Cosmetic

Abstract

Provided is a cosmetic that is stable and exhibits less discoloration, odor alteration, activity deterioration, and the like even after being stored for a long period of time, and that has excellent moisture retention and excellent feeling of use. The cosmetic is characterized by comprising a component (A) which is an ascorbic acid derivative characterized by being represented by general formula (1) and a component (B) which is a polyhydric alcohol. The cosmetic is characterized in that the mass ratio [component (A) / component (B)] of the component (A) to the component (B) is not less than 0.01 to less than 10.0. [In formula (1): R1 represents -(CH2)n-* (n represents an integer of 2-4), -CH2CH(OH)CH2-* (* represents the position to be bound to O at position 2 of ascorbic acid) or the like, or a bismethyloxetane group; R2 and R3 each represent hydrogen, -COR4, a linear or branched alkyl group having 1-22 carbon atoms, or a benzyl group; and R4 represents an alkyl group having 1-22 carbon atoms.]

Description

Cosmetics

[0001] The present invention relates to a cosmetic composition, and more specifically to a novel cosmetic composition containing a specific ascorbic acid derivative and a water-soluble polyhydric alcohol, which has high stability over a wide pH range.

[0002] Ascorbic acid is a safe and useful antioxidant, known for its excellent skin-whitening properties. However, its instability to light, heat, and oxidation, and its poor long-term stability, have hindered its use in the cosmetics industry.

[0003] Therefore, the present inventors have proposed various ascorbic acid derivatives or salts thereof that have improved long-term stability compared to ascorbic acid (Patent Documents 1 and 2). However, there has been a need for an ascorbic acid derivative that further improves long-term stability under alkaline conditions and has high stability over a wide pH range.

[0004] On the other hand, moisturizing performance is an important quality for many cosmetics. Many cosmetics are commercially available that are expected to have a moisturizing effect on the skin and hair. Traditionally, in such cosmetics, water-soluble polyhydric alcohols such as glycerin and 1,3-butylene glycol have been added as humectants to provide moisturizing properties.

[0005] However, while cosmetics containing polyhydric alcohols, as mentioned above, have excellent moisturizing effects, they also have problems with their feel, such as feeling sticky.

[0006] Patent No. 4681670 Patent No. 7267657

[0007] The present invention aims to solve the problems of the prior art and to provide a novel cosmetic composition that contains a specific ascorbic acid derivative and a polyhydric alcohol, which have the excellent effects inherent in ascorbic acid, high stability over a wide pH range, excellent physiological activity, and a moisturizing effect due to the inclusion of a polyhydric alcohol, as well as suppressed stickiness when applied to the skin, resulting in an excellent feel.

[0008] As a result of intensive studies conducted in view of the above circumstances, the present inventors have found that the ascorbic acid derivative represented by the following general formula (1) is stable in a wide pH range as compared with ascorbic acid and other conventional ascorbic acid derivatives, and provides an excellent use feeling such as suppressed stickiness when a water-soluble polyhydric alcohol is incorporated into a cosmetic within a specific mass ratio range. The present invention has been completed based on these findings.

[0009] A first aspect of the present invention is a cosmetic characterized by comprising component (A): an ascorbic acid derivative represented by the following general formula (1) and component (B): a polyhydric alcohol, wherein the mass ratio of component (A) to component (B) [component (A) / component (B)] is 0.01 or more and less than 10.0 (Claim 1).

[0010]

[0011] [In formula (1), R １ is -(CH ２ ) ｎ -* (n is an integer of 2 to 4), -CH ２ CH(OH)CH ２ -*, -CH ２ CH(CH ２ OH)-*, -CH(CH ２ OH)CH ２ -*, -C(CH ３ ) ２ CH ２ -*, -CH ２ C(CH ３ ) ２ -* (* represents a position bonding to oxygen at the 2-position of ascorbic acid), or a divalent group represented by the following formula (2); R ２ and R ３ each represent hydrogen, -COR ４ , a linear or branched alkyl group having 1 to 22 carbon atoms, or a benzyl group; and R ４ is a linear or branched alkyl group having 1 to 22 carbon atoms.]

[0012]

[0013] Ascorbic acid derivatives represented by general formula (1) exhibit superior long-term stability in the neutral to weakly alkaline range (pH 6 to 10) compared to ascorbic acid and conventional ascorbic acid derivatives. In particular, even when stored for several weeks in high-temperature environments above room temperature, a high retention rate is maintained across a wide pH range, and problems such as odor generation and discoloration are suppressed.

[0014] The second aspect of the present invention is a preferred aspect of the first aspect of the present invention, wherein R in the general formula (1) １ However, - (CH ２ ) ｎ - * (n is 3 or 4), - CH ２ CH(OH)CH ２ -*, -CH ２ CH (CH ２ OH)-*,-CH(CH ２ OH)CH ２ -* (where * represents the position where it bonds with the oxygen at position 2 of ascorbic acid), and R ２ and R ３ is hydrogen, or R １ ga- (CH ２ ) ｎ - * (n is 3 or 4), R ２ ga-COR ４ And R ３ is hydrogen or -COR ４ And R ４ The cosmetic composition contains an ascorbic acid derivative characterized by having a linear or branched alkyl group having 4 to 18 carbon atoms. Cosmetics containing the compound are preferred in that they exhibit higher physiological activity, such as a hyaluronic acid production promoting effect.

[0015] The third aspect of the present invention is a preferred aspect of the second aspect of the present invention, wherein R in the general formula (1) １ However, - (CH ２ ) ３ -*, -CH ２ CH(OH)CH ２ -* (where * represents the position where it bonds with the oxygen at position 2 of ascorbic acid), and R ２ and R ３ Each of them is hydrogen, or R １ ga- (CH ２ )３ -* and R ２ ga-COR ４ And R ３ is hydrogen or -COR ４ And R ４ The cosmetic composition contains an ascorbic acid derivative characterized in that R is a linear or branched alkyl group having 8 to 18 carbon atoms. A cosmetic composition containing the compound is particularly preferred in that it has excellent long-term stability. Among them, R １ However, - (CH ２ ) ３ -* and R ２ and R ３ is hydrogen, or R １ ga- (CH ２ ) ３ -* and R ２ ga-COR ４ And R ３ is hydrogen or -COR ４ And R ４ Cosmetics containing an ascorbic acid derivative characterized by having 8 to 18 carbon atoms in a straight chain or branched alkyl group are particularly excellent and preferred.

[0016] The fourth aspect of the present invention is a preferred embodiment among the first to third aspects of the present invention, characterized in that component (B) polyhydric alcohol is glycerin, 1,3-butylene glycol, or 1,2-pentanediol. The aforementioned compounds are preferred because they provide excellent moisturizing effects.

