KR100632794B1 - 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, preparation method thereof and whitening composition containing the same - Google Patents

Abstract

The present invention relates to a novel compound 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, and a method for preparing the same, more specifically 1,3-benzodioxol-5 represented by the following formula (1) -Ylmethyl methyl sulfone and its derivatives have a whitening effect of inhibiting melanogenesis by having an excellent tyrosinase inhibitory activity.

[Formula 1]

In the above formula, R is a C ₁ to C ₄ alkyl group.

The present invention also relates to a whitening composition containing 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient.

1,3-benzodioxol-5-ylmethyl methyl sulfone * Inhibits tyrosinase * Inhibits melanin production * Composition for whitening * Skin external preparation

Description

1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, preparation method about and whitening composition containing the same}

1 is a graph showing the cytotoxicity test results of the compounds prepared in the present invention.

Figure 2 is a graph showing the results of the melanin secretion experiments of the compounds prepared in the present invention.

3 is a graph showing the results of tyrosinase inhibition of the compounds prepared in the present invention.

The present invention relates to a novel compound 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, and a method for preparing the same, more specifically 1,3-benzodioxol-5 represented by the following formula (1) -Ylmethyl methyl sulfone and its derivatives have a whitening effect of inhibiting melanogenesis by having an excellent tyrosinase inhibitory activity.

[Formula 1]

In the above formula, R is a C ₁ to C ₄ alkyl group.

The present invention also relates to a whitening composition containing 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient.

Human skin produces melanin to eliminate naturally occurring free radicals, free radicals, and the like, or to block UV transmission. Looking at the melanin production process, the starting material for making melanin is tyrosine, a type of amino acid normally present in the human body. Tyrosine is oxidized by tyrosinase in melanocytes to 3,4-dihydroxyphenylalanine (hereinafter referred to as "DOPA"), and DOPA is further oxidized to DOPA It turns into quinone. DOPA quinones then undergo an auto-oxidation reaction through 5,6-dihydroxyindole to form indole-5,6-quinone, which finally produces a dark brown melanin [Goldsmith, LA] , Physiology, Biochemistry, and Molecular Biology of the Skin, Oxford University Press (1991).

Methods for preventing excessive deposition of melanin in the skin may include methods for blocking each step of the melanin biosynthetic pathway, for example, (i) preventing skin exposure to ultraviolet rays, (ii) tyrosinase inhibitors. And (i) administration of a substance that is specifically toxic to melanocytes, and (iii) a method of promoting the discharge of the melanin produced to the outside of the skin.

The substances to prevent hyper pigmentation on the skin are classified by the mechanism of action. There are UV absorbers and inorganic pigments such as UV absorbers to block the UV rays irradiated to the skin, and vitamin C or kojic acid. Substances that are toxic to melanocytes such as tyrosinase inhibitors, hydroquinone, etc. -hydroxyl acid). Among them, arbutin, which binds sugar to hydroquinone, which is known to be toxic to melanocytes, is well known as a tyrosinase inhibitor along with kojic acid and is a form of functional cosmetics for the purpose of inhibiting skin whitening and aging. It is used a lot in. In addition, retinol and ascorbic acid, which are known to inhibit skin aging, are also attracting much attention both at home and abroad, and many products are commercially available. The mechanism of action is not yet known, but studies have shown that the inhibitory action of tyrosinase enzymes is associated with whitening and even anti-aging effects [Curto, EV et al ., Biochemical Pharmacology , 57 , 663]. -672 (1999); Cabanes, J. et al ., J. Pharm. Pharmacol ., 46 , 982-985 (1994)].

As such, tyrosinase inhibitors have been developed and used as various whitening agents, but various problems have been raised at the same time. Indeed, 4-hydroxyanisol and hydroquinone, which are used locally for the treatment of hyperpigmentation such as blemishes, freckles, spots and hyperpigmentation in pregnancy, have potent melanogenesis inhibitory activities, but at the same time cause denaturation or lethality of pigment cells and There was a problem of showing side effects such as impairing the original function. In particular, the hydroquinone-based compound has been developed and used as a whitening cream that inhibits melanin biosynthesis, but is known to cause skin irritation or skin disease due to cytotoxicity, and is currently used only in some countries.

