HK1094451B - Ascorbic acid derivatives and skin-whitening cosmetics - Google Patents

Description

Ascorbic acid derivative and whitening cosmetic material

Technical Field

The present invention relates to an ascorbic acid derivative which can be used in cosmetics or non-medical drugs for whitening purposes, a method for producing the same, and a whitening cosmetic material.

Background

It is known that L-ascorbic acid (vitamin C) generally has an effect of inhibiting the synthesis of melanin in the skin and reducing the synthesized melanin to lighten it, in addition to a lipid peroxidation inhibiting effect, a collagen production promoting effect, an immune function enhancing effect, and the like, and can be used as a component of a whitening cosmetic material for improving symptoms such as "spots of old people" or "freckles" due to the melanin synthesis inhibiting effect and the melanin reduction effect.

However, L-ascorbic acid is very unstable to acids or oxidation and easily inactivated or decomposed, and thus sufficient physiological effects may not necessarily be obtained.

In order to improve such instability, it is known to use a derivative obtained by phosphorylating a diol moiety of L-ascorbic acid which is easily oxidized (see patent document 1) or a derivative obtained by glucuronidation (see patent document 2).

However, these L-ascorbic acid derivatives have a disadvantage that they are not desirable in terms of skin permeability because they have high hydrophilicity.

On the other hand, substances for improving skin permeability are known, which acylate the 6-position of L-ascorbic acid (patent document 3) and acylate the 4-position of L-ascorbic acid (patent document 4).

Further, as an L-ascorbic acid derivative improved in both stability and skin permeability, a derivative obtained by acylating L-ascorbic acid at the 6-position and then phosphorylating L-ascorbic acid at the 2-position is known (patent document 5).

Patent document 1: japanese patent publication No. 52-18191

Patent document 2: japanese unexamined patent publication Hei 03-139288

Patent document 3: japanese patent laid-open publication No. 59-170085

Patent document 4: japanese patent laid-open publication No. 45-23634

Patent document 5: japanese unexamined patent publication Hei 10-298174

However, as described above, the acyl group at the 6-position of L-ascorbic acid is esterified with a fatty acid in order to impart lipid solubility, and the resultant product is not satisfactory in thermal or light stability over time in a storage state, and the acyl group at the 2-position is esterified with a fatty acid, and thus, the conversion to L-ascorbic acid cannot be performed rapidly or sufficiently because there is not enough esterase or lipase in the epidermis.

In addition, a substance obtained by esterifying the acyl group at the 6-position of L-ascorbic acid and phosphorylating the acyl group at the 2-position does not have sufficient esterase or lipase in the epidermis as described above, and thus cannot be converted to L-ascorbic acid sufficiently.

Disclosure of Invention

Accordingly, the present invention has been made to solve the above-mentioned problems of L-ascorbic acid, and an object of the present invention is to provide a novel ascorbic acid derivative which can stabilize L-ascorbic acid against heat or light, has good storage stability and high skin permeability, can be rapidly hydrolyzed by phosphatase widely distributed in the living body, and can exert the original physiological activity of L-ascorbic acid useful for health, and a method for producing the same.

It is another object of the present invention to solve the problems of conventional whitening components for cosmetic materials and to provide a novel whitening cosmetic material which can maintain stable L-ascorbic acid against heat or light, has good storage stability and high skin permeability, can be rapidly decomposed by the action of enzymes widely distributed in the living body, and can exert the original physiological activity of L-ascorbic acid useful for whitening the skin.

In order to solve the above problems, the present invention provides an ascorbic acid derivative comprising L-ascorbic acid-2-phosphate represented by the following formula 5 having an alkyl group branched at the 2-position in the phosphate moiety, or a salt thereof.

[ solution 5]

(in the formula, R¹、R²Represents hydrogen (H) or an alkyl group having 3 to 30 carbon atoms and having a branched chain at the 2-position. Wherein R is¹＝R²Except for the case of hydrogen (H). The alkyl group branched at the 2-position is a 2-methyldecyl group, a 2-ethyldecyl group, a 2-propyldecyl group, a 2-butyldecyl group, a 2-pentyldecyl group, a 2-hexyldecyl group, a 2-heptyldecyl group, a 2-octyldecyl group, a 2-nonyldecyl group, a 2-methylundecyl group, a 2-ethylundecyl group, a 2-propylundecyl group, a 2-butylundecyl group, a 2-pentylundecyl group, a 2-hexylundecyl group, a 2-heptylundecyl group, a 2-octylundecyl group, a 2-nonylundecyl group, a 2-decyldecyl group, a 2-methyldecyl group, a 2-ethyldodecyl group, a 2-propyldodecyl group, a 2-butyldodecyl group, a 2, 2-hexyldodecyl group, 2-heptyldodecyl group, 2-octyldodecyl group, 2-nonyldodecyl group, 2-decyldodecyl group, 2-undecyldodecyl group, 2-isoheptylideneundecyl group, or 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl group. )

The ascorbic acid derivative has a phosphate moiety at a predetermined position (2-position) in the molecular structure, and has a branched alkyl group at the phosphate moiety, and therefore has a property of being moderately fat-soluble and easily introduced into cells.

