KR19990069211A - Novel polyhydroxy-diphenylalkane derivatives having tyrosinase inhibitory activity and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel polyhydroxy-diphenylalkane derivative represented by the following Chemical Formula 1 having excellent melanin biosynthesis inhibitory effect due to its tyrosinase inhibitory activity and a preparation method thereof:

Where

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n ₁ and n ₂ are as defined in the specification.

Description

Novel polyhydroxy-diphenylalkane derivatives having tyrosinase inhibitory activity and preparation method thereof

The present invention relates to a novel polyhydroxy-diphenylalkane derivative represented by the following Chemical Formula 1 having excellent melanin biosynthesis inhibitory effect due to its tyrosinase inhibitory activity and a preparation method thereof:

Formula 1

Where

R ₁ represents hydrogen or C _1-10 alkyl,

R ₂ represents C _1-5 alkyl,

R ₃ represents hydrogen or C _1-10 alkyl, or

R ₂ together with R ₃ may form C _2-3 alkylene unsubstituted or substituted by C _1-5 alkyl,

R ₄ represents hydrogen or hydroxy,

R ₅ and R ₆ each independently represent hydrogen or C _1-10 alkyl,

n ₁ is an integer of 0 or 1,

n ₂ is an integer of 1 or 2, wherein hydroxy is at the ortho, meta or para position,

Provided that when n ₁ is 1 and n ₂ is 2, at least one hydroxy is present at the meta position.

Melanin is produced by non-enzymatic oxidation after conversion from tyrosine to dopa (DOPA) and dopaquinone (Dopaquinone) by the action of an enzyme called tyrosinase in pigment cells. Melanin has an important function of protecting the body by distributing it to the skin, but the overproduction of melanin is known to be closely related to the occurrence of skin cancer (Melonoma), causing skin blackening and producing spots, freckles, etc. There is an active development of cosmetics and drugs for the purpose of preventing overproduction of melanin.

In order to suppress melanin overproduction, hydroquinone has been mainly used. However, this compound has side effects such as degeneration or lethality of pigment and impaired cell function. Currently, the compound is prohibited from being used in cosmetics in Korea and Japan. In addition, melanogenesis inhibitors containing albutin, a sugar derivative of hydroquinone, have been developed, but the effect is weak, and ascorbic acid or kojic acid has problems in terms of product stability. There is a disadvantage in that the use is limited. It is known that it has a skin whitening effect as a traditional slander, such as licorice extract and lettuce extract, but these extracts are very difficult to maintain the homogeneity of the product due to the difference in efficacy depending on the origin ( Fragrance, J. , 6, 59, 1990). On the other hand, recently, Kazinol F ( Chem. Pharm. Bull ., 34 (5), 1968, 1986; Cosmetics & Toiletries , 101, 51, 1995), extracted from the mulberry, showed good tyrosinase inhibitory activity. Although commercialized according to the present invention, there is a problem that it is difficult to maintain the homogeneity of the product quality since this raw material is also an extract, and its use is limited because data on human irritation and stability are not sufficient. In particular, Casinol F has a disadvantage in that it is difficult to synthesize because a prenyl catechol group is attached.

Accordingly, the present inventors have conducted continuous studies to solve the above problems of known conventional compounds having tyrosinase inhibitory activity and to provide a stable inhibitor showing excellent tyrosinase inhibitory activity even in a small amount. As a result, it was confirmed that the novel polyhydroxy-diphenylalkane derivative of Formula 1 satisfies this purpose and completed the present invention.

Accordingly, the present invention aims to provide a novel compound of formula (I).

It is also an object of the present invention to provide a novel process for preparing the compound of formula (1).

The present invention relates to a novel polyhydroxy-diphenylalkane derivative of formula (I) having tyrosinase inhibitory activity:

Formula 1

Where

R ₁ represents hydrogen or C _1-10 alkyl,

R ₂ represents C _1-5 alkyl,

R ₃ represents hydrogen or C _1-10 alkyl, or

R ₂ together with R ₃ may form C _2-3 alkylene unsubstituted or substituted by C _1-5 alkyl,

R ₄ represents hydrogen or hydroxy,

R ₅ and R ₆ each independently represent hydrogen or C _1-10 alkyl,

n ₁ is an integer of 0 or 1,

n ₂ is an integer of 1 or 2, wherein hydroxy is at the ortho, meta or para position,

Provided that when n ₁ is 1 and n ₂ is 2, at least one hydroxy is present at the meta position.