The present inventors studied a substance that can effectively suppress tyrosinase and reduce side effects. As a result, the inventors have developed a novel substance that inhibits tyrosinase, and confirmed that the substance can inhibit melanin production. .

An object of the present invention is to provide a novel substance having excellent tyrosinase inhibitory effect, 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, and a preparation method thereof.

It is also an object of the present invention to provide a whitening composition containing the 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives as an active ingredient.

In order to achieve the above object, the present invention provides 1,3-benzodioxol-5-ylmethyl methyl sulfone and derivatives thereof represented by the following Chemical Formula 1.

In the above formula, R is a C ₁ to C ₄ alkyl group.

Preferred examples of the compound of Formula 1 include the following compounds:

1,3-benzodioxol-5-ylmethyl methyl sulfone of Formula 1a;

1,3-benzodioxol-5-ylmethyl ethyl sulfone of formula (Ib);

1,3-benzodioxol-5-ylmethyl propyl sulfone of formula (1c);

1,3-benzodioxol-5-ylmethyl isopropyl sulfone of formula (Id);

1,3-benzodioxol-5-ylmethyl butyl sulfone of formula (1e);

The present invention also relates to a method for preparing 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives.

The preparation method of 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives according to the present invention comprises the following steps, which is shown in Scheme 1 below:

1) reacting 1,3-benzodioxol-5-ylmethanol of formula 2 in the presence of thionyl chloride to prepare 5- (chloromethyl) -1,3-benzodioxol of formula 3 step; And

2) Methyl and [1,3-bis (diphenylphosphino) proran] dichloronickel (5- (chloromethyl) -1,3-benzodioxol of Chemical Formula 3 and alkylsulfonyl chloride of Chemical Formula 4) II) reacting in the presence of 1 to prepare 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives;

Wherein R is alkyl.

The step 2) is carried out in an organic solvent such as diethyl ether, tetrahydrofuran or a mixed solvent thereof, and the reaction is carried out at 0 to 50 ° C. for 1 hour.

In addition, 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives of the present invention have excellent tyrosinase inhibitory activity and thus can be used as a whitening agent by inhibiting melanin production.

Accordingly, the present invention provides a composition for whitening containing 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives of Formula 1 as an active ingredient.

The composition of the present invention is formulated as an external skin preparation or oral dosage form, such as a dry powder which is in the form of a solution, a suspension or an emulsion in an oil or an aqueous medium, or dissolved in sterile, water-free water before use. It may be formulated as a parenteral formulation such as subcutaneous injection, intravenous injection or intramuscular injection.

In the case of an external preparation for skin, the external preparation composition of the present invention may be formulated in a conventional formulation applicable to the skin, for example, softening longevity, astringent longevity, nourishing longevity, nutrition cream, massage cream, essence, eye cream Liquid soap, as well as cosmetics such as eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil, body essence, makeup base, foundation, body cleanser, toothpaste or mouthwash It may be formulated with a solid soap, a human cleanser such as a cleansing foam, or the like. Each of these formulations may contain various bases and additives necessary and appropriate for the formulation of the formulations, and the types and amounts of these components can be readily selected by those skilled in the art.

In the case of oral dosage forms, for example, tablets, troches, sugar-containing tablets, aqueous or oily suspensions, dispersible powders, etc., in a known manner using a pharmaceutically acceptable carrier or forming agent. Or in the form of oral dosage forms in the form of particles, emulsions, soft or hard capsules, syrups, elixirs, which may be suitably prepared according to unit dosages, forms and the like.

