JP2003277392A - Vitamin e derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a vitamin E derivative having antioxidation activity and excellent moisture retention. <P>SOLUTION: The invention relates to a vitamin E derivative expressed by general formula (1) (R<SB>1</SB>, R<SB>2</SB>and R<SB>3</SB>are each independently H or methyl; R<SB>4</SB>is H, a lower alkanoyl, a lower alkyl, SO<SB>3</SB>H, P(O)(OH)<SB>2</SB>, CH<SB>2</SB>COOH or COCH<SB>2</SB>CH(SO<SB>3</SB>H)COOH; EO is ethylenoxy group; PO is propylenoxy group; (1) and (n) are each independently 0-30; and (m) is 1-30) and its salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a vitamin E derivative having an antioxidative activity and an excellent moisturizing property, and a salt thereof.

[0002]

2. Description of the Related Art In recent years, as the relationship between active oxygen and skin aging has been clarified, antioxidants such as vitamins E, C, B ₂ and carotenoids having antioxidant bioactive functions for preventing skin aging have been developed. It is getting attention. However, although they have an antioxidant effect, they are not effective in protection against dryness which is necessary for cosmetics, external ointment for skin and the like. A polyethoxylated vitamin E derivative having improved moisturizing properties of vitamin E is known (see, for example, Patent Document 1).
However, its moisturizing property is slightly better than that of α-tocopherol, and further improvement is desired.

[0003]

[Patent Document 1] US Pat. No. 5235073

[0004]

DISCLOSURE OF THE INVENTION The present inventors have earnestly studied to provide a vitamin E derivative having both antioxidant activity and excellent moisturizing property. As a result, they have found that a vitamin E derivative having a hydrophobic propyleneoxy group at the 6-position substituent of the chroman skeleton of vitamin E has antioxidant activity and excellent moisturizing properties, and completed the present invention.

[0005]

The present invention has the following general formula (I):

[0006]

[Chemical 2]

[In the formula, R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or a methyl group, and R ₄ represents a hydrogen atom, a lower alkanoyl group, a lower alkyl group, a SO ₃ H group or P (O).
Represents an (OH) ₂ group, EO represents an ethyleneoxy group,
PO represents a propyleneoxy group, l and n each independently represent 0 to 30, and m represents 1 to 30. ] It is a vitamin E derivative or a salt thereof.

Further, the present invention is a pharmaceutical, cosmetic or food containing the above vitamin E derivative or a salt thereof.

The present invention is also a pharmaceutical additive, cosmetic additive or food additive containing the above vitamin E derivative or a salt thereof.

In the general formula (I) of the present invention, R₁,
R₂, R₃R is a suitable combination of₁, R₂And R
₃Is a methyl group (raw material vitamin E is α-tocopherol
R), R₁And R₂Is a methyl group, and R₃But water
Elementary atom (vitamin E as the raw material is β-tocopherol
R), R ₂And R₃Is a methyl group, and R₁Is hydrogen
Child (when the raw material vitamin E is γ-tocopherol
R) or R₁, R₂And R₃Is a hydrogen atom (the raw material
Min E is δ-tocopherol).
It

In the general formula (I) of the present invention, the alkanoyl group having 1 to 6 carbon atoms for R ₄ is 1 carbon atoms.
A linear or branched alkanoyl group having 6 to 6, for example, acetyl, propanoyl, butyryl, isobutyryl or pivaloyl group, preferably acetyl, propanoyl or pivaloyl group, particularly preferably An acetyl group is mentioned.

The alkyl group having 1 to 6 carbon atoms of R ₄ is a linear or branched alkanoyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, butyl and isobutyl. , T-butyl, pentyl or hexyl group, preferably methyl, ethyl, propyl or butyl group, particularly preferably methyl or ethyl group.

Preferable R ₄ is hydrogen atom, acetyl group, methyl group, ethyl group, SO ₃ H group, P (O) (O
H) ₂ group, CH ₂ COOH group or COCH ₂ CH (SO
₃ H) COOH group can be mentioned, but a hydrogen atom is particularly preferable.

In the general formula (I) of the present invention, l and n independently of each other are 0 to 30, preferably 0 to 25, and particularly preferably 0 to 20.

In the general formula (I) of the present invention, m is 1 to 30, preferably 1 to 10, and particularly preferably 1 to 5.

As a particularly preferred combination of l, m and n, a combination in which l and n are 0 to 20 and m is 1 to 5 can be mentioned.

SO ₃ H group of R ₄ , P (O) (OH) ₂ group,
CH ₂ COOH group or COCH ₂ CH (SO ₃ H) COO
The H group can combine with a base to form a salt. The base is not particularly limited as long as it has low toxicity and does not affect the antioxidant activity and moisturizing property of the compound (1).
Examples of such salts include sodium salts, potassium salts, alkali metal salts such as lithium salts, calcium salts, alkaline earth metal salts such as magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, Metal salts such as nickel salts and cobalt salts; inorganic salts such as ammonium salts, t-
Octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt,
Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt,
Examples thereof include amine salts such as organic salts such as tris (hydroxymethyl) aminomethane salt, preferably alkali metal,
Alkaline earth metal or ammonium salts, preferably sodium, potassium, 1/2 magnesium, 1/2 calcium or ammonium salts, particularly preferably sodium or ammonium salts.