[0017] Component (A), an ascorbic acid derivative represented by general formula (1), possesses the excellent functions inherent in ascorbic acid, is stable even during long-term storage across a wide pH range, exhibits minimal discoloration, odor changes, and activity reduction, and has high physiological activity such as collagen production promoting and hyaluronic acid production promoting effects. Therefore, by combining component (A), an ascorbic acid derivative represented by general formula (1), with component (B), a polyhydric alcohol that imparts moisturizing properties, a cosmetic composition, such as a moisturizing cosmetic, is provided that is excellent in moisturizing properties, stable even during long-term storage, and has high physiological activity. Furthermore, this cosmetic composition has reduced stickiness and is provided with an excellent feel. Thus, the present invention provides a cosmetic composition that is stable even during long-term storage across a wide pH range, has high physiological activity, is excellent in moisturizing properties, and is provided with an excellent feel.

[0018] The following are embodiments for carrying out the present invention, but the scope of the present invention is not limited to the embodiments shown below.

[0019] Specific examples of ascorbic acid derivatives represented by general formula (1) include 2,3-O-(1,2-ethanediyl)ascorbic acid, 2,3-O-(1,3-propanediyl)ascorbic acid, 2,3-O-(1,4-butanediyl)ascorbic acid, 2,3-O-(2-hydroxypropane-1,3-diyl)ascorbic acid, 2,3-O-(1-hydroxymethyl-1,2-ethanediyl)ascorbic acid, 2,3-O-(2-hydroxymethyl-1,2-ethanediyl)ascorbic acid, 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid, 2,3-O-(2,2-dimethyl-1,2-ethanediyl)ascorbic acid, 2,3-O-(1,1-dimethyl-1,2-Ethanediyl)ascorbic acid, 6-O-butanoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-dibutanoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-dioctanoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-dilauroyl-2,3-O-(1,4-butanediyl) Ascorbic acid, 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-dipalmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 6-O-isostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-diisostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 5-O-butanoyl-6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid, 6-O-butanoyl-2,3-O-(1,3-propanediyl)ascorbic acid, 5,6-O-dibutanoyl-2,3-O-(1,3-propanediyl)ascorbic acid, 6-O-octanoyl-2,3-O-(1,3-propanediyl)ascorbic acid, 5,6-O-dioctanoyl-2,3-O-(1,3-propanediyl)ascorbic acid, 6-O-lauroyl-2,3-O-(1,3-propanediyl)ascorbic acid, 5,6-O-dilauroyl-2,3-O-(1,3-propanediyl) Examples include (diisostearoyl) ascorbic acid, 6-O-palmitoyl-2,3-O-(1,3-propanediyl) ascorbic acid, 5,6-O-dipalmitoyl-2,3-O-(1,3-propanediyl) ascorbic acid, 6-O-isostearoyl-2,3-O-(1,3-propanediyl) ascorbic acid, 5,6-O-diisostearoyl-2,3-O-(1,3-propanediyl) ascorbic acid, 5-butanoyl-6-O-palmitoyl-2,3-O-(1,3-propanediyl) ascorbic acid, 6-O-isostearoyl-2,3-O-(1,2-ethanediyl) ascorbic acid, and 5,6-O-diisostearoyl-2,3-O-(1,2-ethanediyl) ascorbic acid.

[0020] The ascorbic acid derivative represented by the general formula (1) can be produced by various methods. For example, by reacting dihaloalkanes, 2-halomethyloxiranes, bishalomethyloxetanes, etc., with the hydroxyl groups at the 2nd and 3rd positions of ascorbic acid to form a cyclic structure from these hydroxyl groups, the derivative represented by the general formula (1) can be produced. ２ and R ３ Ascorbic acid derivatives in which are hydrogen can be obtained. Furthermore, after the above reaction, by acylation, alkylation, or benzylation of the hydroxyl groups bonded to the 5th and 6th positions by known means, R represented by general formula (1) can be obtained. ２ and / or R ３ Ascorbic acid derivatives in which the element is other than hydrogen can be obtained. Alternatively, ascorbic acid derivatives represented by general formula (1) can be obtained by acylation, alkylation, or benzylation of the hydroxyl groups bonded to the 5th and 6th positions of ascorbic acid by known means, and then forming a cyclic structure from the hydroxyl groups at the 2nd and 3rd positions with a dihaloalkane or the like.

[0021] Compounds that can react with the hydroxyl groups at the 2nd and 3rd positions of ascorbic acid to form a cyclic structure include, but are not particularly limited to, dihaloalkanes, 2-halomethyloxiranes, and bishalomethyloxetanes. Examples of dihaloalkanes include dibromoethane, dibromopropane, dibromobutane, dichloroethane, dichloropropane, dichlorobutane, diiodoethane, diiodopropane, and diiodobutane. Examples of 2-halomethyloxiranes include 2-bromomethyloxiranes, 2-chloromethyloxiranes, and 2-iodomethyloxiranes. Examples of bishalomethyloxetanes include bisbromomethyloxetane and bischloromethyloxetane.

[0022] In the synthesis of ascorbic acid derivatives represented by general formula (1), there are no particular restrictions on the amount of dihaloalkane, 2-halomethyloxirane, and bishalomethyloxetane used to react with the hydroxyl groups at the 2nd and 3rd positions of ascorbic acid to form a cyclic structure. However, it is preferable that the amount is 0.5 to 2.0 moles, and more preferably 1.0 to 1.5 moles, per mole of ascorbic acid.

[0023] Specifically, an ascorbic acid derivative represented by general formula (1), where R １ However, - (CH ２ ) ｎ Those with the formula -* (where n is an integer from 2 to 4) can be obtained by reacting ascorbic acid with a dihaloalkane (with 2 to 4 carbon atoms) to form a cyclic structure from the hydroxyl groups at positions 2 and 3 of ascorbic acid.

[0024] Furthermore, an ascorbic acid derivative represented by general formula (1), R １ However, -CH ２ CH(OH)CH ２ - * or R １ However, -CH ２ CH (CH ２ OH) - *, or - CH (CH ２ OH)CH ２ Those marked with -* can be obtained by reacting ascorbic acid with 2-halomethyloxirane to form a cyclic structure from the hydroxyl groups at positions 2 and 3 of ascorbic acid.

[0025] Furthermore, an ascorbic acid derivative represented by general formula (1), R １ However, the divalent group represented by the general formula (2) can be obtained by reacting ascorbic acid with bishalomethyloxetane to form a cyclic structure from the hydroxyl groups at positions 2 and 3 of ascorbic acid.

[0026] The reaction for synthesizing the ascorbic acid derivative represented by general formula (1) can be carried out in various solvents. Examples of the solvent include water, lower alcohols such as methanol, ethanol and isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran (THF), N-methylpyrrolidone, acetonitrile, or mixed solvents thereof, and there is no particular limitation. The reaction temperature is not particularly limited, but is preferably in the range of 30 to 100°C, more preferably in the range of 50 to 90°C, and particularly preferably in the range of 60°C to 90°C.