Parenteral formulations may be injected as a sterile injectable solution or as a suspension in which the active ingredient is suspended in a solvent such as a non-toxic usable diluent or 1,3-butanediol. Excipients or solvents that may be used include water, Ringer's solution, and isotonic saline solution. Cosolvents such as ethanol, polyethylene glycol, and polypropylene glycol may be used. In addition, sterile, nonvolatile oils can be customarily used as solvents or suspending solvents. The suppository form is formulated by mixing the drug with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, which is solid at room temperature but becomes liquid at the rectal temperature and will melt in the rectum to release the drug, followed by rectal To be administered.

When treating a disease using the composition of the present invention, the dose of the compound of formula 1 as an active ingredient is determined by the age, weight, general state of health, sex, meal, time of administration, rate of excretion, combination of drugs, during treatment. Depending on the severity of the disease, depending on the disease can be used every day up to 0.01 ~ 140mg / kg body weight, 0.5mg ~ 7g can be used per day per patient.

On the other hand, the amount of the compound of the present invention mixed with the carrier material to determine one formulation depends on the mode of administration and the patient being treated. For example, formulations intended for application to oral dermal application to humans will contain from 5 to 95% by weight of carrier materials and 0.5 mg to 5 g of active ingredient in the total composition, and parenteral administration to humans will be possible. The desired formulation will contain from 5 to 99% of the carrier material and from 0.1 mg to 2.5 g of active ingredient.

Hereinafter, the present invention will be described in detail by examples. However, the examples are only to illustrate the invention and the present invention is not limited by the following examples.

Example 1 Synthesis of 1,3-benzodioxol-5-ylmethyl methyl sulfone

(Step 1) Preparation of 5- (chloromethyl) -1,3-benzodioxole

20 g of 1,3-benzodioxol-5-ylmethanol was dissolved in 50 ml of thionyl chloride at 0 ° C., stirred for 30 minutes, and then reacted at 30 ° C. for 2 hours. The reaction mixture was dried under reduced pressure, and then subjected to column chromatography using ethyl acetate: n-nucleic acid (1: 3) as the eluent to obtain 19 g of the title compound of formula (3) (Rf: 0.55, yield: 86%).

[Formula 3]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 4.53 (s, 2H), 5.98 (s, 2H), 6.75-6.88 (m, 3H).

(Step 2) Preparation of 1,3-benzodioxol-5-ylmethyl methyl sulfone

9.7 g of 5- (chloromethyl) -1,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether, and then added to magnesium at 0 ° C. for 10 minutes, followed by heating to 50 ° C. for 1 hour. Reaction. After cooling to 0 ° C., the mixture was slowly added to the flask containing [1,3-bis (diphenylphosphino) proran] dichloronickel (II) catalyst. 5 g of methane sulfonyl chloride was added thereto, followed by reaction for 30 minutes, followed by heating to 50 ° C. for 1 hour. To the reaction mixture was added aqueous hydrochloric acid solution to adjust pH 7. The mixture was extracted with diethyl ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and the column was chromatographed using ethyl acetate: n-nucleic acid (1: 3) as eluent. To give 0.75g of the title compound of the general formula 1a (Rf: 0.35, yield: 5%).

[Formula 1a]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 2.75 (s, 3H), 4.14 (s, 2H), 5.97 (s, 2H), 6.81-6.88 (m, 3H).

Example 2 Preparation of 1,3-benzodioxol-5-ylmethyl ethyl sulfone

8.6 g of 5- (chloromethyl) -1,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether, and then added to magnesium at 0 ° C. for 10 minutes, followed by heating to 50 ° C. for 1 hour. Reaction. After cooling to 0 ° C., the mixture was slowly added to the flask containing [1,3-bis (diphenylphosphino) proran] dichloronickel (II) catalyst. Then, 3.7 ml of ethane sulfonyl chloride was added thereto to react for 30 minutes, and then heated to 50 ° C. for 1 hour. After adding the aqueous hydrochloric acid solution to the reaction mixture to adjust the pH to 7, extracted with diethyl ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and then purified by column chromatography using ethyl acetate: n-nucleic acid (1: 3) as eluent. To give 0.3g of the title compound of the general formula 1b (Rf: 0.35, yield: 3%).

