KR0133533B1 - Ascorbic acid derivatives - Google Patents

Abstract

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Description

Ascorbic acid derivatives

The present invention relates to an ascorbic acid derivative, a method for preparing the same, and an antioxidant containing the ascorbic acid derivative.

Ascorbic acid acts as an antioxidant and is used to prevent browning of foods and to maintain the flavor or freshness of foods.

However, ascorbic acid is liable to decompose and sometimes it is difficult to obtain the effect for a long time.

Therefore, a first object of the present invention is to provide a novel ascorbic acid derivative in which the above disadvantage of ascorbic acid is solved. It is a second object of the present invention to provide a method for preparing the novel ascorbic acid derivative. Furthermore, a third object of the present invention is to provide an antioxidant containing an ascorbic acid derivative.

A first object of the present invention is achieved by an ascorbic acid derivative of the general formula (Ia).

(Wherein R ₁ is a group selected from the group consisting of a heterocyclic-containing alkyl group, an alkylcarbonylalkyl group, an arylcarbonylalkyl group and an alkoxycarbonylalkyl group containing a terminal alkoxy group of at least 7 carbon atoms)

A second object of the present invention is ascorbic acid of the general formula (Ia), characterized in that the compound of the general formula (II) is treated with an acid to open the dioxolane ring in the compound to produce a vic-glycol group. It is achieved by a process for the preparation of derivatives.

(Wherein R ₁ is a group selected from the group consisting of a heterocyclic-containing alkyl group, an alkylcarbonylalkyl group, an allylcarbonylalkyl group and an alkoxycarbonylalkyl group containing a terminal alkoxy group of at least 7 carbon atoms)

Furthermore, a third object of the present invention is achieved by an antioxidant containing an ascorbic acid derivative of the general formula (IA).

(Wherein R ₂ is a group selected from the group consisting of an alkyl group, a heterocyclic containing-alkyl group, an aralkyl group, a hydroxykicarbonylalkyl group, an almoxicarbonylalkyl group, an alkylcarbonylalkyl group and an arylcarbonylalkyl group.)

The group R ₁ in the general formula (Ia) representing the novel ascorbic acid derivative of the present invention is different from the number of substituents defined in the group R ₂ in the general formula (IA) representing the antioxidant-ascorbic acid derivative of the present invention. R ₁ contains four substituents, but R ₂ contains a total of seven substituents including these four. While the alkoxycarbonylalkyl group in the R ₁ group of formula (Ia) is limited to containing at least seven carbon atom terminal alkoxy groups, this limitation does not apply to the alkoxycarbonylalkyl group in the R ₂ group of formula (IA). . This means that ascorbic acid derivatives except general formula (Ia), which defines novel ascorbic acid derivatives, can also be used as antioxidants of the present invention.

First, the novel ascorbic acid derivative of the present invention will be described below.

The novel ascorbic acid derivative of the present invention is represented by the following general formula (Ia).

(Wherein R ₁ is a group selected from the group consisting of a heterocyclic-containing alkyl group, an alkylcarbonylalkyl group, an allylcarbonylalkyl group and an alkoxycarbonylalkyl group containing a terminal alkoxy group of at least 7 carbon atoms)

Here, as the heterocyclic-containing alkyl group, a heterocyclic-containing alkyl group containing 1 to 3 nitrogen atoms in the ring is preferable, and examples thereof include the groups generally shown below.

Wherein R ₃ is an alkylene group which may optionally contain a side chain.

In particular, preferred heterocyclic-containing alkyl groups are pyridylmethyl group, pyrimidylmethyl group, triazylmethyl group and the like.

Examples of the alkylcarbonylalkyl group include a group represented by the following general formula.

(Wherein R ₄ is an alkylene group which may not optionally contain a side chain; R ₅ is an alkyl group which may optionally contain a side chain.)

Particularly preferred alkylcarbonylalkyl groups are -CH ₂ -CO-CH ₃ , -CH ₂ -CO-C ₂ H _5, and the like.

Moreover, examples of the arylcarbonylalkyl group include a group represented by the following general formula.

(Wherein R ₆ is an alkylene group which may optionally contain a side chain; Ar is an aryl group which may optionally contain a substituent on the ring.)

Particularly preferred arylcarbonylalkyl groups are -CH ₂ -CO-C ₆ H ₅ and the like.

Examples of the alkoxycarbonylalkyl group containing at least seven carbon atom terminal alkoxy groups include groups represented by the following general formula.

(Wherein R ₇ is an alkylene group which may optionally contain a side chain and R ₈ is an alkyl group of 7 or more carbon atoms which may optionally contain a side chain.)