The compound represented by the general formula (I) of the present invention has an asymmetric carbon atom in the molecule and has stereoisomers of D-form and L-form. Any mixture mixed in any proportion is included in the present invention.

When the compound (I) of the present invention is left to stand in the air, it may absorb water and become adsorbed with water or become a hydrate. Included in the invention.

Further, the compound (I) of the present invention may absorb some other solvent to form a solvate, and such salts are also included in the present invention.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the general formula (I) of the present invention
The compound has the following formula (wherein R is₁To R_FourIs the same as
Show the same meaning. ), As shown in Vitamin E,
Ethylene oxide and / or propylene in the presence of a medium
Oxide is added to produce an alcohol (process
1), optionally lower alkanoyl group, lower alkyl
Base, SO ₃H group, P (O) (OH)₂Group, CH₂COOH
Group or COCH₂CH (SO₃H) Made by introducing COOH group
Build (step 2).

[0022]

[Chemical 3]

(Step 1) Step 1 is a commercially available natural vitamin E (for example, D-α-tocopherol, manufactured by Sigma-Aldrich Japan KK) or synthetic vitamin E (for example, DL-α-tocopherol, pure Wako). Yaku Co., Ltd.)
In the presence of a basic catalyst, ethylene oxide and / or propylene oxide is added in the presence or absence of a solvent to produce an alcohol.

The basic catalyst used in the addition reaction is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, sodium methoxide or potassium t-.
Examples thereof include alkali metal alkoxides such as butoxide, metal hydrides such as sodium hydride and aluminum hydride, and quaternary ammonium hydroxides such as quaternary trimethylammonium hydroxide. The amount of the catalyst varies depending on the reaction conditions and is not particularly limited, but in order to suppress side reactions, it is usually 0.
It is preferable to use 05% to 10%, and particularly preferably 0.05% to 5%.

If the solvent used does not participate in the reaction,
Although not particularly limited, aromatic hydrocarbons such as toluene, xylene and benzene, aliphatic hydrocarbons such as hexane, heptane and octane, alicyclic hydrocarbons such as cyclohexane and cycloheptane, tetrahydrofuran, Cyclic ethers such as dioxane, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethyl sulfoxide. Preferred are aromatic hydrocarbons such as toluene, xylene and benzene, alicyclic hydrocarbons such as cyclohexane and cycloheptane, tetrahydrofuran and dioxane. Cyclic ethers, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethers such as diethylene glycol dimethyl ether are particularly preferred.

Ethylene oxide and / or propylene oxide are usually pressed in.

The press-in temperature and the reaction temperature (aging temperature) are usually room temperature to 200 ° C., preferably 50 to 200 ° C., particularly preferably 80 to 180 ° C. The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 12 hours, and particularly preferably 1 to 10 hours.
It's time.

After the reaction, the reaction solution is cooled and the base used is neutralized with an acid. Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid, organic acids such as methanesulfonic acid, ethanesulfonic acid, acetic acid and p-toluenesulfonic acid, and are preferably used. Is hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid or acetic acid, and particularly preferably hydrochloric acid, phosphoric acid, methanesulfonic acid or acetic acid.

After neutralization, conventional treatments such as adding water and an organic solvent insoluble in water, extracting, drying and distilling off the solvent to obtain the desired product. When the salt is insoluble, the desired product can be obtained by filtering and distilling off the solvent. If necessary, the obtained target compound can be separated and purified by a conventional method such as recrystallization, reprecipitation or silica gel column chromatography. (Step 2) The desired compound thus obtained may be a lower alkanoyl group, a lower alkyl group, SO ₃
H group, P (O) (OH) ₂ group, CH ₂ COOH group or CO
The CH ₂ CH (SO ₃ H) COOH group-introduced derivative can be converted using a generally known technique. (1) The lower alkanoyl group is introduced by reacting an acid chloride or an acid anhydride in the presence of a base or in the presence or absence of a solvent.

Examples of the base used include triethylamine, diisopropylethylamine, pyridine, 4-
Mention may be made of organic bases such as dimethylaminopyridine, 1-methylpiperazine, 4-methylmorpholine, 1,4-dimethylpiperazine or 1-methylpyrrolidine, alone or in a mixture.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as toluene, xylene or benzene, aliphatic hydrocarbons such as hexane, heptane or octane, cyclohexane or cyclohexane. Alicyclic hydrocarbons such as heptane, cyclic ethers such as tetrahydrofuran or dioxane, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether, dimethylformamide or dimethylacetamide. Amides or sulfoxides such as dimethyl sulfoxide, aromatic hydrocarbons such as toluene, xylene or benzene, and silanes. Preferred are alicyclic hydrocarbons such as rohexane or cycloheptane, cyclic ethers such as tetrahydrofuran or dioxane, or ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether. Is.

The reaction temperature varies depending on the type of acid chloride and acid anhydride, but is usually -20 to 100 ° C, preferably 0 to 100 ° C, and particularly preferably 0 to 50 ° C.
℃.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 8 hours, and particularly preferably 1 to 4 hours.