[0027] Examples of the pH adjuster used in the reaction include hydrochloric acid, sulfuric acid, lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, gluconic acid, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, triethylamine, diazabicycloundecene, p-toluenesulfonic acid monohydrate, and the like.

[0028] From the reaction product of the ascorbic acid derivative represented by general formula (1) produced as described above, a desired compound can be separated and purified by means such as HPLC (high performance liquid chromatography), column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, etc.

[0029] Further, in the ascorbic acid derivative represented by general formula (1), R １ is -(CH ２ ) ｎ -* (n is an integer of 2 to 4), and R ２ and / or R ３ is -COR ４ can be produced by synthesizing an ascorbic acid derivative having a cyclic structure formed from the 2- and 3-hydroxyl groups as described above, and further carrying out various known methods. For example, in the ascorbic acid derivative represented by general formula (1), R １ is -(CH ２ ) ｎ -* (n is an integer of 2 to 4), wherein R ２ and / or R３ is -COR ４ can be synthesized by a method of mixing the ascorbic acid derivative having said cyclic structure formed with various acid halides or various acid anhydrides, or by a method of mixing the ascorbic acid derivative having said cyclic structure formed with various carboxylic acids in concentrated sulfuric acid. Furthermore, it is an ascorbic acid derivative represented by general formula (1) wherein R １ is -(CH ２ ) ｎ -* (n is an integer of 2 to 4), and when R ２ is a benzyl group, the ascorbic acid derivative can be synthesized by a method of reacting dialkoxyalkyl, α,α-dialkoxytoluene or the like under a strong acid condition, and then carrying out ring opening using a reducing agent.

[0030] Examples of the acid halide used in the above reaction include acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride, dodecanoyl chloride, tridecanoyl chloride, tetradecanoyl chloride, pentadecanoyl chloride, hexadecanoyl chloride, heptadecanoyl chloride, octadecanoyl chloride, nonadecanoyl chloride, eicosanoyl chloride, henicosanoyl chloride, docosanoyl chloride, 2-ethylhexanoyl chloride, 3-ethylhexanoyl chloride, 5-methylheptanoyl chloride, isostearoyl chloride (for example, 2-octyldecanoyl chloride or 16-methylheptadecanoyl chloride), isononanoyl chloride, isodecanoyl chloride, isoundecanoyl chloride, isododecanoyl chloride, isotridecanoyl chloride, isotetradecanoyl chloride, isopentadecanoyl chloride, isohexadecanoyl chloride, isoheptadecanoyl chloride, isononadecanoyl chloride, isoeicosanoyl chloride, isohenicosanoyl chloride, isodocosanoyl chloride, and the like.

[0031] Furthermore, when using acid halides derived from branched fatty acids among the above-mentioned acid halides, commercially available products may contain a mixture of acid halides with different branching points. Therefore, reaction products with fatty acids with different branching points added may be obtained as by-products. For example, when using a commercially available product as 16-methylheptadecanoyl chloride, compounds resulting from the reaction of 2-octyldecanoyl chloride with different branching points may also be produced as by-products. In this case, the ascorbic acid derivative of the present invention will also include these by-products.

[0032] There are no particular restrictions on the amount of acid halide used, but when mainly obtaining a product in which the acid halide is introduced to either the 5th or 6th hydroxyl group, it is preferable to use 0.5 to 1.5 moles, and particularly preferable to use 0.8 to 1.5 moles, per mole of the ascorbic acid derivative forming the cyclic structure. When the amount of acid halide used is 1.5 to 5.0 moles, preferably 1.5 to 3.0 moles, per mole of the ascorbic acid derivative forming the cyclic structure, a mixture of products in which the acid halide is introduced to only one position and products in which it is introduced to both positions can be obtained. Furthermore, after obtaining a product in which the acid halide is introduced to either the 5th or 6th hydroxyl group under the above conditions, a product in which the acid halide is introduced to both positions can be obtained by further reacting it with an acid halide or the like.

[0033] The reaction with acid halides can be carried out by adjusting the solvent, reaction temperature, and pH to be the same as for the reaction that forms a cyclic structure. By purifying the reaction using methods such as silica gel chromatography, column chromatography using resins such as ion exchange resins, activated carbon treatment, extraction, distillation, and crystallization, ascorbic acid derivatives with the desired structure can be obtained.

[0034] The amount of the ascorbic acid derivative represented by the general formula (1) in the cosmetic composition according to the present invention varies depending on the application and is not particularly limited, but is usually preferably in the range of 0.1 to 20% by mass, and more preferably 1 to 10% by mass. If it is less than 0.1% by mass, the expected effect may not be obtained, on the other hand, if it exceeds 20% by mass, the effect commensurate with the amount added may not be expected, or the dosage form may be damaged.

[0035] Furthermore, the cosmetic composition of the present invention contains component (A) an ascorbic acid derivative represented by general formula (1) and component (B) a polyhydric alcohol as essential components, possessing the excellent physiological activity effect of the ascorbic acid derivative and the excellent moisturizing effect of the polyhydric alcohol. Moreover, when the mixing ratio of component (A) and component (B) is within a specific range, it is possible to improve the feel of the product, such as stickiness, which has been a problem when polyhydric alcohols are incorporated.

[0036] In the present invention, the component (B) polyhydric alcohol can be a polyhydric alcohol having two or more hydroxyl groups. Examples include 1,3-butylene glycol, glycerin, diglycerin, xylitol, sorbitol, erythritol, pentaerythritol, 1,2-propanediol (propylene glycol), 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 2,3-butanediol, 2-methyl-2,3-propanediol, 1,2-pentanediol, 2-methyl-2,4-butanediol, 1,2-hexanediol, 1,6-hexanediol, 2,5-hexanediol, 2-methyl-2,4-pentanediol, dipropylene glycol, ethylhexylglycerin, glyceryl caprylate, caprylyl glycol, etc., which can be used individually or in combination of two or more. In particular, glycerin, 1,2-propanediol, 1,3-butylene glycol, and 1,2-pentanediol are preferred because they provide high moisturizing effects, are inexpensive, and are easily available. Glycerin, 1,3-butylene glycol, and 1,2-pentanediol are even more preferred, as they provide even better moisturizing effects.

