JP5893442B2 - Tyrosinase activity inhibitor - Google Patents

Description

  The present invention relates to a resorcinol derivative and a tyrosinase activity inhibitor.

  Polyphenol oxidase (including tyrosinase), which is an oxidoreductase, has an action of promoting the chemical reaction of phenols contained in the cell constituent tissues of animals and plants. These polyphenol oxidases cause browning (sunburn) in human skin, reduce the commercial value of foods such as fruits and seafood by browning, and are useful in polyphenols with beneficial antioxidant activity. It is known as an oxidoreductase that breaks down.

  In particular, tyrosinase (polyphenol oxidase) is deeply involved in the initial stage of the pigment formation reaction in animals and plants. Tyrosinase is an oxidoreductase containing a copper atom as an active center and catalyzes the initial reaction of various browning phenomena observed in nature. For example, when the skin is exposed to ultraviolet rays, the action of tyrosinase, which controls the first stage of melanin biosynthesis, is activated in the melanocytes of the skin, and as a result, excessive accumulation of melanin causes skin browning such as spots and freckles. cause. In order to effectively suppress this melanin biosynthesis, research has been conducted on compounds capable of inhibiting or suppressing the action of tyrosinase (hereinafter also referred to as “tyrosinase activity inhibitors”).

  The tyrosinase activity inhibitor is expected to be widely applied as an additive to functional cosmetics, as a browning inhibitor for fruits and vegetables, and as a pharmaceutical product. Tyrosinase activity inhibitors that have been developed to date are broadly divided into two types: substrate analogs and copper chelators, based on structure and enzymatic chemistry. In particular, it is known that a substrate analog having a resorcinol skeleton has strong activity performance (also referred to as “tyrosinase inhibitory activity”) that inhibits the action of tyrosinase. Examples of the substrate analog having a resorcinol skeleton include kojic acid, arbutin, 4-substituted alkylresorcinol (for example, 4-butylresorcinol) and the like.

  Of these, kojic acid has long been added to cosmetics and foods to prevent sunburn and browning, but its toxicity was suggested and its use in quasi-drugs (medicinal cosmetics) was temporarily banned in 2003. . Arbutin is a natural phenol glycoside contained in plants such as cowberry and pear, but its tyrosinase inhibitory activity is very weak. However, arbutin is used as a cosmetic ingredient having a whitening effect because of its water solubility and low toxicity. It is known that 4-butylresorcinol, which is a fat-soluble 4-substituted alkylresorcinol, has a resorcinol skeleton and thus exhibits a strong inhibitory activity.

  In addition, this inventor has already proposed the activity inhibitor of tyrosinase containing a bibenzyl derivative (refer patent document 1, nonpatent literature 1, 2).

JP 2008-56651 A

K. Nihei, et.al., "Molecular design of potent tyrosinase inhibitors having the bibenzyl skeleton", Bioorg. Med. Chem. Lett., 18, 5252-5254 (2008). K. Nihei, et.al., "Synthesis and evaluation of bibenzyl glycosides as potent tyrosinase inhibitors", Eur.J.Med.Chem., 46, 1374-1381 (2011).

  An object of the present invention is to provide a novel resorcinol derivative and to provide a tyrosinase activity inhibitor comprising the resorcinol derivative.

  The present inventors have conducted research and development on a novel resorcinol derivative having tyrosinase inhibitory activity. In the synthesis of alkylresorcinol having strong tyrosinase inhibitory activity, it was necessary to perform C-alkylation. However, direct C-alkylation is difficult, and as an alternative method, for example, a method of reducing after alkenylation by Wittig reaction, The synthesis was performed using a multistage reaction such as a method of dehydration and reduction after the Grignard reaction. The inventor has further investigated and attempted to apply O-alkylation to the synthesis of alkylresorcinol. It was found that this O-alkylation can be achieved in a single step with a high yield by the Williamson ether synthesis method using an alkyl halide and a base, as compared with a multi-step reaction. Then, when this inventor synthesize | combined paying attention to the O-alkyl body (analog resorcinol analog) which can be synthesize | combined more simply than C-alkyl body, the new resorcinol derivative was synthesize | combined. And since the new resorcinol derivative had tyrosinase inhibitory activity, it discovered that it was useful as a new tyrosinase activity inhibitor. The inventor further studied the side chain of the resorcinol derivative exhibiting tyrosinase inhibitory activity, and completed the present invention.

  The resorcinol derivative according to the present invention for solving the above problems is a resorcinol derivative represented by formula 1 (in formula 1, R is a methyl group, a branched alkyl group having 3 to 10 carbon atoms, a phenyl group) A cyclic compound, an oxygen-containing heterocyclic compound, or a residue of any of monosaccharides or oligosaccharides or a methylated product thereof, n is 0 to 15.).

  According to the present invention, a novel resorcinol derivative exhibiting tyrosinase inhibitory activity is provided. In particular, when R is a methyl group, n showed a strong tyrosinase inhibitory activity in the range of 7-10.

  The tyrosinase activity inhibitor according to the present invention for solving the above problems comprises a resorcinol derivative represented by formula 1 (in formula 1, R is a methyl group, a branched alkyl group having 3 to 10 carbon atoms, A phenyl group, a cyclocyclic compound, an oxygen-containing heterocyclic compound, or a residue of either monosaccharide or oligosaccharide or a methylated product thereof, n is 0 to 15.).

  According to this invention, since a novel resorcinol derivative exhibiting tyrosinase inhibitory activity is used as a tyrosinase activity inhibitor, it can be preferably used for cosmetic applications such as whitening agents. When R is a methyl group, n showed a strong tyrosinase inhibitory activity in the range of 7-10. In addition, when R is a residue of either monosaccharide or oligosaccharide or a glycoside thereof, tyrosinase inhibitory activity is not so strong, but it is water-soluble and has low toxicity. It can be preferably used for food applications.

  According to the present invention, a novel resorcinol derivative can be provided.

  Moreover, according to this invention, the tyrosinase activity inhibitor using the novel resorcinol derivative which shows tyrosinase inhibitory activity can be provided. The tyrosinase activity inhibitor thus obtained is used as an additive having a function of preventing browning for the purpose of maintaining the freshness of cosmetics having a skin browning prevention function (ie, skin whitening cosmetics) and vegetable-cut foodstuffs such as vegetables. Applications can be expected. In addition, since it can be produced efficiently and with high yield, it can be expected to be supplied on a gram scale.

  Hereinafter, the resorcinol derivative and tyrosinase activity inhibitor according to the present invention will be described in detail. The technical scope of the present invention is not limited to the items described below and the items described in the examples.

