Preparation method of arbutin intermediates

Details Preparation method of arbutin intermediates Preparation method of arbutin intermediates

2001-04-20

2002-05-14

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S460000

Reexamination Certificate

active

06388103

ABSTRACT:

FIELD OF INVENTION
This invention is related to a preparation method of pentaacetylarbutin which is a key intermediate in the synthesis of arbutin. In detail, pentaacetylarbutin can be prepared by new and stereoselective &bgr;-O-glycosylation of hydroquinone or monoprotected hydroquinone with pentaacetyl-&bgr;-D-glucose in the presence of BF
3
·Et
2
O and base.
BACKGROUND OF THE INVENTION
Arbutin is a natural product extracted from leaves of blueberry and has been used as a stabilizer for color photographic image, a diuretic (Merck Index: 12
th
ed. p 816) and recently, a whitening agent in cosmetics (K. Maeda et al. The Journal of Pharmacology and Experimental Therapeutics, 276, 765-769, 1996). Three kinds of preparative methods of arbutin have been reported; 1) extraction from plants, 2) plant cell culture, 3) organic synthesis. The first method seems to be limited to production on a small scale because of the lack of resources.
The second one has been reported by many authors since 1990 (Japanese patents: JP hesei1-269498, JP hesei4-131091, JP hesei5-176785, Helv. Chim. Acta. 2009, 75, 1992), however, hasn't been developed yet for mass production.
The third one is the general preparation method in industry. Arbutin has been prepared by deprotection of variously protected arbutins. Variously protected arbutins were prepared by &bgr;-O-glycosylation of hydroquinone or monoprotected hydroquinones with pentaacetyl-&bgr;-D-glucose.
Reaction (1) shows a synthesis of arbutin (V).
where Ac is acetyl group and R′ is acetyl or benzyl group.
The general preparation methods of arbutin were the deprotection of benzyl teteracetylarbutin (R′=benzyl, U.S. Pat. No. 3,201,385) or pentaacetylarbutin (R″=acetyl, JP: sho62-226974) as shown in reaction (1). Because pentaacetylarbutin has only one kind of protecting group, only one step of deprotection was needed in order to obtain arbutin. However, for benzyl tetraacetylarbutin, two steps of deprotecting reaction are required and during debenzylation step, hydrogen gas was used which is dangerous due to the risk of explosion.
Reaction (2) represents the preparation of pentaacetylarbutin (chemical formula VIII) (Japanese patent: JP sho62-263195). During the reaction of pentaacetyl-&bgr;-D-glucose (chemical formula III) with hydroquinone (chemical formula VI) in the presence of p-toluenesulfonic acid as a catalyst, acetic acid is removed by vacuum distillation (15 mmHg) which is prepared as a side product. Pentaacetylarbutin which has excellent recrystalization property is obtained by acetylation with acetic anhydride in one-pot reaction without separation of tetraacetylarbutin.
where Ac is acetyl group.
As shown in reaction formular (2), during the reaction of pentaacetyl-&bgr;-D-glucose with hydroquinone, octaacetyl diglucosyl hydroquinone(chemical formula X) is obtained as a side product. Diacetylhydroquinone (chemical formula IX) is also produced during acetylation due to the use of excess hydroquinone. The side product, octaacetyl diglucosyl hydroquinone cannot be separated completely during the purification of pentaacetyl-&bgr;-D-arbutin. Additionally, during the preparation of arbutin by the solvolysis of pentaacetyl-&bgr;-D-arbutine, diglucosyl hydroquinone (chemical formula XI) remains in product as an impurity owing to similar properties with arbutin
Therefore, the purpose of present invention is to resolve the problems. This invention will provide a new and &bgr;-stereoselective glycosylation of mono-protected hydroquinone with pentaacetyl-&bgr;-D-glucose for the preparation of pentaacetylarbutin in high yield.
SUMMARY OF THE INVENTION
The purpose of this invention mentioned above can be achieved by new and stereoselective glycosylation of hydroquinone or monoprotected hydroquinones (chemical formula II) with pentaacetyl-&bgr;-D-glucose (chemical formula III) in the presence of Lewis acid and base as shown in reaction (3).
where Ac is acetyl group, R is hydrogen, alkyl group or cycloalkyl group with 1 to 10 carbon, or aliphatic or aromatic acyl group with 1 to 10 carbon.
DETAILD DESCRIPTION OF INVENTION
For a Lewis acid, tin tetrachloride, boron trifluoride etherate, boron trichloride, zinc chloride, ferric chloride, trimethylsilyl trifluoromethane sulfonate, or their mixture can be used and boron trifluoride etherate is advantageous. The amount of Lewis acid is 0.1 to 4 molar equivalent to pentaacetylglucose, and, 1 to 2 equivalent is desirable.
Organic base such as triethylamine, tributylamine, pyridine or lutidine and inorganic base such as potassium carbonate or sodium carbonate, or their mixture can be used for base. The amount should be used is 0.1 to 4 equivalent weight, and 0.5-2 equivalent molar weight is proper.
For solvent, toluene, benzene, xylene, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile or their mixture also can be used. Reaction temperature is from room temperature to 100 C. and from room temperature to 40 C. is desirable.
The invention has following advantages over the previous methods of arbutin synthesis.
1) the absence of octaacetyldiglucosyl hydroquinone
2) minimum production of pentaacetyl-&agr;-D-arbutin
3) high yield (more than 90%) of pentaacetyl-&bgr;-D-arbutin (chemical formula I) or tetraacetyl-&bgr;-D-arbutin with mono-protecting group.
The following examples describe the invention in detail. They are just for explaining the invention and the extent of the patent is not limited to them.


REFERENCES:
patent: 3201385 (1965-08-01), Jarrett
patent: 62226974 (1987-05-01), None
patent: 62263195 (1987-11-01), None
F. Ponticelli et al, Carbohydrate Research 330 (2001) 459-468.*
Halkes et al, Carbohydrate Research 309 (1998) 175-188.

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