In addition, the ascorbic acid derivative does not have a modified portion other than the alkyl phosphate portion, and when it penetrates into the skin, even if esterase or lipase is not present, it can be hydrolyzed into L-ascorbic acid (vitamin C) or phospholipid by the action of phosphatase, other enzymes, or the like distributed in almost all tissues of the living body, and can provide a useful effect in the living body.

Among the ascorbic acid derivatives having the preferable effects as described above, representative is an ascorbic acid derivative in which the branched alkyl group is 2-heptylundecyl group, 2-octyldecyl group, 2-octyldodecyl group, 2-hexyldecyl group, 2-hexyldodecyl group, 2-isoheptylidenyl group or 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl group.

Similarly, in order to form a salt of an ascorbic acid derivative having the above-described preferable effects, it is preferable to form a sodium salt, a potassium salt, a magnesium salt or a calcium salt of L-ascorbic acid-2-phosphate.

In order to produce such an ascorbic acid derivative, a method can be employed in which a branched alkanol represented by the following formula 6 is reacted with phosphorus oxychloride to synthesize monoalkyl dichlorophosphate represented by the general formula 7 or dialkyl monochlorophosphate represented by the general formula 8, and the resulting product is reacted with 5, 6-O-isopropylidene-L-ascorbic acid, followed by acid hydrolysis, wherein the 5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone.

[ solution 6]

R-OH

(wherein R represents an alkyl group having 3 to 30 carbon atoms and having a branched chain.)

[ solution 7]

(wherein R represents an alkyl group having 3 to 30 carbon atoms and having a branched chain.)

[ solution 8]

(in the formula, R¹、R²Represents hydrogen (H) or an alkyl group having 3 to 30 carbon atoms and having a branched chain. Wherein R is¹＝R²Except for the case of hydrogen (H). )

The present invention also provides a whitening cosmetic material containing an ascorbic acid derivative represented by the general formula of formula 5, wherein the ascorbic acid derivative is L-ascorbic acid-2-phosphate having a branched alkyl group in the phosphate moiety, or a salt thereof.

The ascorbic acid derivative has a phosphate moiety at a predetermined position (2-position) in the molecular structure, and has a branched alkyl group at the phosphate moiety, and therefore has a property that the compound is moderately fat-soluble and is easily introduced into cells.

In addition, the ascorbic acid derivative has no modified portion other than the alkyl phosphate portion, and when it penetrates into the skin, even if esterase or lipase is not present, it can be hydrolyzed into L-ascorbic acid (vitamin C) or phospholipid by the action of phosphatase or other enzymes distributed in almost all tissues of the body, thereby providing a whitening effect to the skin.

The content of the L-ascorbic acid-2-phosphate or a salt thereof to be blended in the whitening cosmetic material of the present invention is preferably 0.05 to 80% by weight because sufficient whitening effect can be exhibited.

Further, the pH of the whitening cosmetic material is preferably adjusted to pH4.0 to 9.0, since the stability of the ascorbic acid derivative can be improved and the ascorbic acid derivative can effectively and sufficiently function.

The novel ascorbic acid derivative and the process for producing the same according to the present invention can stabilize L-ascorbic acid which is unstable to heat or oxidation by converting L-ascorbic acid into L-ascorbic acid-2-phosphate having a branched alkyl group in the phosphate moiety or a salt thereof, and therefore can suppress the decomposition of L-ascorbic acid in a storage state before use, and can rapidly decompose L-ascorbic acid and phospholipids by the action of phosphatase which is widely distributed in the living body and exhibit the physiological activity useful for health inherent in L-ascorbic acid when used.

In addition, in the invention relating to the whitening cosmetic material, the effective component L-ascorbic acid is changed into L-ascorbic acid-2-phosphate or a salt thereof having a branched alkyl group in a phosphate moiety, which has the following advantages: l-ascorbic acid is stable against heat or oxidation, and therefore, it is possible to inhibit decomposition of L-ascorbic acid in a state of storage before use of the cosmetic material, and further, when the cosmetic material is used, it is rapidly decomposed into L-ascorbic acid, phospholipids, and the like by the action of phosphatase, other enzymes, and the like present in the skin, and the physiological activity of L-ascorbic acid originally useful for whitening the skin, that is, the effect of preventing "age spots" and "freckles", is exhibited. The ascorbic acid derivative can more effectively and sufficiently act in the whitening cosmetic material adjusted to a predetermined pH.

Drawings

FIG. 1 is a process diagram showing the production process of an ascorbic acid derivative of example 1 by the reaction formula.

FIG. 2 is a process diagram showing the production process of an ascorbic acid derivative of example 6 by the reaction formula.

Detailed Description

The 2- (branched alkyl) -L-ascorbic acid phosphate ester represented by the general formula of formula 5 above, which is L-ascorbic acid-2-phosphate ester, can be produced by the following method.

