KR20070046577A - Gentisic acid derivatives and preparation method thereof and whitening cosmetic composition containing it - Google Patents

Abstract

The present invention relates to a gentisic acid derivative compound bonded with an amide represented by the following formula (I) which is excellent in inhibiting melanogenesis and is safe for skin, a preparation method thereof, and a whitening cosmetic composition comprising the same as an active ingredient.

[Formula I]

In Formula I R is an aromatic group, a straight-chain or branched C ₁ -C ₂₀ group is an alkyl group or an alkoxy-substituted aromatic group, a cycloalkyl group of C ₅ -C _7, C ₅ -C cycloalkenyl group, an aralkyl group of ₇ , A C ₅ -C ₇ cycloalkyl group or a C ₅ -C ₇ cycloalkenyl group substituted with a C ₁ -C ₁₀ alkyl group, a fused ring.

Gentisic acid derivatives, amides, melanin, whitening, cosmetics

Description

Gentisic acid derivatives and preparation method thereof and whitening cosmetic composition containing the same

The present invention relates to a gentisic acid derivative compound bonded with an amide represented by the following formula (I) which is excellent in inhibiting melanogenesis and is safe for skin, a preparation method thereof, and a whitening cosmetic composition comprising the same as an active ingredient.

[Formula 1]

In Formula I R is an aromatic group, a straight-chain or branched C ₁ -C ₂₀ group is an alkyl group or an alkoxy-substituted aromatic group, a cycloalkyl group of C ₅ -C _7, C ₅ -C cycloalkenyl group, an aralkyl group of ₇ , A C ₅ -C ₇ cycloalkyl group or a C ₅ -C ₇ cycloalkenyl group substituted with a C ₁ -C ₁₀ alkyl group, a fused ring.

Human skin color is complexly determined by red blood cells, carotene and melanin in the blood, but differences in race skin color, hyperpigmentation such as blemishes and freckles are influenced by melanin. Melanin exists in the epidermal layer, which is the outer skin of the skin, and acts as a sunscreen to protect skin organs under the dermis and to protect free radicals generated in the skin, thereby protecting proteins and genes in the skin. Do it.

However, melanin produced by internal and external stress stimulus does not disappear until it is released to the outside through skin keratinization even if stress disappears. The production of melanin in vivo is a polymerization oxidation process using tyrosine or dopa as a substrate and catalyzing enzymes such as tyrosinase to increase free radical production in the skin, or inflammatory reactions. In the presence of ultraviolet rays, melanogenesis is increased. In particular, ultraviolet rays may increase the production of melanin, which may result in undesired results due to the development of partially increased melanin, such as blemishes, or even worse, may cause skin cancer.

Due to the above problems, melanogenesis inhibitors containing kojic acid, arbutin, glutathione, vitamin A, vitamin C, and the like have been developed, and ointments, creams, and lotions containing them are commercially available. This difficult, severe skin irritation was restricted to use, and the whitening action was not strong enough to satisfy.

In addition, the whitening agent containing hydroquinone, which improves excessive pigmentation, has an excellent whitening effect but has severe skin irritation and toxicity, so its use is limited.

In order to solve the above problems of the ingredients contained in the whitening agent, research is being conducted to reduce skin side effects by using a steroid compound which is an anti-irritant, but there is a problem that side effects caused by the steroid compound occur. In addition, by using hydroquinone fatty acid ester compounds such as hydroquinone monocaprylate, hydroquinone monolaurylate, hydroquinone monopalmitate, etc., it is used as a cosmetic raw material to reduce skin irritation and whitening effect, but the hydroquinone derivatives are whitened. Not only is the effect insignificant, but the product stability is not good, there is a problem that the use is limited.

The present inventors studied the hydroquinone derivative compound in order to solve the problem of the whitening agent, and synthesized by reacting with various lipophilic groups using 2,5-dihydroxy benzoic acid (gentisic acid) similar in structure to hydroquinone. The majority of the gentidic acid derivative compounds bound with the amide were found to be not only excellent in inhibiting melanin production but also safe for the skin, thus completing the present invention.

Accordingly, an object of the present invention is to provide a gentidic acid derivative compound having a novel chemical structure and a preparation method thereof.

It is another object of the present invention to provide a whitening cosmetic composition comprising 0.01-20% by weight of the gentidic acid derivative compound showing an excellent whitening effect as an active ingredient.