After the completion of the reaction, a conventional treatment is carried out, for example, water and an organic solvent insoluble in water are added, neutralization is carried out if necessary, and then extraction, drying and removal of the solvent are carried out to obtain the desired product. Further, when the produced salt is insoluble, the desired product can be obtained by filtering and distilling off the solvent. The obtained target compound is, if necessary,
It can be separated and purified by a conventional method such as recrystallization, reprecipitation or silica gel column chromatography. (2) The lower alkyl group is introduced by reacting an alkyl halide in the presence of a base or in the presence or absence of a solvent.

The base used is, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal alkoxide such as sodium methoxide or potassium t-butoxide, sodium hydride or aluminum hydride. Mention may be made of metal hydrides or quaternary ammonium hydroxides such as quaternary trimethyl ammonium hydroxide.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as toluene, xylene or benzene, aliphatic hydrocarbons such as hexane, heptane or octane, cyclohexane or cyclohexane. Alicyclic hydrocarbons such as heptane, cyclic ethers such as tetrahydrofuran or dioxane, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether, dimethylformamide or dimethylacetamide. Amides or sulfoxides such as dimethyl sulfoxide, aromatic hydrocarbons such as toluene, xylene or benzene, and silanes. Preferred are alicyclic hydrocarbons such as rohexane or cycloheptane, cyclic ethers such as tetrahydrofuran or dioxane, or ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether. Is.

The reaction temperature will differ depending on the type of acid chloride and acid anhydride, but is usually -20 to 100 ° C, preferably 0 to 100 ° C, and particularly preferably 0 to 50 ° C.
℃.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 8 hours, particularly preferably 1 to 4 hours.

After completion of the reaction, conventional treatment is carried out, for example, water and an organic solvent insoluble in water are added, neutralized as necessary, extracted, dried, and the solvent is distilled off to obtain the desired product. Further, when the produced salt is insoluble, the desired product can be obtained by filtering and distilling off the solvent. If necessary, the obtained target compound can be separated and purified by a conventional method such as recrystallization, reprecipitation or silica gel column chromatography. (3) The SO ₃ H group is introduced by reacting sulfamic acid or sulfuric anhydride in the presence or absence of a solvent or in the presence of urea.

First, sulfamic acid or sulfuric anhydride is reacted in the presence or absence of a solvent and in the presence of urea to obtain SO.
Introduce a ₃ H group.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as toluene, xylene or benzene, aliphatic hydrocarbons such as hexane, heptane or octane, cyclohexane or cyclohexane. Alicyclic hydrocarbons such as heptane, cyclic ethers such as tetrahydrofuran or dioxane, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether, dimethylformamide or dimethylacetamide. Amides or sulfoxides such as dimethyl sulfoxide, aromatic hydrocarbons such as toluene, xylene or benzene, and silanes. Preferred are alicyclic hydrocarbons such as rohexane or cycloheptane, cyclic ethers such as tetrahydrofuran or dioxane, or ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether or diethylene glycol dimethyl ether. Is.

The reaction temperature varies depending on the type of acid chloride and acid anhydride, but is usually -20 to 100 ° C, preferably 0 to 100 ° C, and particularly preferably 0 to 50 ° C.
℃.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 8 hours, and particularly preferably 1 to 4 hours. If necessary, the obtained target compound can be separated and purified by a conventional method such as recrystallization, reprecipitation or silica gel column chromatography. (4) The P (O) (OH) ₂ group is introduced by reacting phosphorus pentoxide or polyphosphoric acid in the presence or absence of a solvent.

The solvent to be used is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as toluene, xylene and benzene, aliphatic hydrocarbons such as hexane, heptane and octane, cyclohexane and cyclohexane. Alicyclic hydrocarbons such as heptane, tetrahydrofuran, cyclic ethers such as dioxane, diethyl ether,
Suitable are ethers such as diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethyl sulfoxide, such as toluene, xylene and benzene. Aromatic hydrocarbons, cyclohexane, cycloaliphatic hydrocarbons such as cycloheptane, tetrahydrofuran,
Cyclic ethers such as dioxane, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
Ethers such as diethylene glycol dimethyl ether are particularly suitable. The reaction temperature is not particularly limited,
The temperature is usually room temperature to 200 ° C, preferably room temperature to 15 ° C.
It is 0 ° C., and particularly preferably room temperature to 100 ° C.

The reaction temperature varies depending on the type of acid chloride and acid anhydride, but is usually room temperature to 200 ° C., preferably room temperature to 150 ° C., particularly preferably room temperature to 1 ° C.
It is 00 ° C.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, preferably 1 to 8 hours, particularly preferably 1 to 4 hours.

If necessary, the desired compound thus obtained is subjected to a conventional method,
For example, it can be separated and purified by recrystallization, reprecipitation or silica gel column chromatography. (5) The CH ₂ COOH group is reacted with a monochloroacetic acid alkyl ester or a monobromoacetic acid alkyl ester in the presence of a base, and then the ester group is alkali-hydrolyzed and introduced.

