Ascorbic acid derivatives and cosmetic containing same

Abstract

Ascorbic acid derivatives represented by general formula (1), (3), or (4) and cosmetics, collagen production promoters, and hyaluronic acid production promoters that contain them are provided as novel ascorbic acid derivatives that have excellent functions inherent to ascorbic acid such as a collagen promoting action and a moisturizing action and that are stable with little loss of activity even with long-term storage, etc., and as cosmetics and drugs that contain them. [In formula (1), (3), or (4), R1 is –(CH2)n-* (n is an integer of 2-4), -CH2CH(OH)CH2-* (* represents a position that bonds with the position-2 O of the ascorbic ring), or a bis-methyloxetane group, R2 and R3 are hydrogen, -COR4, an alkyl group, or a benzyl group, R4 is a C1-22 alkyl group, and in formula (3), R5 and R6 are hydrogen, a methyl group, or a phenyl group.]

Description

Ascorbic acid derivatives and cosmetics containing them

[0001] The present invention relates to an ascorbic acid derivative that is suitable for use as a raw material for cosmetics, and further to a cosmetic containing the ascorbic acid derivative.

[0002] Ascorbic acid is a safe and useful antioxidant and is known as a compound with excellent whitening properties. However, its use in the cosmetics field has been hindered due to its instability to light, heat, and oxidation, and its insufficient stability over time. Therefore, various ascorbic acid derivatives or salts thereof have been proposed as derivatives with improved stability over time compared to ascorbic acid, and their incorporation into topical skin whitening preparations (Patent Documents 1 and 2) and into cosmetics (Patent Document 3) have been proposed.

[0003] However, many of the above-mentioned ascorbic acid derivatives and their salts still have insufficient stability over time, and have problems such as a decrease in pH in the formulation over time, accelerated decomposition under alkaline conditions, etc. Furthermore, the duration of activity in vivo is not sufficient, and improvements in this respect are desired.

[0004] The present inventors have solved these problems by proposing an ascorbic acid derivative that is inhibited from decomposing under alkaline conditions (Patent Document 4). However, there is a need for an ascorbic acid derivative that has further improved stability over time under alkaline conditions and high stability over a wide pH range.

[0005] JP-A No. 62-221611 JP-A No. 2005-060239 JP-A No. 1-228978 Patent No. 4681670

[0006] An object of the present invention is to provide an ascorbic acid derivative that not only has the excellent properties inherent to ascorbic acid, such as moisturizing activity, but also has high stability over a wide pH range and excellent physiologically active effects.A further object of the present invention is to provide cosmetics and pharmaceuticals that contain the ascorbic acid derivative and exhibit excellent moisturizing activity, etc., as well as high stability over a wide pH range and excellent physiologically active effects.

[0007] The present inventors have conducted extensive research in light of the above-mentioned circumstances, and have found that novel ascorbic acid derivatives represented by the following formula (1), (3) or (4) have excellent moisturizing properties, and some of them are highly stable over a wide pH range, and have excellent physiologically active effects such as the effect of promoting hyaluronic acid production. Furthermore, they have found that cosmetics and pharmaceuticals containing the ascorbic acid derivatives represented by the following formula (1), (3) or (4) have excellent moisturizing properties, are stable over a wide pH range, and further have excellent physiologically active effects such as the effect of promoting hyaluronic acid production. The present invention has been completed based on these findings.

[0008] The first aspect of the present invention is an ascorbic acid derivative represented by the following general formula (1), (3) or (4) (claim 1).

[0009]

[0010]

[0011]

[0012] [In formula (1), (3) or (4), 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 the position of bonding to O at the 2-position of the ascorbic acid ring), or a divalent group represented by the following formula (2): ２ and R ３ are hydrogen and -COR ４ , a linear or branched alkyl group having 1 to 22 carbon atoms, or a benzyl group; R ４ is a linear or branched alkyl group having 1 to 22 carbon atoms, and in formula (3), R ５and R ６ are each hydrogen, a methyl group, or a phenyl group.

[0013]

[0014] In formulas (1), (3), and (4), carbon atoms and hydrogen atoms bonded to the carbon atoms are omitted. For example, in formula (1), positions 1, 2, and 3 are carbon atoms, positions 4 and 5 are CH groups, and position 6 is CH ２ In the structural formulas below, hydrogen atoms and carbon atoms are omitted, just as in this formula.

[0015] The ascorbic acid derivatives represented by general formula (1) have superior stability over time in the neutral to weakly alkaline range (pH range of about 6 to 10) compared to ascorbic acid and conventional ascorbic acid derivatives, and maintain a high residual rate over a wide pH range even when stored for several weeks in a high-temperature environment above room temperature, and also suppress problems such as odor generation and discoloration.Furthermore, some of the ascorbic acid derivatives represented by general formula (1), (3) or (4) have superior collagen production promoting effects and hyaluronic acid production promoting effects compared to conventional ascorbic acid derivatives such as glyceryl ascorbic acid.

[0016] The second aspect of the present invention is a preferred embodiment of the first aspect of the present invention, which is represented by the general formula (1), wherein R １ But -(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 -* (* represents the position of bonding to O at the 2nd position of the ascorbic acid ring), or a divalent group represented by the formula (2), R ２ and R ３ is hydrogen, or R １ Ga-(CH ２ ) ｎ -* (n is 3 or 4), and R ２ Ga-COR ４ and R ３is hydrogen or -COR ４ and R ４ is a linear or branched alkyl group having 4 to 18 carbon atoms. These compounds are preferred because they have particularly excellent stability over time in the neutral to weakly alkaline range.

[0017] The third aspect of the present invention is a preferred embodiment of the second aspect of the present invention, which is represented by the general formula (1), and in the general formula (1), R １ But -(CH ２ ) ３ -*, -CH ２ CH(OH)CH ２ -* (* represents the position of bonding to O at the 2nd position of the ascorbic acid ring), or a divalent group represented by the formula (2), R ２ and R ３ are each 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 is a linear or branched alkyl group having 8 to 18 carbon atoms. These compounds are preferred because they are particularly effective in promoting collagen production and hyaluronic acid production. １ But -(CH ２ ) ３ -*, or a divalent group represented by the formula (2), 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 is a linear or branched alkyl group having 8 to 18 carbon atoms, is particularly effective in promoting hyaluronic acid production and is therefore preferred.