[Resorcinol derivative]
The resorcinol derivative according to the present invention is a resorcinol derivative represented by Formula 1.

  In Formula 1, R is a methyl group, a branched alkyl group having 3 to 10 carbon atoms, a phenyl group, a cyclo ring compound, an oxygen-containing heterocyclic compound, or any residue of a monosaccharide or an oligosaccharide, or Those methylated products are preferred. n is preferably 0-15.

When R is a methyl group, 4-alkoxyresorcinol having an alkoxy group composed of —O (CH ₂ ) _n CH ₃ in the side chain is obtained. In the alkoxy group of 4-alkoxyresorcinol, for example, when n is 0, it becomes a methoxy group, and when n is 1, it becomes an ethoxy group. This 4-alkoxyresorcinol exhibits tyrosinase inhibitory activity when n is in the range of 0-15, but 4-alkoxyresorcinol where n is in the range of 7-10 is the same as kojic acid, as will be described in Examples below. It exhibits a strong tyrosinase inhibitory activity.

  In addition, the following compounds 2-7 are examples of 4-alkoxy resorcinol which has an alkoxy group in a side chain. Compound 2 is 4-propoxyresorcinol with n = 2, Compound 3 is 4-pentyloxyresorcinol with n = 4, Compound 4 is 4-heptyloxyresorcinol with n = 6, Compound 5 has n = 8 4-nonyloxyresorcinol, compound 6 is 4-undecyloxyresorcinol with n = 10, and compound 7 is 4-tridecyloxyresorcinol with n = 12.

  When R is a branched alkyl group having 3 to 10 carbon atoms, the alkyl group may be isopropyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, 2-methylbutyl. Group, 2-ethylbutyl group, 2-methylpentyl group, 2-methylhexyl group, 2-ethylhexyl group, 2-methylheptyl group and the like. When R is a branched alkyl group having 3 to 10 carbon atoms, n is preferably in the range of 0 to 15. The following compound 8 is 4-((2-ethylhexyl) oxy) resorcinol in which a 2-ethylhexyl group having 8 carbon atoms is provided in R and n is 0.

  When R is a phenyl group, n is also preferably in the range of 0-15. The phenyl group may have a substituent. The following compound 9 is 4-phenoxyresorcinol in which a phenyl group is provided in R and n is 2.

  When R is a cyclocyclic compound, examples of the cyclocyclic compound include a five-membered ring or a derivative thereof, a six-membered ring or a derivative thereof, a seven-membered ring or a derivative thereof, and the like. In this case, n is preferably in the range of 0-15. The following formula is an example in which R is provided with a cyclo ring compound. The first line is an example where R is a five-membered ring, the second line is an example where R is a six-membered ring, and the third line is an example where R is a five-membered ring and a seven-membered ring. The first column is when n is 0, the second column is when n is 1, and the third column is when n is 2. Hereinafter, the compound described in the second column and the second column is also referred to as “compound 10”. Compound 10 is 4-cyclohexylmethoxyresorcinol in which R is a 6-membered ring and n is 1.

  When R is an oxygen-containing heterocyclic compound, examples of the oxygen-containing heterocyclic compound include five-membered, six-membered or seven-membered oxygen-containing heterocyclic compounds and derivatives thereof. In this case, n is preferably in the range of 0-15. The following compound 15 is 4- (2- (1,3-dioxan-2-yl) ethoxy) resorcinol in which n is 2 and the oxygen-containing heterocyclic compound is dioxane.

  When R is any residue of monosaccharide or oligosaccharide or methylated product thereof, the monosaccharide may be any of 3-7 heptosaccharides, preferably pentose saccharide or hexose saccharide. is there. Specific examples of the pentose saccharide include ribose, xylose, arabinose, and the like. Specific examples of the hexose saccharide include glucose, mannose, galactose, fructose, and the like. In particular, pentose saccharide xylose (Xyl) and hexose saccharide glucose (Glc) are preferable. The oligosaccharide is preferably a di-hexasaccharide, and particularly preferably a disaccharide. Specific examples of the disaccharide include sucrose, maltose, lactose, cellobiose, trehalose and the like, and cellobiose (Cel) or maltose (Mal) is particularly preferable. In addition, examples of the trisaccharide include raffinose, panose, melezitose, and gentianose, and examples of the tetrasaccharide include stachyose. Other glycosyl groups also include deoxy sugars such as deoxyribose, fucose, and rhamnose, uronic acids such as glucuronic acid, and amino sugars such as glucosamine. Moreover, any isomers such as D-form, L-form or a mixture thereof can be used as these saccharides. In these cases, n is preferably in the range of 0-15. The following formula is an example when n is 1 to 3.

  Examples of more specific compounds 21 to 24 are shown below.

  Since the resorcinol derivative comprised as mentioned above shows tyrosinase inhibitory activity, it can be preferably used as a tyrosinase activity inhibitor. When the resorcinol derivative according to the present invention is used as an activity inhibitor of tyrosinase, it may be used alone as it is, but it is usually desirable to use it according to various applications. Specifically, the resorcinol derivative obtained and various components generally used in pharmaceuticals, cosmetics, etc. (for example, aqueous components, oily components, powder components, surfactants, moisturizers, thickeners, colorants, fragrances, 1 type (s) or 2 or more types of pH adjuster, antioxidant, antiseptic | preservative, or ultraviolet-ray protective agent etc.) can be mix | blended in the range which does not impair the effect of this invention.

  For example, the resorcinol derivative according to the present invention or a tyrosinase activity inhibitor containing the resorcinol derivative is mixed with water or a paste agent to prevent skin browning for application, ie, skin whitening cosmetics (skin with high whitening effect) It can be used as an external preparation or a whitening skin external preparation). Moreover, it can mix with water and can also be used as a browning prevention functional additive of a plant cut foodstuff. Moreover, if it is used as a spraying agent, it can be used as a spraying agent for maintaining the freshness of vegetables. Moreover, it can also be used as an insect puppeting inhibitor and a harmless insecticide for humans.

  In particular, the resorcinol derivative according to the present invention or the tyrosinase activity inhibitor containing the resorcinol derivative is useful as a whitening agent because it suppresses the production of melanin, and is suitably blended into a skin external preparation. When used as a skin external preparation, other components usually used in skin external preparations such as cosmetics and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, higher fatty acids, higher alcohols, lower alcohols, polyhydric alcohols, esters, Silicone, various surfactants, moisturizers, water-soluble polymer compounds, thickeners, UV absorbers, sequestering agents, sugars, amino acids, organic amines, pH adjusters, skin nutrients, vitamins, oxidation An inhibitor, an antioxidant assistant, a fragrance, water, and the like can be appropriately blended as necessary. Furthermore, other whitening agents such as vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, arbutin, and kojic acid can be appropriately blended.