The base used is, for example, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium t-butoxide, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, sodium hydride or hydrogenated. Examples thereof include metal hydroxides such as aluminum, and particularly preferable examples include alkali metal alkoxides. The organic solvent used is not particularly limited as long as it does not participate in the reaction, but aromatic hydrocarbons such as toluene, xylene and benzene, aliphatic hydrocarbons such as hexane, heptane and octane, cyclohexane and cycloheptane. Alicyclic hydrocarbons such as, tetrahydrofuran, cyclic ethers such as dioxane, diethyl ether, diisopropyl ether,
Ethers such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dimethylformamide,
Amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide are preferable, and aromatic hydrocarbons such as toluene, xylene and benzene, cyclohexane, alicyclic hydrocarbons such as cycloheptane, tetrahydrofuran, Cyclic ethers such as dioxane, diethyl ether, diisopropyl ether,
Ethers such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether are particularly suitable. The reaction temperature is not particularly limited, but is usually room temperature to 200 ° C., preferably room temperature to 150 ° C., and particularly preferably room temperature to 120 ° C.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, particularly preferably 1 to 12 hours, and particularly preferably 1 to 8 hours.

The obtained target compound can be used as it is in the next step, but if necessary, it can be separated and purified by a conventional method such as recrystallization, reprecipitation or silica gel column chromatography.

The step of alkali-hydrolyzing the ester group to a carboxylic acid or a carboxylic acid salt is accomplished using an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

If the solvent used does not participate in the reaction,
Although not particularly limited, alcohols such as methanol, ethanol, propanol, butanol and t-butanol,
Tetrahydrofuran, cyclic ethers such as dioxane, amides such as dimethylformamide, dimethylacetamide are preferable, and methanol, ethanol,
Alcohols such as propanol, butanol and t-butanol are particularly suitable.

The reaction temperature is not particularly limited, but is usually room temperature to 100 ° C., preferably room temperature to 80 ° C.,
Particularly preferably, the temperature is from room temperature to 50 ° C.

The reaction time varies depending on the reaction temperature, but is usually 1 to 24 hours, particularly preferably 1 to 12 hours, and particularly preferably 1 to 6 hours.

After the reaction, the acid can be adjusted to pH 2 to 4 with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, extracted with a solvent, dried and the solvent is distilled off to obtain a carboxylic acid.

Solvents used for extraction include halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene, xylene and benzene, esters such as ethyl acetate and methyl acetate, diethyl. Ethers such as ether and diisopropyl ether are preferable, and halogenated hydrocarbons such as methylene chloride and chloroform are particularly preferable.

If necessary, the desired compound thus obtained is subjected to a conventional method,
For example, it can be separated and purified by recrystallization, reprecipitation or column chromatography. (6) COCH ₂ CH
The (SO ₃ H) COOH group can be obtained by esterification reaction with maleic anhydride in the presence of a catalytic amount of sodium acetate, and then reaction with an aqueous solution of sodium sulfite.

The reaction temperature for the esterification is usually 50 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C., particularly preferably 70 ° C. to 100 ° C.

The reaction temperature with an aqueous solution of sodium sulfite is
Usually, it is 50 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C., and particularly preferably 70 ° C. to 100 ° C.

The compounds obtained in the above (3), (4), (5) and (6) can be converted into a desired salt by reacting a base with a conventional method, if necessary.

The vitamin E derivative of the present invention is vitamin E.
Alternatively, it is more excellent in moisturizing property than polyethoxylated vitamin E and has an antioxidant effect, and therefore it is useful as a base for cosmetics, external ointment for skin, etc., either alone or as a mixture.
Furthermore, since the vitamin E derivative of the present invention also has properties as a surfactant such as an emulsifier or a solubilizer, it can be used as an emulsifier for medicines, foods, cosmetics and the like.