First, a monoalkyl dichlorophosphate represented by the general formula 7 or a dialkyl monochlorophosphate represented by the general formula 8 is produced by reacting a branched alkanol represented by the general formula 6 with phosphorus oxychloride in the presence of a base selected from trimethylamine, triethylamine, N-dimethylaniline or the like at-20 to 20 ℃ using a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene or the like. Upon removal, the solution may be isolated by distillation or may be introduced into the next step as a solution of the above-mentioned nonpolar solvent.

Then, the monoalkyl dichlorophosphate or dialkyl monochlorophosphate obtained in the above step is reacted with 5, 6-O-isopropylidene-L-ascorbic acid, and the reaction product is hydrolyzed with acid and purified by a conventional method, whereby L-ascorbic acid-2-phosphate represented by the general formula of the above formula 5 can be produced, wherein the 5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone.

Specific examples of the branched alkanol represented by the general formula of formula 6 include 2-methyldecanol, 2-ethyldecanol, 2-propyldecanol, 2-butyldecanol, 2-pentyldecanol, 2-hexyldecanol, 2-heptyldecanol, 2-octyldecanol, 2-nonyldecanol, 2-methylundecanol, 2-ethylundecanol, 2-propylundecanol, 2-butylundecanol, 2-pentylundecanol, 2-hexylundecanol, 2-heptylundecanol, 2-octylundecanol, 2-nonylundecanol, 2-decylanol, 2-methyldodecanol, 2-ethyldodecanol, 2-propyldodecanol, 2-butyldodecanol, and mixtures thereof, 2-pentyldodecanol, 2-hexyldodecanol, 2-heptyldodecanol, 2-octyldodecanol, 2-nonyldodecanol, 2-decyldododecanol, 2-undecyldodecanol, 2-isoheptylisoundecanol, etc., and certainly, alkanols branched at positions other than the 2-position, such as 16-methylheptadecanol, 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octanol, etc., are also included.

5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone at-30 to 20 ℃ in the presence of a dehydrating agent such as acetyl chloride or fuming sulfuric acid, and then isolating the reaction product by a method such as filtration.

5, 6-O-isopropylidene-L-ascorbic acid obtained in the above step is reacted with monoalkyl dichlorophosphate represented by the general formula 7 or dialkyl monochloro phosphate represented by the general formula 8 at-20 to 20 ℃ in the presence of a base selected from trimethylamine, triethylamine, N-dimethylaniline or the like in the presence of a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene or the like, and then hydrolyzed at-10 to 50 ℃ in the presence of an acid selected from hydrochloric acid, sulfuric acid, acetic acid or the like.

In this case, in order to remove the residual base, the reaction mixture is washed with an acid such as hydrochloric acid, sulfuric acid, or acetic acid, or an aqueous solution of an inorganic salt such as sodium chloride, potassium chloride, ammonium chloride, sodium carbonate, potassium carbonate, or sodium hydrogencarbonate, and the nonpolar solvent is distilled off, but when higher quality is required, 2- (branched alkyl) -L-ascorbic acid phosphate (L- アスコルビルホスフエ - ト) represented by the general formula of the above chemical formula 5 can be isolated by column chromatography or the like. Alternatively, the solution may be taken out with a solution of ethanol, glycerin, or the like. As described above, the isolation and purification method of the ascorbic acid derivative of the present invention can be carried out by a conventional method, and is not particularly limited.