  As mentioned above, according to this invention, the novel resorcinol derivative which shows tyrosinase inhibitory activity can be provided. In addition, the tyrosinase activity inhibitor according to the present invention has a browning prevention function for the purpose of maintaining the freshness of cosmetics having a skin browning prevention function (ie, skin whitening cosmetics) and vegetable-cut foodstuffs such as vegetables. Use as an additive can be expected. In addition, since it can be produced efficiently and with high yield, it can be expected to be supplied on a gram scale.

[Production method]
The resorcinol derivative according to the present invention can be produced by the following steps. First, (A) a method for producing a resorcinol derivative having an alkyl group such as a methyl group or a cyclic compound in the side chain will be described, and then (B) either a monosaccharide or oligosaccharide residue or a methylated product thereof. A method for producing a resorcinol derivative having in the side chain will be described.

  (A) The method for producing a resorcinol derivative having an alkyl group such as a methyl group or a cyclo ring compound in the side chain comprises the following synthetic route, and is obtained using 2,4-dihydroxybenzaldehyde (10) as a starting material. A step of benzylating the hydroxyl group of a benzaldehyde derivative to obtain an ether (11); a step of Dakin oxidation of the aldehyde group of the ether (11) followed by hydrolysis to obtain a phenol body (12); and a phenol body (12 ) To obtain an O-alkyl compound (13) by a Willamson ether synthesis reaction using an alkyl halide and a base, and hydrolyzing the O-alkyl compound (13) to obtain 4 represented by the above-mentioned formula 1. -Obtaining alkoxyresorcinol (2-7).

  According to this production method, the O-alkyl compound (13) can be obtained in a single step with a good yield by a Willamson ether synthesis reaction using an alkyl halide and a base. As a result, 4-alkoxyresorcinol is much more efficient and has a higher yield compared to the case of using a multi-step reaction such as the conventional reduction method after alkenylation by Wittig reaction or the dehydration / reduction method after Grignard reaction. (2-7) can be obtained.

  In the step of obtaining ether (11), the mixture is stirred using benzyl bromide, a base and a solvent, and in some cases, heated to about 60 ° C. Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium fluoride and sodium hydride. Examples of the solvent include dimethylformamide, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide and the like.

  In the step of obtaining the phenolic body (12), Dakin oxidation is performed by stirring and heating to about 60 ° C. using an oxidizing agent, and hydrolysis is performed under basic conditions in order to remove the formyl group. Examples of the oxidizing agent include m-chloroperbenzoic acid, hydrogen peroxide, perbenzoic acid, and peracetic acid. As a solvent for this reaction, water, dioxane, chloroform, carbon tetrachloride and the like are used in addition to dichloromethane. Examples of the base used for the hydrolysis include sodium hydroxide, potassium hydroxide and lithium hydroxide.

  In the Wilsonson ether synthesis reaction in the step of obtaining the O-alkyl compound (13), it is important to use an alkyl halide, a base and a solvent, stir, and possibly warm to about 60 ° C. Examples of the alkyl halide include methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentyl iodide, hexyl iodide, heptyl iodide, octyl iodide, nonyl iodide, decyl iodide, and iodide. Mention may be made of alkyl iodides such as undecyl, dodecyl iodide, tridecyl iodide, alkyl bromides, and alkyl chlorides. Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium fluoride and sodium hydride. Examples of the solvent include dimethylformamide, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide and the like.

  In the step of obtaining 4-alkoxyresorcinol, a hydrogenolysis reaction using hydrogen gas and a metal catalyst is performed. Examples of the metal catalyst include palladium hydroxide-activated carbon, palladium-activated carbon, platinum oxide and Raney nickel. Examples of the solvent used in this reaction include ethyl acetate, methanol, ethanol, propanol, acetonitrile, acetone, and tetrahydrofuran.

  (B) A method for producing a resorcinol derivative having either a monosaccharide or an oligosaccharide residue or a methylated product thereof in the side chain uses Dakin oxidation and a trichloroacetimidate method as key reactions, and combines benzaldehyde and sugar. This is a method of chemically synthesizing, for example, glycosides such as the above compounds 21 to 24 or derivatives thereof using a simple chemical synthesis route of glycosides as starting materials.

  Specifically, as shown in the following synthesis route, 2,4-dihydroxybenzaldehyde (31) and benzyl bromide (BnBr) are dissolved in N, N-dimethylformamide (DMF), and the reaction is performed by adding a base. (32) is synthesized. Next, the ether (32) is converted into a formyl compound by Dakin oxidation, and then a phenol compound (33) is obtained by alkaline hydrolysis.

  On the other hand, after D-glucose (34) is converted to acetyl (Ac) and led to acetate (35), the acetyl group at the anomeric position of acetate (35) is selectively removed to synthesize hemiacetal (36). . This hemiacetal (36) and trichloroacetonitrile are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) to give imidate (37).

  The resulting phenol (33) and imidate (37) are coupled using a Lewis acid to obtain a glycoside (38). The glycoside (14) is not isolated, but is subsequently subjected to hydrogenolysis under a catalyst to remove the benzyl group and convert it to the phenol (36). Thereafter, the acetyl group of the phenol compound (36) is deprotected by transesterification, and the reaction solution is neutralized, followed by filtration and drying to obtain a glycoside represented by the compound 21.

  The glycosides represented by the above-mentioned compounds 22, 23 and 24 can also be synthesized in the same manner. For example, following the same route as the synthesis of imidate (37), imidate (41, 42, 43) is synthesized using D-xylose, D-cellobiose and D-maltose as starting materials. Thereafter, these imidates (41, 42, 43) and phenolic form (33) are coupled by the trichloroacetimidate method, and then the benzyl and acetyl groups are removed to give compounds 22, 23, and 24. Each of the glycosides shown can be synthesized.

  Arbutin is known as a natural phenol glycoside contained in plants such as cowberry and pear, but its tyrosinase inhibitory activity is very weak. However, this arbutin is sometimes used as a cosmetic ingredient having a whitening effect because of its water solubility and low toxicity. On the other hand, 4-butylresorcinol is fat-soluble and has limited use, but has a resorcinol skeleton and therefore exhibits very strong tyrosinase inhibitory activity. In the present invention, by synthesizing a resorcinol derivative having a sugar part of water-soluble and low-toxic arbutin and a resorcinol part of 4-butylresorcinol having strong tyrosinase inhibitory activity, it is easily soluble in water and sufficiently inhibits tyrosinase. Since it has activity, it is a new glycoside having both characteristics.