[0062]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto. Example 1 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
28 (l = 14, n = 14), m = 2) An autoclave was charged with 60.5 g of DL-α-tocopherol (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.24 g of potassium hydroxide as an alkali catalyst. After replacing the inside of the can with nitrogen gas, raise the temperature to 100 to 110 ° C.,
Dehydrate for 0.5 hour. Then, the temperature is raised to 130 to 140 ° C., and 86.5 g of ethylene oxide (Nippon Shokubai Co., Ltd.) is injected under pressure over 1.5 hours. Aging for 1.0 hour while maintaining the same temperature. Next, 16.3 g of propylene oxide (Nippon Shokubai Co., Ltd.) was injected under pressure over 0.5 hours and then aged for 2.0 hours. Finally, 86.3 g of ethylene oxide was press-fitted over 1.0 hour, followed by aging for 1.0 hour. After the completion of aging, the mixture was cooled, the product was neutralized and purified with a phosphoric acid aqueous solution, and the produced salt was filtered to obtain the desired product 210.
0 g (yield 84.0%) was obtained. Infrared absorption spectrum
ν cm ^-1 (neat): 2868.0, 1458.1, 134
9.2, 1253.2, 1105.9, 1043.1, 99
5.2, 941.7, 869.1, 854.2. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ
ppm: 0.83 to 0.87 (12H, m), 1.05
1.83 (32H, m), 2.07 (3H, s), 2.1
3 (3H, s), 2.17 (3H, s), 2.56 (1
H, t, J = 6.7 Hz), 3.38 to 3.81 (120
H, m). Example 2 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
18 (l = 9, n = 9), m = 2) 65.0 of DL-α-tocopherol was added to the autoclave.
g, and 0.26 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature is raised to 40 ° C., and 59.8 g of ethylene oxide is injected under pressure for 1.0 hour. Aging for 1.0 hour while maintaining the same temperature. Next, 17.5 g of propylene oxide was injected under pressure for 0.5 hours and then aged for 2.0 hours. Finally, 59.8 g of ethylene oxide was injected under pressure over 1.0 hour, followed by aging for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 171.0 g of the desired product (yield 84.5%). Infrared absorption spectrum νcm ^-1 (neat): 2919.
8,2869.7,1460.4,1348.8,125
7.3, 1105.6, 951.4, 924.9. Example 3 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
18 (l = 18, n = 0), m = 2) 96.9 of DL-α-tocopherol was added to the autoclave.
g, and 0.39 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature was raised to 40 ° C, and 26.1 g of propylene oxide
Is pressed in for 0.5 hour. 2.5 while maintaining the same temperature
Let it mature for hours. Next, 178.2 g of ethylene oxide
After press-fitting over 2.5 hours, it is aged for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The generated salt was filtered to obtain 256.5 g of the desired product (yield 85.0%). Infrared absorption spectrum νcm ^-1 (neat): 2864.
2,1461.3,1347.7,1250.1,110
5.5, 944.5. Example 4 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
16 (l = 16, n = 0), m = 4) 94.5 of DL-α-tocopherol was added to the autoclave.
g, and potassium hydroxide 0.38 g as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature was raised to 40 ° C, and propylene oxide was 50.9 g.
Is pressed in for 1.5 hours. 2.0 while maintaining the same temperature
Let it mature for hours. Next, ethylene oxide 154.5g
After press-fitting over 1.5 hours, it is aged for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 246.5 g of the desired product (yield 82.1%). Infrared absorption spectrum νcm ^-1 (neat): 2866.
6,1458.2,1375.8,1254.9,110
8.9, 938.5. Example 5 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
30 (l = 16, n = 14), m = 2) 46.4 with DL-α-tocopherol in an autoclave
g, and 0.18 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature is raised to 40 ° C., and 66.4 g of ethylene oxide is injected under pressure for 1.5 hours. Aging for 2.0 hours while maintaining the same temperature. Next, 12.5 g of propylene oxide was injected under pressure over 0.5 hours, and then aged for 1.5 hours. Finally, 75.8 g of ethylene oxide was injected under pressure over 1.0 hour, followed by aging for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 161.0 g of the desired product (yield 80.0%). Infrared absorption spectrum νcm ^-1 (neat): 2868.
6,1462.9, 1350.0, 1252.8, 110
1.8, 942.6, 873.6. Example 6 Polyoxyethylene polyoxypropylene
Recall-mono-D-α-tocopherol (l + n = 3
0 (l = 16, n = 14), m = 2) 83.3 D-α-tocopherol was added to the autoclave.
g, and 0.22 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature is raised to 40 ° C., and 79.8 g of ethylene oxide is injected under pressure for 1.0 hour. Aging for 2.0 hours while maintaining the same temperature. Next, 15.0 g of propylene oxide was injected under pressure over 0.5 hours, and then aged for 1.5 hours. Finally, 91.2 g of ethylene oxide was press-fitted over 1.5 hours, followed by aging for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 238.0 g of the desired product (yield 88.3%). Infrared absorption spectrum νcm ^-1 (neat): 2862.
7,2925.0,1460.3,1254.6,124
8.9, 1105.7, 952.9, 846.0. Example 7 Polyoxyethylene polyoxypropylene
Recall-mono-DL-α-tocopherol (l + n =
28 (l = 14, n = 14), m = 2) sulfate ester