In the definitions for the above substituents, the term "alkyl" means straight or branched chain saturated hydrocarbon radicals such as methyl, ethyl, n-propyl, isopropyl or various butyl isomers and the like.

Preferred compounds among the novel compounds of the formula (1) R ₁ represents hydrogen, R ₂ a represents a methyl, R ₃ is or represents hydrogen, R ₂ is optionally substituted by methyl with R ₃ or unsubstituted C ₃ ring Alkylene is formed, R ₄ represents hydrogen or hydroxy, R ₅ and R ₆ each independently represent methyl, n ₁ is an integer of 0 or 1, n ₂ is an integer of 1 or 2, wherein , Hydroxy is a compound present in the ortho, meta or para position.

The novel compounds of formula (1) according to the present invention may be prepared by (a) coupling a compound of formula (3) with an aldehyde of formula (4) to obtain a compound of formula (5) and then deprotecting to obtain a compound of formula (1a) (b) dehydrating the compound of formula 5 in the presence of an acid catalyst to prepare a compound of formula 6, and then performing a hydrogenation and deprotection reaction on the compound of formula 6 to obtain a compound of formula 1b. It is also an object of the present invention to provide a method for preparing such a compound of formula (I).

Where

n ₁ , n ₂ , R ₂ , R ₅ and R ₆ are as defined above,

Pro ₁ and Pro ₂ each represent a conventional hydroxyprotecting group.

Examples of conventional hydroxyprotecting groups Pro ₁ and Pro ₂ include benzyl, alkyl, tetrahydropyran, methoxymethyl, methoxyethoxymethyl and paramethoxybenzyl. In addition, the protection and deprotection processes can be carried out using methods known to those skilled in the art.

The compound of formula 5 is prepared by coupling the compound of formula 3 to the aldehyde compound of formula 4 in the presence of n-butyllithium. This reaction is usually carried out in an ether solvent such as diethyl ether and tetrahydrofuran at a temperature between -78 and -30 ° C. Preferably, the reaction is carried out by adding 1 equivalent of n-butyllithium to the compound of formula 3 at -78 ° C in anhydrous diethyl ether solvent and then adding 1 equivalent of the aldehyde compound of formula 4.

Among the compounds of formula (1), compounds of formula (I) wherein R ₁ and R ₃ are hydrogen and R ₄ is hydroxy are prepared by deprotecting the compound of formula (5) obtained above. The deprotection reaction may be carried out by applying conditions known in the art, for example, when the protecting group is benzyl, hydrogenation in ethyl acetate or an alcoholic solvent such as methanol or ethanol or mixing of hydrochloric acid and acetic acid Deprotection may be effected by refluxing in a solvent.

In addition, in the compound of Formula 1, the compound of Formula 1b wherein R ₁ , R ₃ and R ₄ are each hydrogen may be selected from the group consisting of inorganic acids such as phosphoric acid and sulfuric acid in one or more nonpolar solvents selected from benzene, toluene and xylene, or Dehydration in the presence of paratoluenesulfonic acid or benzenesulfonic acid affords a compound of formula 6, which is then prepared by carrying out a hydrogenation and deprotection reaction on the compound of formula 6. Preferably, the dehydration reaction proceeds by using paratoluenesulfonic acid as an acid catalyst and stirring in a benzene solvent for 5 to 24 hours. In addition, when the protecting group is benzyl, when the hydrogenation reaction is carried out in an ethyl acetate solvent, the deprotection reaction is also performed at the same time.

When R ₂ and R ₃ together represent C _2-3 alkylene unsubstituted or substituted by C _1-5 alkyl, the compound of Formula 8 may be protected by protecting the hydroxyl group of the following Formula 7 compound. By preparing and using it instead of the compound of Formula 3 it can be prepared a target compound.

The compound of Formula 7 may be prepared using a known method (see J. Chem. Soc. Perkin Trans I , 1437, 1981), and the method of introducing a protecting group to the compound of Formula 7 is the same as mentioned above. .

On the other hand, the compound of formula (3) used as a starting material to prepare a compound of formula (1) can be prepared by brominating the compound of formula (2) which is commercially available.

Where

R ₂ , R ₅ , R ₆ and Pro ₁ are as defined above.