Particularly preferred alkoxycarbonylalkyl groups are -CH ₂ -CO-OnC ₁₀ H ₂₁ and the like.

The novel ascorbic acid derivatives of the present invention have excellent antioxidant activity and can preferably be used as antioxidants in foods or cosmetic and whitening cosmetics.

The method for producing a novel ascorbic acid derivative of general formula (Ia) described above will be described below.

In the preparation of the present invention, the compound of the following general formula (II) is used as starting material.

(Wherein R ₁ is a group selected from the group consisting of a heterocyclic-containing alkyl group, an alkylcarbonylalkyl group, an arylcarbonylalkyl group and an alkoxycarbonylalkyl group containing a terminal alkoxy group of at least 7 carbon atoms)

Compound of formula (II) catalyzes ascorbic acid by a conventional method to prepare 5,6-O-isopropylidene ascorbic acid of the following formula (III), and then to prepare compound (III) Is reacted with an organic halide of formula R ₁ X (wherein R ₁ is the same as R _{1 in} formula (II) and X is a halogen atom) to etherify the hydroxyl group at position 3 of compound (III). Obtained by. This dehydrohalation reaction can be carried out by the Williamson reaction or in an organic phase-aqueous phase using a phase transfer catalyst.

According to the production method of the present invention, a vic-glycol group is prepared by subjecting compound (II) as a starting material to ring-open the dioxolane ring of the compound. Thus, the ascorbic acid derivative of the objective represented by general formula (Ia) is obtained.

Examples of the acid used for the reaction include hydrochloric acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid and the like. The reaction is preferably carried out in at least one organic solvent selected from methanol, ethanol, dioxane, tetrahydrofuran and 1,2-dimethoxyethane.

The antioxidant of the present invention will be described below.

As mentioned above, the antioxidant of the present invention contains an ascorbic acid derivative of the general formula (IA).

The R ₂ group in formula (IA) is within a broader range than the R ₁ group in formula (Ia), which represents a novel ascorbic acid derivative as constant, so ascorbic acid derivatives of formula (IA) are also known compounds It may also include.

That is, the R ₂ group contains four kinds of substituents (heterocyclic-containing alkyl group, alkylcarbonylalkyl group, arylcarbonylalkyl group and alkoxycarbonylalkyl group) similar to the R ₁ group, and in addition to these, an alkyl group, an aralkyl group and a hydroxycar It contains three types of substituents of a carbonylalkyl group. The term alkyl in the above substituents refers to a straight or branched chain alkyl group. Although the alkoxycarbonylalkyl group in the R ₁ group of formula (Ia) is limited to containing at least 7 carbon atom terminal alkoxy groups, the R ₂ group of formula (IA) includes a wide range of alkoxycarbonylalkyl groups without such limitation.

Ascorbic acid derivatives represented by the general formula (IA) are preferably used as antioxidants because they do not have radical scavenging ability and are superior in stability to ascorbic acid and conventional ascorbic acid derivatives.

Examples of the present invention will be described below.

Preparation Example 1 [Preparation of New Ascorbic Acid Derivative (Ia)]

(1) Synthesis of L-5,6-O-isopropylidene ascorbic acid

180 g of ascorbic acid is stirred in 750 ml of acetone and warmed to 40 ° C. 20 ml volume of acetylchloride is added and a suspension layer is formed with continuous stirring.

After 3 hours, the suspension layer is ice cooled and the precipitate is collected by filtration. The precipitate obtained is washed with acetone-n-hexane cold mixture (3: 7) on a funnel and dried over silica gel under reduced pressure.

After recrystallization with acetone, 190 g of L-5,6-O-isopropylidene ascorbic acid (melting point: 206-208 DEG C) is obtained.

(2) Synthesis of L-5,6-O-isopropylidene-3-O-benzoylmethyl ascorbic acid

4.32 g of the compound obtained in (1) is dissolved in 30 ml of DMSO. After adding 1.78 g of NaHCO ₃ , the resulting solution is stirred at room temperature for 30 minutes. To this solution is added 4.37 g of phenacylbromide and the resulting solution is warmed to 40 ° C. and stirred for 18 hours. After cooling, 80 ml of H ₂ O was added and the pH was adjusted to 5 with 4N hydrochloric acid. The pH-adjusted solution is shaken with ethyl acetate (100 ml x 2). The organic layer is combined with water and saturated aqueous sodium chloride solution, washed, dried over sodium sulfate and concentrated under reduced pressure. The obtained oily substance is subjected to silica gel column chromatography and coagulated with a mixture of benzene-ethyl acetate to give L-5,6-O-isopropylidene-3-O-benzoylmethylascorbic acid.