  Hereinafter, the present invention will be described more specifically by way of examples. However, the technical scope of the present invention is not limited to these examples.

[Synthesis of 2,4-dibenzyloxybenzaldehyde]
Dissolve 2,4-dihydroxybenzaldehyde (1.0 g, 7.2 mmol) in 5 mL of DMF, add BnBr (2.15 mL, 18 mmol) and K ₂ CO ₃ (3.0 g, 22 mmol), and stir at 60 ° C. for 3 hours. did. Ethyl acetate (50 mL) was added to the reaction solution, and the obtained organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The product was crystallized by adding hexane to obtain 2.0 g of white crystalline 2,4-dibenzyloxybenzaldehyde represented by the following formula (yield: 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.38 (s, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.39 (m, 10 H), 6.63 (dd, J = 2.0, 8.3 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.12 (s, 2H), 5.09 (s, 2H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 188.3 (d), 165.1 (s), 162.7 (s), 135.89 (s), 135.85 (s), 130.5 (d ), 128.7 (d, 2C), 128.4 (d), 128.3 (d, 2C), 127.5 (d), 127.3 (d), 119.5 (s), 107. 0 (d), 100.1 (d), 70.42 (t), 70.36 (t).

[Synthesis of 2,4-dibenzyloxyphenol]
Under an argon atmosphere, 2,4-dibenzyloxybenzaldehyde (2.0 g, 6.3 mmol) and mCPBA (3.6 g, 16 mmol) were dissolved in 30 mL of dichloromethane and refluxed overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the organic layer was washed with 5% aqueous sodium thiosulfate solution (10 mL), water (10 mL), 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). Anhydrous sodium sulfate was added to the obtained organic layer for drying, sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. 20 mL of methanol and 8 mL of 6M NaOH aqueous solution were added to the concentrate, and the resulting solution was stirred at room temperature for 3 hours. The reaction was acidified with 2M hydrochloric acid and ethyl acetate (50 mL) was added. The organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (20-30% ethyl acetate / hexane) to obtain 1.4 g of white crystalline 2,4-dibenzyloxyphenol represented by the following compound (yield: 72). %).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 10H), 6.85 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 2.9 Hz, 1H), 6 .49 (dd, J = 2.9, 8.8 Hz, 1H), 5.29 (s, 1H), 5.06 (s, 2H), 4.99 (s, 2H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 153.5 (s), 149.7 (s), 143.8 (s), 137.2 (s), 137.1 (s), 128.5 (d) , 2C), 127.9 (d), 127.7 (d), 127.6 (d, 2C), 127.2 (d), 115.5 (d), 105.7 (d), 104. 0 (d), 71.8 (t), 71.1 (t).

[Example 1: 4-propoxyresorcinol (compound 2)]
2,4-Dibenzyloxyphenol (100 mg, 0.33 mmol) was dissolved in 1 mL of DMF, 1-iodopropane (36 μL, 0.37 mmol) and K ₂ CO ₃ (91 mg, 0.67 mmol) were added, and 50 ° C. Stir overnight. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-2% ethyl acetate / hexane) to obtain 86 mg of colorless oily 2,4-dibenzyloxy-1-propoxybenzene (yield: 76%). .

  2,4-Dibenzyloxy-1-propoxybenzene (75 mg, 0.22 mmol) is dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) is added, and the mixture is stirred overnight at room temperature in a hydrogen atmosphere. did. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10 to 20% ethyl acetate / hexane) to obtain 37 mg of 4-propoxyresorcinol represented by the compound 2 (yield: 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1H), 5.70 (bs, 1H), 3.92 (t, J = 6.6 Hz, 2H), 1.78 (sext, J = 6.6 Hz, 2H), 1. 01 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.8 (d), 102.7 (d ), 71.2 (t), 22.6 (t), 10.5 (q).

[Example 2: 4-pentyloxyresorcinol (compound 3)]
2,4-Dibenzyloxyphenol (100 mg, 0.33 mmol) was dissolved in 1 mL of DMF, 1-bromopentane (46 μL, 0.37 mmol) and K ₂ CO ₃ (91 mg, 0.67 mmol) were added, and the mixture was stirred at 50 ° C. Stir overnight. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-2% ethyl acetate / hexane) to obtain 120 mg of colorless oily 2,4-dibenzyloxy-1-pentyloxybenzene (yield: 97%). .

  2,4-Dibenzyloxy-1-pentyloxybenzene (100 mg, 0.27 mmol) is dissolved in 2 mL of ethyl acetate, and 20% palladium hydroxide-activated carbon (10 mg) is added to the solution overnight at room temperature under a hydrogen atmosphere. Stir. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10 to 20% ethyl acetate / hexane) to obtain 53 mg of 4-pentyloxyresorcinol represented by the compound 3 (yield: 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1 H), 5.68 (bs, 1 H), 4.52 (bs, 1 H), 3.95 (t, J = 6.6 Hz, 2 H), 1.76 (quint, J = 6.6 Hz, 2H), 1.39 (m, 2H), 0.91 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.8 (d), 102.7 (d ), 69.7 (t), 29.0 (t), 28.1 (t), 22.4 (t), 14.0 q).

[Example 3: 4-heptyloxyresorcinol (compound 4)]
2,4-Dibenzyloxyphenol (200 mg, 0.65 mmol) was dissolved in 2 mL of DMF, 1-bromoheptane (160 μL, 1.0 mmol) and K ₂ CO ₃ (200 mg, 1.4 mmol) were added, Stir overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the obtained organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-2% ethyl acetate / hexane) to obtain 260 mg of colorless oily 2,4-dibenzyloxy-1-heptyloxybenzene (yield: 99%). .

  2,4-Dibenzyloxy-1-heptyloxybenzene (100 mg, 0.25 mmol) was dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) was added, and the mixture was overnight at room temperature under a hydrogen atmosphere. Stir. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10 to 20% ethyl acetate / hexane) to obtain 54 mg of 4-heptyloxyresorcinol represented by the above compound 4 (yield: 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1H), 5.67 (bs, 1H), 4.49 (bs, 1H), 3.94 (t, J = 6.6 Hz, 2H), 1.76 (quint, J = 6.6 Hz, 2H), 1.42 (m, 2H), 1.29 (m, 4H), 0.87 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.8 (d), 102.7 (d ), 69.8 (t), 31.7 (t), 29.3 (t), 29.0 (t), 26.0 (t), 22.6 (t), 14.1 (q) .