The reaction can be carried out in chlorine-based hydrocarbons such as dichloromethane and chloroform or in organic solvents such as acetic acid and propionic acid. Preferably, 1 equivalent of bromine is added to the compound of formula 2 in chloroform and stirred at room temperature for 2 to 5 hours. Is performed.

The preparation method for preparing the compounds of Formulas 1a and 1b from the compound of Formula 2 is shown in Scheme 1 below.

In addition, the compound of formula (1) wherein R ₁ and R ₃ are each alkyl may be obtained by reacting the compound of formula (2) in which the corresponding position is substituted with alkyl as shown in Scheme 1, and of course deprotection process May be omitted.

Representative examples of the compound of formula 1 prepared according to the method described above are shown in Table 1 below.

Example number R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ n ₁ One H Me H OH Me Me One 2 H Me H OH Me Me One 3 H Me H H Me Me One 4 H Me H H Me Me One 5 H H Me Me 0

Example number R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ n ₁ 6 H Me H OH Me Me 0

The present inventors also confirmed the tyrosinase inhibitory activity of the compound of formula 1 prepared according to the present invention by the following method. In other words, the sample was placed in a microplate, and L-tyrosine solution in phosphate buffer (pH 6.8) was added thereto, followed by reaction with the addition of tyrosinase enzyme solution and measurement of absorbance at 475 nm. The inhibition rate for the agent was calculated (see Experimental Example 1).

As a result, it was confirmed that the compound of Formula 1 according to the present invention exhibits an excellent inhibitory effect on tyrosinase activity, which is superior or equivalent to conventional whitening substances. Therefore, the compound of the present invention having such an effect can be applied to medicines, quasi-drugs and cosmetics, the amount of application may vary depending on the formulation, purpose of use, and the like.

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples, Examples and Experimental Examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Preparation Example 1 Synthesis of 2-bromo-1,4-dibenzyloxy-3,5,6-trimethylbenzene

2.89 g (8.70 mmol) of 1,4-dibenzyloxy-3,5,6-trimethylbenzene was dissolved in 50 ml of chloroform, followed by vigorous stirring at room temperature. Bromine 1.39 g was added dropwise to the solution, followed by vigorous stirring at the same temperature. The organic layer was washed twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution, and the organic layer was washed with 50 ml of water. The combined organic layers were dried over anhydrous manganese, distilled under reduced pressure, and purified by column chromatography (eluent: n-hexane / ethyl acetate = 10/1, v / v) to give 2.86 g of the title compound (yield: 80% of theory). ) Was obtained.

Preparation Example 2 Synthesis of 3- (3,5-Dibenzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol

347 mg of 2-bromo-1,4-dibenzyloxy-3,5,6-trimethylbenzene obtained in Preparation Example 1 was dissolved in 5 ml of diethyl ether, and the reactor was filled with nitrogen gas. The temperature of the reaction solution was lowered to −78 ° C., and 0.53 mL (1.6M) of n-butyllithium was slowly added dropwise. Stirred at the same temperature for 30 minutes. 0.295 g of 3,5-dibenzyloxyhydrocinnamaldehyde was dissolved in 5 ml of anhydrous diethyl ether, and then added dropwise to the reaction solution. Then, the mixture was stirred for 2 hours while the temperature was raised to room temperature. 1N hydrochloric acid aqueous solution was added dropwise to the reaction solution to adjust the pH to 7. The organic layer was separated and the aqueous layer was extracted twice with 50 ml of diethyl ether again. The combined organic layers were washed with water, dried over anhydrous manganese, distilled under reduced pressure, and purified by column chromatography (eluent: n-hexane / ethyl acetate = 5/1, v / v) to give the title compound (477 mg, yield: theoretical value). 83%) were obtained.

Preparation Example 3 Synthesis of 3- (4-benzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol

2-bromo-1,4-dibenzyloxy-3,5,6-trimethylbenzene 920 mg (2.24 mmol) obtained in Production Example 1, 540 mg of 4-benzyloxyhydrocinnamaldehyde and 1.4 ml of n-butyllithium The title compound was obtained in the same manner as in Preparation Example 2, except that 720 mg (yield: 64% of theory) was obtained.