[0037] The mass ratio [component (A) / component (B)] of component (A) an ascorbic acid derivative represented by general formula (1) and component (B) a polyhydric alcohol varies depending on the application, but from the viewpoint of usability, it is preferably 0.01 or higher, and more preferably 0.1 or higher. If the mass ratio is less than 0.01, the stickiness derived from the polyhydric alcohol may be more easily felt, and the usability may decrease. On the other hand, from the viewpoint of moisturizing properties, it is preferably less than 10.0, more preferably less than 5.0, and most preferably less than 1.0. If the mass ratio is 10.0 or higher, the functionality derived from the polyhydric alcohol may not be fully exhibited, and the moisturizing properties may decrease.

[0038] The cosmetic composition of the present invention may appropriately contain ingredients commonly used in cosmetics, such as oily raw materials, surfactants, humectants, polymer compounds, antioxidants, whitening agents, pharmaceuticals, UV absorbers, metal ion chelating agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, and the like.

[0039] Examples of oily raw materials, surfactants, other humectants, polymer compounds, antioxidants, whitening agents, other drugs, UV absorbers, metal ion chelating agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, etc., are similar to those described in Publication WO2022 / 080287.

[0040] The cosmetic composition of the present invention is not particularly limited, but can be in the form of liquid, emulsion, paste, cream, gel, etc., with liquid, cream, emulsion, and gel forms being preferred. For example, it can be used as a skincare cosmetic composition such as a lotion, emulsion, cream, or sunscreen cream.

[0041] Next, specific embodiments for carrying out the present invention will be described in detail with reference to examples, but the scope of the present invention is not limited by the examples. Prior to the examples, a synthesis example of the production of the ascorbic acid derivative of the present invention used in the examples is shown.

[0042] Synthesis Example 1 (Synthesis of 2,3-O-(1,2-ethanediyl)ascorbic acid) In a round-bottom flask, DMF (9.0 g), ascorbic acid (0.88 g), potassium carbonate (0.76 g), and dibromoethane (1.0 g) were added and stirred at 80°C for 3 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was performed using isobutyl alcohol, and the organic layer was recovered. Magnesium sulfate was then added. The mixture was then filtered again, and the filtrate was concentrated under reduced pressure. The resulting residue (1.2 g) was subjected to silica gel chromatography and eluted with a chloroform / methanol / water mixture of 20 / 3 / 0.3. Further concentration under reduced pressure was performed to obtain 0.51 g of the product.

[0043] The obtained product was subjected to mass spectrometry. 1 H-NMR, １３ 13C-NMR measurements were performed, and the results confirmed that the product is 2,3-O-(1,2-ethanediyl)ascorbic acid, represented by the following structural formula.

[0044] Furthermore, in the synthesis examples shown below, the obtained products were subjected to mass spectrometry. 1 H-NMR, １３ 13C-NMR measurements were performed, and the results confirmed that the product is an ascorbic acid derivative represented by the structural formula or compound name shown in each synthesis example (including cases where there are two or more ascorbic acid derivatives), or that it is mainly composed of the said ascorbic acid derivative. Mass spectrometry was performed on the products obtained in each synthesis example. 1 H-NMR, １３ The 1C-NMR measurement results are shown in Tables 1 to 9.

[0045]

[0046] Synthesis Example 2 (Synthesis of 2,3-O-(1,3-propanediyl)ascorbic acid) In a round-bottom flask, 35.0 g of DMF, 3.5 g of ascorbic acid, 3.0 g of potassium carbonate, and 4.4 g of dibromopropane were added and stirred at 80°C for 16 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was performed using isobutyl alcohol, and the organic layer was recovered. Magnesium sulfate was then added. The mixture was then filtered again, and the filtrate was concentrated under reduced pressure. The resulting residue (4.2 g) was subjected to silica gel chromatography, eluted with a chloroform / methanol / water mixture of 20 / 3 / 0.3, and concentrated under reduced pressure to obtain 2,3-O-(1,3-propanediyl)ascorbic acid (0.56 g), represented by the following structural formula.

[0047]

[0048] Synthesis Example 3 (Synthesis of 2,3-O-(1,4-butanediyl)ascorbic acid) In a round-bottom flask, 35.0 g of DMF, 3.5 g of ascorbic acid, 3.0 g of potassium carbonate, and 4.8 g of dibromobutane were added and stirred at 80°C for 16 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was performed using isobutyl alcohol, and the organic layer was recovered. Magnesium sulfate was then added. The mixture was then filtered again, and the filtrate was concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography and eluted with a mixture of chloroform / methanol / water = 25 / 3 / 0.3 to 20 / 3 / 0.3. The mixture was concentrated under reduced pressure to obtain 2,3-O-(1,4-butanediyl)ascorbic acid (1.1 g), represented by the following structural formula.

[0049]

[0050] Synthesis Example 4 Synthesis Example 5 (Synthesis of 2,3-O-(2-hydroxypropane-1,3-diyl)ascorbic acid and 2,3-O-(1-hydroxymethyl-1,2-ethanediyl)ascorbic acid) In a round-bottom flask, 13.6 g of DMF, 6.3 g of water, 3.5 g of ascorbic acid, 2.0 g of triethylamine, and 2.2 g of 2-chloromethyloxirane were added and stirred at 60°C for 3 hours. After cooling, the filtrate was concentrated under reduced pressure, and the resulting concentrate was dissolved in water. Extraction was performed using isobutyl alcohol, and the organic layer was recovered, after which magnesium sulfate was added. Subsequently, filtration was performed, and the filtrate was concentrated under reduced pressure. The resulting residue (2.4 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform / methanol / water = 15 / 3 / 0.3 to 10 / 3 / 0.3, and concentrated under reduced pressure to obtain the crude product (140 mg). The obtained crude product was separated and purified by HPLC to obtain 2,3-O-(2-hydroxypropane-1,3-diyl)ascorbic acid (58.0 mg) (Synthesis Example 4: left structural formula below) and 2,3-O-(1-hydroxymethyl-1,2-ethanediyl)ascorbic acid (6.6 mg) (Synthesis Example 5: right structural formula below), represented by the following structural formulas.

[0051]

[0052] Synthesis Example 6 (Synthesis of 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid) In a round-bottom flask, 5.0 g of DMF, 0.53 g of ascorbic acid, 0.46 g of potassium carbonate, and 0.81 g of 3,3-bis(bromomethyl)oxetane were added and stirred at 80°C for 7 hours. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was performed using isobutyl alcohol, and the organic layer was recovered. Magnesium sulfate was then added. The mixture was filtered again, and the filtrate was concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography, eluted with a chloroform / methanol / water mixture of 20 / 3 / 0.3, and concentrated under reduced pressure to obtain 0.14 g of 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid.