Specific examples of the ascorbic acid derivative of the present invention represented by the general formula of formula 5 include 2- (2-methyldecyl) -L-ascorbic acid phosphate, 2- (2-ethyldecyl) -L-ascorbic acid phosphate, 2- (2-propyldecyl) -L-ascorbic acid phosphate, 2- (2-butyldecyl) -L-ascorbic acid phosphate, 2- (2-pentyldecyl) -L-ascorbic acid phosphate, 2- (2-hexyldecyl) -L-ascorbic acid phosphate, 2- (2-heptyldecyl) -L-ascorbic acid phosphate, 2- (2-octyldecyl) -L-ascorbic acid phosphate, and the like, 2- (2-nonyldecyl) -L-ascorbic acid phosphate, 2- (2-methylundecyl) -L-ascorbic acid phosphate, 2- (2-ethylundecyl) -L-ascorbic acid phosphate, 2- (2-propylundecyl) -L-ascorbic acid phosphate, 2- (2-butylundecyl) -L-ascorbic acid phosphate, 2- (2-pentylundecyl) -L-ascorbic acid phosphate, 2- (2-hexylundecyl) -L-ascorbic acid phosphate, 2- (2-heptylundecyl) -L-ascorbic acid phosphate, 2- (2-octylundecyl) -L-ascorbic acid phosphate, sodium lauryl sulfate, sodium lauryl, 2- (2-nonylundecyl) -L-ascorbic acid phosphate, 2- (2-decyldundecyl) -L-ascorbic acid phosphate, 2- (2-methyldodecyl) -L-ascorbic acid phosphate, 2- (2-ethyldodecyl) -L-ascorbic acid phosphate, 2- (2-propyldodecyl) -L-ascorbic acid phosphate, 2- (2-butyldodecyl) -L-ascorbic acid phosphate, 2- (2-pentyldodecyl) -L-ascorbic acid phosphate, 2- (2-hexyldodecyl) -L-ascorbic acid phosphate, 2- (2-heptyldodecyl) -L-ascorbic acid phosphate, 2- (2-decyldecyldodecyl) -L-ascorbic acid phosphate, and mixtures thereof, 2- (2-octyldodecyl) -L-ascorbic acid phosphate, 2- (2-nonyldodecyl) -L-ascorbic acid phosphate, 2- (2-decyldodecyl) -L-ascorbic acid phosphate, 2- (2-undecyldodecyl) -L-ascorbic acid phosphate, 2- (2-isoheptylidenodecyl) -L-ascorbic acid phosphate, 2- (16-methylheptadecyl) -L-ascorbic acid phosphate, 2-bis (2-methyldecyl) -L-ascorbic acid phosphate, 2-bis (2-ethyldecyl) -L-ascorbic acid phosphate, 2-bis (2-propyldecyl) -L-ascorbic acid phosphate, sodium chloride, potassium chloride, sodium chloride, potassium, 2-bis (2-butyldecyl) -L-ascorbic acid phosphate, 2-bis (2-pentyldecyl) -L-ascorbic acid phosphate, 2-bis (2-hexyldecyl) -L-ascorbic acid phosphate, 2-bis (2-heptyldecyl) -L-ascorbic acid phosphate, 2-bis (2-octyldecyl) -L-ascorbic acid phosphate, 2-bis (2-nonyldecyl) -L-ascorbic acid phosphate, 2-bis (2-methylundecyl) -L-ascorbic acid phosphate, 2-bis (2-ethylundecyl) -L-ascorbic acid phosphate, 2-bis (2-propylundecyl) -L-ascorbic acid phosphate, 2-bis (2-pentyldecyl) -L-ascorbic, 2-bis (2-butylundecyl) -L-ascorbic acid phosphate, 2-bis (2-pentylundecyl) -L-ascorbic acid phosphate, 2-bis (2-hexylundecyl) -L-ascorbic acid phosphate, 2-bis (2-heptylundecyl) -L-ascorbic acid phosphate, 2-bis (2-octylundecyl) -L-ascorbic acid phosphate, 2-bis (2-nonylundecyl) -L-ascorbic acid phosphate, 2-bis (2-decyldundecyl) -L-ascorbic acid phosphate, 2-bis (2-methyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-ethyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-pentylundecyl) -L-ascorbic acid phosphate, 2-bis (2-octylundecyl, 2-bis (2-propyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-butyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-pentyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-hexyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-heptyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-octyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-nonyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-decyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-undecyldodecyl) -L-ascorbic acid phosphate, 2-bis (2-butyldodecyl) -L-ascorbic acid, 2-bis (2-isoheptylisoundecyl) -L-ascorbic acid phosphate, 2-bis (16-methylheptadecyl) -L-ascorbic acid phosphate, 2-bis [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate, and the like. The above is an alkyl group having a branch at the 2-position, but the ascorbic acid derivative of the present invention naturally includes substances having an alkyl group having a branch at a position other than the above, such as 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate.

In the present invention, salts of these ascorbic acid derivatives can be used, and for example, alkali metal salts such as sodium salts and potassium salts thereof, alkaline earth metal salts such as calcium salts and magnesium salts thereof, basic amino acids such as arginine, and organic amines such as triethanolamine can be used.

The content of the L-ascorbic acid-2-phosphate or a salt thereof to be blended in the whitening cosmetic material of the present invention is preferably 0.05 to 80% by weight because sufficient whitening effect can be exhibited. When the content is less than 0.05% by weight, the whitening effect may not be expected or may not be reliably obtained, and when the content is more than 80% by weight, a good feeling of use may not be obtained, which is not preferable. From such a tendency, the amount of the additive is more preferably about 2to 50% by weight.

The pH of the whitening cosmetic material of the present invention is not particularly limited, but is preferably 4.0 to 9.0 in order to improve the stability of the cosmetic material in a general storage state, and hydrolysis of an ester is likely to occur in other pH regions, and a stable preparation may not be obtained.

The whitening cosmetic material of the present invention may contain, in addition to the essential components, various components used in general cosmetic materials, non-pharmaceuticals, and the like, for example, an oily component, an emulsifier, a humectant, a thickener, a medicinal component, an antiseptic, a pigment, a powdery substance, a pH adjuster, an ultraviolet absorber, an antioxidant, a perfume, and the like, as appropriate.

Specific examples of the above oily component include liquid paraffin, vaseline, microcrystalline wax, squalane (squalane), ホホバ oil, beeswax, carnauba wax, lanolin, olive oil, coconut oil, higher alcohols, fatty acids, esters of higher alcohols and fatty acids, and silicone oil. Examples of the emulsifier include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, and polyoxyethylene hardened castor oil, anionic surfactants such as sodium stearoyl lactylate, amphoteric surfactants such as soybean phospholipid, and cationic surfactants such as alkyltrimethylammonium chloride. Examples of the humectant include glycerin, sorbitol, xylitol, maltitol, propylene glycol, polyethylene glycol, 1, 3-butanediol, 1, 2-pentanediol, and the like. Examples of the thickener include a carboxyvinyl polymer, xanthane gum, methyl cellulose, polyvinylpyrrolidone, gelatin, a clay mineral such as bentonite, and the like. Examples of the active ingredient include various vitamins and derivatives thereof, allantoin, glycyrrhizic acid and derivatives thereof, and various animal and plant extracts.