[Example 4: 4-nonyloxyresorcinol (compound 5)]
2,4-Dibenzyloxyphenol (200 mg, 0.65 mmol) was dissolved in ₂ mL of DMF, 1-iodononane (153 μL, 0.78 mmol) and K ₂ CO ₃ (180 mg, 1.3 mmol) were added, and the mixture was mixed at 50 ° C. Stir overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the obtained organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1 to 3% ethyl acetate / hexane) to obtain 276 mg of colorless oily 2,4-dibenzyloxy-1-nonyloxybenzene (yield: 99%). .

  2,4-Dibenzyloxy-1-nonyloxybenzene (100 mg, 0.23 mmol) was dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) was added, and the mixture was overnight at room temperature under a hydrogen atmosphere. Stir. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (5-20% ethyl acetate / hexane) to obtain 58 mg of 4-nonyloxyresorcinol represented by the compound 5 (yield: 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1H), 5.66 (bs, 1H), 4.40 (bs, 1H), 3.93 (t, J = 6.6 Hz, 2H), 1.75 (m, 2H) 1.41 (m, 2H), 1.24 (m, 10H), 0.86 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.2 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.7 (d), 102.7 (d ), 69.8 (t), 31.8 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.2 (t), 26.0 (t) , 22.6 (t), 14.1 (q).

[Example 5: 4-Undecyloxyresorcinol (Compound 6)]
2,4-Dibenzyloxyphenol (200 mg, 0.65 mmol) was dissolved in ₂ mL of DMF, 1-bromoundecane (170 μL, 0.76 mmol) and K ₂ CO ₃ (180 mg, 1.3 mmol) were added, and the mixture was stirred at 50 ° C. Stir overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the obtained organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-2% ethyl acetate / hexane) to obtain 297 mg of colorless oily 2,4-dibenzyloxy-1-undecyloxybenzene (yield: 100%). ).

  2,4-Dibenzyloxy-1-undecyloxybenzene (100 mg, 0.22 mmol) was dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. Stir overnight. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-15% ethyl acetate / hexane) to obtain 58 mg (95%) of 4-undecyloxyresorcinol represented by Compound 6 above.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1 H), 5.66 (bs, 1 H), 4.45 (bs, 1 H), 3.94 (t, J = 6.6 Hz, 2 H), 1.75 (quint, J = 6.6 Hz, 2H), 1.41 (m, 2H), 1.25 (m, 14H), 0.86 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.7 (d), 102.7 (d ), 69.8 (t), 31.9 (t), 29.59 (t), 29.57 (t), 29.54 (t), 29.36 (t), 29.33 (t) 29.31 (t), 26.0 (t), 22.7 (t), 14.1 (q).

[Example 6: 4-tridecyloxyresorcinol (compound 7)]
2,4-Dibenzyloxyphenol (200 mg, 0.65 mmol) was dissolved in ₂ mL of DMF, 1-bromotridecane (395 mg, 1.5 mmol) and K ₂ CO ₃ (360 mg, 2.6 mmol) were added, and 50 ° C. Stir overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the obtained organic layer was washed with water (10 mL) and saturated brine (10 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (10 mL) three times, and all organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-2% ethyl acetate / hexane) to obtain 318 mg of colorless oily 2,4-dibenzyloxy-1-undecyloxybenzene (yield: 100%). ).

  2,4-Dibenzyloxy-1-tridecyloxybenzene (100 mg, 0.21 mmol) was dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. Stir overnight. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-15% ethyl acetate / hexane) to obtain 56 mg of 4-tridecyloxyresorcinol represented by the compound 7 (yield: 86%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.68 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 2. 9, 8.8 Hz, 1H), 5.68 (bs, 1H), 4.57 (bs, 1H), 3.94 (t, J = 6.6 Hz, 2H), 1.75 (quint, J = 6.6 Hz, 2H), 1.41 (m, 2H), 1.24 (m, 18H), 0.86 (t, J = 6.6 Hz, 3H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.3 (s), 112.7 (d), 105.8 (d), 102.7 (d ), 69.8 (t), 31.9 (t), 29.54 (t), 29.62 (t, 2C), 29.57 (t), 29.54 (t), 29.36 ( t), 29.33 (t, 2C), 26.0 (t), 22.7 (t), 14.1 (q).

[Example 7: 4-O-glucopyranosyl resorcinol (compound 21)]
2,4-Dibenzyloxyphenol (270 mg, 0.88 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl trichloroacetimidate (1.73 g, 3.5 mmol) ) Was dissolved in 7 mL of dichloromethane and ice-cooled. Trimethylsilyl trifluoromethanesulfonate (25 μL, 0.14 mmol) was added dropwise to the solution, and the mixture was stirred at 0 ° C. for 30 minutes. Ethyl acetate (100 mL) was added to the reaction solution, and the obtained organic layer was washed with water (20 mL) and saturated brine (20 mL) three times. The aqueous layers were combined, further extracted with ethyl acetate (20 mL) three times, and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (20 to 40% ethyl acetate / hexane) to give 1-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl as a white solid. ) -2,4-dibenzyloxybenzene was obtained. This compound was not isolated and used for the next reaction.

  The obtained 1-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) -2,4-dibenzyloxybenzene was dissolved in 12 mL of ethyl acetate and 20% hydroxylated. Palladium-activated carbon (100 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (40-50% ethyl acetate / hexane), and 4-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl). 212 mg of resorcinol was obtained (yield: 53%).

4-O- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) resorcinol (185 mg, 0.41 mmol) was dissolved in 11 mL of methanol and ice-cooled. To the resulting solution, 0.8 mL of a methanol solution of sodium methoxide (28%, 4.2 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes. Amberlite IR-120 in H ⁺ form was added little by little to the reaction solution, neutralized, the amberlite was filtered and the filtrate was concentrated under reduced pressure, and a white solid 4-O-glucose represented by the compound 21 was obtained. 105 mg of pyranosylresorcinol was obtained (yield: 100%). This compound was purified by reverse phase HPLC (10% MeCN / H ₂ O, flow rate 1 mL / min, elution time 4.0 min) and used for evaluation of tyrosinase inhibitory activity.

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.01 (d, J = 8.7 Hz, 1H), 6.31 (d, J = 2.9 Hz, 1H), 6.19 (dd, J = 2) .9, 8.7 Hz, 1H), 4.56 (m, 1H), 3.87 (dd, J = 2.2, 12.0 Hz, 1H), 3.70 (dd, J = 5.1) 12.0 Hz, 1H), 3.40 (m, 4H).
¹³ C-NMR (100 MHz, CD ₃ OD) δ 155.3 (s), 149.8 (s), 140.2 (s), 121.0 (d), 107.1 (d), 106.0 ( d), 104.4 (d), 78.2 (d), 77.7 (d), 74.9 (d), 71.2 (d), 62.4 (t).

