KR100550160B1 - METHOD FOR PREPARING INTERMEDIATES OF ARBUTIN AND alpha-TYPE ARBUTIN - Google Patents

Abstract

The present invention relates to a method for preparing intermediates for producing arbutin and α (alpha) type arbutin, and more specifically, β-D-glucose pentabenzoate and α-D-glucose pentabenzoate and monobenzoylhydroquinone are Lewis acid catalysts. In the presence, 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside was reacted with β-O-glycosylation and α-O-glycosylation. To prepare benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside, the obtained 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β- Arbutin was prepared by deprotecting D-glucopyranoside, and the deprotected 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside obtained above was It relates to a process for producing an arbutin and an intermediate for producing α-albutin, characterized by producing type arbutin.

Arbutin, alpha-type arbutin, beta-D-glucose pentabenzoate, alpha-D-glucose pentabenzoate, hydroquinone, Lewis acid

Description

 Method for preparing intermediates for arbutin and alpha type arbutin {Method for preparing intermediates of arbutin and α-type arbutin}

1 is a proton nuclear magnetic resonance ( ¹ H-NMR) spectrum of 4'- benzoxiphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside according to the present invention,

Figure 2 is a proton nuclear magnetic resonance ( ¹ H-NMR) spectrum of 4'- benzoxiphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside according to the present invention.

The present invention relates to a method for producing intermediates for producing arbutin and α-type arbutin, and more specifically, β-D-glucose pentabenzoate represented by Formula 1 and α-D-glucose pentabenzoate represented by Formula 2 And 4'-benzoxyphenyl-2,3, represented by the formula (4) by reacting the monobenzoylhydroquinone represented by the formula (3) with β-O-glycosylation and α-O-glycosylation in the presence of a Lewis acid catalyst. To prepare 4,6-tetrabenzoyl-β-D-glucopyranoside and 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside represented by the formula (5) Arbutin represented by the formula (6) by deprotecting the 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside represented by Chemical Formula 4 obtained above ) And 4'-benzoxyphenyl-2,3,4,6- represented by Chemical Formula 5 Trad benzoyl -α-D- gluconic be expensive to the nose side pyrano Talbot it relates to a process for the preparation of α-type Arbutin Arbutin and for preparing intermediates, characterized in that for producing the α-type arbutin represented by the following formula (7).

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

With the proviso that Bz represents a benzoyl group.

Arbutin has been used as a color image stabilizer and diuretic (Merck Index, p. 816, p. 816), but recently, cosmetic whitening agents (K. maeda., T he Journal of Pharmacology and Experimental Therapeutics , 765-769) , 1996).

Arbutin is a natural product extracted from plants, in addition to the method of extracting from plants, there are plant tissue culture methods, a production method using an enzyme as a catalyst and a method of manufacturing by organic synthesis, organic synthesis is the most advantageous for mass production. Arbutin, which is an optical isomer of arbutin, has attracted attention as a next-generation potent whitening functional substance over conventional arbutin (β-arbutin) in the whitening effect.

In the conventional organic synthesis method of arbutin, it is prepared by condensation reaction between glucose and hydroquinone. However, the raw material used in the above synthesis method contains two or more hydroxyl groups, and as a result of the condensation reaction, various side reactants are not preferable. After reacting glucose and hydroquinone with each of the reactants, a suitable protecting group is introduced, followed by reaction to synthesize an arbutin intermediate to which the protecting group is bound, and then deprotection to remove arbutin. To manufacture. Many methods are known in this regard. <US Patent No. 3,201,385, Japanese Patent Publication No. 62-226973, Korean Patent No. 66098, Korean Patent Publication No. 2001-105119, Korean Patent Publication No. 2002-0095422>

U.S. Patent No. 3,201,385, the β-D- glucose pentaacetate and hydroquinone monobenzyl ether by reacting phosphorous oxychloride (POCl ₃₎ catalyst benzyl arbutin synthesizing tetra acetate, and removal of the acetyl group with sodium in a methanol solvent, it Next, a method of producing arbutin by hydrogen reaction under a carbon-palladium (C / Pd) catalyst is disclosed. However, the overall process is complicated by a multi-step process, the manufacturing cost is increased, in particular, since a hydrogen reaction apparatus is required, there is a disadvantage in that industrial application is restricted.