(3) Synthesis of L-3-O-benzoylmethyl ascorbic acid

Dissolve 3.3 g of the compound obtained in (2) in 40 ml of tetrahydrofuran-methanol mixture (3: 1), add 10 ml of 2N hydrochloric acid, and stir the resulting solution for 20 hours at room temperature. The reaction solution is concentrated under reduced pressure and the residue is recrystallized from ethyl acetate-petroleum ether to give L-3-O-benzoylmethyl ascorbic acid (corresponding to compound number 112 of Table 1).

The obtained compound (No. 112) of the present invention is used in the antioxidant test described below.

Preparation Example 2 [Preparation of New Ascorbic Acid Derivative (Ia)]

The process was carried out in the same manner as in Preparation Example 1 to obtain novel compounds (No. 110 and 115) shown in Table 1 below.

These compounds are used in the antioxidant tests described below.

Preparation Example 3 [Preparation of New Ascorbic Acid Derivative (Ia)]

(1) Synthesis of L-5,6-isopropylidene-3-O- (3-phycoyl) ascorbic acid

Dissolve 1.66 g of NaHCO ₃ in 40 ml of distilled water and add 80 ml of methylethylcatone. 4.32 g of L-5,6-O-isopropylidene ascorbic acid obtained in Preparation Example 1 (1) was added to the resulting solution. The resulting mixture is stirred and 3.26 g of 3-phycoylchloride, 1.66 g of NaHCO ₃ and 1.60 g of tetrabutylammonium bromide are added thereto. The resulting mixture is heated to 70 ° C. and stirred vigorously for 10 hours. The organic layer was separated and the aqueous layer was adjusted to pH 4 with 4NB hydrochloric acid and shaken with 100 ml of ethyl acetate. The organic layer is combined with water, washed, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography to elute with a benzene-ethyl acetate mixture to give L-5,6-isopropylidene-3-O- (3- picoyl) ascorbic acid.

(2) Synthesis of L-3-O- (3-Picoyl) Ascorbic Acid

The same procedure as in (3) of Production Example 1 was carried out except that the compound obtained in (1) was used. Recrystallization with benzene-petroleum ether yields L-3-O- (3-phycoyl) ascorbic acid (corresponding to compound number 113 in Table 1).

The obtained compound (No. 113) of the present invention is used in the antioxidant test described below.

Reference Example 1 Preparation of Other Ascorbic Acid Derivatives Contained in Ascorbic Acid Derivative (IA)

The process is carried out in the same manner as in Preparation Example 1 to obtain the compounds shown in Table 1 (Nos. 1,1, 102, 103, 104,105, 106, 107,108,109,111, and 114).

The compounds obtained are also used in the antioxidant test described below.

TABLE 1

Test Example 1 [Antioxidation Tested Using Stable Radicals]

The reducing activity of the stable free group α, α-diphenyl-β-picrylhydrazyl (DPPH) was tested by MSBlois method (Nature, vol. 181, page 1199, 1958) and used as an index for antioxidant activity. do. In this way, the sample is added to 3 ml of 0.1 mM-DPPH solution in ethanol, and after 20 minutes, the absorbance at 517 nm wavelength is measured using a spectrophotometer. The absorbance difference with the solvent control [0.5% or less of dimethylformamide (DMF)] is set as the reducing activity.

The 50% radical removal concentration for the test compound is shown in Table 2.

As can be seen from Table 2, the test compound of the present invention has improved antioxidant activity. It was also clarified that other compounds of Nos. 102 to 115 were superior in antioxidant power to those of No. 101 wherein R ₁ is a long chain alkyl group.

TABLE 2

As described above, the present invention provides a novel ascorbic acid derivative having excellent antioxidant activity and a method for producing the same. Moreover, the present invention also provides novel antioxidants containing the ascorbic acid derivatives described above or other known ascorbic acid derivatives.

Claims (23)

Ascorbic acid derivative represented by the following general formula (Ia).

[Wherein, R_OneIs a heterocyclic ring containing one nitrogen atom_One~ C₄Alkyl group, formula -R₄-CO-R₅(Wherein R₄ C_One~ C₄Alkylene group, R₅ C_One~ C₄Alkyl group), a formula -R₆-CO- t15 (where R₆ C_One~ C |₄Arylcarbonylalkyl group of the formula: -R₇-COOR₈(Wherein R₇ Is straight or branched C_One~ C₆Alkylene group, R₈ C₇~ C₁₂Alkyl group.] Is an alkoxycarbonylalkyl group. The ascorbic acid derivative according to claim 1, wherein the hetero ring-containing alkyl group is represented by the following general formula.