The whitening cosmetic material of the present invention is not particularly limited except for the incorporation of the above-mentioned predetermined ascorbic acid derivative as a whitening active ingredient, and can be produced by a known method for producing a cosmetic material, and is not limited to general skin cosmetic materials, and can be applied to non-pharmaceuticals, external pharmaceuticals, and the like, and the form of the cosmetic material can be selected from cream, emulsion, liquid, gel, ointment, pack (pack), stick (stick), powder, and the like, depending on the purpose.

Example 1

[ production example 1 of ascorbic acid derivative ]

[2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] as monoalkyldichlorophosphate was synthesized by reacting 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octanol as a branched alkanol with phosphoryl chloride according to the steps shown in the reaction formula of FIG. 1]And (3) dichlorophosphate. Reacting the resulting product with 5, 6-O-isopropylidene-L-ascorbic acid to produce isostearyl (isostearyl) -2-O-isopropylidene ascorbic acid phosphate, hydrolyzing the produced isostearyl-2-O-isopropylidene ascorbic acid phosphate with hydrochloric acid, washing, isolating and purifying to produce 2- (2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl) -L-ascorbic acid phosphate (FIG. 1 shows the description of the latter¹³Number of peaks in C-NMR), and the 5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone. Each synthesis step is described in detail below.

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

557.8g (9.6 mol) of acetone was cooled to-5 ℃ under nitrogen substitution, 54.3g (0.2 mol) of 28% oleum was added dropwise thereto, and 176.1g (1.0 mol) of L-ascorbic acid was added dropwise. This was allowed to react at the same temperature for 17 hours, filtered and washed with cold acetone to give 249.5g of 5, 6-O-isopropylidene-L-ascorbic acid (purity 86.7%) as a wet cake.

(2) Synthesis of [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] dichlorophosphate

540ml of toluene and 138.0g (0.9 mol) of phosphorus oxychloride were charged under nitrogen replacement, and the mixture was cooled to-10 ℃. Then, a solution of 243.5g (0.9 mol, 1.0 mol ratio) of 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octanol and 91.1g (0.9 mol) of triethylamine was added dropwise thereto, and the reaction was carried out at 0 ℃ for 12 hours. After warming to 25 ℃ the hydrochloride salt of triethylamine was removed by filtration to yield 1003.9g of a toluene solution of [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] dichlorophosphate (concentration 34.7%).

(3) Synthesis of 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate

249.5g (1.0 mol) of the above 5, 6-O-isopropylidene-L-ascorbic acid was placed in 2000mL of toluene under nitrogen substitution, and 202.4g of triethylamine was added dropwise thereto at room temperature, followed by stirring for 1 hour. Subsequently, it was cooled to-10 ℃ and 1003.9g (0.9 mol) of the above toluene solution of [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] dichlorophosphate was added dropwise over a period of 1 hour, followed by stirring at the same temperature for 14 hours. To the obtained reaction mixture, 12312g of a 6.7% aqueous hydrochloric acid solution was added, hydrolysis was performed at 35 ℃ for 4 hours, and the toluene layer was washed 2 times with 1000g of a 10% hydrochloric acid/7.1% aqueous sodium chloride solution, and then washed 1 time with a 20% aqueous sodium chloride solution. Then, the toluene layer was analyzed by column chromatography, and the toluene was distilled off by concentrating the separated fraction under reduced pressure (35 ℃ C., 2Torr), whereby 338.9g of 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate (purity 94.6%) was obtained. The yield was 66.6% (relative to L-ascorbic acid).

By infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (C¹H-NMR、¹³C-NMR) on the resulting 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl group]The molecular structure of L-ascorbic acid phosphate was identified, and the results (groups or carbon atoms corresponding to the positions of peaks) are summarized in tables 1 to 3. It was confirmed that the compound thus obtained was 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] as an ascorbic acid derivative having a desired molecular structure]-L-ascorbic acid phosphate.

[ Table 1]

[ Table 2]]

[ Table 3]]

Example 2

[ production example 2 of ascorbic acid derivative ]

In example 1, the compound obtained in the same manner as in example 1 was analyzed by infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (R) (I)¹H-NMR、¹³C-NMR), and the results (groups or carbon atoms corresponding to the positions of the peaks) are summarized in tables 4 to 6.

The compound thus obtained was confirmed to be 2-bis [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate (purity 91.1%) as an ascorbic acid derivative having a desired molecular structure. The yield was 20.1% (relative to L-ascorbic acid).

The molecular structure of the obtained compound is shown by the following formula 9, wherein the same symbols are given¹³Number of peak in C-NMR.