The methods of Japanese Patent Laid-Open Nos. 62-263914 and 62-226973 use a hydroquinone without a protecting group and the reaction temperature is maintained at a high temperature, so that a large amount of by-products are produced, and thus the yield is reduced. In particular, octaacetyl diglucosyl hydroquinone produced as a by-product has a problem in that separation and removal are not easy because physical properties with the desired arbutin are similar.

The method of Korean Patent No. 66098 improves the preparation method described above, and arbutin is prepared by reacting β-D-glucose pentaacetate and hydroquinone monoacetate under reduced pressure at 70 ° C. and 10 to 20 mmHg in the presence of an eutectic acid catalyst. do. In this method, one hydroxy group of hydroquinone is protected by acetylation, thereby reducing the formation of by-products, and the effect of yield improvement and cost reduction can be achieved by using no solvent. However, in order to remove acetic acid produced during the reaction, a temperature of 70 ° C. and a reduced pressure condition of 10-20 mmHg are required, and the maintenance of the temperature and reduced pressure condition for removing acetic acid generated during the reaction limits the mass production of arbutin. .

In Korean Patent Laid-Open No. 2001-105119, a condition in which a Lewis acid and a base are simultaneously used as a reaction catalyst is a hydroquinone having a β-D-glucose pentaacetate and a hydroquinone or a mono protecting group (where the protecting group is a cycloalkyl group or an acyl group). It is known to produce arbutin by reacting at. The method has a relatively high yield but uses more than equivalent Lewis acid as a catalyst, thereby increasing the manufacturing cost, and in the process of preparing a hydroquinone having a mono protecting group, which is used as a raw material, hydroquinone having a die protecting group is produced and separated therefrom. There is a further disadvantage that a process is required.

Meanwhile, Korean Patent Publication No. 10-2004-0065830 introduced a mono or ditrimethylsilyl group as a protecting group for hydroquinone used as a reaction raw material. Hydroquinones substituted with mono or ditrimethylsilyl groups can be used as raw materials, which can lower the manufacturing cost or reduce the production of by-products. There is a problem that is not suitable for the production of arbutin.

Therefore, the known production methods up to now have a large amount of by-products due to the reaction characteristics, there is a limit to the economic production of arbutin, such as the addition of a separate process for the separation or the use of expensive catalysts, the arbutin characteristic of the production method Even when 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside, which is an intermediate of, reacts with hydroquinone derivatives under Lewis acid catalyst, the acetyl group is relatively insensitive to Lewis acid, so the reaction time is If it is long, the concentration of the acid catalyst is high or not completely anhydrous, acetyl is hydrolyzed and has a disadvantage of low yield. In addition, the conventional techniques are all methods of producing arbutin (β-arbutin), which is not suitable for the production of α-arbutin, which is rapidly increasing demand due to its excellent effect, and in particular, the selective production of arbutin and α-arbutin is also impossible. There are disadvantages.

Accordingly, the present inventors have solved the disadvantages of the conventional method as described above, and while searching for a method for preparing α-arbutin and a method for selectively producing α- and β-arbutin, The present invention was completed by confirming that the protecting group and the benzoyl group as the mono protecting group of the hydroquinone are easy to introduce and deprotect the protecting group, and that the production of α-albutin and selective production of arbutin and α-albutin are possible by changing the reaction conditions. .

Accordingly, the present invention provides the above-described 4'-benzoxylphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside and 4'-benzone as intermediates useful for mass production of arbutin and α-type arbutin. It is an object of the present invention to provide a method for preparing ciphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside.

In order to achieve the above object, the present invention provides 4'-benzoxylphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside and 4'-benzoxoxy as intermediates for arbutin and α-arbutin preparation. Provided is a process for preparing phenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside.

In the present invention, the preparation method is a benzoylation of D-glucose (benzoylation) to prepare pentabenzoyl glucopyranoside, from the compound represented by the following formula (4)-benzoxiphenyl-2, 3,4,6-tetrabenzoyl-β-D-glucopyranoside was prepared, and arbutin was prepared by deprotecting the compound of Formula 4 obtained above, and the pentabenzoylglucopyranoside was changed under different conditions. To prepare 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside represented by the following Chemical Formula 5, followed by deprotection to prepare α-type arbutin. It is done.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

With the proviso that Bz represents a benzoyl group.