[0018] The ascorbic acid derivative of the present invention can be blended into cosmetics. A fourth aspect of the present invention is a cosmetic characterized by blending the ascorbic acid derivative of any one of the first to third aspects of the present invention. The fourth aspect of the present invention is a cosmetic that has excellent moisturizing properties, is stable over a wide pH range, and exhibits excellent physiologically active effects such as promoting collagen production and hyaluronic acid production.

[0019] The fifth aspect of the present invention is a collagen production promoter containing the ascorbic acid derivative of the third aspect of the present invention. The fifth aspect of the present invention is stable over a wide pH range, exhibits excellent physiological activity, and exhibits a particularly excellent collagen production-promoting effect, making it suitable for use as a collagen production promoter.

[0020] The sixth aspect of the present invention is a hyaluronic acid production promoter characterized by being blended with the ascorbic acid derivatives of the first to third aspects of the present invention.The sixth aspect of the present invention is stable in a wide pH range, and has excellent physiological activity effect, and has excellent hyaluronic acid production promoting effect, so it is suitable for use as a hyaluronic acid production promoter.Among the sixth aspect of the present invention, the one characterized by being blended with the ascorbic acid derivative of the third aspect of the present invention has particularly excellent hyaluronic acid production promoting effect, so it is more suitable for use as a hyaluronic acid production promoter.

[0021] The ascorbic acid derivatives of the present invention represented by the general formula (1), (3) or (4) have the excellent functions that ascorbic acid originally has, such as moisturizing effect, and are stable in a wide pH range even after long-term storage, with little discoloration, odor change, or activity reduction, and have high physiological activities such as collagen production promoting effect and hyaluronic acid production promoting effect.Therefore, by incorporating the ascorbic acid derivatives represented by the general formula (1), (3) or (4) into cosmetics such as skin external preparations and hair cosmetics, cosmetics with excellent moisturizing effect, stable even after long-term storage, and high physiological activities, such as moisturizing cosmetics, can be provided.Furthermore, by incorporating the ascorbic acid derivatives represented by the general formula (1), (3) or (4), a collagen production promoter that exhibits excellent collagen production promoting effect and a hyaluronic acid production promoter that exhibits excellent hyaluronic acid production promoting effect can be provided.

[0022] The following describes an embodiment of the present invention, but the scope of the present invention is not limited to the embodiment described below.

[0023] Specific examples of the ascorbic acid derivatives represented by general formula (1), (3) or (4) 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, 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) ascorbic acid 6-O-palmitoyl-2,3-O-(1,3-propanediyl) 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, 5,6-O-Diisostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid, 5,6-O-Isopropylidene-2,3-O-(1,3-propanediyl)ascorbic acid, 5,6-O-isopropylidene-2,3-O-(1,4-butanediyl)ascorbic acid, 5,6-O-(phenylmethylene)-2,3-O-(1,3-propanediyl)ascorbic acid, 5,6-O-(phenylmethylene)-2,3-O-(1,4-butanediyl)ascorbic acid, 4-hydroxy-2,6,9,14-tetraoxatricyclo[6.6.0.0, １．５ ] tetradecan-7-one, 4-hydroxy-2,6,9,13-tetraoxatricyclo[6.5.0.0 １．５ ]tridecan-7-one, 6-O-benzyl-2,3-O-(1,4-butanediyl)ascorbic acid, and the like.

[0024] Ascorbic acid derivatives represented by general formula (1), (3), or (4) can be produced by various methods. For example, a dihaloalkane, 2-halomethyloxirane, bishalomethyloxetane, or the like can be reacted with the hydroxyl groups at the 2- and 3-positions of ascorbic acid to form a cyclic structure from the hydroxyl groups, and then, by known means, acylation, alkylation, benzylation, or acetalization of the oxygen atoms bonded to the 5- and 6-positions to produce the ascorbic acid derivative represented by general formula (1) or (3). Alternatively, the ascorbic acid derivative represented by general formula (1) or (3) can be obtained by known means, such as acylation, alkylation, benzylation, or acetalization of the oxygen atoms bonded to the 5- and 6-positions of ascorbic acid, followed by formation of a cyclic structure from the hydroxyl groups at the 2- and 3-positions with a dihaloalkane, or the like. The ascorbic acid derivative represented by general formula (4) can be obtained by forming a cyclic structure from the hydroxyl groups at the 2- and 3-positions of ascorbic acid as described above, followed by an intramolecular reaction in the presence of a strong alkali and then a strong acid.

[0025] Examples of compounds capable of forming a cyclic structure upon reaction with the hydroxyl groups at the 2- and 3-positions of ascorbic acid include, but are not limited to, dihaloalkanes, 2-halomethyloxiranes, bishalomethyloxetanes, etc. Examples of dihaloalkanes include dibromoethane, dibromopropane, dibromobutane, dichloroethane, dichloropropane, dichlorobutane, diiodoethane, diiodopropane, diiodobutane, etc. Examples of 2-halomethyloxiranes include 2-bromomethyloxirane, 2-chloromethyloxirane, 2-iodomethyloxirane, etc. Examples of bishalomethyloxetanes include bisbromomethyloxetane, bischloromethyloxetane, etc.

[0026] In the synthesis of the ascorbic acid derivative represented by general formula (1), (3), or (4), the amount of dihaloalkane, 2-halomethyloxirane, or bishalomethyloxetane used to form a cyclic structure by reacting with the hydroxyl groups at the 2- and 3-positions of ascorbic acid is not particularly limited, but is preferably 0.5 to 2.0 mol, more preferably 1.0 to 1.5 mol, per 1 mol of ascorbic acid.

[0027] Specifically, ascorbic acid derivatives represented by general formula (1), (3) or (4), R １ But -(CH ２ ) ｎ -* (n is an integer of 2 to 4) can be obtained by reacting ascorbic acid with a dihaloalkane (having 2 to 4 carbon atoms) to form a cyclic structure between the hydroxyl groups at the 2nd and 3rd positions of ascorbic acid and the dihaloalkane.

[0028] Also, ascorbic acid derivatives represented by general formula (1), (3) or (4), R １ But -CH ２ CH(OH)CH ２ - * and R １ But -CH ２ CH (CH ２ OH)-* or -CH(CH ２ OH)CH ２The compound represented by -* can be obtained by reacting ascorbic acid with 2-halomethyloxirane to form a cyclic structure from the hydroxyl groups at the 2- and 3-positions of ascorbic acid.

[0029] Also, ascorbic acid derivatives represented by general formula (1), (3) or (4), 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 the 2- and 3-positions of ascorbic acid.