[Example 8: 4-((2-ethylhexyl) oxy) resorcinol (Compound 8)]
2,4-Dibenzyloxyphenol (0.20 g, 0.6 mmol) was dissolved in 3 mL of DMF, and 3-bromomethylheptane (0.25 g, 1.2 mmol) and K ₂ CO ₃ (0.27 g, 1. 90 mmol) was added and stirred at 50 ° C. overnight. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-5% ethyl acetate / hexane) to obtain 0.23 g of colorless oily 2,4-dibenzyloxy-1-((2-ethylhexyl) oxy) benzene. (Yield 82%).

  2,4-dibenzyloxy-1-((2-ethylhexyl) oxy) benzene (100 mg, 0.24 mmol) is dissolved in 5 mL of ethyl acetate, and 20% palladium hydroxide-activated carbon (10 mg) is added to form a hydrogen atmosphere. The mixture was stirred overnight at room temperature. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10-20% ethyl acetate / hexane) to obtain 57 mg of 4-((2-ethylhexyl) oxy) resorcinol represented by the compound 8 (yield: 100). %).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.79 (d, J = 8.7 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 6.27 (dd, J = 8. 7, 3.0 Hz, 1H), 5.63 (bs, 1H), 3.84 (d, J = 5.6 Hz, 2H), 2.61 (s, 1H), 1.71 (sep, J = 5.6 Hz, 1H), 1.39 (m, 8H), 0.91 (t, J = 7.5 Hz, 2H), 0.88 (t, J = 7.0 Hz, 2H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.1 (s), 146.7 (s), 140.5 (s), 112.5 (d), 102.7 (d), 72.1 (t ), 39.5 (d), 30.5 (t), 29.1 (t), 23.9 (t), 23.0 (t), 14.0 (q), 11.1 (q) .

[Example 9: 4-phenoxyresorcinol (Compound 9)]
2,4-Dibenzyloxyphenol (0.20 g, 0.6 mmol) was dissolved in 2 mL of DMF and (2-bromoethyl) benzene (0.24 g, 1.2 mmol) and K ₂ CO ₃ (0.27 g, 1 .90 mmol) was added and stirred at 50 ° C. overnight. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-7% ethyl acetate / hexane) to obtain 0.21 g of colorless oily 2,4-dibenzyloxy-1-phenoxybenzene (yield 79%). ).

  2,4-Dibenzyloxy-1-phenethylbenzene (99 mg, 0.24 mmol) was dissolved in 5 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) was added, and the mixture was overnight at room temperature under a hydrogen atmosphere. Stir. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (15-30% ethyl acetate / hexane) to obtain 53 mg of 4-phenoxyresorcinol shown in Compound 9 (yield 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.34 (m, 3H), 7.25 (m, 2H), 6.70 (d, J = 8.6 Hz, 1H), 6.42 (d, J = 2.9 Hz, 1 H), 6.25 (dd, J = 8.6, 2.9 Hz, 1 H), 5.43 (s, 1 H), 4.43 (bs, 1 H), 4.17 (t , J = 6.8 Hz, 2H), 3.06 (td, J = 6.8 Hz, 2H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.5 (s), 147.0 (s), 140.0 (s), 138.0 (d), 128.9 (d, 2C), 128.7 (D, 2C), 126.7 (d), 113.7 (d), 105.9 (d), 102.9 (d), 70.7 (t), 35.9 (t).

[Example 10: 4-cyclohexylmethoxyresorcinol (compound 10)]
Dissolve 2,4-dibenzyloxyphenol in 2 mL of DMF and add bromomethylcyclohexane (0.23 g, 1.2 mmol) and K ₂ CO ₃ (0.46 g, 3.30 mmol) and overnight at 50 ° C. Stir. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1 to 2.5% ethyl acetate / hexane) to obtain 0.25 g of colorless oily 2,4-dibenzyloxy-1- (cyclohexylmethoxy) benzene ( Yield 90%).

  2,4-Dibenzyloxy-1- (cyclohexylmethoxy) benzene (50 mg, 0.12 mmol) is dissolved in 2 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (10 mg) is added, and hydrogen atmosphere is used at room temperature. Stir overnight. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (10 to 25% ethyl acetate / hexane) to obtain 27 mg of 4-cyclohexylmethoxyresorcinol shown in Compound 10 (yield 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.67 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 6.26 (dd, J = 8. 6, 2.9 Hz, 1 H), 5.65 (s, 1 H), 4.38 (bs, 1 H), 3.74 (d, J = 6.2 Hz, 2 H), 1.76 (m, 5 H) , 1.69 (m, 6H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 150.0 (s), 146.7 (s), 140.5 (s), 112.7 (d), 105.7 (d), 102.7 (d ), 75.1 (t), 37.7 (d), 29.9 (t, 2C), 26.4 (d), 25.7 (t, 2C).

[Example 11: 4- (2- (1,3-dioxan-2-yl) ethoxy) resorcinol (Compound 15)]
2,4-Dibenzyloxyphenol (0.20 g, 0.6 mmol) is dissolved in 2 mL of DMF, and 2- (2-bromoethyl) -1,3-dioxane (0.26 g, 1.2 mmol) and K ₂ CO 2 are dissolved. ₃ (0.27 g, 1.90 mmol) was added and stirred at 50 ° C. overnight. Ethyl acetate (30 mL) was added to the reaction solution, and the obtained organic layer was washed with water (5 mL) and saturated brine (5 mL) three times. The aqueous layers were combined and extracted three times with ethyl acetate (5 mL), and all the organic layers obtained were dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (1-25% ethyl acetate / hexane) to give colorless oily 2,4-dibenzyloxy-1- (2- (1,3-dioxane-2-yl). 0.22 g of ethoxy) benzene was obtained (yield 80%).

  2,4-Dibenzyloxy-1- (2- (1,3-dioxan-2-yl) ethoxy) benzene (98 mg, 0.23 mmol) was dissolved in 4 mL of ethyl acetate, and 20% palladium hydroxide-activated carbon. (10 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The palladium catalyst was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (15-40% ethyl acetate / hexane), and 4- (2- (1,3-dioxan-2-yl) ethoxy) resorcinol represented by compound 15 above. 55 mg was obtained (yield 100%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.86 (bs, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.43 (d, J = 2.9 Hz, 1H), 6 .25 (dd, J = 8.6, 2.9 Hz, 1H), 4.80 (t, J = 4.5 Hz, 1H), 4.57 (bs, 1H), 4.14 (dd, J = 12.0, 5.0 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.80 (td, J = 12.0, 2.4 Hz, 2H), 2.15 (m , 1H), 2.07 (dd, J = 6.0, 4.5, 2H), 1.38 (m, 1H).
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 151.4 (s), 148.6 (s), 140.0 (s), 117.0 (d), 105.9 (d), 103.0 (d ), 100.6 (d), 67.5 (d), 67.1 (t, 3C), 34.7 (t), 25.5 (t).