[0053]

[0054] Synthesis Example 7 (Synthesis of 2,3-O-(2,2-dimethyl-1,2-ethanediyl)ascorbic acid) 2-O-(2-hydroxyisobutyl)ascorbic acid was synthesized by the method described as Synthesis Example 1 in Japanese Patent Publication No. 7267657. 2-O-(2-hydroxyisobutyl)ascorbic acid (0.50 g), THF (5.0 g), and p-toluenesulfonic acid monohydrate (0.52 g) were added to a round-bottom flask and stirred at 80°C for 24 hours. After the reaction was complete, water and isobutanol were added and liquid-liquid extraction was performed. The isobutanol layer was recovered and concentrated under reduced pressure. The obtained residue (0.60 g) was subjected to silica gel chromatography, eluted with a chloroform / methanol mixture of 10 / 0 to 9.5 / 0.5, and concentrated under reduced pressure to obtain 2,3-O-(2,2-dimethyl-1,2-ethanediyl)ascorbic acid (37.0 mg).

[0055]

[0056] Synthesis Example 8 (Synthesis of 2,3-O-(1,1-dimethyl-1,2-ethanediyl)ascorbic acid) 3-O-(2-hydroxyisobutyl)ascorbic acid was synthesized by the method described as Synthesis Example 2 in Japanese Patent Publication No. 7267657. 3-O-(2-hydroxyisobutyl)ascorbic acid (4.2 g), THF (25 g), and p-toluenesulfonic acid monohydrate (4.2 g) were added to a round-bottom flask and stirred at 90°C for 18 hours. After the reaction was complete, water and ethyl acetate were added and liquid-liquid extraction was performed. Ethyl acetate was recovered and concentrated under reduced pressure. The resulting residue (0.21 g) was subjected to silica gel chromatography and eluted with a chloroform / methanol mixture of 10 / 0 to 9.5 / 0.5. The mixture was concentrated under reduced pressure to obtain 2,3-O-(1,1-dimethyl-1,2-ethanediyl)ascorbic acid (15.0 mg).

[0057]

[0058] Synthesis Example 9 Synthesis Example 10 (Synthesis of 6-O-butanoyl-2,3-O-(1,4-butanediyl)ascorbic acid and 5,6-O-dibutanoyl-2,3-O-(1,4-butanediyl)ascorbic acid) 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g), N-methylpyrrolidone (30 g), and triethylamine (5.1 g) obtained in Synthesis Example 3 were added to a round-bottom flask. Butanoyl chloride (5.1 g) was added while stirring at 25°C, and the mixture was stirred at 25°C for 5 hours. Extraction was performed using ethyl acetate. After washing with water three times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (2.5 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-butanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (0.9 g) (Synthesis Example 9: structural formula on the left below) and 5,6-O-dibutanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.4 g) (Synthesis Example 10: structural formula on the right below).

[0059]

[0060] Synthesis Example 11 Synthesis Example 12 (Synthesis of 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid and 5,6-O-dioctanoyl-2,3-O-(1,4-butanediyl)ascorbic acid) 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g), N-methylpyrrolidone (30 g), and triethylamine (3.4 g) obtained in Synthesis Example 3 were added to a round-bottom flask, and octanoyl chloride (5.0 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 2 hours and extracted with ethyl acetate. After washing with water three times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (5.1 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 5 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.4 g) (Synthesis Example 11: left structural formula below) and 5,6-O-dioctanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.6 g) (Synthesis Example 12: right structural formula below), represented by the following structural formulas.

[0061]

[0062] Synthesis Example 13 Synthesis of 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g) obtained in Synthesis Example 3, N-methylpyrrolidone (30 g), and triethylamine (1.7 g) were added, and dodecanoyl chloride (3.4 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 4 hours and extracted with ethyl acetate. After washing with water three times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (6.1 g) was subjected to silica gel chromatography and eluted with a hexane / ethyl acetate = 8 / 3 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid (3.1 g) represented by the following structural formula.

[0063]

[0064] Synthesis Example 14 Synthesis of 5,6-O-dilauroyl-2,3-O-(1,4-butanediyl)ascorbic acid 1.5 g of 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid obtained in Synthesis Example 13, 4-dimethylaminopyridine (DMAP: 19.0 mg), and dodecanoyl chloride (1.2 g) were added to a round-bottom flask and stirred at 25°C for 4 hours. The resulting residue (3.2 g) was subjected to silica gel chromatography and eluted with a hexane / ethyl acetate = 4 / 1 mixture. The mixture was concentrated under reduced pressure to obtain 5,6-O-dilauroyl-2,3-O-(1,4-butanediyl)ascorbic acid (0.9 g) represented by the following structural formula.

[0065]

[0066] Synthesis Example 15 Synthesis of 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,4-butanediyl)ascorbic acid (2.0 g) obtained in Synthesis Example 3, N-methylpyrrolidone (30 g), and triethylamine (1.1 g) were added, and hexadecanoyl chloride (2.6 g) was added while stirring at 0°C. The mixture was stirred at 25°C for 5 hours and extracted with ethyl acetate. After washing twice with water and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (4.7 g) was subjected to silica gel chromatography and eluted with a hexane / ethyl acetate = 5 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.3 g) represented by the following structural formula.

[0067]

[0068] Synthesis Example 16 Synthesis of 5,6-O-Dipalmitoyl-2,3-O-(1,4-Butanediyl)Ascorbic Acid 1.6 g of 6-O-palmitoyl-2,3-O-(1,4-Butanediyl)Ascorbic Acid obtained in Synthesis Example 15, 22 mg of DMAP, and 1.8 g of hexadecanoyl chloride were added to a round-bottom flask. The mixture was stirred at 60°C for 4 hours, and then stirred at 25°C for 16 hours. The mixture was then extracted using hexane / ethyl acetate = 1:1, and after recovering the organic layer, magnesium sulfate was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (3.3 g) was subjected to silica gel chromatography, eluted with hexane / ethyl acetate = 4 / 1 mixture, and concentrated under reduced pressure to obtain 5,6-O-Dipalmitoyl-2,3-O-(1,4-Butanediyl)Ascorbic Acid (0.9 g), represented by the following structural formula.

[0069]

[0070] Synthesis Example 17 Synthesis Example 18 Synthesis of 6-O-isostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid and 5,6-O-diisostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g), N-methylpyrrolidone (30 g), and triethylamine (3.4 g) obtained in Synthesis Example 3 were added. Isostearoyl chloride (9.4 g) was added while stirring at 25°C, and the mixture was stirred at 25°C for 3 hours. Extraction was performed with ethyl acetate. After washing twice with water and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (9.8 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.5 g) (Synthesis Example 17: upper structural formula below) and 5,6-O-diisostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.8 g) (Synthesis Example 18: lower structural formula below), represented by the following structural formulas.

