Compositions – Preservative agents – Anti-oxidants or chemical change inhibitants
Reexamination Certificate
2000-09-27
2002-09-03
Toomer, Cephia D. (Department: 1714)
Compositions
Preservative agents
Anti-oxidants or chemical change inhibitants
C549S315000
Reexamination Certificate
active
06444144
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel ascorbic acid derivatives and their synthetic method represented by the following general formula (I).
wherein R
1
and R
2
are different from each other and independently H or —CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OR
3
, wherein n is an integer from 2 to 400; and R
3
is a lower alkyl group having 1 to 10 carbon atoms.
BACKGROUND ART
L-ascorbic acid is one of the most potent compounds causing as an antioxidant in biological systems by scavenging active oxygen species and free radicals.
L-ascorbic acid is a well-known water-soluble antioxidant that has a whitening effect and serves as a cofactor of prolinehydroxylase to promote synthesis of collagen (see. Quaglino, D. Jr., et al.,
J. Biol. Chem,
p272-345, 1997).
L-ascorbic acid is also used in various products requiring a long-term antioxidation effect. But, its usefulness for such products is not so reliable because it is susceptible to heat, light and air.
As such, many studies have been made on the development of ascorbic acid derivatives with enhanced stability while maintaining the antioxidation activity. Notably, a common way to improve the stability of L-ascorbic acid is converting a 2 - or 3-hydroxyl group of L-ascorbic acid to another substituent (see. U.S. Pat. Nos. 5,143,648; 4,780,549; and 4,177,445, Japanese Patent Sho 52-18191, and Korean Patent No. 91-8733).
L-ascorbic acid, which is a water-soluble antioxidant, is almost insoluble in oil and fat (e.g., salad oil and lard oil). Thus, there is a need of developing ascorbic acid derivatives that have a relatively high solubility in both water and organic solvents, for various use as an antioxidant in foods and cosmetics.
Examples of commercially available derivatives of vitamin C include L-ascorbic acid-6-palmitate, 2,6-dipalmitate, 6-stearate, L-ascorbic acid-3-O-ethyl and magnesium L-ascorbic acid-2-phosphate (see. Korean Patent No. 91-8733, and U.S. Pat. Nos. 5,143,648; and 7,179,445).
Among these compounds, relatively fat-soluble derivatives of ascorbic acid are L-ascorbic acid-6-palmitate, 2,6-dipalmitate and 6-stearate. Despite the improved chemical stability, these derivatives still have a limitation in lasting their anti-oxidative activity because of their rapid decomposition in vitro.
In an attempt to overcome these problems, the inventors of this invention derive novel ascorbic acid derivatives having considerably high solubilities in both water and organic solvents due to a polyethylene glycol moiety introduced at the 2 - or 3-hydroxyl group of L-ascorbic acid. The invention also includes a novel ascorbic acid derivative having high stability and long-lasting anti-oxidation effect.
DISCLOSURE OF INVENTION
The present invention relates to a new stable ascorbic acid.
It is therefore an object of the present invention is to provide a novel ascorbic acid derivative that overcomes the drawbacks of the related art methods.
The invention has solved the problems by introducing a polyethylene glycol moiety at the 2 - or 3-hydroxyl group of L-ascorbic acid. The invention is also directed to an ascorbic acid derivative having a high solubility in both water and most organic solvents and an inhibitory activity against tyrosinase.
It is another object of the present invention to provide a method for preparing such an ascorbic acid derivatives.
To achieve the above object, there is provided a novel ascorbic acid derivative by the formula (I) and a method for preparing the same:
wherein R
1
and R
2
are independently H or —CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OR
3
, wherein n is an integer from 2 to 400; and R
3
is a lower alkyl group having 1 to 10 carbon atoms.
There is also provided a method for preparing an ascorbic acid derivative represented by the formula (I), wherein R
1
represents —CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OR
3
, wherein n and R
3
are defined as above. The method includes: (i) reacting cesium ascorbate represented by the formula (V) with a derivative of polyethylene glycol represented by the formula (IV) in an appropriate solvent,
wherein R
3
is a lower alkyl group having 1 to 10 carbon atoms; n is an integer from 2 to 400; and X is a halogen atom such Cl, Br and I, or sulfonate such as tosylate, triflate or tresylate.