[ solution 9]

[ Table 4]

[ Table 5]

[ Table 6]

Example 3

[ production example 3 of ascorbic acid derivative ]

In example 1, the compound obtained in the same manner as in example 1 except that 2-hexyldecanol was used in place of 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octanol was used, and the infrared absorption spectrum (IR) and the nuclear magnetic structure spectrum (C: (R))¹H-NMR、¹³C-NMR), and the results (groups or carbon atoms corresponding to the positions of the peaks) are summarized in tables 7 to 9.

The compound thus obtained was confirmed to be 2- (2-hexyldecyl) -L-ascorbic acid phosphate (purity: 69.7%) as an ascorbic acid derivative having a desired molecular structure. The yield was 63% (relative to L-ascorbic acid).

The molecular structure of the compound obtained by the following formula 10 is also shown in the formula¹³Number of peak in C-NMR.

[ solution 10]

[ Table 7]]

[ Table 8]]

[ Table 9]

Example 4

[ production example 4 of ascorbic acid derivative ]

In example 1, the compound obtained in the same manner as in example 1 was analyzed by infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (R), (I), (II), (III), (IV), (V), (¹H-NMR、 ¹³C-NMR), and the results (groups or carbon atoms corresponding to the positions of the peaks) are summarized in tables 10 to 12.

The compound thus obtained was confirmed to be 2- (2-octyldodecyl) -L-ascorbic acid phosphate (purity 87.0%) as an ascorbic acid derivative having a desired molecular structure.

The yield was 45.4% (relative to L-ascorbic acid).

The molecular structure of the compound obtained by the following formula 11 is also shown in the formula¹³Number of peak in C-NMR.

[ solution 11]

[ Table 10]]

[ Table 11]

[ Table 12]]

Example 5

[ production example 5 of ascorbic acid derivative ]

The sodium salt of 2- (2-heptylundecyl) -L-ascorbic acid phosphate was produced using the following method.

249.5g (1.0 mol) of the above 5, 6-O-isopropylidene-L-ascorbic acid was placed in 2000mL of toluene under nitrogen replacement, and 202.4g of triethylamine was added dropwise thereto at room temperature, followed by stirring for 1 hour. Subsequently, it was cooled to-10 ℃ and 1003.9g (0.9 mol) of the above-mentioned toluene solution of (2-heptylundecyl) dichlorophosphate was added dropwise over a period of 1 hour, followed by stirring at the same temperature for 14 hours. To the obtained reaction mixture, 12312g of a 6.7% aqueous hydrochloric acid solution was added, hydrolysis was performed at 35 ℃ for 4 hours, and the toluene layer was washed 2 times with 1000g of a 10% hydrochloric acid/7.1% aqueous sodium chloride solution, and further washed 1 time with a 20% aqueous sodium chloride solution.

Then, a 30% aqueous NaOH solution was added to the toluene layer to adjust the pH to 7. Ethanol was added to the aqueous layer after separation, water and ethanol were distilled off by concentration under reduced pressure, and the resulting crystals deposited were filtered and dried to obtain 344.9g of 2- (2-heptylundecyl) -L-ascorbic acid phosphoric acid ester-sodium salt (purity 92.3%). The yield thereof was 60.0% (relative to L-ascorbic acid).

By infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (C¹H-NMR、¹³C-NMR) was carried out to identify the molecular structure of the obtained compound, and the salt was identified as having2- (2-heptylundecyl) -L-ascorbic acid phosphate-sodium salt of an ascorbic acid derivative of the expected molecular structure. The identification of the result based on the group or carbon atom corresponding to the position of the peak is represented by example 1, and the description thereof is omitted.

Example 6

[ production example 6 of ascorbic acid derivative ]

(2-heptylundecyl) dichlorophosphate as a monoalkyldichlorophosphate was synthesized by reacting 2-heptylundecyl alcohol as a branched alkanol with phosphorus oxychloride in the respective steps shown in the reaction formula of FIG. 2. Reacting the resulting product with 5, 6-O-isopropylidene-L-ascorbic acid, hydrolyzing the resulting isostearyl (isostearyl) -2-O-isopropylidene ascorbic acid phosphate with hydrochloric acid, washing, isolating and purifying to obtain 2- (2-heptylundecyl) -L-ascorbic acid phosphate (shown in FIG. 2 and described later)¹³The number of assignment of peaks in C-NMR), wherein the 5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone. Each synthesis step is described in detail below.

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

Under nitrogen replacement, 557.8g (9.6 mol) of acetone was cooled to-5 ℃ and 54.3g (0.2 mol) of 28% oleum was added dropwise, followed by adding 176.1g (1.0 mol) of L-ascorbic acid. This was allowed to react at the same temperature for 17 hours, filtered, and washed with cold acetone to obtain 249.5g of 5, 6-O-isopropylidene-L-ascorbic acid (purity 86.7%) as a wet cake.

(2) Synthesis of (2-heptylundecyl) dichlorophosphate

540ml of toluene and 138.0g (0.9 mol) of phosphorus oxychloride were charged under nitrogen replacement, and the mixture was cooled to-10 ℃. Then, a solution of 243.5g (0.9 mol, 1.0 mol ratio) of 2-heptylundecanol and 91.1g (0.9 mol) of triethylamine was added dropwise thereto, and the mixture was reacted at 0 ℃ for 12 hours. After warming to 25 ℃ the hydrochloride salt of triethylamine was removed by filtration to give 1003.9g of a toluene solution of (2-heptylundecyl) dichlorophosphate (concentration 34.7%).