[0071]

[0072] Synthesis Example 19 Synthesis of 5-O-butanoyl-6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid In a round-bottom flask, 1.0 g of 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid obtained in Synthesis Example 11, 5.0 g of acetonitrile, and 0.6 g of triethylamine were added, and butanoyl chloride (0.5 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 2 hours and extracted with ethyl acetate. After washing twice with water and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (1.5 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 3 / 1 mixture, and concentrated under reduced pressure to obtain 5-O-butanoyl-6-O-octanoyl-2,3-(1,4-butanediyl)ascorbic acid (0.8 g), represented by the following structural formula.

[0073]

[0074] Synthesis Example 20 Synthesis Example 21 Synthesis of 6-O-butanoyl-2,3-O-(1,3-propanediyl)ascorbic acid and 5,6-O-dibutanoyl-2,3-O-(1,3-propanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22 g), and triethylamine (5.0 g) obtained in Synthesis Example 2 were added, and butanoyl chloride (2.6 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 2 hours and extracted with ethyl acetate. After washing with water four times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (4.2 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 3 / 1 to 2 / 3 mixture, and concentrated under reduced pressure to obtain 6-O-butanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.7 g) (Synthesis Example 20: left structural formula below) and 5,6-O-dibutanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.9 g) (Synthesis Example 21: right structural formula below), represented by the following structural formulas.

[0075]

[0076] Synthesis Example 22 Synthesis Example 23 Synthesis of 6-O-octanoyl-2,3-O-(1,3-propanediyl)ascorbic acid and 5,6-O-dioctanoyl-2,3-O-(1,3-propanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22 g), and triethylamine (5.0 g) obtained in Synthesis Example 2 were added, and octanoyl chloride (6.0 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 3 hours and extracted with ethyl acetate. After washing with water four times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (7.6 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-octanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) (Synthesis Example 22: left structural formula below) and 5,6-O-dioctanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.3 g) (Synthesis Example 23: right structural formula below), represented by the following structural formulas.

[0077]

[0078] Synthesis Example 24 Synthesis Example 25 Synthesis of 6-O-lauroyl-2,3-O-(1,3-propanediyl)ascorbic acid and 5,6-O-dilauroyl-2,3-O-(1,3-propanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22 g), and triethylamine (11 g) obtained in Synthesis Example 2 were added, and dodecanoyl chloride (7.8 g) was added while stirring at room temperature. The mixture was stirred at 25°C for 3 hours and extracted with ethyl acetate. After washing with water three times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (6.6 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-lauroyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) (Synthesis Example 24: upper structural formula below) and 5,6-O-dilauroyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.3 g) (Synthesis Example 25: lower structural formula below), represented by the following structural formulas.

[0079]

[0080] Synthesis Example 26 Synthesis Example 27 Synthesis of 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid and 5,6-O-dipalmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22 g), and triethylamine (3.9 g) obtained in Synthesis Example 2 were added, and hexadecanoyl chloride (9.9 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 3 hours and extracted with ethyl acetate. After washing twice with water and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (13.4 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 6 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) (Synthesis Example 26: upper structural formula below) and 5,6-O-dipalmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.6 g) (Synthesis Example 27: lower structural formula below), represented by the following structural formulas.

[0081]

[0082] Synthesis Example 28 Synthesis of 6-O-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid In a round-bottom flask, 2,3-O-(1,3-propanediyl)ascorbic acid (3.0 g) obtained in Synthesis Example 2, N-methylpyrrolidone (30 g), and triethylamine (1.8 g) were added, and isostearoyl chloride (5.0 g) was added while stirring. The mixture was stirred at 25°C for 4 hours and extracted with ethyl acetate. After washing with water three times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (8.6 g) was subjected to silica gel chromatography and eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.4 g) represented by the following structural formula.

[0083]

[0084] Synthesis Example 29 Synthesis of 5,6-O-diisostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid 6-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.4 g), DMAP (22.0 mg), and isostearoyl chloride (1.4 g) obtained in Synthesis Example 28 were added to a round-bottom flask. N-methylpyrrolidone (14.0 g) was then added, and the mixture was stirred at 25°C for 7 hours and concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 mixture, and concentrated under reduced pressure to obtain 5,6-O-diisostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.17 g) represented by the following structural formula.

[0085]

[0086] Synthesis Example 30 Synthesis of 5-butanoyl-6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid 0.8 g of 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid obtained in Synthesis Example 26, acetonitrile (4.0 g), and triethylamine (0.36 g) were added to a round-bottom flask, and butanoyl chloride (0.3 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 2 hours and extracted with ethyl acetate. After washing twice with water and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (0.9 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 3 / 1 mixture, and concentrated under reduced pressure to obtain 5-O-butanoyl-6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.6 g), represented by the following structural formula.

[0087]

[0088] Synthesis Example 31 Synthesis Example 32 Synthesis of 6-O-isostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid and 5,6-O-diisostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid In a round-bottom flask, 1.9 g of 2,3-O-(1,2-ethanediyl)ascorbic acid obtained in Synthesis Example 1, 20 g of N-methylpyrrolidone, and 4.8 g of triethylamine were added, and isostearoyl chloride (6.8 g) was added while stirring at 25°C. The mixture was stirred at 25°C for 3 hours and extracted with ethyl acetate. After washing with water four times and recovering the organic layer, magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The obtained residue (9.2 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate = 4 / 1 to 1 / 1 mixture, and concentrated under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid (1.0 g) (Synthesis Example 31: upper structural formula below) and 5,6-O-diisostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid (1.0 g) (Synthesis Example 32: lower structural formula below), represented by the following structural formulas.

[0089]

[0090] Mass spectrometry was performed on the products obtained in Synthesis Examples 1 to 32 using LC-MS-2020 (Shimadzu Corporation). The measurement results are shown in Tables 1 and 2.

[0091]

[0092]

[0093] ¹H-NMR measurements were performed on the products obtained in Synthesis Examples 1 to 32 using a JNM-ECS400 (manufactured by JEOL Ltd.). The measurement results are shown in Tables 3 to 5.

[0094]

[0095]

[0096]

[0097] Products obtained in Synthesis Examples 1 to 32 1３¹³C-NMR measurements were performed using a JNM-ECS400 (manufactured by JEOL Ltd.). The measurement results are shown in Tables 6 to 8.

[0098]

[0099]

[0100]

[0101] Test Example 1 [Stability Test - 1] For the samples from Synthesis Examples 1 to 6, 1% aqueous solutions were prepared with dilute potassium hydroxide aqueous solution to pH 3, 5, 7, 8, and 9, respectively, and placed in 50 mL screw-cap tubes, which were then sealed. After storage at 50°C for 4 weeks, HPLC measurement (using a Shimadzu Corporation instrument) was performed, and the remaining percentage was determined from the peak area. The results regarding the remaining percentage based on the following criteria are shown in Table 9. In addition, for the sample adjusted to pH 7, the odor and coloration were evaluated based on the following methods and criteria, and the results are shown in Table 10.