Pentabenzoyl-β-D-glucopyranoside and pentabenzoyl-α-D-glucopyranoside represented by Formula 4 and Formula 5 may be prepared by reacting D-glucose with benzoyl chloride, as is known. Can be. At this time, the solvent used is pyridine, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylformamide and the like. Temperature is preferably room temperature, but is preferably carried out at 0 ~ 100 ℃, pyridine, dimethylaminopyridine and the like can be used as a catalyst.

As another production method, pentabenzoyl-β-D-glucopyranose and pentabenzoyl-α-D-glucopyranoside represented by the above-mentioned formulas (4) and (5) include D-glucose and dicyclohexylcarbodiimide. You may make it react. At this time, the solvent may be used, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylaminopyridine and the like can be used as a catalyst. As for reaction temperature, 0-60 degreeC is preferable.

In the present invention, 4'- benzoxiphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside represented by the formula (4) and 4'-benzoxyl- represented by the formula (5) 2,3,4,6-tetrabenzoyl-α-D-glucopyranoside binds pentabenzoyl-β-D-glucopyranoside and pentabenzoyl-α-D-glucopyranoside under Lewis acid conditions. Characterized in that it is prepared by reaction with benzoylhydroquinone. At this time, if the reaction time is shortened or a catalytic amount of Lewis acid is used, 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside represented by Formula 4 may be prepared and Lewis. When the acid is used in excess, the reaction time is long, and the temperature is high, 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside represented by Formula 5 may be prepared.

Lewis acids usable in the preparation of the α-isomers include tin tetrachloride, boron trifluoride, boron trichloride, zinc chloride, iron trichloride, trimethylsilyltrifluoromethanesulfonate, aluminum chloride, etc., using 2 to 5 equivalents. It is desirable to. In addition, dichloromethane, acetonitrile, THF, DMF, benzene, toluene, chloroform, trichloroethane, dichloroethane, and the like may be used as the solvent. The reaction temperature is carried out at room temperature to 80 ℃ but is preferably 50 ~ 60 ℃, the reaction time is about 12 to 48 hours, 24 hours is preferable because the compound may be decomposed when the reaction is too long.

Meanwhile, in preparing β-isomers, Lewis acids may be formed of tin tetrachloride, boron trifluoride, boron trichloride, zinc chloride, iron trichloride, trimethylsilyltrifluoromethanesulfonate, and aluminum chloride similarly to the α-isomer. When the amount of the catalyst is excessively used, conversion to the α-isomer is possible, so that 0.1 to 2 equivalents is preferably used. Dichloromethane, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), benzene, toluene, chloroform, trichloroethane, dichloroethane and the like may be used as the solvent, and the reaction temperature is from room temperature to 80 degrees. At room temperature, preferably at room temperature. The reaction time is about 6 to 24 hours, but 12 hours is preferable since the reaction time can be converted to the α-isomer.

The α-type arbutin represented by the formula (7) is derivatized with 4'-benzoxyphenyl-2,3,4,6-tetra-O-benzoyl-α-D-glucopyranose represented by the formula (5) as a base. It can be prepared by gelatinization, and also β-type arbutin represented by the formula (6) is 4'- benzoxiphenyl-2,3,4,6-tetra-O-benzoyl-β-D- represented by the formula (4) It can be prepared by deprotecting the glucopyraside with a base.

In both cases, deprotection is possible under the same conditions, and the solvent used is preferably a solvent having a hydroxyl group such as methanol, ethanol, isopropanol, water, or the like. Bases for deprotection include ammonia, diethylamine, diisopropylamine, methylamine, sodium hydroxide, potassium hydroxide and the like. 24 to 48 hours are suitable for reaction time, Preferably it advances for 36 hours.

Therefore, the above-described method for producing arbutin and α-type arbutin and a method for selectively producing arbutin and α-type arbutin may be included in the scope of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

Example 1. Preparation of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside (1)

In the presence of argon (Ar), 50 ml of dry acetonitrile was added to a mixture of 3.5 g of pentabenzoyl-α-glucopyranoside and 2 g of monobenzoylhydroquinone, and 2.5 ml of boron trifluoride diethyl etherate was stirred. Slowly added, the mixture was stirred at 60 ° C for 12 hours, and then cooled to room temperature.