[Wherein, R₃ Is straight or branched C_One~ C₄Alkylene group.] The ascorbic acid derivative according to claim 2, wherein the heterocyclic-containing alkyl group is pyridylmethyl. The compound of claim 1 wherein R₄ Is straight or branched C_One~ C₄Alkylene group, R₄ Is straight or branched C_One~ C₄Ascorbic acid derivatives which are alkyl groups. The ascorbic acid derivative according to claim 4, wherein the alkylcarbonyl alkyl group is selected from the group consisting of -CH ₂ -CO-CH ₃ and -CH ₂ -CO-C ₂ H ₅ . The compound of claim 1 wherein R₆ Is straight or branched C_One~ C₄Ascorbic acid derivatives which are alkylene groups. The ascorbic acid derivative according to claim 6, wherein the allylcarbonylalkyl group is -CH ₂ -CO-C ₆ H ₅ . The compound of claim 1 wherein R₈ Is straight or branched C₇~ C₁₂Ascorbic acid derivatives which are alkyl groups. The ascorbic acid derivative according to claim 8, wherein the alkoxycarbonylalkyl group is -CH ₂ -COO-nC ₁₀ H ₂₁ . A process for producing an ascorbic acid derivative of formula (Ia), wherein the compound of formula (II) is treated with an acid to ring-open the dioxolane ring of the compound to produce a vic-glycol group.

[Wherein, R_OneIs a heterocyclic ring containing one nitrogen atom_One~ C₄Alkyl group, formula -R₄-CO-R₅(Wherein R₄ C_One~ C₄Alkylene group, R₅ C_One~ C₄Alkyl group), a formula -R₆-CO- t18 (where R₆ C_One~ C |₄Arylcarbonylalkyl group of the formula: -R₇-COOR₈(Wherein R₇ Is straight or branched C_One~ C₆Alkylene group, R₈ C₇~ C₁₂Alkyl group.] Is an alkoxycarbonylalkyl group. The production method according to claim 10, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and camphorsulfonic acid. The process according to claim 10, wherein the reaction is carried out in at least one organic solvent selected from the group consisting of methanol, ethanol, dioxane, tetrahydrofuran and 1,2, -dimethoxyethane. Antioxidant containing the ascorbic acid derivative of the following general formula (IA).

[Wherein, R₂Is a heterocyclic ring containing one nitrogen atom_One~ C₄Alkyl group, formula -R₄-CO-R₅(Wherein R₄ C_One~ C₄Alkylene group, R₅ C_One~ C₄Alkyl group), a formula -R₆-CO- t20 (where R₆ C_One~ C |₄Arylcarbonylalkyl group of the formula: -R₇-COOR₈(Wherein R₇ Is straight or branched C_One~ C₆Alkylene group, R₈ C_One~ C₁₂An alkoxycarbonylalkyl group, C_One~ C₂₀Alkyl group and C_One~ C₁₂And a hydroxycarbonylalkyl group having an alkyl group. The antioxidant according to claim 13, wherein the hetero ring-containing alkyl group is represented by the following general formula.

[Wherein, R₃ Is straight or branched C_One~ C₄Alkylene group.] 15. The antioxidant of claim 14, wherein said heterocyclic-containing alkyl group is pyridylmethyl. The compound of claim 13, wherein R₄ Is straight or branched C_One~ C₄Alkylene group, straight or branched C_One~ C₄Antioxidant which is an alkyl group. The antioxidant according to claim 16, wherein said alkylcarbonyl alkyl group is selected from the group consisting of -CH ₂ -CO-CH ₄ and -CH ₂ -CO-C ₂ H ₅ . The compound of claim 13, wherein R₆ Is straight or branched C_One~ C₄Antioxidant which is an alkylene group. 19. The antioxidant of claim 18, wherein said arylcarbonylalkyl group is -CH ₂ -CO-C ₆ H ₅ . The compound of claim 13, wherein R₈ C of this straight or branched chain_One~ C₁₂Antioxidant which is an alkyl group. The antioxidant of claim 20 wherein the alkoxycarbonylalkyl group is -CH ₂ -COO-nC ₁₀ H ₂₁ . The antioxidant according to claim 13, wherein the alkyl group is a straight or branched C ₁ to C ₂₀ alkyl group. The antioxidant according to claim 13, wherein the alkyl moiety of the hydroxycarbonylalkyl group is a straight chain or branched alkyl group.