[Formula 1b]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 1.57-1.64 (t, 3H, J = 7.3 Hz), 2.78 (s, 2H), 3.60-3.78 (q, 2H, J = 7.3 Hz), 5.90 (s, 2H), 6.56-6.79 (m, 3 H).

Example 3 Preparation of 1,3-benzodioxol-5-ylmethyl propyl sulfone

5.0 g of 5- (chloromethyl) -1,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether, and then added to magnesium at 0 ° C. for 10 minutes, followed by heating to 50 ° C. for 1 hour. Reaction. After cooling to 0 ° C., the mixture was slowly added to the flask containing [1,3-bis (diphenylphosphino) proran] dichloronickel (II) catalyst. Then, 2.8 ml of propane sulfonyl chloride was added and reacted for 30 minutes, and then heated to 50 ° C for 1 hour. After adding the aqueous hydrochloric acid solution to the reaction mixture to adjust the pH to 7, extracted with diethyl ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and then purified by column chromatography using ethyl acetate: n-nucleic acid (1: 3) as eluent. To give 0.8g of the title compound of the general formula 1c (Rf: 0.35, yield: 7%).

[Formula 1c]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 1.16-1.19 (t, 3H, J = 7.0 Hz), 2.10-2.15 (q, 2H, 7.4 Hz), 2.81 (s, 2H), 3.66-3.69 (t, 2H, J = 7.8 Hz ), 5.94 (s, 2H), 6.61-6.63 (d of d, 1H), 6.68 (s, 1H), 7.28 (d, 1H, J = 0.8).

Example 4 Preparation of 1,3-benzodioxol-5-ylmethyl isopropyl sulfone

7.8 g of 5- (chloromethyl) -1,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether, and then added to magnesium at 0 ° C. for 10 minutes, followed by heating to 50 ° C. for 1 hour. Reaction. After cooling to 0 ° C., the mixture was slowly added to the flask containing [1,3-bis (diphenylphosphino) proran] dichloronickel (II) catalyst. Then, 3.9 ml of isopropane sulfonyl chloride was added and reacted for 30 minutes, and then heated to 50 ° C for 1 hour. After adding the aqueous hydrochloric acid solution to the reaction mixture to adjust the pH to 7, extracted with diethyl ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and then purified by column chromatography using ethyl acetate: n-nucleic acid (1: 3) as eluent. To give 0.6g of the title compound of the general formula 1d (Rf: 0.35, yield: 5%).

[Formula 1d]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 1.60-1.62 (d, 6H, J = 6.7 Hz), 2.79 (s, 2H), 3.75-3.78 (m, 1H), 5.91 (s, 2H), 6.66 (m, 3H)

Example 5 Preparation of 1,3-benzodioxol-5-ylmethyl butyl sulfone

7.1 g of 5- (chloromethyl) -1,3-benzodioxol was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of diethyl ether, and then added to magnesium at 0 ° C. for 10 minutes, and then heated to 50 ° C. for 1 hour. Reaction. After cooling to 0 ° C., the mixture was slowly added to the flask containing [1,3-bis (diphenylphosphino) proran] dichloronickel (II) catalyst. Then, 4.1 ml of butane sulfonyl chloride was added thereto to react for 30 minutes, and then heated to 50 ° C. for 1 hour. After adding the aqueous hydrochloric acid solution to the reaction mixture to adjust the pH to 7, extracted with diethyl ether and water, dried over anhydrous magnesium sulfate, the solvent was removed, and then purified by column chromatography using ethyl acetate: n-nucleic acid (1: 3) as eluent. To give 0.2g of the title compound of the general formula 1e (Rf: 0.35, yield: 2%).