Example 1: Synthesis of 2- [1-hydroxy-3- (3,5-dihydroxyphenyl) propyl] -3,5,6-trimethyl-benzene-1,4-diol

300 mg (0.45) of 3- (3,5-dibenzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol obtained in Preparation Example 2 Mmol) was dissolved in 6 ml of ethyl acetate. 30 mg (10%) of palladium-carbon catalyst was added dropwise thereto, followed by hydrogenation for 12.5 hours under hydrogen pressure of 4 atmospheres. 50 ml of ethyl acetate was added to the reaction mixture, and the mixture was diluted and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography (eluent: n-hexane / ethyl acetate = 1/2, v / v) to give 130 mg (yield: 92% of theory) of the title compound.

¹ H NMR (acetone-d ₆ ): 9.10 (s, 1H), 8.12 (s, 1H), 6.50 (s, 1H), 6.30 (d, 2H), 6.25 (d, 1H), 5.75 (d, 2H ), 5.20 (brs, 1H), 2.52-2.92 (m, 2H), 2.21 (s, 3H), 2.08-1.95 (m, 2H), 2.12 (s, 3H), 2.09 (s, 3H)

Example 2: Synthesis of 2- [1-hydroxy-3- (4-hydroxyphenyl) propyl] -3,5,6-trimethyl-benzene-1,4-diol

100 mg (0.178 mmol) of 3- (4-benzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol obtained in Preparation Example 3, and 48 mg (yield: 95% of theory) of the title compound were obtained in the same manner as in Example 1 except for using 10 mg of palladium-carbon.

¹ H NMR (acetone-d ₆ ): 9.02 (s, 1H), 8.07 (s, 1H), 7.08 (d, 2H), 6.73 (d, 2H), 6.41 (s, 1H), 5.64 (brs, 1H ), 5.08 (d, 1H), 2.65-2.91 (m, 2H), 2.33-2.16 (m, 1H), 2.13 (s, 3H), 2.06 (s, 3H), 1.96 (s, 3H), 1.87- 1.82 (m, 1 H)

Preparation Example 4 Synthesis of 2- [3- (3,5-Dibenzyloxy-phenyl) -1-propenyl] -1,4-dibenzyloxy-3,5,6-trimethylbenzene

477 mg of 3- (3,5-dibenzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol obtained in Production Example 2 was benzene. Dissolved in 30 ml. 24 mg (5%) of paratoluenesulfonic acid was added dropwise thereto, and the mixture was stirred at reflux for 5 hours while removing water. The reaction solution was cooled to room temperature and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane, combined with the original organic layer, dried over anhydrous manganese, distilled under reduced pressure, and purified by column chromatography (eluent: n-hexane / ethyl acetate = 10/1, v / v) to give the title compound. 420 mg (yield: 89% of theory) were obtained.

Preparation Example 5 Synthesis of 2- [3- (4-benzyloxy-phenyl) -1-propenyl] -1,4-dibenzyloxy-3,5,6-trimethylbenzene

108 mg (0.193 mmol) of 3- (4-benzyloxy-phenyl) -1- (2,5-dibenzyloxy-3,4,6-trimethyl-phenyl) -propan-1-ol obtained in Preparation Example 3, and 80 mg (yield: 78% of theory) of the title compound were obtained in the same manner as in Preparation Example 4, except that 5 mg of paratoluenesulfonic acid was used.

Example 3: Synthesis of 2- [3- (3,5-Dihydroxyphenyl) propyl] -3,5,6-trimethyl-benzene-1,4-diol

210 mg of 2- [3- (3,5-dibenzyloxy-phenyl) -1-propenyl] -1,4-dibenzyloxy-3,5,6-trimethylbenzene obtained in Preparation Example 4 and palladium-carbon Reaction was carried out in the same manner as in Example 1 using 20 mg, and then purified by column chromatography (eluent: n-hexane / ethyl acetate = 1/1, v / v) to obtain 86 mg of the title compound (yield: 90% of theory). Obtained.

¹ H NMR (CDCl ₃ ): 6.24 (d, 2H), 6.18 (d, 2H), 2.54 (t, 2H), 2.47 (t, 2H), 1.99 (s, 3H), 1.96 (s, 3H), 1.69 (m, 2 H)

Example 4: Synthesis of 2- [3- (4-hydroxyphenyl) -propyl] -3,5,6-trimethylbenzene-1,4-diol

80 mg (0.147 mmol) of 2- [3- (4-benzyloxy-phenyl) -1-propenyl] -1,4-dibenzyloxy-3,5,6-trimethylbenzene obtained in Production Example 5 and palladium- The reaction was carried out in the same manner as in Example 3, except that 8 mg of carbon was used, to obtain 38 mg (yield: 91% of theory) of the title compound.