[0030] The above-described reaction for synthesizing the ascorbic acid derivative represented by general formula (1), (3), or (4) 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, and mixtures thereof, and are not particularly limited. 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 to 90°C.

[0031] Examples of pH adjusters used during the reaction include lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, gluconic acid, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, ammonium hydrogencarbonate, triethylamine, diazabicycloundecene, and p-toluenesulfonic acid monohydrate.

[0032] From the reaction product of the ascorbic acid derivative represented by general formula (1), (3) or (4) produced as described above, the desired compound can be separated and purified by means of HPLC (liquid chromatography), column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, or the like.

[0033] Also, an ascorbic acid derivative represented by general formula (1) is １ Ga-(CH ２) ｎ -* (n is an integer from 2 to 4), and R ２ and / or R ３ Ga-COR ４ , a linear or branched alkyl group having 1 to 22 carbon atoms, or a benzyl group; an ascorbic acid derivative represented by the general formula (3), １ Ga-(CH ２ ) ｎ -* (n is an integer from 2 to 4), and R ５ and / or R ６ is hydrogen, a methyl group, or a phenyl group, and an ascorbic acid derivative represented by general formula (4), wherein R １ Ga-(CH ２ ) ｎ -* (n is an integer of 2 to 4) can be produced by synthesizing an ascorbic acid derivative in which a cyclic structure is formed from the hydroxyl groups at the 2- and 3-positions as described above, and then carrying out various known methods. For example, １ Ga-(CH ２ ) ｎ -* (n is an integer of 2 to 4), ２ and / or R ３ Ga-COR ４ can be synthesized by mixing the ascorbic acid derivative having the cyclic structure with various acid halides or various acid anhydrides, or by mixing the ascorbic acid derivative having the cyclic structure with various carboxylic acids in concentrated sulfuric acid. １ Ga-(CH ２ ) ｎ -* (n is an integer of 2 to 4), ２ is a benzyl group, R ５ is a phenyl group, R ６ It can be synthesized by a method in which an ascorbic acid derivative in which R is hydrogen is synthesized and then the ring is opened using a reducing agent. １ Ga-(CH ２ ) ｎ -* (n is an integer from 2 to 4), and R ５ and / or R６ Ascorbic acid derivatives in which R is hydrogen, a methyl group, or a phenyl group can be synthesized by synthesizing an ascorbic acid derivative in which a cyclic structure is formed from the hydroxyl groups at the 2- and 3-positions, and then reacting the resulting compound with a dialkoxyalkyl, α,α-dialkoxytoluene, or the like under strong acid conditions. １ Ga-(CH ２ ) ｎ -* (n is an integer of 2 to 4) can be obtained by forming a cyclic structure from the 2- and 3-positions of ascorbic acid as described above, followed by an intramolecular reaction in the presence of a strong alkali and then a strong acid.

[0034] 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, and the like. Xanoyl 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, isonadecanoyl chloride, isoeicosanoyl chloride, isoheneicosanoyl chloride, isodocosanoyl chloride, and the like can be used.

[0035] When an acid halide derived from a branched fatty acid is used among the above acid halides, the commercially available product may contain a mixture of acid halides with different branching points, and thus a reaction product to which a fatty acid with a different branching point is added may be obtained as a by-product. For example, when commercially available 16-methylheptadecanoyl chloride is used, a compound formed by reaction with 2-octyldecanoyl chloride, which has a different branching point, may also be produced as a by-product. In this case, the ascorbic acid derivative of the present invention will also contain this by-product.

[0036] The amount of the acid halide used is not particularly limited, but when obtaining a compound mainly introduced into either the 5- or 6-hydroxyl group, the amount is preferably 0.5 to 2.0 mol, and particularly preferably 0.8 to 1.5 mol, per mol of the ascorbic acid derivative forming a cyclic structure. When the amount of acid halide used is 1.5 to 5.0 mol, preferably 1.5 to 3.0 mol, per mol of the ascorbic acid derivative forming a cyclic structure, a mixture of a compound introduced into only one hydroxyl group and a compound introduced into both hydroxyl groups is obtained. Furthermore, after obtaining a compound introduced into either the 5- or 6-hydroxyl group under the above conditions, further reaction with an acid halide or the like can be carried out to obtain a compound introduced into both hydroxyl groups.

[0037] The dialkoxyalkyl or α,α-dialkoxytoluene used in the above reaction may be dimethoxymethane, dimethoxypropane, α,α-dimethoxytoluene, etc. There are no particular restrictions on the amount of the dialkoxyalkyl or α,α-dialkoxytoluene used, but it is preferably 0.8 to 2.5 mol, and particularly preferably 1.0 to 2.0 mol, per mol of the ascorbic acid derivative having a cyclic structure.

[0038] The reaction with an acid halide, a dialkoxyalkyl, or an α,α-dialkoxytoluene can be carried out by adjusting the solvent, reaction temperature, and pH in the same manner as in the reaction for forming a cyclic structure, and the ascorbic acid derivative of the present invention having the desired structure can be obtained by purifying the reaction by means of chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, or the like.

[0039] The ascorbic acid derivative of the present invention can be suitably used as a component of various cosmetics such as external skin preparations and hair cosmetics, and can also be used as a food additive, animal feed, etc.

[0040] When the ascorbic acid derivative of the present invention is blended into various cosmetic preparations, the blending amount is preferably 1 to 20% by mass, and particularly preferably 3 to 10% by mass, of the total amount of the cosmetic preparation. If the blending amount is less than 1% by mass, the effects of the ascorbic acid derivative of the present invention, such as the effect of promoting hyaluronic acid production, often cannot be fully exerted. On the other hand, if the blending amount is more than 20% by mass, the formulation system may be damaged, and even if the blending amount is increased, improvement in the effect may not be expected in many cases.

[0041] In addition to these essential ingredients, the cosmetic of the present invention may contain, as appropriate, commonly used ingredients such as oily raw materials, surfactants, moisturizers, polymeric compounds, antioxidants, whitening agents, pharmaceuticals, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, etc. The ascorbic acid derivative of the present invention also exhibits an effect as a moisturizer, and other moisturizers may also be incorporated into the cosmetic of the present invention as appropriate.

[0042] Examples of the oily raw materials, surfactants, other moisturizers, polymeric compounds, antioxidants, whitening agents, other drugs, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, and the like can include those similar to those described in WO2022 / 080287.

[0043] The cosmetic of the present invention may be formulated in any system, including a solution system, a solubilized system, an emulsion system, a gel system, a powder dispersion system, and a water-oil two-layer system, and can be produced by blending the ascorbic acid derivative represented by the above general formula (1), (3), or (4) with the above optional ingredients according to the desired product.