The present invention relates to a gentisic acid derivative compound bonded with an amide represented by the following formula (I) which is excellent in inhibiting melanogenesis and is safe for skin, a preparation method thereof, and a whitening cosmetic composition comprising the same as an active ingredient.

[Formula I]

In Formula I R is an aromatic group, a straight-chain or branched C ₁ -C ₂₀ group is an alkyl group or an alkoxy-substituted aromatic group, a cycloalkyl group of C ₅ -C _7, C ₅ -C cycloalkenyl group, an aralkyl group of ₇ , A C ₅ -C ₇ cycloalkyl group or a C ₅ -C ₇ cycloalkenyl group substituted with a C ₁ -C ₁₀ alkyl group, a fused ring.

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

The gentic acid derivatives of the present invention represented by Formula I are prepared according to Scheme 1 below.

1) preparing an acetylated compound of formula (II) by substituting an acetyl group with a hydrogen atom of 2,5-dihydroxy group using 2,5-dihydroxy benzoic acid, acetic anhydride, a base, and a catalyst;

2) preparing an amide compound of formula III using the acetylated compound of formula II prepared in step 1) using an amine having a lipophilic group with ethylchloroformate;

3) hydrolyzing the acetyl group of the amide compound of Formula III prepared in step 2) to prepare the gentic acid derivative compound of Formula I;

It includes.

Scheme 1

Wherein R is the same as defined in formula (I).

Method for producing a compound of the gentian acid derivative according to the present invention, as can be seen in the above Scheme 1, specifically described as follows.

In the reaction of substituting the hydrogen atom of the 2,5-dihydroxy group of step 1) with an acetyl group, pyridine, triethylamine, etc. may be used as a base, and dichloromethane, chloroform, tetrahydrofuran, etc. may be used as a reaction solvent. have. In addition, to facilitate the reaction, the compound should be prepared using dimethylaminopyridine as a catalyst, and if not used, the reaction will not proceed well and the yield will be lowered. The reaction temperature is suitable 10 to 80 ℃, preferably carried out at 40 ℃.

The reaction for preparing the amide compound (III) using the acetylated compound (II) of step 2) using ethylchloroformate and an amine having a lipophilic group is carried out by an acid halide method, an active ester method and an acid anhydride method. Although all are possible, Preferably, the amide compound (III) is prepared by substituting an anhydride using ethyl chloroformate and substituting with an amine having a lipophilic group. The equivalent ratio of the amine having a lipophilic group reacting with the acetylated compound (II) is preferably 1.1 to 1.3, and when the equivalent ratio is less than 1: 1, the amount of the amide compound (III) is reduced.

In addition, a base such as pyridine and triethylamine may be used as the base, preferably triethylamine is used, and as a reaction solvent, dichloromethane, acetone, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc. Can be used, preferably N, N-dimethylformamide and tetrahydrofuran are used. On the other hand, the reaction temperature is suitable 10-60 ℃, preferably proceed the reaction at 30 ℃.

Hydrolysis of the acetyl group of the amide compound (III) to prepare the gentic acid derivative compound of formula (I) in step 3) uses an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide as a base, and the reaction solvent is water. , Methanol, ethanol, propanol, tetrahydrofuran, dichloromethane, and the like may be used, and tetrahydrofuran and methanol may be mixed in a volume ratio of 1: 1 to 1: 5, preferably 1: 1, in the fastest time. The reaction can be completed.

The specific example of the gentic acid derivative compound of general formula (I) obtained by said manufacturing method is as follows.

N- (4-ethoxyphenyl) -2,5-dihydroxybenzamide

N- (2-cyclohexenylethyl) -2,5-dihydroxybenzamide

N-cycloheptyl-2,5-dihydroxybenzamide

N-cyclohexyl-2,5-dihydroxybenzamide

N- (4-isopropylphenyl) -2,5-dihydroxybenzamide

N- (2,3-dihydrobenzo [1,4] dioxin-7-yl) -2,5-dihydroxybenzamide

N- (benzo [1,3] -dioxol-6-yl) -2,5-dihydroxy-benzamide

N-adamantyl-1-yl-2,5-dihydroxybenzamide

The gentic acid derivative (I) of the present invention prepared by the above process may be contained as an active ingredient of a whitening cosmetic, the amount of which is effective to achieve a whitening action, for example, 0.01 to 20.0 weight of the total weight of the composition. It may be contained in an amount of%, and may have various non-limiting formulations such as creams, lotions, lotions, massage creams, or essences.