¹ H NMR (CDCl ₃ ): 7.04 (d, 2H), 6.75 (d, 2H), 2.61 (t, 3H), 2.48 (t, 3H), 2.00 (s, 6H), 1.94 (s, 3H), 1.68 (s, 3H)

Preparation Example 6 Synthesis of 6-benzyloxy-5- [2- (2,4-dibenzyloxyphenyl) -1-hydroxy-ethyl] -2,2,7,8-tetramethyl-chroman

700 mg (1.68 mmol) of 6-benzyloxy-5-bromo-2,2,7,8-tetramethyl-chroman, 1.2 ml (1.6 M) of n-butyllithium and 2,4-dibenzyloxyphenylacetaldehyde Except for using 560 mg (1.68 mmol) was carried out in the same manner as in Preparation Example 2 to give 799 mg (yield: 78% of theory) of the title compound.

Preparation Example 7 Synthesis of 6-benzyloxy-5- [2- (2,4-dibenzyloxy-phenyl) -vinyl] -2,2,7,8-tetramethyl-chroman

799 mg of 6-benzyloxy-5- [2- (2,4-dibenzyloxyphenyl) -1-hydroxy-ethyl] -2,2,7,8-tetramethyl-chroman obtained in Preparation Example 6 ( 1.31 mmol) and 40 mg (5%) of paratoluenesulfonic acid were reacted in the same manner as in Preparation Example 4 to obtain 630 mg (yield: 81% of theory) of the title compound.

Example 5: Synthesis of 4- [2- (6-hydroxy-2,2,7,8-tetramethyl-chroman-5-yl) -ethyl] -benzene-1,3-diol

310 mg (0.53 mmol) of 6-benzyloxy-5- [2- (2,4-dibenzyloxy-phenyl) -vinyl] -2,2,7,8-tetramethyl-chroman obtained in Preparation Example 7 and 30 mg of palladium-carbon was reacted in the same manner as in Example 1 to give 160 mg (yield: 88% of theory) of the title compound.

¹ H NMR (CDCl ₃ ): 7.01 (d, 1H), 6.51 (s, 1H), 6.46 (d, 1H), 2.60-2.85 (m, 4H), 2.18 (s, 3H), 2.12 (s, 3H ), 2.07 (s, 3H), 1.80 (t, 2H), 1.31 (s, 6H), 1.30 (t, 2H)

Preparation Example 8 Synthesis of 1- [2- (2,5-Dibenzyloxy-3,4,6-trimethylphenyl) -2-hydroxy-ethyl] -3,5-dibenzyloxybenzene

360 mg (0.878 mmol) of 2-bromo-1,4-dibenzyloxy-3,5,6-trimethylbenzene obtained in Preparation Example 1, 0.7 ml (1.6M) of n-butyllithium and 3,5-dibenzyl 401 mg (yield: 68% of theory) of the title compound were obtained in the same manner as in Preparation Example 2, except that 303 mg of oxyphenylacetaldehyde was used.

Example 6: Synthesis of 1- [2- (2,5-Dihydroxy-3,4,6-trimethylphenyl) -2-hydroxy-ethyl] -benzene-3,5-diol

100 mg (0.148 mmol) of 1- [2- (2,5-dibenzyloxy-3,4,6-trimethylphenyl) -2-hydroxy-ethyl] -3,5-dibenzyloxybenzene obtained in Preparation Example 8 ) And 41 mg (yield: 92% of theory) of the title compound were obtained in the same manner as in Example 1, except that 10 mg of palladium-carbon was used.

¹ H NMR (acetone-d ₆ ): 8.11 (s, 1H), 6.40 (d, 1H), 6.25 (d, 1H), 5.10 (m, 1H), 4.22 (d, 1H), 3.02 (d, 1H ), 2.90 (dd, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H)

Experimental Example 1: Determination of Tyrosinase Activity Inhibitory Effect

Tyrosinase inhibitory activity of the compound of formula 1 according to the present invention was measured by the following method.