Thorium salt Polyoxyethylene polyoxypropylene glycol-mono-DL-α-synthesized in Example 1 in a four-necked flask
5 tocopherols (l = 14, m = 2, n = 14)
0.4 g is sampled and heated to 100 to 110 ° C. for dehydration. While maintaining the same temperature, 0.81 g of urea and 3.96 g of sulfamic acid were added in several portions. After aging at the same temperature for 3 hours, the mixture is cooled, 50 g of methanol and 1.3 g of aqueous ammonia are added, and filtration is performed. 50% in the obtained liquid
2.5 g of an aqueous sodium hydroxide solution was added and heated to remove methanol to obtain 49.0 g of the desired product (yield 91.8%). Infrared absorption spectrum νcm ^-1 (neat): 2868.
2,1459.6,1348.8,1253.6,110
5.7, 1032.3, 859.7, 946.8. Example 8 Polyoxyethylene polyoxypropylene
Recall-mono-D-α-tocopherol (l + n = 1
0 (l = 8, n = 2), m = 2) 142. DL-α-tocopherol in autoclave.
9 g and 0.57 g of potassium hydroxide as an alkali catalyst are charged. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130 ~
The temperature was raised to 140 ° C and 29.2 g of ethylene oxide was added.
Is pressed in for 15 minutes. Aging for 1.0 hour while maintaining the same temperature. Next, 38.5 g of propylene oxide was injected under pressure over 0.5 hours and then aged for 3.0 hours. Finally, 117.2 g of ethylene oxide was injected under pressure for 1.5 hours, and then aged for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 245.0 g of the desired product (yield 74.6%). Infrared absorption spectrum νcm ^-1 (neat): 2925.
3,1459.7, 1376.0, 1350.4, 125
6.5, 1113.5, 943.3. Example 9 Polyoxyethylene polyoxypropylene
Recall-mono-D-α-tocopherol (l + n = 1
2 (l = 10, n = 2), m = 2) 142. DL-α-tocopherol in autoclave.
7 g and 0.57 g of potassium hydroxide as an alkali catalyst are charged. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130 ~
The temperature was raised to 140 ° C, and ethylene oxide 29.1 g
Is pressed in for 15 minutes. Aging for 1.0 hour while maintaining the same temperature. Next, 38.4 g of propylene oxide was injected under pressure over 0.5 hours and then aged for 3.0 hours. Finally, 146.2 g of ethylene oxide was injected under pressure over 1.0 hour, followed by aging for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 276.0 g of the desired product (yield 77.3%). Infrared absorption spectrum νcm ^-1 (neat): 2925.
8,1459.6,1375.9,1350.2,125
6.1, 1124.0, 943.3. Example 10 Polyoxyethylene polyoxypropylene
Glycol-mono-D-α-tocopherol (l + n =
14 (l = 12, n = 2), m = 2) 135-DL-α-tocopherol in the autoclave.
4 g and 0.54 g of potassium hydroxide as an alkali catalyst are charged. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130 ~
The temperature is raised to 140 ° C. and ethylene oxide 27.7 g
Is pressed in for 15 minutes. Aging for 1.0 hour while maintaining the same temperature. Next, 36.5 g of propylene oxide was injected under pressure over 0.5 hours, and then aged for 3.0 hours. Finally, 167.2 g of ethylene oxide was press-fitted over 1.5 hours, followed by aging for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The generated salt was filtered to obtain 303.0 g of the desired product (yield 82.5%). Infrared absorption spectrum νcm ^-1 (neat): 2926.
0,1459.3, 1413.6, 1375.7, 135
0.0,1297.3,1255.7,1116.6,94
3.9. Example 11 Polyoxyethylene polyoxypropylene
Glycol-mono-D-α-tocopherol (l + n =
16 (l = 14, n = 2), m = 2) 119. DL-α-tocopherol in the autoclave.
Charge 5 g and 0.48 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130 ~
The temperature was raised to 140 ° C, and ethylene oxide 24.4 g
Is pressed in for 15 minutes. Aging for 1.0 hour while maintaining the same temperature. Next, 32.1 g of propylene oxide was press-fitted over 0.5 hours and then aged for 3.0 hours. Finally, 171.9 g of ethylene oxide was injected under pressure for 1.5 hours, and then aged for 2.0 hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 265.6 g (yield: 76.2%) of the desired product. Infrared absorption spectrum νcm ^-1 (neat): 2868.
1,1459.6,1413.6,1375.7,134
9.8, 1297.3, 1255.3, 1116.4, 94
4.8. Example 12 Polyoxyethylene polyoxypropylene
Glycol-mono-DL-α-tocopherol (l + n
= 14 (l = 14, n = 0), m = 2) sulfate Es Terqa
Lithium salt 111. Add DL-α-tocopherol to the autoclave.
Charge 0 g and 0.44 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130 ~
The temperature was raised to 140 ° C, and propylene oxide was 29.9.
Then, the solution is agitated for 0.5 hour and then aged for 3.0 hours. Next, 158.7 g of ethylene oxide was injected under pressure for 1.5 hours, and then aged for 2.0 hours. After completion of aging, the mixture was cooled, and 280.0 g of polyoxyethylene polyoxypropylene glycol-mono-DL-α-tocopherol (l = 14, m = 2, n = 0) synthesized in a four-necked flask was collected,
Dehydration is performed by raising the temperature to 100 to 110 ° C. While maintaining the same temperature, 4.41 g of urea and 30.9 g of sulfamic acid are added in several portions. After aging at the same temperature for 3 hours, the mixture is cooled, 260 g of methanol and 4.3 g of aqueous ammonia are added, and the mixture is filtered. 1 part of potassium hydroxide was added to the obtained liquid.