There is also provided a method for preparing a ascorbic acid derivative represented by the formula (I), wherein R
1
is a hydrogen atom and R
2
represents —CH
2
CH
2
—(O—CH
2
—CH
2
)
n
OR
3
, wherein n and R
3
are defined as above. More specifically, according to Scheme 1, the method includes: (i) reacting the compound of the formula (V) with benzyl bromide in the presence of a solvent to form 3-O-benzyl ascorbic acid represented by the formula (VI); (ii) reacting 3-O-benzyl ascorbic acid of the formula (VI) with PEG-I in the presence of cesium carbonate in a solvent to form 3-O-benzyl-2-polyethyleneglycolyl-ascorbic acid represented by the formula (VII); and (iii) hydrogenating the compound of the formula (VII) in the presence of a catalyst.
wherein Bn is benzyl group; and PEG is CH
2
CH
2
—(O—CH
2
—CH
2
)
n
—OR
3
, wherein n and R
3
are defined as above.
Furthermore, a method for preparing a compound of the formula (I) includes: (i) reacting a compound represented by the formula (VIII) with a derivative of polyethylene glycol represented by the formula (IV) in the presence of a base in a solvent; and (ii) hydrolyzing the product in the presence of an acid catalyst,
wherein R
4
and R
5
are the same or different and independently hydrogen atom, methyl group, ethyl group, or —CH
2
)
m
bonded to R
4
and R
5
, wherein m is 4 or 5; and R
6
is hydrogen atom, benzyl group or paramethoxybenzyl group.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in further detail.
The invention relates to an ascorbic acid derivative which stability is improved by introducing of polyethylene glycol group at the 2 - or 3-hydroxyl group of ascorbic acid.
The novel ascorbic acid derivative can be prepared by two methods: (1) the one method involves preparing a 5,6-O-acetal or ketal of ascorbic acid, introducing a polyethylene glycol group at the 3-OH position of the protected ascorbic acid in the presence of a base, and then eliminating the acetal or ketal group; and (2) the other method involves direct coupling of non-protected ascorbic acid with a polyethoxylated intermediate.
In the first method, in which the final product is obtained from non-protected ascorbic acid, cesium ascorbate represented by the formula (V) reacts with a derivative of polyethylene glycol represented by the formula (IV) in a suitable solvent to produce the compound represented by the formula (II).
wherein PEG is —CH
2
CH
2
—(O—CH
2
—CH
2
—O)
n
OR
3
, wherein n and R
3
are defined as above;
wherein R
3
is a lower alkyl group having 1 to 10 carbon atoms; n is an integer from 2 to 400; and X is a halogen atom (e.g., Cl, Br or I) or sulfonate (e.g., tosylate, triflate or tresylate).
The compound represented by the formula (IV) is denoted by PEG
n
—X.
The solvent used in this reaction is selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), hexamethyl phosphoramide (HMPA), N-methylpyrrolidone, pyrrolidone, dimethylacetamide (DMAC), 1,3-dimetyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), and mixtures thereof.
The compound of the formula (V) as used herein is prepared by reacting ascorbic acid with cesium carbonate in water as a solvent and crystallzing the crude cesium ascorbate in isopropyl alcohol.
In the second method, the final product is obtained from non-protected ascorbic acid, the compound represented by the formula (V) reacts with benzyl bromide in a solvent to give 3-O-benzyl ascorbic acid represented by the formula (VI) and then the compound of formula (VI) is coupled with PEG-I in the presence of cesium carbonate, followed by catalytic hydrogenation, to give a compound represented by the formula (III).
The solvent used in the above reaction is selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), h
Cho Wan Goo
Chung Bong Youl
Kim Young Keun
Lee In Sang
Park Bong Jun
Davidson Davidson & Kappel LLC
LG Chemical Ltd.
Toomer Cephia D.
LandOfFree
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