After the reaction, distilled water and ethyl acetate were added to separate the organic layer, and the remaining water in the separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.

The material was recrystallized from 30 mL of ethanol to give 3.17 g (80% obtained) of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside.

The compound obtained above was subjected to nuclear magnetic resonance experiment using Avance 400 (400 MHz) of Bruker, wherein deuterium chloroform (CDCl ₃ ) was used as a solvent.

Proton ( ¹ H) nuclear magnetic resonance spectrum at this time is shown in Figure 1, summarized as follows.

¹ H-NMR (400 MHz) δ: 7.90 to 8.20 (m, 10H), 7.3 to 7.6 (m, 15H), 7.22 (d, 2H), 7.07 (d, 2H), 6.41 (t, 1H), 5.99 (d, 1H), 5.77 (t, 1H), 5.49 (d, 1H), 4.63-4.48 (m, 3H)

Where m, s, and d are coupling states, and represent multiplet, singlet, and doublet, respectively, and the numbers in parentheses represent the coupling constants.

Example 2. Preparation of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside (2)

In the presence of argon (Ar), 50 ml of dry acetonitrile was added to a mixture of 3.5 g of pentabenzoyl-β-D-glucopyranoside and 2 g of monobenzoylhydroquinone, and with stirring, boron trifluoride diethyl ether 2.5 ML was slowly added and reacted with stirring at 60 ° C for 12 hours.

After the reaction was completed, the mixture was cooled to room temperature, distilled water and ethyl acetate were added to separate the organic layer, and the separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.

The material was recrystallized from 30 mL of ethanol to give 3.20 g (80.8% obtained) of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside.

The compound obtained above was subjected to nuclear magnetic resonance experiment using Avance 400 (400 MHz) of Bruker, wherein deuterium chloroform (CDCl ₃ ) was used as a solvent.

Although the result of the proton ( ¹ H) nuclear magnetic resonance spectrum at this time is not shown, the 4'- benzoxiphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopy prepared in Example 1 The same spectrum as that of lanoside was obtained.

Example 3. Preparation of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside (3)

In the presence of argon (Ar), 50 ml of dry acetonitrile was added to a mixture of 3.5 g of a mixture of pentabenzoyl-β-D-glucopyranoside and pentabenzoyl -β-D-glucopyranoside and 2 g of monobenzoylhydroquinone. 2.5 ml of boron trifluoride diethyl etherate was added slowly with stirring, the reaction was stirred at 60 ° C for 12 hours, cooled to room temperature, distilled water and ethyl acetate were added to separate the organic layer, and the separated organic layer. The solvent was dried over anhydrous magnesium sulfate and then depressurized to remove the solvent.

The material was recrystallized from 30 mL of ethanol to give 3.19 g (80.6% obtained) of 4′-benzoxylphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside.

The compound obtained above was subjected to nuclear magnetic resonance experiment using Avance 400 (400 MHz) of Bruker, wherein deuterium chloroform (CDCl ₃ ) was used as a solvent.

Although the result of the proton ( ¹ H) nuclear magnetic resonance spectrum at this time is not shown, the 4'- benzoxiphenyl-2,3,4,6-tetrabenzoyl-α- prepared in Examples 1 and 2 above. The same spectrum as D-glucopyranoside was obtained.

Example 4. Preparation of 4′-Benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside

In the presence of argon, 100 ml of dry dichloromethane was added to a mixture of 7 g of pentabenzoyl-α-glucopyranoside and 3 g of monobenzoylhydroquinone, and 0.5 ml of boron trifluoride diethyl etherate was slowly added with stirring. It was.

After stirring at room temperature for 24 hours, water was added to separate the organic layer, and the organic layer separated above was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure.

Compounds by removal of the solvent was recrystallized with ethanol to 4 '- l, when phenyl 2,3,4,6-tetra-benzoyl -β-D- gluconic nose side pyrano 7.13 g to give a (yield 90%).

The compound obtained above was subjected to nuclear magnetic resonance experiment using Avance 400 (400 MHz) of Bruker, wherein deuterium chloroform (CDCl ₃ ) was used as a solvent.

The results of the proton ( ¹ H) nuclear magnetic resonance spectrum are shown in FIG. 2, which is summarized as follows.