The compositions of the present invention may also include other conventional ingredients depending on their formulations, and the types and amounts of these conventional ingredients are well known to those skilled in the art. The composition of the present invention may further contain other existing whitening components in addition to the above-described gentic acid derivative (I) for its whitening action, and the types and contents of these existing whitening components are well known to those skilled in the art.

Hereinafter, the preparation method of the gentive acid derivative compound according to the present invention will be described in more detail with reference to Examples and Formulation Examples. However, the present invention is not limited to these examples and formulation examples.

Example 1 N- (4-ethoxyphenyl) -2,5-dihydroxybenzamide

Dissolve 2,5-dihydroxy benzoic acid (100g, 0.65mol) in 1000ml of dichloromethane, add dimethylaminopyridine in catalytic amount (4g, 0.03mol) and reflux for 5 minutes, then triethylamine (199ml, 1.43 mol) was added dropwise, acetic anhydride (135 mL, 1.43 mol) was slowly added dropwise to the reaction solution, and the mixture was refluxed at a reaction temperature of 40 ° C. for 2 hours. After completion of the reaction, dichloromethane (1000 ml) was added to dilute the reaction solution, washed with 1000 ml of water, washed with 500 ml of 1M HCl solution, dried over anhydrous manganese (100 g), filtered and concentrated to hexane. After crystallization, 129 g (yield = 83%) of an acetylated compound in which the hydrogen atom of the 2,5-dihydroxy group of 2,5-dihydroxy benzoic acid was substituted with an acetyl group was obtained. This compound (100g, 0.42mol) was dissolved in tetrahydrofuran (1500ml), triethylamine (76.1ml, 0.55mol) was added dropwise, and 1.3 equivalent of ethylchloroformate (52.2ml, 0.55mol) was slowly added dropwise. Then stirred for 30 minutes. After stirring, 4-ethoxyphenylamine (94.6g, 0.50mol) and triethylamine (84.3ml, 0.60ml) were dissolved in 1500ml of N, N-dimethylformamide by heating, and then the stirring was completed. The solution was slowly added dropwise and further stirred for 3 hours. After the reaction was completed, the mixture was filtered, the reaction solution was concentrated, and 1500 ml of dichloromethane was added to dissolve the reaction mixture. The mixture was washed with distilled water (500 ml) and washed with 500 ml of saturated sodium hydrogen carbonate. After drying, the mixture was filtered and concentrated to crystallize with hexane and then filtered to obtain 107 g (yield = 88%) of the amide compound. The compound (100 g, 0.27 mol) was dissolved in 1500 mL of tetrahydrofuran and methanol (1: 1) solvent, and then 100 mL of 15% potassium hydroxide was added thereto, followed by stirring for 30 minutes. After the reaction was completed, acid was added to neutralize the solution, the reaction solution was concentrated, and 1500 ml of ethyl acetate was added to dissolve the reaction mixture. Washed with 1000 ml of water, filtered, concentrated to crystallize with hexane, filtered and filtered to give 70 g (yield = 91%) of the title compound N- (4-ethoxyphenyl) -2,5-dihydroxybenzamide as pale yellow. Obtained as a solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.70

¹ H NMR (DMSO-d ₆ , δ): 11.23 (s, OH, 1H), 10.28 (s, OH, 1H), 9.07 (s, NH, 1H), 7.65 (d, 2H), 7.38 (d, 2H), 6.88 (m, 4H), 4.05 (q, 2H), 1.25 (t, 3H).

Example 2 N- (2-cyclohexenylethyl) -2,5-dihydroxybenzamide

The title compound N- (2-cyclohexenylethyl) -2,5 using the same method as Example 1 except for using (2-cyclohexenylethyl) amine instead of 4-ethoxyphenylamine -Dihydroxybenzamide was obtained as a pale yellow solid in 63 g (78% yield).

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.69

¹ H NMR (DMSO-d ₆ , δ): 11.73 (s, OH, 1H), 8.78 (s, OH, 1H), 8.47 (s, NH, 1H), 7.25 (s, 1H), 6.84 (d, 1H), 6.73 (d, 1H), 5.42 (s, 1H), 3.24 (m, 2H), 2.16 (m, 2H), 1.96 (m, 4H), 1.56 (m, 4H).