[Formula 1e]

Dissolved in CDCl ₃ and TMS and measured by 1 H NMR were as follows;

¹ H NMR δ: 1.16-1.18 (t, 3H, J = 7.0 Hz), 2.09-2.19 (m, 4H), 2.81 (s, 2H), 3.69-3.73 (t, 2H), 5.94 (s, 2H) , 6.50-6.68 (m, 3H),

Test Example 1 Cytotoxicity Test

In order to examine the cytotoxicity of the compounds prepared in Examples 1 to 5, 3- (4,5-dimethyl thiazol-2-yl) -2,5-diphenyl tetrazolium bromide (3- (4,5- dimethyl thiazole-2-yl) -2,5-diphenyl tetrazolium bromide, hereinafter abbreviated as "MTT") test was conducted by Mosmann [Mosmann, T .: J. Immunol. Methods 65, 55-63, (1983)] was tested for toxicity to melanocytes according to the method. The cytotoxic effects of the drugs were examined by MTT assay. The method is based on the ability of live cells to break down tetrazolium salts, preventing MTT's intracellular accumulation. MTT stock solution (5 mg / ml) was dissolved in phosphate buffer saline (abbreviated as "PBS") and filtered through a 0.22 μm filter to remove formazan crystals and stored in a dark room at room temperature. . For the experiment, B16 melanoma cells were transferred to 96-well microplates at a concentration of 10,000 cells / well, followed by compound, arbutin, vitamin C and hydroquinone (Sigma products) prepared in Examples 1-5. ) Was treated at a concentration of 10 ug / ml each. After incubation for a period of time, 10-fold diluted MTT was added to each well, and after 4 hours, the plate was centrifuged at 3,000 rpm for 1 minute, and then 100 µl of the supernatant was removed. To remove formazan crystals, DMSO was added and shaken until the DMSO was completely dissolved in a microplate shaker, followed by a microplate ELISA reader (El 312e, Bio-Tek). Absorbance was measured at a wavelength of 560 nm. Cell viability in each drug treatment group was measured by% control compared to the control group drug-free treatment, the results are shown in FIG.

According to FIG. 1, arbutin and vitamin C, which are known to have a whitening effect, showed almost 100% cell viability up to a concentration of 10 ug / ml, but hydroquinone, as known, was highly cytotoxic. In contrast, the compounds prepared in Examples 1 to 5 showed very high cell viability. All the compounds prepared in Examples 1 to 5 showed a cell survival rate close to 100%, which suggests that the compounds of Examples 1 to 5 were very safe substances in skin cells.

[Test Example 2] melanin secretion inhibitory effect test using B16 melanoma cell line

In order to examine the whitening effect of the compounds according to the present invention, the method of Warter Siegrist (Warter Siegrist et al., Analytical Biochemistry 159, 191-197, 1986) was modified and tested using whitened B16 mouse melanoma cells. It was. B16 cells were 10% heat inactivated fetal bovine serum (abbreviated as "FBS"), 100 mg / ml streptomycin and 100 U / ml penicillin, Dulbecco's modified Eagle's medium; invitrogenin) medium. B16 cells cultured for the experiment were treated with trypsin, detached, and dispensed into 96-well microplates at a concentration of 1 × 10 ⁴ cells / ml. After one day, the cell culture was replaced with a modified dulcogel medium without phenol red containing 2 μM α-melanocyte stimulating hormone and 2 mM theophylline. Compounds prepared in 5, arbutin, vitamin C and hydroquinone were added at various concentration final concentrations of 10 ug / ml and incubated for 7 days. The whitening effect of the added active ingredients was determined by the amount of melanin pigment secreted by B16 cells. After 7 days of drug treatment, the cell culture medium of each well was collected, the cells were removed by centrifugation, and enzyme-linked immunosorbent assay reader at 405 nm. The absorbance was measured to measure the amount of melanin secreted, and the results are shown in FIG. 2. The inhibitory effect of each substance was calculated using the following formula:

As a result, arbutin, vitamin C and hydroquinone showed a tendency to inhibit melanin secretion from B16 melanoma cell line in a whitening effect.

In addition, the compounds prepared in Examples 1 to 5 showed similar or potent secretion inhibitory effect with arbutin.