[Example 12: 4-O-xylopyranosyl resorcinol (Compound 22)]
2,4-dibenzyloxyphenol (1.0 g, 3.3 mmol) and 2,3,4-tri-O-acetyl-α-D-xylopyranosyl trichloroacetimidate (4.12 g, 9.8 mmol) ) Was vacuum-dried under an argon atmosphere, then dissolved in 20 mL of dehydrated dichloromethane, trimethylsilyl trifluoromethanesulfonate (70 μl, 0.21 mmol) was added with ice cooling, and the mixture was stirred for 30 seconds. Thereafter, ethyl acetate was added, and the organic layer was washed with distilled water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-40% ethyl acetate / hexane) and 1-O- (2,3,4-tri-O-acetyl-β-D-xylopyranosyl) -2,4-dibenzyl. 1.83 g of oxybenzene was obtained (99% yield). This compound was not isolated and used for the next reaction.

  1-O- (2,3,4-tri-O-acetyl-β-D-xylopyranosyl) -2,4-dibenzyloxybenzene (1.83 g, 3.2 mmol) was dissolved in 12 mL of ethyl acetate, and 20 % Palladium hydroxide-activated carbon (183 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere to conduct a hydrogenation reaction. Thereafter, palladium was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-50% ethyl acetate / hexane) to obtain 0.39 g of 4-O- (2,3,4-tri-O-acetyl-β-D-xylopyranosyl) resorcinol. (Yield 31%).

  4-O- (2,3,4-tri-O-acetyl-β-D-xylopyranosyl) resorcinol (0.16 mg, 0.42 mmol) was dissolved in 11 mL of methanol. To this solution was added dropwise a methanol solution of 28% sodium methoxide (0.80 mL, 0.23 mmol) while cooling with ice, and the mixture was stirred overnight at room temperature under an argon atmosphere. Amberlite IR-120H was added little by little to the reaction solution, and it was confirmed that the reaction solution became neutral with pH test paper. Amberlite was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.11 g (99%) of 4-O-xylopyranosylresorcinol represented by the above-mentioned compound 22 as the target product.

¹ H-NMR (400 MHz, CD ₃ OD) δ 6.90 (d, J = 8.7 Hz, 1H), 6.31 (d, J = 2.9 Hz, 1H), 6.18 (dd, J = 8 .7, 2.9 Hz, 1H), 4.59 (d, J = 7.4 Hz, 1H), 3.91 (dd, J = 11.4, 5.4 Hz, 1H), 3.54 (ddd, J = 11.2, 10.4, 5.4 Hz, 1H), 3.41 (dd, J = 9.0, 7.4 Hz, 1H), 3.39 (dd, J = 11.2, 9.H). 0 Hz, 1H), 3.24 (dd, J = 11.4, 10.4 Hz, 1H).
¹³ C-NMR (100 MHz, CD ₃ OD) δ 155.5 (s), 149.9 (s), 139.9 (s), 121.1 (d), 107.0 (d), 106.5 ( d), 104.4 (d), 77.5 (d), 74.8 (d), 71.0 (d), 67.1 (t).

[Example 13: 4-β-glucopyranosyl-4′-β-glucopyranosyl resorcinol (compound 23)]
2,4-dibenzyloxyphenol (0.25 g, 0.82 mmol) and 1-α-trichloroacetimidoyl-2,3,6-O-triacetyl-glucopyranosyl-4-β- (2 ′, 3 ′ , 4 ′, 6′-O-tetraacetyl) -glucopyranoside (1.10 g, 1.4 mmol) was vacuum dried under an argon atmosphere, then dissolved in 7 mL of dehydrated dichloromethane, and trimethylsilyl trifluoromethanesulfonate ( 10 μL, 0.08 mmol) was added, and the mixture was stirred at 0 ° C. for 30 seconds. Thereafter, ethyl acetate was added, and the organic layer was washed with distilled water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-40% ethyl acetate / hexane) to give 1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-β- (2 ″ , 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2,4-bis-benzyloxybenzene was obtained (yield 89%).

  1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-β- (2 ″, 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2, 4-Bis-benzyloxybenzene (0.58 g, 0.63 mmol) was dissolved in 6 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (58 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Reaction was performed. Thereafter, palladium was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-50% ethyl acetate / hexane) to give 1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-β- (2 ″ , 3 ", 4", 6 "-O-tetraacetyl) -glucopyranosyl-2,4-dihydroxybenzene (0.44 g, yield 95%).

  1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-β- (2 ″, 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2, 4-dihydroxybenzene (0.44 g, 0.59 mmol) was dissolved in 10 mL of methanol. To this solution, a methanol solution of 28% sodium methoxide (0.90 μL, 319 mmol) was added dropwise while cooling with ice, and the mixture was stirred overnight at room temperature under an argon atmosphere. Amberlite IR-120H was added little by little to the reaction solution, and it was confirmed that the reaction solution became neutral with pH test paper. The amberlite was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.14 g of 4-β-glucopyranosyl-4′-β-glucopyranosyl resorcinol represented by the above-mentioned compound 23 as a target product (yield 53%). ).

¹ H-NMR (400 MHz, CD ₃ OD) δ 6.98 (d, J = 8.8 Hz, 1H), 6.31 (d, J = 2.9 Hz, 1H), 6.19 (dd, J = 8 .8, 2.9 Hz, 1H), 4.59 (d, J = 7.8 Hz, 1H), 4.43 (d, J = 7.8 Hz, 1H), 3.88 (m, 2H), 3 .62 (m, 3H), 3.48 (m, 2H), 3.34 (m, 2H), 3.22 (m, 1H).
¹³ C-NMR (100 MHz, CD ₃ OD) δ 155.4 (s), 149.8 (s), 140.1 (s), 121.1 (d), 107.1 (d), 105.8 ( d), 104.6 (d), 104.4 (d), 80.1 (d), 78.1 (d), 77.8 (d), 76.7 (d), 76.0 (d ), 74.9 (d), 74.7 (d), 71.3 (d), 62.4 (t), 61.5 (t).