[0044] 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 to these Examples. Prior to the Examples, examples of the production of the ascorbic acid derivatives of the present invention used in the Examples will be shown as Synthesis Examples.

[0045] Synthesis Example 1 (Synthesis of 2,3-O-(1,2-ethanediyl)ascorbic acid) DMF (9.0 g), ascorbic acid (0.88 g), potassium carbonate (0.76 g), and dibromoethane (1.03 g) were placed in a recovery flask and stirred at 80°C for 3 hours. After cooling, the mixture was filtered and concentrated under reduced pressure. The resulting residue (1.2 g) was subjected to silica gel chromatography and eluted with a mixture of chloroform / methanol / water (20 / 3 / 0.3). Further concentration under reduced pressure gave 2,3-O-(1,2-ethanediyl)ascorbic acid (0.505 g).

[0046] The resulting product was analyzed by mass spectrometry. 1 H-NMR, １３ C-NMR measurement was carried out, and the measurement results confirmed that the product was 2,3-O-(1,2-ethanediyl)ascorbic acid represented by the following structural formula.

[0047] In the synthesis examples shown below, the products obtained were analyzed by mass spectrometry, 1 H-NMR, １３ C-NMR measurements were carried out, and the results confirmed that the products were ascorbic acid derivatives represented by the structural formulas or compound names shown in each synthesis example (including cases where there were two or more ascorbic acid derivatives), or that the products were mainly composed of the ascorbic acid derivatives. 1 H-NMR, １３ The results of C-NMR measurements are shown in Tables 1 to 9.

[0048]

[0049] Synthesis Example 2 (Synthesis of 2,3-O-(1,3-propanediyl)ascorbic acid) DMF (35.0 g), ascorbic acid (3.50 g), potassium carbonate (3.0 g), and dibromopropane (4.4 g) were placed in a recovery flask 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, to which magnesium sulfate was added. Subsequently, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue (4.2 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol / water (20 / 3 / 0.3), and then concentrated under reduced pressure to obtain 2,3-O-(1,3-propanediyl)ascorbic acid (0.56 g) represented by the following structural formula:

[0050]

[0051] Synthesis Example 3 (Synthesis of 2,3-O-(1,4-butanediyl)ascorbic acid) DMF (35.0 g), ascorbic acid (3.50 g), potassium carbonate (3.0 g), and dibromobutane (4.8 g) were placed in a recovery flask 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, to which magnesium sulfate was added. Subsequently, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol / water (25 / 3 / 0.3 to 20 / 3 / 0.3), and then concentrated under reduced pressure to obtain 2,3-O-(1,4-butanediyl)ascorbic acid (1.066 g) represented by the following structural formula:

[0052]

[0053] 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) DMF (13.6 g), water (6.3 g), ascorbic acid (3.5 g), triethylamine (2.0 g), and 2-chloromethyloxirane (2.2 g) were placed in a recovery flask 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, followed by addition of magnesium sulfate. Subsequently, filtration was performed, and the filtrate was concentrated under reduced pressure. The resulting residue (2.4 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol / water = 15 / 3 / 0.3 to 10 / 3 / 0.3, and then concentrating under reduced pressure to obtain a 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: structural formula on the left below) and 2,3-O-(1-hydroxymethyl-1,2-ethanediyl)ascorbic acid (6.6 mg) (Synthesis Example 5: structural formula on the right below) represented by the following structural formulas.

[0054]

[0055] Synthesis Example 6 (Synthesis of 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid) DMF (5.0 g), ascorbic acid (0.528 g), potassium carbonate (0.456 g), and 3,3-bis(bromomethyl)oxetane (0.805 g) were placed in a recovery flask 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, followed by addition of magnesium sulfate. Subsequently, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography, eluting with a chloroform / methanol / water (20 / 3 / 0.3) mixture and concentrating under reduced pressure to obtain 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid (0.144 g).

[0056]

[0057] 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 in Synthesis Example 1 of Japanese Patent No. 7267657. The synthesized 2-O-(2-hydroxyisobutyl)ascorbic acid (0.50 g), THF (5 ml), and p-toluenesulfonic acid monohydrate (0.52 g) were placed in a recovery flask and stirred at 80°C for 24 hours. After completion of the reaction, ion-exchanged water and isobutanol were added, and the mixture was separated. The isobutanol layer was recovered and concentrated under reduced pressure. The resulting residue (0.60 g) was subjected to silica gel chromatography, eluting with a chloroform / methanol mixture (10 / 0 to 9.5 / 0.5), and concentrated under reduced pressure to give 2,3-O-(2,2-dimethyl-1,2-ethanediyl)ascorbic acid (37.3 mg).

[0058]

[0059] 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 in Synthesis Example 2 of Japanese Patent No. 7267657. The synthesized 3-O-(2-hydroxyisobutyl)ascorbic acid (4.21 g), THF (25 ml), and p-toluenesulfonic acid monohydrate (4.19 g) were placed in a recovery flask and stirred at 90°C for 18 hours. After completion of the reaction, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate was recovered and concentrated under reduced pressure. The resulting residue (0.21 g) was subjected to silica gel chromatography, eluting with a chloroform / methanol mixture (10 / 0 to 9.5 / 0.5), and concentrated under reduced pressure to give 2,3-O-(1,1-dimethyl-1,2-ethanediyl)ascorbic acid (15.3 mg).

[0060]

[0061] 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) obtained in Synthesis Example 3, N-methylpyrrolidone (30.0 g), and triethylamine (5.1 g) were placed in a recovery flask, and butanoyl chloride (5.1 g) was added while stirring at 25°C. After stirring at 25°C for 5 hours, the mixture was extracted with ethyl acetate. The mixture was washed with water three times, and the organic layer was recovered, to which 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, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to give 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).

[0062]

[0063] 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) obtained in Synthesis Example 3, N-methylpyrrolidone (30.0 g), and triethylamine (3.4 g) were placed in a recovery 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. The mixture was washed with water three times, and the organic layer was recovered, to which 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, eluting with a mixed solvent of hexane / ethyl acetate = 5 / 1 to 1 / 1, and concentrated under reduced pressure to give 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.4 g) represented by the structural formulas below (Synthesis Example 11: structural formula on the left below) and 5,6-O-dioctanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.6 g) (Synthesis Example 12: structural formula on the right below).