Taken together with the cytotoxicity results of the MTT assay of Test Example 1, the compounds of Examples 1 to 5 according to the present invention are not more cytotoxic in the concentration range of 0.1 to 10 ug / ml, the release of melanin more than 80% It was found that suppression.

[Test Example 3] Tyrosinase inhibitory effect measurement

The most commonly used furnaces (Life Science, 65, 21, pl 241-246, 1999) to determine the effect of the compounds prepared in Examples 1 to 5 inhibit the tyrosinase play a most important role in melanin synthesis The method was modified and tested. Mushroom tyrosinase inhibitory effect was investigated using commercial mushroom tyrosinase (Sigma). Compounds, arbutin, vitamin C and hydroquinone prepared in Examples 1 to 5 to be irradiated on 96-well microplates were diluted to a final concentration of 10 ug / ml, and 20 µl each was added thereto. As a substrate, L-tyrosine was added so as to have a final concentration of 1 × 10 ⁻³ M, and then 50 μl of tyrosinase solution 100 units / ml was added thereto. Phosphate buffer solution (pH 7.4) was used as the buffer solution. After the plate was reacted for 1 hour at 37 ° C. incubator, the absorbance was measured at 490 nm using an enzyme-linked immunosorbent test reader, and the degree of blackening was compared. The results are shown in FIG. 3.

In general, arbutin and hydroquinone are known to exhibit whitening activity by inhibiting the activity of tyrosinase during various stages of melanin synthesis. As a result of the experiment, both substances showed more than 60% of inhibitory activity, indicating that they were tyrosinase inhibitors.

As can be seen from the results, it was found that the compounds prepared in Examples 1 to 5 exhibited higher tyrosinase activity than arbutin, thereby showing a whitening effect through strong tyrosinase activity inhibition.

Although the present invention has been described through the preferred embodiments so far, those skilled in the art can make various modifications without departing from the spirit and scope disclosed in the present invention. Such modifications are also included within the scope of the present invention.

As described above, the novel compounds according to the present invention exhibited excellent tyrosinase inhibitory activity, effectively inhibited melanin production, and have no whitening effect because they are not harmful to the human body because of no cytotoxicity, and thus can be used as an active ingredient of a whitening composition. Can be.

Claims (5)

1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives represented by the following general formula (1): [Formula 1]

In the above formula, R is a C ₁ to C ₄ alkyl group. According to claim 1, wherein the compound of Formula 1 1,3-benzodioxol-5-ylmethyl methyl sulfone; 1,3-benzodioxol-5-ylmethyl ethyl sulfone; 1,3-benzodioxol-5-ylmethyl propyl sulfone; 1,3-benzodioxol-5-ylmethyl isopropyl sulfone; And 1,3-benzodioxol-5-ylmethyl methyl sulfone and its derivatives, characterized in that it is selected from the group consisting of 1,3-benzodioxol-5-ylmethyl butyl sulfone. Method for preparing 1,3-benzodioxol-5-ylmethyl methyl sulfone comprising the following steps: 1) reacting 1,3-benzodioxol-5-ylmethanol of formula 2 in the presence of thionyl chloride to prepare 5- (chloromethyl) -1,3-benzodioxol of formula 3 step; And [Formula 2]

[Formula 3]

2) Methyl and [1,3-bis (diphenylphosphino) prolan] dichloronickel (5- (chloromethyl) -1,3-benzodioxol of Chemical Formula 3 and methylsulfonyl chloride of Chemical Formula 4) II) reacting in the presence of 1 to prepare 1,3-benzodioxol-5-ylmethyl methyl sulfone of formula 1; [Formula 4]

Wherein R is CH ₃ The method of claim 3, wherein The method of claim 2, wherein the reaction of step 2 is carried out in an organic solvent such as diethyl ether, tetrahydrofuran or a mixed solvent thereof. A composition for whitening agent comprising the 1,3-benzodioxol-5-ylmethyl methyl sulfone and derivatives thereof according to claim 1 as an active ingredient.

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