(3) Synthesis of 2- (2-heptylundecyl) -L-ascorbic acid phosphate

249.5g (1.0 mol) of the above 5, 6-O-isopropylidene-L-ascorbic acid was placed in 2000mL of toluene under nitrogen substitution, and 202.4g of triethylamine was added dropwise thereto at room temperature, followed by stirring for 1 hour. Subsequently, it was cooled to-10 ℃ and 1003.9g (0.9 mol) of the above-mentioned toluene solution of (2-heptylundecyl) dichlorophosphate was added dropwise over a period of 1 hour, followed by stirring at the same temperature for 14 hours. To the obtained reaction mixture, 12312g of a 6.7% aqueous hydrochloric acid solution was added, hydrolysis was performed at 35 ℃ for 4 hours, and the toluene layer was washed 2 times with 1000g of a 10% hydrochloric acid/7.1% aqueous sodium chloride solution, and further washed 1 time with a 20% aqueous sodium chloride solution. Then, the toluene layer was analyzed by column chromatography, and the toluene was distilled off by concentrating the separated fraction under reduced pressure (35 ℃ C., 2Torr), whereby 338.9g of 2- (2-heptylundecyl) -L-ascorbic acid phosphate (purity 94.6%) was obtained. The yield was 66.6% (relative to L-ascorbic acid).

By infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (C¹H-NMR、¹³C-NMR) the molecular structure of the obtained 2- (2-heptylundecyl) -L-ascorbic acid phosphate was identified, and from these results, it was confirmed that the obtained compound was 2- (2-heptylundecyl) -L-ascorbic acid phosphate as an ascorbic acid derivative having the molecular structure shown in formula 12.

[ solution 12]

Example 7

[ production example 7 of ascorbic acid derivative ]

In example 6, except that a molar ratio of phosphorus oxychloride to phosphorus oxychloride of2.0 except for 2-heptylundecanol, a compound obtained by the same method as in example 6 was analyzed by infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (¹H-NMR、¹³C-NMR), and based on these results (groups or carbon atoms corresponding to the positions of the peaks), it was confirmed that the resulting compound was 2-bis (2-heptylundecyl) -L-ascorbic acid phosphate (purity 91.1%) which is an ascorbic acid derivative having an expected molecular structure. The yield was 20.1% (relative to L-ascorbic acid).

Example 8

[ production example 8 of ascorbic acid derivative ]

The sodium salt of 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate was produced using the following method.

249.5g (1.0 mol) of the above 5, 6-O-isopropylidene-L-ascorbic acid was placed in 2000mL of toluene under nitrogen replacement, and 202.4g of triethylamine was added dropwise thereto at room temperature, followed by stirring for 1 hour. Subsequently, it was cooled to-10 ℃ and 1003.9g (0.9 mol) of the above toluene solution of [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] dichlorophosphate was added dropwise over a period of 1 hour, followed by stirring at the same temperature for 14 hours. To the obtained reaction mixture, 12312g of a 6.7% aqueous hydrochloric acid solution was added, hydrolysis was performed at 35 ℃ for 4 hours, and the toluene layer was washed 2 times with 1000g of a 10% hydrochloric acid/7.1% aqueous sodium chloride solution, and further washed 1 time with a 20% aqueous sodium chloride solution.

Then, a 30% aqueous NaOH solution was added to the toluene layer to adjust the pH to 7. Ethanol was added to the aqueous layer after separation, water and ethanol were distilled off by concentration under reduced pressure, and the resulting precipitated crystals were filtered and dried to obtain 344.9g of 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] -L-ascorbic acid phosphate-sodium salt (purity 92.3%). The yield thereof was 60.0% (relative to L-ascorbic acid).

By infrared absorption spectroscopy (IR) and nuclear magnetic structure spectroscopy (C¹H-NMR、¹³C-NMR) pair to obtainThe molecular structure of the compound (2) was identified, and it was confirmed that the obtained compound was 2- [2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl ] as an ascorbic acid derivative having a desired molecular structure]-L-ascorbic acid phosphate-sodium salt.

The cosmetic compositions (lotions) of examples 8 to 12 were prepared at the compounding ratios shown in table 13 below using the ascorbic acid derivatives obtained in production examples 1, 3 and 4 as described above as active ingredients, and the whitening effect was evaluated.

Watch 13

[ judgment of whitening Effect ]

Subjects with troubles such as age spots, freckles, and dark skin were grouped into 20 groups, each cosmetic material was applied every morning and evening, the cumulative effect of application after 3 months was self-judged according to the following criteria after 3 months of use, and the results of the judgment were evaluated according to the following criteria. Shown in table 14.

The method is remarkably effective: the pigmentation was hardly noticeable.

The method has the following advantages: and (4) lightening.

Somewhat effective: slightly shallower.

And (4) invalidation: there was no change.