[0064]

[0065] Synthesis Example 13: Synthesis of 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid Into a recovery flask were added 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g), N-methylpyrrolidone (30.0 g), and triethylamine (1.7 g), and then 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. The mixture was washed with water three times, and the organic layer was recovered, to which magnesium sulfate was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (6.1 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate mixture (8 / 3 to 1 / 1), 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:

[0066]

[0067] Synthesis Example 14: Synthesis of 5,6-O-dilauroyl-2,3-O-(1,4-butanediyl)ascorbic acid 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.5 g) obtained in Synthesis Example 13, 4-dimethylaminopyridine (DMAP: 19.0 mg), and dodecanoyl chloride (1.2 g) were placed in a recovery flask and stirred for 4 hours at 25° C. The resulting residue (3.2 g) was subjected to silica gel chromatography, eluted with a 4:1 mixture of hexane / ethyl acetate, and 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.

[0068]

[0069] Synthesis Example 15: Synthesis of 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid. 2.0 g of 2,3-O-(1,4-butanediyl)ascorbic acid obtained in Synthesis Example 3, 30.0 g of N-methylpyrrolidone, and 1.1 g of triethylamine were placed in a recovery flask, and 2.6 g of hexadecanoyl chloride 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, the organic layer was recovered and magnesium sulfate was added. The extract was then filtered and concentrated under reduced pressure. The resulting residue (4.7 g) was subjected to silica gel chromatography, eluting with a hexane / ethyl acetate mixture (5 / 1 to 1 / 1), and concentrated under reduced pressure to obtain 1.3 g of 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid represented by the following structural formula:

[0070]

[0071] Synthesis Example 16: Synthesis of 5,6-O-dipalmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.6 g) obtained in Synthesis Example 15, DMAP (22.0 mg), and hexadecanoyl chloride (1.8 g) were placed in a recovery flask and stirred at 60°C for 4 hours, followed by stirring at 25°C for 16 hours. Extraction was then performed using hexane / ethyl acetate (1:1), and the organic layer was recovered, followed by addition of magnesium sulfate. The resulting mixture was filtered and concentrated under reduced pressure. The resulting residue (3.3 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-dipalmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid (0.9 g) represented by the following structural formula:

[0072]

[0073] 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 Into a recovery flask were added 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g), N-methylpyrrolidone (30.0 g), and triethylamine (3.4 g), and then isostearoyl chloride (9.4 g) was added while stirring at 25°C. The mixture was then stirred at 25°C for 3 hours and extracted with ethyl acetate. The mixture was washed with water twice, and the organic layer was recovered, to which magnesium sulfate was added. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (9.8 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to give 6-O-isostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.5 g) represented by the structural formulas below (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).

[0074]

[0075] Synthesis Example 19: Synthesis of 5-O-butanoyl-6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid Into a recovery flask were placed 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.0 g), acetonitrile (5.0 g), and triethylamine (0.6 g), and then 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. The mixture was washed twice with water, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (1.5 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 3 / 1, 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.

[0076]

[0077] 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 Into a recovery flask were added 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22.0 g), and triethylamine (5.0 g), and then 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. The mixture was washed with water four times, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (4.2 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 3 / 1 to 2 / 3, and concentrated under reduced pressure to give 6-O-butanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.7 g) represented by the structural formulas below (Synthesis Example 20: structural formula on the left below) and 5,6-O-dibutanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.9 g) (Synthesis Example 21: structural formula on the right below).

[0078]

[0079] 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 Into a recovery flask were placed 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22.0 g), and triethylamine (5.0 g), and then 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. The mixture was washed with water four times, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (7.6 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to obtain 6-O-octanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) represented by the structural formulas below (Synthesis Example 22: structural formula on the left below) and 5,6-O-dioctanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.3 g) (Synthesis Example 23: structural formula on the right below).

[0080]

[0081] 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 Into a recovery flask were added 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22.0 g), and triethylamine (11.0 g), and then dodecanoyl chloride (7.8 g) was added with stirring at room temperature. The mixture was stirred at 25°C for 3 hours and extracted with ethyl acetate. The mixture was washed with water three times, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (6.6 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to give 6-O-lauroyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) represented by the structural formulas below (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).

[0082]

[0083] 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 Into a recovery flask were added 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g), N-methylpyrrolidone (22.0 g), and triethylamine (3.9 g), and then 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. The mixture was washed twice with water, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (13.4 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 6 / 1 to 1 / 1, and concentrated under reduced pressure to give 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) represented by the structural formulas below (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).

[0084]

[0085] Synthesis Example 28: Synthesis of 6-O-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid Into a recovery flask were added 2,3-O-(1,3-propanediyl)ascorbic acid (3.0 g) obtained in Synthesis Example 2, N-methylpyrrolidone (30.0 g), and triethylamine (1.8 g), and then isostearoyl chloride (5.0 g) was added with stirring. The mixture was stirred at 25°C for 4 hours and extracted with ethyl acetate. The mixture was washed with water three times, and the organic layer was recovered, to which magnesium sulfate was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (8.6 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate mixture (4 / 1 to 1 / 1), 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:

[0086]

[0087] Synthesis Example 29: Synthesis of 5,6-O-diisostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid

[0111] Into a recovery flask were placed 6-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.4 g) obtained in Synthesis Example 28, DMAP (22.0 mg), and isostearoyl chloride (1.4 g). 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 4:1 mixture of hexane / ethyl acetate, 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:

[0088]

[0089] Synthesis Example 30 Synthesis of 5-butanoyl-6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.8 g) obtained in Synthesis Example 26, acetonitrile (4.0 g), and triethylamine (0.36 g) were placed in a recovery 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. The mixture was washed twice with water, and the organic layer was recovered, to which magnesium sulfate was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (0.9 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 3 / 1, 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.

[0090]

[0091] 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 Into a recovery flask were added 2,3-O-(1,2-ethanediyl)ascorbic acid (1.9 g) obtained in Synthesis Example 1, N-methylpyrrolidone (20.0 g), and triethylamine (4.8 g), and then 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. The mixture was washed with water four times, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. The obtained residue (9.2 g) was subjected to silica gel chromatography, eluting with a mixed solvent of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid (1.0 g) represented by the structural formulas below (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).