Add 3.8 g and heat to remove methanol to give 230
g (yield 75.8%) was obtained. Example 13 Polyoxyethylene polyoxypropylene
Glycol-mono-DL-α-tocopherol (l + n
= 14 (l = 14, n = 0), m = 2) phosphate ester
DL-α-tocopherol 96.2 in potassium salt autoclave
g, and potassium hydroxide 0.38 g as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
The temperature was raised to 40 ° C., and 25.9 g of propylene oxide
After press-fitting over 0.5 hour, it is aged for 3.0 hours. Next, 137.5 g of ethylene oxide was injected under pressure over 1.5 hours and then aged for 2.0 hours. After completion of aging, the mixture was cooled and synthesized in a beaker. Polyoxyethylene polyoxypropylene glycol-mono-DL-α-tocopherol (l = 1
4, m = 2, n = 0) 240.0 g was collected, and 100-
Dehydration is performed by raising the temperature to 110 ° C. Cool after dehydration 40
While raising the temperature from 80 ° C to 80 ° C, 10.21 g of phosphoric anhydride was added in several batches. After aging at 80 ° C for 4.5 hours, the mixture was cooled and 70 g of methanol and potassium methylate 9.
Add 71 g. After filtering the obtained methanol solution, methanol was removed to obtain 171.3 g of the target product (yield: 68.5%). Example 14 Monopolyoxyethylene polyoxypropyene
Lenglycol-mono-DL-α-tocopherol (l
+ N = 16 (l = 14, n = 2), m = 2) sulfocoha
Polyoxyethylene polyoxypropylene glycol prepared in Example 11 to click disodium autoclave - mono -DL-alpha
-10 tocopherols (l = 14, m = 2, n = 2)
Collect 0.0g and charge 7.84g of maleic anhydride and 0.50g of anhydrous sodium acetate. After replacing the inside of the can with nitrogen gas, the temperature is raised to 70 to 80 ° C. and the esterification reaction is carried out for 3 hours. 104.1 g of the maleate compound obtained by the reaction in an autoclave is charged in advance in 174.3 g of pure water into a four-neck flask in which 10.1 g of anhydrous sodium sulfite is dissolved at 40 to 50 ° C. The temperature was raised to 70 to 80 ° C., and the mixture was sulfonated and stirred at the same temperature for 3.0 hours. Cool the reaction and 20
The pH was adjusted to 6.5 with an aqueous sodium hydroxide solution to obtain 290.0 g (yield 98.0%) of an aqueous solution of the target product. Example 15 Monopolyoxyethylene polyoxypropyene
Lenglycol-mono-DL-α-tocopherol (l
+ N = 16 (l = 14, n = 2), m = 2) sodium acetate
Polyoxyethylene polyoxypropylene glycol-mono-DL-α synthesized in Example 11 in a four-necked Umium salt flask.
-2 tocopherols (l = 14, m = 2, n = 2)
Collect 5.0 g. After 750 ml of toluene is added, azeotropic dehydration is carried out at 100 to 110 ° C. for 1 hour under a nitrogen atmosphere, and then cooled to 30 ° C. 32.0 ml of 1.0 M potassium-tert-butoxide / tert-butanol solution was added, and the mixture was stirred at room temperature for 1 hour.
Stir for hours. After 1 hour, ethyl bromoacetate 18.68 g
Is added and the mixture is heated to reflux for 2 hours with stirring at 110 ° C. to react. After reaction, let stand to cool to 30 ° C and keep at room temperature for 1
Stir for 8 hours. After completion of stirring, celite filtration was performed and toluene was removed by an evaporator to obtain 20.5 g of carboxylic acid ethyl ester. Next, 20.5 g of carboxylic acid ethyl ester obtained in a four-necked flask and 1
Charge 200 ml of N-NaOH and react at room temperature for 4 hours. After completion of the reaction, the mixture is cooled to 5 ° C and the pH is adjusted to 3 with 2N-HCl. The reaction solution is 100 ml of methylene chloride
After extracting 5 times with water and washing with 50 ml of pure water, the solvent was distilled off to obtain 20.1 g of carboxylic acid. Carboxylic acid 20.
1 g was dissolved in 100 ml of methanol and 0.83 g of sodium methoxide in methanol was added to replace sodium.
9%) was obtained. Comparative Example Polyoxyethylene glycol-mono-DL-α
-Tocopherol (l + n = 30 (l = 30, n =
0), m = 0) DL-α-tocopherol was added to the autoclave at 50.7
g, and 0.20 g of potassium hydroxide as an alkali catalyst. After substituting the inside of the can with nitrogen gas, the temperature is raised to 100 to 110 ° C. and dehydration is performed for 0.5 hour. Then 130-1
155.3g of ethylene oxide
Is pressed in for 4.0 hours. 2.0 while maintaining the same temperature
Let it mature for hours. After the completion of aging, the mixture is cooled and the product is neutralized and purified with a phosphoric acid aqueous solution. The produced salt was filtered to obtain 172.0 g of the title compound (yield 83.4%). Infrared absorption spectrum νcm ^-1 (neat): 2865.
9, 1458.7, 1350.7, 1252.2, 11
04.9, 946.3. Test Example 1. Moisture retention test Example 1, Example 2, Example 7, Comparative Example and DL-α-
Using tocopherol as a sample, it is dried in a desiccator, and about 0.2 g of each is collected in a petri dish. The collected sample is left in a desiccator whose humidity is adjusted in advance, and the moisturizing property of the sample is determined over time. In addition, the measurement is for 48 hours after leaving it in a desiccator with a humidity of 75% for 48 hours.
After 72 hours.