[Example 14: 4-β-glucopyranosyl-4′-α-glucopyranosyl resorcinol (compound 24)]
2,4-dibenzyloxyphenol (0.25 g, 0.82 mmol) and 1-α-trichloroacetimidoyl-2,3,6-O-triacetyl-glucopyranosyl-4-α- (2 ′, 3 ′ , 4 ′, 6′-O-tetraacetyl) -glucopyranoside (1.10 g, 1.4 mmol) was sufficiently vacuum-dried under an argon atmosphere, dissolved in 7 mL of dehydrated dichloromethane, and trimethylsilyltrifluoromethane with ice cooling. Sulfonate (10 μL, 0.08 mmol) was added and stirred for 30 seconds. Thereafter, ethyl acetate was added, and the organic layer was washed with distilled water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-40% ethyl acetate / hexane) to give 1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-α- (2 ″ , 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2,4-bis-benzyloxybenzene (0.75 g) was obtained.

  1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-α- (2 ″, 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2, 4-Bis-benzyloxybenzene (0.72 g, 0.79 mmol) was dissolved in 10 mL of ethyl acetate, 20% palladium hydroxide-activated carbon (72 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Reaction was performed. Thereafter, palladium was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40-50% ethyl acetate / hexane) to give 1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-α- (2 ″ , 3 ", 4", 6 "-O-tetraacetyl) -glucopyranosyl-2,4-dihydroxybenzene (0.37 g, yield 62%).

  1-β- (2 ′, 3 ′, 6′-O-triacetyl) -glucopyranosyl-4′-α- (2 ″, 3 ″, 4 ″, 6 ″ -O-tetraacetyl) -glucopyranosyl-2, 4-dihydroxybenzene (0.35 g, 0.47 mmol) was dissolved in 10 mL of methanol. To this solution was added dropwise a methanol solution of 28% sodium methoxide (0.90 mL, 254 mmol) while cooling with ice, and the mixture was stirred overnight at room temperature under an argon atmosphere. Amberlite IR-120H was added little by little to the reaction solution, and it was confirmed that the reaction solution became neutral with pH test paper. The amberlite was filtered, and the filtrate was concentrated under reduced pressure to obtain 0.21 g of 4-β-glucopyranosyl-4′-α-glucopyranosyl resorcinol represented by the above-mentioned compound 24 as a target product (yield 99). %).

¹ H-NMR (400 MHz, CD ₃ OD) δ 7.00 (d, J = 8.7 Hz, 1H), 6.31 (d, J = 2.8 Hz, 1H), 6.19 (dd, J = 8 .7, 2.8 Hz, 1H), 5.18 (d, J = 3.8 Hz, 1H), 4.59 (d, J = 7.9 Hz, 1H), 3.86 (m, 3H), 3 .63 (m, 5H), 3.46 (m, 3H), 3.26 (m, 1H).
¹³ C-NMR (100 MHz, CD ₃ OD) δ 155.4 (s), 149.8 (s), 140.1 (s), 121.1 (d), 107.1 (d), 105.9 ( d), 104.4 (d), 103.0 (d), 80.8 (d), 77.4 (d), 76.8 (d), 75.1 (d), 74.8 (d) ), 74.5 (d), 74.2 (d), 71.5 (d), 62.7 (t), 61.9 (t).

[Evaluation of Tyrosinase Inhibitory Activity]
49 mg of DOPA was dissolved in purified water to prepare a 5 mM DOPA aqueous solution. The synthesized compounds 2 to 7 and 21 were dissolved in DMSO to prepare a 3 mM sample solution. Tyrosinase was dissolved in 50 mM sodium phosphate buffer using mushroom-derived tyrosinase (“EC 1.14.18.1”, purchased by Sigma-Aldrich), and 0.67 mg / mL tyrosinase was used. A solution was prepared.

In a cuvette (3 mL volume), sample solution 0.1 mL diluted with DMSO in 10 stages (0 to 0.1 mM), 250 mM sodium phosphate buffer 0.6 mL, 5 mM DOPA aqueous solution 0.3 mL, purified water 1.9 mL Then, 0.1 mL of tyrosinase solution was added and mixed well, and the change in absorbance at 475 nm was measured with a spectrophotometer. Each measurement was performed at 30 ° C. for 30 seconds, and the absorbance value was stored in a computer every second. The obtained absorbance was linearly regressed, and the 50% inhibitory concentration (IC ₅₀ ) was calculated with the slope at blank measurement as 100%. The data shown for IC ₅₀ in Table 1 indicates the concentration of each derivative that inhibits 50%, and the lower the value, the stronger the inhibitory activity against tyrosinase.

As can be seen from Table 1, the compounds 2 to 7 of 4-alkoxyresorcinol according to the present invention have an IC ₅₀ in the range of 14 to 75 μM, and all showed strong tyrosinase inhibitory activity. In particular, 4-nonyloxyresorcinol of compound 5 and 4-undecyloxyresorcinol of compound 6 are comparable to kojic acid that was once used as a tyrosinase inhibitor in cosmetics and foods in Japan, and is a strong tyrosinase. It was found to show inhibitory activity. In the present invention, 4-alkoxyresorcinol having such a strong tyrosinase inhibitory activity can be synthesized in an extremely efficient and high yield via an O-alkyl compound, so that it is extremely useful industrially.

Further, 4-O-glucopyranosyl resorcinol of Compound 21 has an IC ₅₀ of 1100 μM and is not strong as a tyrosinase inhibitory activity, but it is water-soluble and low-toxic, so a fat-soluble cream, a water-soluble lotion, etc. The tyrosinase inhibitor according to a use can be provided.

  For the synthesized compounds 8 to 10, 15, 23 and 24, a 3 mM sample solution was prepared in the same manner as in the above compounds 2 to 7 and 21, and tyrosinase inhibitory activity was evaluated in the same manner as described above. The results are shown in Table 2.

As can be seen from Table 2, Compound 8 has an IC ₅₀ of 44 μM, Compound 9 has an IC ₅₀ of 32 μM, Compound 10 has an IC ₅₀ of 60 μM, Compound 15 has an IC ₅₀ of 46 μM, and Compound 23 has IC ₅₀ was 300 μM and compound 24 had an IC ₅₀ of 1100 μM.

Claims (1)

Among tyrosinase activity inhibitor (Formula 1 consisting of resorcinol derivatives of formula 1, R is a methyl group, having 3 to 10 branched alkyl group carbon atoms, a phenyl group, a cycloalkyl compounds, oxygen-containing heterocyclic compounds, Or a residue of either a monosaccharide or an oligosaccharide or a methylated product thereof, n is 0 to 15.).