Example 3 N-cycloheptyl-2,5-dihydroxybenzamide

75 g (87% yield) of the title compound N-cycloheptyl-2,5-dihydroxybenzamide using the same method as Example 1 except for using cycloheptylamine instead of 4-ethoxyphenylamine ) As a pale yellow solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.57

¹ H NMR (DMSO-d ₆ , δ): 11.68 (s, OH, 1H), 8.98 (s, OH, 1H), 8.49 (s, NH, 1H), 7.31 (s, 1H), 6.85 (d, 1H), 6.78 (d, 1H), 3.98 (m, 1H), 1.84 (m, 2H), 1.56 (m, 10H).

Example 4 N-cyclohexyl-2,5-dihydroxybenzamide

65 g (77% yield) of the title compound N-cyclohexyl-2,5-dihydroxybenzamide using the same method as Example 1 except for using cyclohexylamine instead of 4-ethoxyphenylamine ) As a pale yellow solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.56

¹ H NMR (DMSO-d ₆ , δ): 11.67 (s, OH, 1H), 8.98 (s, OH, 1H), 8.46 (s, NH, 1H), 7.33 (s, 1H), 6.82 (d, 1H), 6.70 (d, 1H), 3.81 (m, 1H), 1.85 (m, 5H), 1.36 (m, 5H).

Example 5 N- (4-isopropylphenyl) -2,5-dihydroxybenzamide

The title compound N- (4-isopropylphenyl) -2,5-dihydroxy was used in the same manner as in Example 1 except that 4-isopropylphenylamine was used instead of 4-ethoxyphenylamine. Benzamide was obtained as a pale yellow solid in 82 g (87% yield).

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.78

¹ H NMR (DMSO-d ₆ , δ): 11.18 (s, OH, 1H), 10.28 (s, OH, 1H), 9.08 (s, NH, 1H), 7.61 (d, 2H), 7.38 (s, 1H), 7.21 (d, 2H), 6.82 (m, 2H), 3.84 (m, 1H), 1.21 (d, 6H).

Example 6 N- (2,3-dihydrobenzo [1,4] dioxin-7-yl) -2,5-dihydroxybenzamide

Except for using 2,3-dihydrobenzo [1,4] dioxin-7-amine instead of 4-ethoxyphenylamine, the title compound N- (2, 3-dihydrobenzo [1,4] dioxin-7-yl) -2,5-dihydroxybenzamide was obtained as a light yellow solid in 76 g (81% yield).

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.50

¹ H NMR (DMSO-d ₆ , δ): 11.03 (s, OH, 1H), 10.27 (s, OH, 1H), 9.08 (s, NH, 1H), 7.41 (m, 2H), 7.21 (d, 1H), 6.83 (m, 3H), 4.24 (m, 4H).

Example 7 N- (benzo [1,3] -dioxol-6-yl) -2,5-dihydroxy-benzamide

The title compound N- (benzo [1,3]-was used in the same manner as in Example 1 except for using benzo [1,3] -dioxol-6-amine instead of 4-ethoxyphenylamine. Dioxol-6-yl) -2,5-dihydroxy-benzamide was obtained as a light yellow solid in 76 g (81% yield).

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.54

¹ H NMR (DMSO-d ₆ , δ): 11.01 (s, OH, 1H), 10.27 (s, OH, 1H), 9.07 (s, NH, 1H), 7.41 (m, 2H), 7.23 (d, 1H), 6.85 (m, 3H), 6.04 (m, 2H).

Example 8 N-adamantyl-1-yl-2,5-dihydroxybenzamide

The title compound N-adamantyl-1-yl-2,5-dihydroxy was used in the same manner as in Example 1 except that adamantyl-1amine was used instead of 4-ethoxyphenylamine. Benzamide was obtained as a light yellow solid in 78 g (80% yield).

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.57

m. p. 211-212 ℃

¹ H NMR (DMSO-d ₆ , δ): 11.18 (s, OH, 1H), 8.98 (s, OH, 1H), 8.09 (s, NH, 1H), 7.31 (s, 1H), 6.85 (m, 2H), 2.03 (m, 9H), 1.66 (m, 6H).