The moisturizing property was calculated by the following formula.

[0064]

[Formula 1]

The results of the moisture retention test are shown in Table 1.

[0066]

[Table 1]

Polyoxyethylene polyoxypropylene glycol-mono-D of Examples 1, 2 and 7
The L-α-tocopherol derivative is DL-α-tocopherol or polyethylene glycol-mono-DL-of Comparative Example.
It showed higher moisturizing properties than α-tocopherol. Test Example 2. Solubilization test (1) DL-α-tocopherol and the polyoxyethylene polyoxypropylene glycol mono-synthesized in Example 1
DL-α-tocopherol (l + n = 28 (l = 14,
Ion-exchanged water was added to n = 14) and m = 2) so as to have a concentration of 1% by weight. Benzyl acetate (Wako Pure Chemical Industries, Ltd.) was added little by little to this aqueous solution, and the solubilizing power was examined at room temperature. The solubilizing power was visually confirmed. Since DL-α-tocopherol was not dissolved in water at a concentration of 1% by weight, 100 g of a 1% DL-α-tocopherol aqueous solution did not solubilize 0.05 g of benzyl acetate. However, 1% of polyoxyethylene polyoxypropylene glycol-mono-DL-α-tocopherol synthesized in Example 1
100 g of the aqueous solution solubilized 0.35 g of benzyl acetate. Therefore, the compound of Example 1 has an excellent solubilizing power and also has a characteristic as a surfactant. Test Example 3 Solubilization Test (2) Polyoxyethylene polyoxypropylene glycol-mono-DL-α-tocopherol synthesized in Examples 8 to 11 and potassium sulfate salt synthesized in Examples 12 and 13, 0.20 g of each phosphoric acid ester potassium salt was collected in a sample bottle, and 0.10 g of tocopherol acetate (Wako Pure Chemical Industries, Ltd.) was added and dissolved in ethanol. 150 ml of purified ethanol solution
In addition, the solution after washing the sample bottle with 50 ml of pure water is added with stirring to conduct a solubilizing power test. The solubilization was confirmed visually. These solubilizing powers were compared to a 20 mole product of hydrogenated castor oil EO. The results are shown in Table 2.

[0068]

[Table 2]

Hardened castor oil EO 20 mol product has a sample amount of 0.
With 20 g and tocopherol acetate 0.10 g, the solution became white without being solubilized. However, in all the samples of Examples 8 to 13 with a sample amount of 0.20 g, tocopherol acetate of 0.2.
10 g was solubilized. Particularly in Example 8, the sample amount was 0.15.
Also in g, 0.10 g of tocopherol acetate was solubilized. Therefore, the compounds of Examples 8 to 13 have an excellent solubilizing power as compared with the 20 mol EO adduct of hydrogenated castor oil, and have excellent characteristics as a surfactant.

[0070]

INDUSTRIAL APPLICABILITY The vitamin E derivative of the present invention is excellent in moisturizing property as compared with vitamin E or polyethoxylated vitamin E, and has an antioxidant effect, and is therefore extremely useful in practice as a base for cosmetics and external ointment for skin. Is. Further, since the vitamin E derivative of the present invention also has properties as a surfactant such as an emulsifier or a solubilizer, it can be used as an emulsifier for pharmaceuticals, foods, cosmetics and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 39/06 A61P 39/06 F term (reference) 4B018 MD26 ME10 MF10 4C083 AC841 CC01 DD31 EE12 FF01 4C086 AA02 AA03 MA01 MA04 NA05 ZA89 ZB21 4H050 AA01 AA03 AB10 AB12 AB20

Claims (14)

[Claims] 1. The following general formula (I): [Wherein R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or a methyl group, R ₄ represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms] Group, SO ₃ H group, P (O) (OH) ₂ group, CH ₂ COO
H group or COCH ₂ CH (SO ₃ H) COOH group,
EO represents an ethyleneoxy group, PO represents a propyleneoxy group, l and n independently represent 0 to 30, and
m represents 1 to 30. ] The vitamin E derivative which has these, or its salt. 2. The vitamin E derivative or a salt thereof according to claim ₁ , wherein R ₁ , R ₂ and R _{3 in the} general formula (I) are methyl groups. 3. Vitamin E according to claim 1, wherein R ₁ and R ₂ of the general formula (I) are methyl groups and R ₃ is a hydrogen atom.
Derivative or salt thereof. 4. Vitamin E according to claim 1, wherein R ₂ and R _{3 in} the general formula (I) are methyl groups and R ₁ is a hydrogen atom.
Derivative or salt thereof. 5. The vitamin E derivative or a salt thereof according to claim 1, wherein R ₁ , R ₂ and R _{3 in the} general formula (I) are hydrogen atoms. 6. R ₄ of the general formula (I) is a hydrogen atom, acetyl group, methyl group, ethyl group, SO ₃ H group, P (O) (O).
H) ₂ group, CH ₂ COOH group or COCH ₂ CH (SO
The vitamin E derivative or a salt thereof according to any one of claims 1 to 5, which is a ₃ H) COOH group. 7. The vitamin E derivative according to any one of claims 1 to 5, wherein R _{4 in the} general formula (I) is a hydrogen atom. 8. The vitamin E derivative or a salt thereof according to claim 1, wherein 1 is 0 to 20, m is 1 to 5, and n is 0 to 20. 9. A medicine containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8. 10. A cosmetic containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8. 11. A food containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8. 12. A pharmaceutical additive containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8. 13. A cosmetic additive containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8. 14. A food additive containing the vitamin E derivative or the salt thereof according to any one of claims 1 to 8.