[ evaluation ]

Very good: the effective proportion (effective rate) of the tested person is more than 80%.

O: the proportion (effective rate) of the effective components in the tested patient is more than 60% and less than 80%.

And (delta): the proportion (effective rate) of the effective components in the tested patients is more than 40% and less than 60%.

X: the proportion (effective rate) of the effective components in the tested patients is less than 40%.

TABLE 14

As is clear from the results in table 14, in the examples containing a predetermined amount (0.05 wt% or more) of L-ascorbic acid-2-phosphate, at least 40% or more, 60% or 80% of the subjects felt to be significantly effective or effective, and it was confirmed that the whitening cosmetic composition could exhibit physiological activity useful for whitening skin inherent to L-ascorbic acid.

Next, a typical formulation example of a cosmetic material is shown as an example in which a predetermined L-ascorbic acid-2-phosphate is used as an active ingredient. The numerical values at the right end of each line are the compounding ratio (% by weight).

Example 13 (gel-like cream)

2- (2-heptylundecyl) -L-ascorbic acid phosphate 5.0

Glycerol 10.0

Ethanol 5.0

0.5 part of sodium hydroxide

Carboxyvinyl Polymer 0.8

Proper amount of perfume

Proper amount of preservative

Residual amount of purified water

Example 14 (emulsion)

2- (2-hexyldecyl) -L-ascorbic acid phosphate 10.0

1, 3-butanediol 10.0

Carboxyvinyl Polymer 0.3

Squalane 5.0

Cetyl alcohol 0.8

L-arginine 0.3

Proper amount of perfume

Proper amount of preservative

Residual amount of purified water

Example 15 (cream)

2-bis (2-octyldodecyl) -L-ascorbic acid phosphate 10.0

1, 3-butanediol 10.0

Carboxyvinyl Polymer 0.3

Squalane 5.0

Cetyl alcohol 2.0

Beeswax 3.0

L-arginine 0.3

Proper amount of perfume

Proper amount of preservative

Residual amount of purified water

Claims (6)

1. An ascorbic acid derivative which comprises an L-ascorbic acid-2-phosphate represented by the following formula 1 and having an alkyl group branched at the 2-position in the phosphate moiety or a salt thereof,

[ solution 1]

In the formula, R¹、R²Represents a hydrogen atom or a carbon atom having a branch at the 2-positionAn alkyl group of a number of 3 to 30, wherein R¹＝R²Except for the case where the hydrogen atom is present,

the alkyl group branched at the 2-position is a 2-methyldecyl group, a 2-ethyldecyl group, a 2-propyldecyl group, a 2-butyldecyl group, a 2-pentyldecyl group, a 2-hexyldecyl group, a 2-heptyldecyl group, a 2-octyldecyl group, a 2-nonyldecyl group, a 2-methylundecyl group, a 2-ethylundecyl group, a 2-propylundecyl group, a 2-butylundecyl group, a 2-pentylundecyl group, a 2-hexylundecyl group, a 2-heptylundecyl group, a 2-octylundecyl group, a 2-nonylundecyl group, a 2-decyldecyl group, a 2-methyldecyl group, a 2-ethyldodecyl group, a 2-propyldodecyl group, a 2-butyldodecyl group, a 2, 2-hexyldodecyl group, 2-heptyldodecyl group, 2-octyldodecyl group, 2-nonyldodecyl group, 2-decyldodecyl group, 2-undecyldodecyl group, 2-isoheptylideneundecyl group, or 2- (1, 3, 3-trimethyl-n-butyl) -5, 7, 7-trimethyl-n-octyl group.

2. The ascorbic acid derivative of claim 1,

the salt is sodium, potassium, magnesium or calcium salt of L-ascorbic acid-2-phosphate.

3. A process for producing an ascorbic acid derivative according to claim 1,

reacting a branched alkanol represented by the following formula 2 with phosphorus oxychloride to synthesize a monoalkyl dichlorophosphate represented by the following formula 3 or a dialkyl monochlorophosphate represented by the following formula 4, reacting the monoalkyl dichlorophosphate with 5, 6-O-isopropylidene-L-ascorbic acid, and then performing acidolysis, wherein the 5, 6-O-isopropylidene-L-ascorbic acid is obtained by reacting L-ascorbic acid with acetone,

[ solution 2]

R-OH

Wherein R represents an alkyl group having 3 to 30 carbon atoms and having a branched chain,

[ solution 3]

Wherein R represents an alkyl group having 3 to 30 carbon atoms and having a branched chain,

[ solution 4]

In the formula, R¹、R²Represents a hydrogen atom or an alkyl group having a branched carbon number of 3 to 30, wherein R¹＝R²Except for the case of hydrogen atoms.

4. A whitening cosmetic material containing the ascorbic acid derivative as defined in claim 1.

5. The whitening cosmetic material according to claim 4,

the content of L-ascorbic acid-2-phosphate or a salt thereof having a branched alkyl group in the phosphate moiety is 0.05 to 80 wt%.

6. A whitening cosmetic material comprising the whitening cosmetic material according to claim 4, wherein the pH value is adjusted to 4.0 to 9.0.