[0092]

[0093] Synthesis Example 33 4-Hydroxy-2,6,9,14-tetraoxatricyclo[6.6.0.0 １．５ Synthesis of ]tetradecan-7-one In a recovery flask, 2,3-O-(1,4-butanediyl)ascorbic acid (1.3 g), water (8.0 g), and isopropyl alcohol (2.0 g) obtained in Synthesis Example 3 were added, and while stirring at 25°C, 10% aqueous sodium hydroxide solution (4.5 g) was added, followed by stirring at 25°C for 30 minutes. Then, 17% aqueous hydrochloric acid solution (2.4 g) was added, and the mixture was allowed to stand at 25°C for 16 hours, followed by extraction with ethyl acetate. After washing with water three times, the organic layer was recovered, and magnesium sulfate was added. Subsequently, the mixture was filtered and concentrated under reduced pressure. The resulting residue (0.4 g) was subjected to silica gel chromatography, eluted with a hexane / ethyl acetate mixture (3 / 1 to 1 / 1), and concentrated under reduced pressure to obtain 4-hydroxy-2,6,9,14-tetraoxatricyclo[6.6.0.0]tetradecan-7-one represented by the following structural formula: １．５] tetradecan-7-one (125 mg) was obtained.

[0094]

[0095] Synthesis Example 34 4-hydroxy-2,6,9,13-tetraoxatricyclo[6.5.0.0 １．５ Synthesis of ]tridecan-7-one In a recovery flask, 2.5 g of 2,3-O-(1,3-propanediyl)ascorbic acid obtained in Synthesis Example 2, 16.0 g of water, and 4.0 g of isopropyl alcohol were added, and 9.0 g of 10% aqueous sodium hydroxide solution was added while stirring at 25°C. The mixture was then stirred at 25°C for 8 hours. 7.5 g of 17% aqueous hydrochloric acid solution was then added, and the mixture was allowed to stand at 25°C for 16 hours, followed by extraction with ethyl acetate. The mixture was washed with water three times, and the organic layer was recovered, followed by addition of magnesium sulfate. The mixture was then filtered and concentrated under reduced pressure. 1.7 g of the resulting residue was subjected to silica gel chromatography, eluted with a 1 / 1 mixture of hexane and ethyl acetate, and concentrated under reduced pressure to give 4-hydroxy-2,6,9,13-tetraoxatricyclo[6.5.0.0]tridecan-7-one, which is represented by the following structural formula: １．５ ]tridecan-7-one (464 mg) was obtained.

[0096]

[0097] Synthesis Example 35: Synthesis of 5,6-O-isopropylidene-2,3-O-(1,4-butanediyl)ascorbic acid. 2,3-O-(1,4-butanediyl)ascorbic acid (920 mg) obtained in Synthesis Example 3, acetonitrile (9.0 mL), 2,2-dimethoxypropane (824 mg), and p-toluenesulfonic acid monohydrate (76 mg) were added to a recovery flask in this order, and the mixture was stirred at 25°C for 2 hours. The mixture was neutralized with triethylamine and concentrated under reduced pressure. Ethyl acetate was added to the resulting concentrate for extraction. The mixture was washed once with water and twice with saturated brine, and magnesium sulfate was added to the recovered organic layer. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (1.1 g) was dissolved in a 5 / 3 mixture of hexane and ethyl acetate with heating, allowed to cool, and then allowed to stand overnight at room temperature. The precipitated solid was collected by filtration, washed with hexane, and vacuum dried to obtain 5,6-O-isopropylidene-2,3-O-(1,4-butanediyl)ascorbic acid (619 mg) represented by the following structural formula.

[0098]

[0099] Synthesis Example 36: Synthesis of 5,6-O-isopropylidene-2,3-O-(1,3-propanediyl)ascorbic acid. 2,3-O-(1,3-propanediyl)ascorbic acid (650 mg) obtained in Synthesis Example 2, acetone (6.0 mL), 2,2-dimethoxypropane (620 mg), and p-toluenesulfonic acid monohydrate (57 mg) were added to a recovery flask in this order, and the mixture was stirred at 25°C for 2.5 hours. The mixture was neutralized with aqueous sodium hydroxide and concentrated under reduced pressure. Ethyl acetate was added to the resulting concentrate, followed by extraction. The mixture was washed once with water and twice with saturated brine, and magnesium sulfate was added to the recovered organic layer. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (750 mg) was dissolved in a 3:2 mixture of isopropanol and methanol with heating. After allowing to cool, the mixture was left to stand overnight at room temperature. The precipitated solid was collected by filtration, washed with isopropanol, and vacuum dried to obtain 5,6-O-isopropylidene-2,3-O-(1,3-propanediyl)ascorbic acid (303 mg) represented by the following structural formula.

[0100]

[0101] Synthesis Example 37: Synthesis of 5,6-O-(phenylmethylene)-2,3-O-(1,4-butanediyl)ascorbic acid 2,3-O-(1,4-butanediyl)ascorbic acid (920 mg) obtained in Synthesis Example 3, acetonitrile (9.0 mL), α,α-dimethoxytoluene (669 mg), and p-toluenesulfonic acid monohydrate (76 mg) were added to a recovery flask in this order, and the mixture was stirred at 25°C for 19 hours. The mixture was neutralized with triethylamine and concentrated under reduced pressure. Water and ethyl acetate were added to the resulting concentrate, followed by washing. The solid was collected by filtration and dried in vacuo to obtain 5,6-O-(phenylmethylene)-2,3-O-(1,4-butanediyl)ascorbic acid (226 mg) represented by the following structural formula:

[0102]

[0103] Synthesis Example 38: Synthesis of 5,6-O-(phenylmethylene)-2,3-O-(1,3-propanediyl)ascorbic acid. 2,3-O-(1,3-propanediyl)ascorbic acid (650 mg) obtained in Synthesis Example 2, acetonitrile (6.0 mL), α,α-dimethoxytoluene (502 mg), and p-toluenesulfonic acid monohydrate (57 mg) were added to a recovery flask in this order, and the mixture was stirred at 25°C for 5 hours. The mixture was neutralized with triethylamine and concentrated under reduced pressure. The concentrate was washed with water and then with a 5:1 mixture of hexane and ethyl acetate. The solid was collected by filtration and dried in vacuo to obtain 5,6-O-(phenylmethylene)-2,3-O-(1,3-propanediyl)ascorbic acid (303 mg) represented by the following structural formula:

[0104]

[0105] Synthesis Example 39 Synthesis of 6-O-benzyl-2,3-O-(1,4-butanediyl)ascorbic acid 2,3-O-(1,4-butanediyl)ascorbic acid (318 mg) obtained in Synthesis Example 3 and DMF (5.0 mL) were placed in a recovery flask and cooled in an ice bath. 2-picoline borane (1,000 mg) and trimethylsilyl chloride (543 mg) were added and stirred in a water bath at 50°C for 1 hour. Ice water was added, followed by stirring for an additional 1 hour. Ethyl acetate (10 mL) was added and the mixture was separated. The organic layer was recovered, and the aqueous layer was extracted with ethyl acetate (50 mL). The recovered organic layer was washed twice with saturated brine (50 mL). Magnesium sulfate was added, followed by filtration and concentration under reduced pressure. The resulting residue (750 mg) was subjected to silica gel chromatography, eluting with a hexane / ethyl acetate=1 / 1 to 1 / 2 mixed solvent, and concentrated under reduced pressure to give 6-O-benzyl-2,3-O-(1,4-butanediyl)ascorbic acid (90 mg).