The tyrosinase enzyme was extracted from mushrooms, and Sigma Corporation was used. First, the substrate L-tyrosine is dissolved in phosphate buffer solution (0.05M concentration, pH 6.8) to 1.5mM concentration, and then 0.01ml of this solution is added to a 0.3ml volume spectrophotometer cuvette and cofactor ( cofader) was added at a concentration of 0.06 mM to 0.01 ml. To this was added an inhibitor of formula (I), arbutin, kojic acid and hydroquinone, respectively, according to the invention, filled with phosphate buffer to make 0.31 ml. The reaction was advanced by adding 0.1 ml of the enzyme solution in which tyrosinase was dissolved in phosphate buffer at 60 U / ml. In this case, only 0.1 ml of phosphate buffer solution was added instead of tyrosinase. The reaction was carried out for 10 minutes at 37 ℃ using a spectrophotometer (Spectrophotometer, Beckmann DU-7500), the absorbance at 475nm was measured to obtain the tyrosinase inhibition rate according to the following equation (1). In addition, the concentration of the inhibitor reaching 50% enzyme activity inhibition was determined as an IC ₅₀ value, and the results are shown in Table 2 below.

In the above equation,

A represents the absorbance at 475 nm of that to which the inhibitor is added,

B shows absorbance at 475 nm of no inhibitor added.

Inhibitor IC ₅₀ (μg / ml) Compound of Example 1 0.2 Compound of Example 2 112 Compound of Example 3 0.1 Compound of Example 4 122 Compound of Example 5 0.6 Compound of Example 6 2.1 Arbutin 113 Kojisan 3.1 Hydroquinone 0.5

As can be seen from the results of Table 2, the compound of Formula 1 according to the present invention is excellent in the inhibitory effect of tyrosinase activity can exhibit an excellent skin whitening effect through melanin synthesis inhibition in the skin.

Claims (6)

Polyhydroxy-diphenylalkane derivatives of the general formula Formula 1 Where R ₁ represents hydrogen or C _1-10 alkyl, R ₂ represents C _1-5 alkyl, R ₃ represents hydrogen or C _1-10 alkyl, or R ₂ together with R ₃ may form C _2-3 alkylene unsubstituted or substituted by C _1-5 alkyl, R ₄ represents hydrogen or hydroxy, R ₅ and R ₆ each independently represent hydrogen or C _1-10 alkyl, n ₁ is an integer of 0 or 1, n ₂ is an integer of 1 or 2, wherein hydroxy is at the ortho, meta or para position, Provided that when n ₁ is 1 and n ₂ is 2, at least one hydroxy is present at the meta position. 2. 2- [1-hydroxy-3- (3,5-dihydroxyphenyl) propyl] -3,5,6-trimethyl-benzene-1,4-diol, 2- [3- (3,5-Dihydroxyphenyl) propyl] -3,5,6-trimethyl-benzene-1,4-diol, 4- [2- (6-hydroxy-2,2,7,8-tetramethyl -Chroman-5-yl) -ethyl] -benzene-1,3-diol or 1- [2- (2,5-dihydroxy-3,4,6-trimethylphenyl) -2-hydroxy-ethyl ] -Benzene-3,5-diol. A method of preparing a compound of Formula 1a, characterized in that the compound of Formula 3 is coupled with an aldehyde of Formula 4 to obtain a compound of Formula 5 and then deprotected: Formula 3 Formula 4 Formula 5 Formula 1a Where n ₁ , n ₂ , R ₂ , R ₅ and R ₆ are as defined in claim 1, Pro ₁ and Pro ₂ each represent a hydroxyprotecting group. The method of claim 3, wherein 1 equivalent of n-butyllithium is added to the compound of Formula 3 at -78 to -30 ° C in diethyl ether or tetrahydrofuran solvent, and then 1 equivalent of the aldehyde compound of Formula 4 is reacted. Process for preparing the compound of 5. Dehydrating a compound of formula 5 in the presence of an acid catalyst to prepare a compound of formula 6, and then performing a hydrogenation and deprotection reaction to the compound of formula 6 to prepare a compound of formula 1b: Formula 5 Formula 6 Formula 1b Where n ₁ , n ₂ , R ₂ , R ₅ and R ₆ are as defined in claim 1, Pro ₁ and Pro ₂ each represent a hydroxyprotecting group. 6. The compound of formula (6) according to claim 5, wherein the compound of formula (5) is dehydrated in the presence of at least one acid catalyst selected from phosphoric acid, sulfuric acid, paratoluenesulfonic acid, and benzenesulfonic acid in at least one nonpolar solvent selected from How to prepare.