[Test Example 1] melanin production inhibitory effect on melanin pigment-producing cells

While treating melanin-producing skin pigment cells, the mesogenic production of the present invention is treated by treating the genidic acid derivative compound, hydroquinone, 2,5-dihydroxybenzoic acid, and kojic acid, and the results are shown in Table 1 below.

The degree of melanin production in the cells of Examples 1 to 8 was measured by Dooley's method. The cell line was a Mel-Ab cell line derived from C57BL / 6 skin pigment cells. The culture was performed in DMEM medium containing 10% fetal placental serum, 100 nM 12-O-tetradecanoyl Phobol-13-acetate, 1 nM Cholera Toxin, 37 ° C., 5% CO ₂ Under the conditions of.

Cultured Mel-Ab cells were detached with 0.25% Trypsin-EDTA, plated on a 24-well plate again with the same number (1 × 10 ⁵ cells / well), followed by 3 consecutive days. The material treatment was carried out by replacing with a medium containing 10 ppm of samples. After 5 days, the melanin was dissolved in the cells by treatment with 1N NaOH, and the amount of melanin was measured by measuring absorbance at 400 nm. The results are shown in Table 1 below.

The result of Table 1 shows the relative activity of the test substance when the effect of the vesicle only dissolved in the test substance described in Table 1 as a control 100%.

Table 1 Inhibitory Effects of 2,5-Dihydroxy Benzoic Acid Amide Derivatives

Hydroquinone and kojic acid were used as positive controls, and the parent compound, 2,5-dihydroxy benzoic acid, was compared with Example 1 8 compound to measure melanin production inhibition. From the Table 1 it can be seen that the gentic acid derivatives of the present invention of Examples 1 to 8 have a similar or improved melanin production inhibitory effect compared to hydroquinone and kojic acid known as a whitening agent.

However, 2,5-dihydroxy benzoic acid, which is the parent of the gentidic acid derivative of the present invention, did not show melanin production inhibitory effect. From this, it can be seen that lipophilic groups play an important role in showing melanin production inhibitory effect.

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 irradiation, Examples 1-8 each 2% (solvent 1, 3-butylene glycol: ethanol = 7: 3), 2% hydroquinone, 2% lipoic acid, solvent for 10 weeks as a control (one place Was left unapplied), and the color of the skin was measured on a weekly basis with a colorimeter (Colorimeter CR-300, Minolta, Japan), and the degree of increase in the value of “L” (“ΔL”) was evaluated. The results are shown in Table 2.

In the evaluation method, the degree of improvement of pigmentation after use was determined as the higher the value, the higher the relative whitening effect, and the results are shown in Table 2.

[Table 2] Whitening Effect of Gentisic Acid Derivatives on Human Skin

From the Table 1 it can be seen that the gentisic acid derivatives of Examples 1 to 8 of the present invention have a superior whitening effect compared to kojic acid, which is a known whitening agent, in the whitening effect confirmation experiment on the skin, and compared with hydroquinone Similar or improved whitening effect was shown.

Test Example 3 Safety Test of Gentisic Acid Derivative Compound

In order to determine the safety of human body of the gentiic acid derivative compound or the cosmetic of the present invention the gentiic acid derivative compound of the present invention, a solution of 3% concentration of the geniic acid derivative compound in the presence of toxicity and irritation After using the following safety test, it was confirmed that it is a raw material with no toxicity and irritation as a cosmetic.

(3-1) Acute oral toxicity test in mice: Example 1-8 One oral dose of 1 ml / Kg was administered to 24 rats three times each, and no dead animals were observed. There was no significant difference in body weight before and after.

(3-2) Acute dermal toxicity test in mice and rabbits: Example 1-8 0.2 ml / Kg was administered once percutaneously to 24 rats of 3 rats each for 2 weeks. As a result of the observation, no abnormal symptoms were observed in all the administration groups. No abnormalities were observed in the rabbits in the same manner.

(3-3) Primary skin irritation test: 8 rabbits were removed 24 hours prior to application of the test substance, and hairs of Example 1-8 were each 2.5 ml x 2.5 cm wide by 0.1 ml. Application was observed for 24 hours. Observation determined that there was no stimulus.

(3-4) Eye irritation test (Eye irritation test): Example 1-8 was diluted in saline at a 3% concentration, and 3 rabbits each were administered to 24 rabbits at 0.1 ml per rabbit. Experimental results showed no specific eye mucosal irritation to cornea, iris and conjunctiva.