[0102] Survival Rate: ◎: 80% or more ○: 50% or more, less than 80% △: 30% or more, less than 50% ×: Less than 30%

[0103] Odor: Evaluated by 10 panelists using the following criteria: 3: Almost odorless. 2: Slightly unpleasant odor. 1: Strong unpleasant odor. Based on these evaluation results, the following classifications were made: ○: Total score of 10 panelists is 25 or higher. △: Total score of 10 panelists is between 16 and 24. ×: Total score of 10 panelists is 15 or lower.

[0104] Coloring: Ten panelists evaluated the samples according to the following criteria: 3: Almost no change compared to immediately after preparation. 2: Colored compared to immediately after preparation. 1: Strongly colored compared to immediately after preparation. Based on these evaluation results, the samples were classified as follows: ○: Total score of 10 people is 25 or higher △: Total score of 10 people is between 16 and 24 ×: Total score of 10 people is 15 or lower

[0105]

[0106]

[0107] Test Example 2 [Stability Test - 2] For samples from Synthesis Examples 9 to 32, (a) and (b) described in Table 11 were heated and mixed, respectively. After cooling, creams with a pH of 7 or 9 were prepared by adding (c) described in Table 11. The creams were stored at 50°C for 4 weeks, and the remaining percentage was determined in the same manner as in Test Example 1 and evaluated according to the criteria described below. Odor and color were also evaluated based on the same method and criteria as in Test Example 1. The results regarding the remaining percentage are shown in Tables 12 to 13, and the results regarding odor and color are shown in Tables 14 to 15.

[0108] Survival Rate: ◎: 95% or more ○: 85% or more, less than 95% ×: Less than 85%

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] The results of the above test examples show that the ascorbic acid derivative represented by general formula (1) of the present invention does not decrease in remaining amount when stored at 50°C compared to ascorbic acid and conventional ascorbic acid derivatives, exhibiting excellent stability over time, and showing almost no odor generation or discoloration. In Test Example 1, in the neutral to weakly alkaline range of pH 7 to 9, the remaining amount of ascorbic acid decreased to less than 30% after two weeks, while the ascorbic acid derivative represented by general formula (1) of the present invention maintained a remaining amount of 50% or more after two weeks, and even after four weeks, its remaining amount was significantly higher than that of ascorbic acid. Similarly, in Test Example 2, it was clear that the ascorbic acid derivative represented by general formula (1) of the present invention has higher stability in the neutral to weakly alkaline range of pH 7 to 9 than conventional ascorbic acid derivatives such as ascorbyl tetrahexyldecanoate. The ascorbic acid derivative represented by general formula (1) of the present invention possesses the excellent properties inherent in ascorbic acid, but the results shown in Tables 9, 10, and 12-15 further demonstrate improved long-term stability, which was a problem with conventional ascorbic acid derivatives, making it more suitable as a compounding material for cosmetics.

[0115] Test Example 3 [Collagen Production Promoting Effect] Normal human dermal fibroblasts were subjected to 2.5 × 10⁻⁶ ４ After preparing the cells in D-MEM containing 5% (v / v) fetal bovine serum to a cell density of cells / well, the samples were pre-incubated for 24 hours on a 96-well plate. After removing the culture medium, the samples, which had been prepared to the specified concentration in D-MEM containing 5% (v / v) fetal bovine serum, were added to each well and cultured for 48 hours. After the culture period, the amount of free collagen in the supernatant was quantified by ELISA. The measurement was performed on a sample size of N=3.

[0116] The collagen production levels of the samples measured at concentrations of 10 mM or less were compared with the control group, and the results (percentage values ​​with the control group set to 100%) are shown in Table 16 based on the following criteria: <100%: ± 100-140%: + 140%<: ++

[0117]

[0118] The results in Table 16 clearly show that the ascorbic acid derivative represented by general formula (1) of the present invention has a collagen production promoting effect equivalent to or better than known ascorbic acid derivatives, namely 2-O-glyceryl ascorbate and 3-O-glyceryl ascorbate. Therefore, when incorporated into the cosmetic composition of the present invention, it results in a cosmetic composition that exhibits an excellent collagen production promoting effect.

[0119] Test Example 4 [Hyaluronic Acid Production Promoting Effect] Normal human dermal fibroblasts (NHDF) were subjected to 2.5 × 10⁻⁶ ４ After preparing samples in D-MEM containing 5% (v / v) fetal bovine serum to achieve a cell density of cells / well, pre-incubation was performed for 24 hours on a 96-well plate. After removing the medium, samples prepared in serum-free D-MEM were added to each well and cultured for 48 hours. After the culture period, the amount of hyaluronic acid in the supernatant was quantified by ELISA. Measurements were performed on a sample size of N=3.

[0120] The amount of hyaluronic acid produced when the sample was measured at a concentration of 10 mM or less was compared with the control group, and the results (percentage values ​​with the control group set to 100%) are shown in Tables 17 and 18 based on the following criteria: <100%: ± 100-120%: + 120%<: ++

[0121]

[0122]

[0123] The results in Tables 17 and 18 clearly show that the ascorbic acid derivative represented by general formula (1) of the present invention has a higher hyaluronic acid production promoting effect than ascorbic acid or known ascorbic acid derivatives. Therefore, when incorporated into the cosmetic composition of the present invention, it results in a cosmetic composition that exhibits an excellent hyaluronic acid production promoting effect.

[0124] Test Example 5 [Antioxidant Effect] Normal human epidermal keratinocytes, 2.0 × 10 ４Cells were seeded in a 96-well plate using KG2 medium to achieve a cell density of cells / well. After 24 hours of pre-incubation, the sample, adjusted to the specified concentration in KG2 medium, was added to each well. After 24 hours of incubation and removal of the medium, the cells were washed with HBSS(-) and allowed to take up the ROS-reactive fluorescent probe DCFHDA for 30 minutes. The cells were washed again with HBSS(-) and treated with 0.2 mM H2. ２ O ２ The samples were treated and cultured for 2 hours. Fluorescence intensity was measured, and the ROS production per unit protein was calculated by multiplying the fluorescence intensity by the amount of protein quantified by the BCA method, and this was defined as analytical value 1. Furthermore, the ROS production amount calculated without adding the sample adjusted to the predetermined concentration using the above test method was defined as analytical value 2, and the sample and 0.2 mM H were used. ２ O ２ The amount of ROS produced without the addition of [substance name] was set as analytical value 3, and the ROS production inhibition rate was calculated using the following formula. A higher ROS production inhibition rate indicates a higher antioxidant effect. ROS production inhibition rate (%) = [(Analytical value 2) - (Analytical value 1)] / [(Analytical value 2) - (Analytical value 3)] × 100

[0125] The inhibition rate of ROS production when the sample was measured at a concentration of 10 mM or less was evaluated as follows. Measurements were performed with N=4. These results are shown in Table 21. <20%: + 20-40%: ++ 40%<: +++

[0126]

[0127] The results in Table 19 show that the ascorbic acid derivative represented by general formula (1) of the present invention has an antioxidant effect equivalent to or greater than that of known ascorbic acid derivatives. Therefore, when incorporated into the cosmetic composition of the present invention, it results in a cosmetic composition that exhibits excellent antioxidant effects.

