxazaphosphorin P-oxide ;

(B) reacting 2-chlorotetrahydro-2H-l,3,2-oxazaphosphorin P-oxide of step (A) with kojic acid, in an organic solvent, in the presence of a base;

(C) filtering the resultant of step (B), concentrating under reduced pressure, and then hydrolyzing with addition of an acidic solution, at a temperature of

5-100 "C, for 3-10 hours; and

(D) recrystallizing the product of step (C) with a polar organic solvent, to give kojic acid derivative; and is schematized by the following reaction scheme 1 :

[Reaction Scheme 1] (A)

H,N "OH POCl_j

(B) (II)

<π) (M)

(C)

(III) (J)

3. The method according to Claim 2, which comprises further step (E) of neutralizing the kojic acid derivative of step (D) with a neutralizer selected from the group consisting of alkali metal salt; alkaline earth metal salt; metal oxide; basic amino; ammonia; amine; cationic polymer; and cationic surfactant.

4. The method according to Claim 2 or Claim 3, wherein said organic solvent employed in said step (A) or (B) is selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethyl ether, methanol, ethanol and propanol.

5. The method according to any one of Claim 2 to Claim 4, wherein said base employed in said step (A) or (B) is selected from the group consisting of pyridine, triethylamine, sodium, sodium hydroxide and potassium hydroxide.

6. The method according to any one of Claim 2 to Claim 5, wherein said polar organic solvent employed in said step (D) is selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile and dioxane.

7. A skin- whitening cosmetic composition containing said kojic acid derivative according to Claim 1 or obained by the method according to Claim 2.

8. The skin- whitening cosmetic composition according to Claim 7, which contains said kojic acid derivative or its salt in an amount of 0.01-10% by weight based on the total weight of composition.