Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2002-08-23
2003-05-20
Henley, III, Raymond (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S087000, C558S166000
Reexamination Certificate
active
06566545
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a menthol derivative represented by the following Formula 1 and a method for preparing the menthol derivative. More particularly, the present invention relates to a menthol derivative wherein menthol and 3-aminopropylphosphoric acid form a phospho-diester bond, and therefore, it can be decomposed by the enzyme to exhibit both the activities of menthol and 3-aminopropylphosphoric acid in the living body.
2. Description of the Related Arts
Menthol is known as a main component of peppermint, and the peppermint is a well-known fragrant plant. According to oriental medicine, the peppermint has effects of clearing and suppressing cold, and, because it has heat dispelling and perspiration effects, it has been used for itching, pains such as arthritis and neuralgia, tuberculosis and gastroenteric disorder, etc. Further, because it shows the effects on central blood vessel and relaxation of blood vessel, it has been used for paralysis. And, peppermint tea is known as good for stress and nervousness.
These effects of the peppermint seem to originate from L-menthol, the main component of peppermint. L-menthol is expressed chemically as C
15
H
20
O and transparent needle-shaped crystal with fresh fragrance. It is not dissolved in aqueous phase (water), but well dissolved in ethanol, ether and chloroform. The menthol having these features is obtained from extraction of peppermint stems or leaves and synthesized chemically by adding water to the ketones or double bond compounds such as menthone, fragone, piperitone, thymol and isofragone.
The effects of menthol are well known in the modern medicine as well oriental medicine. L-menthol reduces the irritation of skin due to the effect of local anesthesia, and its derivative is reported to have an anti-inflammation effect. Further, it has an antibacterial effect.
Since the menthol has a lot of useful effects as seen above, it is used for toothpaste, jam, candy, tobacco, etc. However, it has not widely used in the field of cosmetics because it has strong fragrance and irritation on the eye. To overcome this problem, there were many studies to prepare menthol derivatives. For example, ester derivative of menthol has the effects of reducing the strong fragrance and irritation on the eye, but on the other hand, its useful effects also reduced.
Under this condition, the inventors of the present invention tried and studied to develop menthol derivatives to overcome the above problems. As the result, a menthol derivative obtained from phospho-diester of menthol and 3-amino propylphosphoric acid, a component used for anti-aging cosmetic composition, was found to reduce the irritation of menthol while maintaining the useful effects of menthol and found to show both the physiological effects of menthol itself and 3-aminopropylphosphoric acid when applied to living body.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a menthol derivative with reduced irritation by comprising phosphorous group therein.
Further, another object of the present invention is to provide a method for preparing menthol derivative comprising phosphorous group.
To accomplish the above objects, the present invention provides a menthol derivative represented by the following Formula 1.
The above menthol derivative has reduced irritation compared with menthol itself, but has all the physiological effects of the menthol.
Further, the above menthol derivative is easily decomposed in the human body by the enzyme, and exhibits both the physiological activities of menthol and 3-aminopropylphosphoric acid.
Further, the present invention provides a method for preparing menthol derivative and its salt, by reacting menthol and phosphorous oxychloride in an organic solvent in the presence of organic base, further reacting with 3-amino propanol in the organic solvent in the presence of the organic base, then hydrolyzing and crystallizing the reaction resultant to obtain menthol derivative and the salt thereof.
More particularly, the method of the present invention comprises the steps of;
(A) reacting menthol and phosphorous oxychloride with an equivalence ratio of 1:1~1.3 in an organic solvent in the presence of organic base at 12~18° C. for 1~2 hours to obtain dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one;
(B) reacting above obtained dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one with 3-amino propanol in the organic solvent in the presence of the organic base to obtain 2[5-methyl-2-(methylethyl)cyclohexyloxy]-1,3,2-oxazaphosphorine P-oxide;
(C) filtering the reaction resultant of step (B), and concentrating the filtrate under reduced pressure, then adding acid solution to the concentrated product and reacting at 5~100° C. for 3~12 hours for hydrolysis; and
(D) crystallizing the product of step (C) with polar and organic solvent.
The present invention is described in detail hereinafter.
The method for preparing the menthol derivative of the present invention is schematized by the following Reaction Scheme 1.
Each steps of the method for preparing the menthol derivative of the present invention is described hereinafter.
Step (A): reacting menthol and phosphorous oxychloride in an organic solvent in the presence of an organic base at 12~18° C. for 1~2 hours to obtain dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one represented by structural formula (II) of the above Reaction Scheme 1.
In step (A), the equivalence ratio of menthol and phosphorous oxychloride is preferably 1:1~1.3. When the equivalence ratio is less than 1:1, the object material is not obtained; while, when the equivalence ratio is more than 1:1.3, an excessive amount of by-products are obtained. Therefore, when menthol and phosphorous oxychloride is reacted with the equivalence ratio of 1:1~1.3, the product, dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one in which menthol and phosphorous oxychloride is bonded with a ratio of 1:1 is obtained about 95%, and a by-product in which menthol and phosphorous oxychloride is bonded with a ratio of 2:1 is obtained less than 1~2%. Further, because that amount of by-product is removed by chromatography or by the separation method using the difference of solubility in toluene, the equivalence ratio of menthol and phosphorous oxychloride is preferably 1:1~1.3.
The reaction is preferably performed at 12~18° C. for 1~2 hours, which can inhibit the production of by-product tha menthol and phosphorous oxychloride are bonded with a ratio of 2:1 or more; and especially, introducing ester group or amide group to protect a chlorine atom in the oxychloride is not needed, which makes the process simple.
The base used in step (A) comprises organic base such as pyridine and triethylamine; and triethylamine is preferable.
The organic solvent in step (A) comprises dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethylether, trichloro ethylene, benzene, toluene, etc.; and toluene is preferable.
The reaction temperature is preferably 12~18° C. When the temperature is more than 18° C., two or more equivalent amount of menthol is bonded to one equivalence of phosphorous oxychloride, which increase the by-product; while, when the reaction temperature is less than 12° C., reaction rate decreases to make the reaction difficult and the yield decreases because non reacted components increases.
Step (B): reacting above obtained dichloro[5-methyl-2(mehtylethyl) cylclohexyloxy]phosphino-1-one and 3-aminopropanol in an organic solvent in the presence of an organic base.
The base used in step (B) comprises organic base such as pyridine and triethylamine that used in step (A), further, such bases as sodiumhydroxide and potassiumhydroxide may be used. Preferably, triethylamine is used.
The organic solvent in step (B) comprises inert solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethylether, etc., and polar solvent such a
An Su Sun
Kim Duck Hee
Kim Soo Hyun
Lee Jin Seon
Moon Seong Joon
Henley III Raymond
Pacific Corporation
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