[0128] Test Example 6 [Sensory Evaluation 1] Lotions were prepared with the compositions shown in Tables 20 and 21, and evaluated for non-stickiness, ease of application, and smoothness based on the evaluation methods and criteria described below. Conventional ascorbic acid and ascorbic acid derivatives used in the comparative example are denoted as component (a).

[0129] (Evaluation Method) The results of the reference example were used as the baseline (0 points), and evaluations were made on a 5-point scale based on the evaluation criteria below. The results are shown as the total score of the 10 panelists, with higher scores indicating better results.

[0130] (Evaluation Criteria) 2 points: Much better than the example 1 point: Better than the example 0 points: Same as the example -1 point: Worse than the example -2 points: Much worse than the example

[0131]

[0132]

[0133] The results in Tables 20 and 21 clearly show that the lotion of the present invention, which contains component (A) an ascorbic acid derivative represented by general formula (1) and component (B) a polyhydric alcohol, receives favorable evaluations in all aspects, including non-stickiness, ease of absorption, and smoothness, compared to lotions containing ascorbic acid or conventional ascorbic acid derivatives and polyhydric alcohols.

[0134] Test Example 7 [Sensory Evaluation 2] Skin creams were prepared with the compositions shown in Tables 22-24 and evaluated for non-greasy texture, spreadability, and ease of absorption. The evaluation method and criteria were the same as in Test Example 6 above.

[0135]

[0136]

[0137]

[0138] The results in Tables 22-24 clearly show that the skin cream, which is a cosmetic composition of the present invention and contains component (A) an ascorbic acid derivative represented by general formula (1) and component (B) a polyhydric alcohol, received favorable evaluations in all aspects of non-greasy texture, spreadability, and ease of absorption compared to skin creams containing ascorbic acid or conventional ascorbic acid derivatives and polyhydric alcohols.

[0139] Example 13 Cream The raw materials for the oil phase (1) to (5) and the raw materials for the aqueous phase (6) to (10) of the composition shown in Table 25 were heated to 70°C and dissolved to prepare the oil phase and aqueous phase, respectively. Then, the oil phase was added to the aqueous phase and pre-emulsified, and after uniform emulsification with a homomixer, the cream, which is the cosmetic composition of the present invention, was prepared by cooling to room temperature while stirring well. Note that in the tables from Table 25 onward, the amounts are expressed in parts by mass.

[0140]

[0141] Example 14 Emulsion The raw materials for the oil phase (1) to (9) and the raw materials for the aqueous phase (10) to (13) of the composition shown in Table 26 were heated to 70°C and dissolved to prepare the oil phase and aqueous phase, respectively. Then, the oil phase was added to the aqueous phase to perform preliminary emulsification, and after uniform emulsification with a homomixer, the emulsion, which is the cosmetic composition of the present invention, was prepared by cooling to room temperature while stirring well.

[0142]

[0143] Example 15 Emulsion The raw materials for the oil phase (5) to (10) and the raw materials for the aqueous phase (1) to (4) and (11) to (12) of the composition shown in Table 27 were heated to 70°C and dissolved to prepare the oil phase and aqueous phase, respectively. Then, the oil phase was added to the aqueous phase to perform preliminary emulsification, and after uniform emulsification with a homomixer, the emulsion, which is the cosmetic composition of the present invention, was prepared by cooling to room temperature while stirring well.

[0144]

[0145] Example 16 Cream The oil phase raw materials (1) to (6) and the aqueous phase raw materials (7) to (11) with the compositions shown in Table 28 were heated and melted at 70°C to prepare the oil phase and aqueous phase, respectively. The oil phase was added to the aqueous phase and pre-emulsified, then emulsified with a homomixer, and the mixture was cooled to room temperature while stirring well to prepare the cream.

[0146]

Claims

1. A cosmetic comprising: component (A) an ascorbic acid derivative represented by the following general formula (1), and component (B) a polyhydric alcohol, wherein a mass ratio of component (A) to component (B) [component (A) / component (B)] is 0.01 or more and less than 10.

0. [In the formula (1), R １ is -(CH ２ ) ｎ -* (n is an integer of 2 to 4), -CH ２ CH(OH)CH ２ -*, -CH ２ CH(CH ２ OH)-*, -CH(CH ２ OH)CH ２ -*, -C(CH ３ ) ２ CH ２ -*, -CH ２ C(CH ３ ) ２ -* (* represents a position bonding to the 2-position O of ascorbic acid), or a divalent group represented by the following formula (2), R ２ and R ３ are each any one of hydrogen, -COR ４ , a linear or branched alkyl group having 1 to 22 carbon atoms, and a benzyl group, and R ４ is a linear or branched alkyl group having 1 to 22 carbon atoms.]] 2. R in the general formula (1) １ However, - (CH ２ ) ｎ - * (n is 3 or 4), - CH ２ CH(OH)CH ２ -*, -CH ２ CH (CH ２ OH)-*,-CH(CH ２ OH)CH ２ -* (where * represents the position where it bonds with the oxygen at position 2 of ascorbic acid), and R ２ and R ３ Each of them is hydrogen, or R １ ga- (CH ２ ) ｎ - * (n is 3 or 4), R ２ ga-COR ４ , R ３ is hydrogen or -COR ４ And R ４ The cosmetic composition according to claim 1, characterized in that is a linear or branched alkyl group having 4 to 18 carbon atoms.

3. R ​​in the general formula (1) １ However, - (CH ２ ) ３ -*, -CH ２ CH(OH)CH ２ -*, (where * represents the position where it bonds with the oxygen at position 2 of ascorbic acid), and R ２ and R ３ Each of them is hydrogen, or R １ ga- (CH ２ ) ３ -* and R ２ ga-COR ４ And R ３ is hydrogen or -COR ４ And R ４ The cosmetic composition according to claim 2, characterized in that the alkyl group is a linear or branched alkyl group having 8 to 18 carbon atoms.

4. The cosmetic composition according to any one of claims 1 to 3, characterized in that the component (B) polyhydric alcohol is glycerin, 1,3-butylene glycol, or 1,2-pentanediol.

5. The cosmetic composition according to any one of claims 1 to 4, characterized in that the mass ratio of component (A) to component (B) [component (A) / component (B)] is 0.1 or more and less than 1.0.

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