[0106]

[0107] Mass spectrometry of the products obtained in Synthesis Examples 1 to 39 was carried out using an LCMS-2020 (manufactured by Shimadzu Corporation). The measurement results are shown in Tables 1 and 2.

[0108]

[0109]

[0110] The products obtained in Synthesis Examples 1 to 39 1 H-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Tables 3 to 6.

[0111]

[0112]

[0113]

[0114]

[0115] The products obtained in Synthesis Examples 1 to 39 1３ C-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Tables 7 to 9.

[0116]

[0117]

[0118]

[0119] Test Example 1 [Stability Test-1] For the samples of Synthesis Examples 1 to 6, 1% aqueous solutions were adjusted to pH 3, 5, 7, 8, and 9 with a dilute potassium hydroxide aqueous solution, and then placed in 50 mL screw tubes and sealed. After storage at 50°C for 4 weeks, HPLC measurement (using a liquid chromatograph manufactured by Shimadzu Corporation) was performed, and the residual rate was determined from the peak area. The results regarding the residual rate based on the following criteria are shown in Table 10. Furthermore, for samples adjusted to pH 7, the odor and coloration were evaluated based on the following methods and criteria, and the results are shown in Table 11.

[0120] Residual rate: ◎: 80% or more ○: 50% or more, less than 80% △: 30% or more, less than 50% ×: Less than 30%

[0121] Odor: Evaluation was made by 10 panelists according to the following criteria: 3: Almost odorless. 2: A slight strange odor is detected. 1: A strong strange odor is detected. Based on the evaluation results, the products were classified as follows: ○: Total score of 25 or more by 10 panelists △: Total score of 16 to 24 by 10 panelists ×: Total score of 15 or less by 10 panelists

[0122] Coloring: Evaluation was made by 10 panelists 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 the evaluation results, the samples were classified as follows: ○: Total score of 25 or more by 10 panelists △: Total score of 16 to 24 by 10 panelists ×: Total score of 15 or less by 10 panelists

[0123]

[0124]

[0125] Test Example 2 [Stability Test-2] For the samples of Synthesis Examples 9 to 32, (a) and (b) shown in Table 12 were each heated and mixed. After cooling, (c) was added to prepare a cream with a pH of 7 or 9. The sample was stored at 50°C for 4 weeks, and the residual rate was determined in the same manner as in Test Example 1 and evaluated according to the criteria described below. The odor and coloring degree were also evaluated according to the same method and criteria as in Test Example 1. The results regarding the residual rate are shown in Tables 13 and 14, and the results regarding the odor and coloring degree are shown in Tables 15 and 16.

[0126] Residual rate: ◎: 95% or more ○: 85% or more, less than 95% ×: Less than 85%

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] The results of the above test examples demonstrate that the ascorbic acid derivatives represented by general formula (1) of the present invention exhibit superior stability over time, with no decrease in residual rate compared to ascorbic acid or conventional ascorbic acid derivatives when stored at 50°C, and little odor or discoloration is observed. In Test Example 1, in the neutral to weakly alkaline pH range of 7 to 9, the residual rates of ascorbic acid and conventional ascorbic acid derivatives decreased to less than 30% after two weeks, whereas the ascorbic acid derivatives represented by general formula (1) of the present invention maintained a residual rate of 50% or more after two weeks, and even after four weeks, the residual rate was significantly higher than that of ascorbic acid and conventional ascorbic acid derivatives. Similarly, Test Example 2 also demonstrated that the ascorbic acid derivatives represented by general formula (1) of the present invention exhibited higher stability than the conventional ascorbic acid derivative, ascorbyl tetrahexyldecanoate, in the neutral to weakly alkaline pH range of 7 to 9. The ascorbic acid derivatives of the present invention represented by general formula (1) have the excellent properties inherent to ascorbic acid, but the results shown in Tables 10, 11, and 13 to 16 further show that they have improved stability over time, which was a problem with conventional ascorbic acid derivatives, and are therefore more suitable as ingredients for cosmetics.

[0133] Test Example 3 [Collagen production promoting effect] Normal human skin fibroblasts were cultured at 2.5 × 10 ４ The cells were prepared in D-MEM containing 5% (v / v) fetal bovine serum to a cell density of 100 cells / well, and then pre-incubated for 24 hours on a 96-well plate. After removing the medium, samples prepared to a predetermined concentration in D-MEM containing 5% (v / v) fetal bovine serum were added to each well and cultured for 48 hours. After the culture was completed, the amount of free collagen in the supernatant was quantified by ELISA. Measurements were performed in triplicate.

[0134] The amount of collagen produced when the sample was measured at a concentration of 10 mM or less was compared with that of the control group, and the results (% values ​​when the control group was taken as 100%) are shown in Table 17 based on the following criteria: <100%: ± 100-140%: + 140%<: ++

[0135]

[0136] The results in Table 17 clearly show that the ascorbic acid derivative represented by the general formula (1) of the present invention has a collagen production-promoting effect equal to or greater than that of known ascorbic acid derivatives, i.e., 2-O-glyceryl ascorbic acid and 3-O-glyceryl ascorbic acid.

[0137] Test Example 4 [Hyaluronic acid production promoting effect] Normal human dermal fibroblasts (NHDF) were cultured at 2.5 × 10 ４ The cells were prepared in D-MEM containing 5% (v / v) fetal bovine serum to a cell density of 100 cells / well, and then pre-incubated on a 96-well plate for 24 hours. After removing the medium, samples prepared in serum-free D-MEM were added to each well and cultured for 48 hours. After the culture was completed, the amount of hyaluronic acid in the supernatant was quantified by ELISA. Measurements were performed in triplicate.