¹ H-NMR (400 MHz) δ: 8.2 to 7.9 (m, 10H) 7.6 to 7.2 (m, 15H), 7.07 (d, 2H), 7.00 (d, 2H), 6.00 (t, 1H), 5.83 ( t, 1H), 5.73 (t, 1H), 5.38 (d, 1H), 4.68 (dd, 1H), 4.55 (dd, 1H), 4.33 (m, 1H)

Where m, s, and d are coupling states, each represented by multiplet, singlet, and doublet, and the numbers in parentheses indicate the coupling constants.

In addition, the preparation of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside according to the present invention is not only pentabenzoyl-α-glucopyranoside as starting material but also penta. Benzoyl-β-glucopyranoside; Or a mixture of pentabenzoyl-α-glucopyranoside and pentabenzoyl-β-glucopyranoside; it was confirmed that the same result could be obtained.

Example 5 Preparation of α-type Arbutin

5 g of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside prepared in Examples 1 to 3 was suspended in 50 ml of methanol, and then ammonia gas The reaction was carried out for 24 hours.

After the completion of the reaction, the solvent was removed and recrystallized with ethyl acetate to obtain 1.56 g (91%) of α-arbutin.

Example 6 Preparation of Arbutin

5 g of 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside prepared in Example 4 was suspended in 50 ml of methanol, and ammonia gas was added for 24 hours. After reaction, the solvent was removed and recrystallized with ethyl acetate to obtain 1.56 g (91%) of arbutin.

As described above, the production method according to the present invention minimizes the production of by-products, which has been a problem in the conventional arbutin production, and enables the production of arbutin and α-type arbutin with a high yield of 90% or more, as well as arbutin and α-arbutin. Selective preparation of is possible.

Claims (10)

Β-D-glucose pentabenzoate represented by Formula 1 and α-D-glucose pentabenzoate represented by Formula 2 and monobenzoylhydroquinone represented by Formula 3 in the presence of a Lewis acid catalyst 4'-benzoxaphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside represented by the formula (4) and 4 represented by the formula (5) by silication and α-O-glycosylation reaction A process for producing an intermediate for producing arbutin and α-albutin, characterized by preparing '-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside. [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

With the proviso that Bz represents a benzoyl group. The method of claim 1, Arbutin represented by the following formula (6) by deprotecting the 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside represented by the above formula (4) with a base (β) A method for producing an intermediate for producing arbutin and α-type arbutin, characterized in that the method further comprises preparing Arbutin). [Formula 6]

 The method of claim 1, Deprotected 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside represented by Formula 5 with a base to form α-albutin represented by Formula 7 below Method for producing an intermediate for producing arbutin and α-type arbutin, characterized in that it further comprises manufacturing. [Formula 7]

The method of claim 1, The 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-α-D-glucopyranoside is an intermediate for producing arbutin and α-albutin, characterized in that 0.1 to 2 equivalents of Lewis acid catalyst is used. Manufacturing method. The method of claim 1, The 4'-benzoxyphenyl-2,3,4,6-tetrabenzoyl-β-D-glucopyranoside is an intermediate for producing arbutin and α-albutin, characterized in that 2-5 equivalents of Lewis acid catalyst is used. Manufacturing method. The method of claim 1, Arbutin, characterized in that the reaction solvent is dichloromethane, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), benzene, toluene, chloroform, trichloroethane, dichloroethane or a mixed solvent thereof The manufacturing method of the intermediate for alpha-arbutin manufacture. The method of claim 1, The reaction is a method for producing an intermediate for arbutin and α-albutin production, characterized in that performed for 6 to 48 hours in the range of room temperature to 80 ℃. The method of claim 1, The method for producing the intermediate for producing arbutin and α-type arbutin further comprises a method for selectively producing arbutin and α-type arbutin. The method according to any one of claims 1 to 5, Said Lewis acid is at least one or more of tin tetrachloride, boron trifluoride, boron trichloride, zinc chloride, iron trichloride, trimethylsilyltrifluoromethanesulfonate, aluminum chloride, the production method of the intermediate for producing arbutin and α-albutin. The method of claim 2 or 3, The base is at least one or more of ammonia, diethylamine, diisopropylamine, methylamine, sodium hydroxide, potassium hydroxide, the production method of the intermediate for producing arbutin and α-albutin.

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