(3-5) Skin sensitization test: In Example 1-8, Magnuson and Kligman test methods were carried out on 24 guinea pigs (3 each). Results Dermatological symptoms such as erythema, edema, and crust formation could not be observed.

In the above toxicity and skin safety experiments, it was confirmed that the gentisic acid derivative compound is a hypoallergenic substance.

Examples of the formulation of the gentically acid derivatives according to the present invention will be described, but the present invention is not intended to be limited thereto, but merely to explain in detail.

The skin whitening composition of Formulation Examples 1 to 5 was prepared according to a conventional method according to the composition components and the composition ratios of the methinin acid derivatives of Examples 1 to 5 excellent in the melanin production inhibitory effect and the whitening effect.

Formulation Example 1 Preparation of Lotion

The loti was prepared according to a conventional method by using the gentidic acid derivative of Example 1 in the lotion formulation ratio of Table 3 below.

TABLE 3

Formulation Example 2 Preparation of Cream

A cream was prepared according to a conventional method in the genidic acid derivative of Example 2 in the ratio of the cream formulation of Table 4 below.

TABLE 4

Formulation Example 3 Preparation of Pack

The pack was prepared according to a conventional method according to the pack formulation ratio of Table 5 in the gentidic acid derivative of Example 3.

TABLE 5

Formulation Example 4 Serum

The gentic acid derivatives of Example 4 were prepared in the usual manner according to the ratio of the cosmetic solution formulations of Table 6 below.

TABLE 6

Formulation Example 5 Ointment

The ointment was prepared according to a conventional method according to the ointment formulation ratio of Table 7 in the gentidic acid derivative of Example 5.

TABLE 7

As described above, the genteric acid derivative compound of the present invention not only has an excellent effect of inhibiting melanin production but is also safe for skin. Can be represented.

Claims (7)

A gentidic acid derivative compound having the structure of formula [Formula I]

R in the general formula (I) is an aromatic group substituted or unsubstituted alkyl or alkoxy group of a straight or branched C ₁ -C ₇ group; A cycloalkyl group which is substituted or unsubstituted with a linear or branched C ₁ -C ₇ alkyl group; A cycloalkenyl group in which a linear or branched C ₁ -C ₇ alkyl group is substituted or unsubstituted; Aralkyl group; An alkyl group substituted with a cycloalkyl group or a cycloalkenyl group; It is a fusion ring. The method of claim 1, R in the above formula (I) is a phenyl group or naphthyl group as an aromatic group, methyl group, ethyl group, n-propyl group or i-propyl group as alkyl group, cyclohexyl group or cycloheptyl group as cycloalkyl group, and cyclohexenyl group as cycloalkenyl group Or a cycloheptenyl group, adamantane, bicyclo [2,2,2] octane or norbornene group as a fused ring. The method of claim 1, A gentidic acid derivative compound having a structure selected from the following formulas I-a to I-h. [Formula I-a]

[Formula I-b]

[Formula I-c]

[Formula I-d]

[Formula I-e]

[Formula I-f]

[Formula I-g]

[Formula I-h]

1) preparing an acetylated compound of formula II by substituting an acetyl group with a hydrogen atom of 2,5-dihydroxy group using 2,5-dihydroxy benzoic acid and acetic anhydride, a base and a catalyst; 2) preparing an amide compound of formula III by reacting the acetylated compound of formula II prepared in step 1) with ethylchloroformate and an amine having a lipophilic group; 3) hydrolyzing the acetyl group of the amide compound of Formula III prepared in step 2) to prepare the gentic acid derivative compound of Formula I; Method for producing a gentidic acid derivative compound, characterized in that consisting of. [Formula II]

[Formula III]

The method of claim 4, wherein Method for producing a gentidic acid derivative compound, characterized in that dimethylaminopyridine is used as the catalyst in step 1). The method of claim 4, wherein Methanol and tetrahydrofuran as a reaction solvent in the step 3) is a method for producing a gentidic acid derivative compound, characterized in that for mixing in a volume ratio of 1: 1 to 1: 5. Cosmetic composition, characterized in that it comprises 0.01 to 20.0% by weight of the gentianic acid derivative compound according to any one of claims 1 to 3.