[0138] The amount of hyaluronic acid produced when the samples were measured at a concentration of 10 mM or less was compared with that of the control group, and the results (% values ​​when the control group is set to 100%) are shown in Tables 18 to 20 based on the following criteria: <100%: ± 100-120%: + 120%<: ++

[0139]

[0140]

[0141]

[0142] The results in Tables 18 to 20 clearly show that the ascorbic acid derivatives of the present invention have a higher effect of promoting hyaluronic acid production than ascorbic acid and known ascorbic acid derivatives.

[0143] Test Example 5 [Antioxidant effect] Normal human epidermal keratinocytes were cultured at 2.0 × 10 ４The cells were seeded onto a 96-well plate using KG2 medium to a cell density of 1000 cells / well. After 24 hours of pre-incubation, samples adjusted to a predetermined concentration with KG2 medium were added to each well. After 24 hours of culture, the medium was removed, followed by washing with HBSS(-) and allowing the ROS-reactive fluorescent probe DCFHDA to be incorporated for 30 minutes. After washing again with HBSS(-), the cells were resuspended in 0.2 mM HBSS(-). ２ O ２ The ROS production amount per unit protein was calculated by measuring the fluorescence intensity and dividing it by the amount of protein quantified by the BCA method, and this was designated as analytical value 1. Furthermore, the ROS production amount calculated without adding the sample adjusted to a predetermined concentration by the above test method was designated as analytical value 2, and the ROS production amount calculated without adding the sample and 0.2 mM H ２ O ２ The calculated amount of ROS production without adding any of the above was designated as analytical value 3, and the ROS production inhibition rate was calculated using the following formula. These results are shown in Table 21. The higher the ROS production inhibition rate, the higher the antioxidant effect can be evaluated. ROS production inhibition rate (%) = [(analytical value 2) - (analytical value 1)] / [(analytical value 2) - (analytical value 3)] x 100

[0144] The ROS production inhibition rate when the sample was measured at a concentration of 10 mM or less was evaluated as follows. Note that the measurement was performed with N=4. <20%: + 20-40%: ++ 40%<: +++

[0145]

[0146] The results in Table 21 show that the ascorbic acid derivatives of the present invention have a high antioxidant effect equal to or greater than that of known ascorbic acid derivatives.

[0147] Example 122 Cream The oil phase ingredients (1) to (5) and the aqueous phase ingredients (6) to (10) of the compositions shown in Table 22 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was homogeneously emulsified using a homomixer. The mixture was then cooled to room temperature while stirring thoroughly to prepare a cream. In Table 22 and subsequent tables, the blend amounts are in parts by mass.

[0148]

[0149] Example 123 Emulsion The oil phase ingredients (1) to (9) and the aqueous phase ingredients (10) to (13) in the compositions shown in Table 23 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase for pre-emulsification, and the mixture was uniformly emulsified using a homomixer. The mixture was then cooled to room temperature with thorough stirring to prepare an emulsion.

[0150]

[0151] Example 124 Emulsion The oil phase ingredients (5) to (10) and the aqueous phase ingredients (1) to (4) and (11) to (12) in the compositions shown in Table 24 were heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was homogeneously emulsified using a homomixer. The mixture was then cooled to room temperature while stirring well to prepare an emulsion.

[0152]

[0153] Example 125 Cream The oil phase ingredients (1) and (2) and the aqueous phase ingredients (3) to (10) in the composition shown in Table 25 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was uniformly emulsified using a homomixer. The mixture was then cooled to room temperature while stirring well to prepare a cream.

[0154]

[0155] Example 126: Lotion A lotion can be prepared by mixing the raw materials (1) to (6) shown in Table 26 with thorough stirring.

[0156]

[0157] Example 127 Cream: (1) to (6) and (7) to (10) in the compositions shown in Table 27 are each heated to 70°C and dissolved. The oil phase is added to the aqueous phase and pre-emulsified, then emulsified with a homomixer, and cooled to room temperature while stirring thoroughly to prepare a cream.

[0158]

[0159] Example 128 Cream The oil phase ingredients (1) to (5) and the aqueous phase ingredients (6) to (10) in the compositions shown in Table 28 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was homogeneously emulsified using a homomixer. The mixture was then cooled to room temperature while stirring thoroughly to prepare a cream.

[0160]

[0161] Example 129 Cream The oil phase ingredients (1) and (2) and the aqueous phase ingredients (3) to (10) in the composition shown in Table 29 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was uniformly emulsified using a homomixer. The mixture was then cooled to room temperature while stirring thoroughly to prepare a cream.

[0162]

Claims

1. An ascorbic acid derivative represented by the following general formula (1), (3) or (4): [In the formula (1), (3) or (4), R １ is -(CH ２ ) ｎ -* (n is an integer from 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 the position of bonding to the O at the 2-position of the ascorbic acid ring), or a divalent group represented by the following formula (2): ２ and R ３ are hydrogen and -COR ４ , a linear or branched alkyl group having 1 to 22 carbon atoms, or a benzyl group; R ４ is a linear or branched alkyl group having 1 to 22 carbon atoms, and in formula (3), R ５ and R ６ are each either hydrogen, a methyl group, or a phenyl group.

2. An ascorbic acid derivative represented by the general formula (1), wherein R １ But -(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 -* (* represents the position of bonding to O at the 2-position of the ascorbic acid ring), or a divalent group represented by the formula (2), R ２ and R ３ are each hydrogen, or R １ - (CH ２ ) ｎ -* (n is 3 or 4), R ２ Ga-COR ４ , R ３ is hydrogen or -COR ４ and R ４ 2. The ascorbic acid derivative according to claim 1, wherein is a straight-chain or branched alkyl group having 4 to 18 carbon atoms.

3. In the general formula (1), R １ But -(CH ２ ) ３ -*, -CH ２ CH(OH)CH ２ -*, (* represents the position of bonding to O at the 2-position of the ascorbic acid ring), or a divalent group represented by the formula (2), R ２ and R ３ are each hydrogen, or R １ - (CH ２ ) ３ -* and R ２ Ga-COR ４ and R ３ is hydrogen or -COR ４ and R ４ The ascorbic acid derivative according to claim 2, characterized in that is a linear or branched alkyl group having 8 to 18 carbon atoms.

4. A cosmetic preparation containing the ascorbic acid derivative according to any one of claims 1 to 3.

5. A collagen production promoter comprising the ascorbic acid derivative according to claim 3.

6. A hyaluronic acid production promoter characterized by containing an ascorbic acid derivative described in any one of claims 1 to 3.

7. A hyaluronic acid production promoter comprising the ascorbic acid derivative according to claim 3.

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