Ascorbic acid derivatives and cosmetic containing the same

Abstract

To provide: novel ascorbic acid derivatives that have excellent functions inherent to ascorbic acid such as a collagen production-promoting action and a moisturizing action and that are stable and reduced in loss of activity and the like even during long-term storage; and cosmetics and drugs that contain the derivatives.SOLUTION: The invention provides: ascorbic acid derivatives represented by the general formula (1) in the figure and the like; and cosmetics, collagen production promoters and hyaluronic acid production promoters that contain the derivatives. [In the formula (1): R1 is -(CH2)n-* (n is an integer of 2-4), -CH2CH(OH)CH2-* (* represents a position bonding to the position-2 O of the ascorbic ring) or the like, or a bis-methyloxetane group; and R2 and R3 are each hydrogen, an alkyl group, a benzyl group, or the like.]SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to ascorbic acid derivatives suitably used as raw materials for cosmetics and the like, and further relates to cosmetics containing the ascorbic acid derivatives.

Background Art

[0002] Ascorbic acid is a safe and useful antioxidant and is known as a compound having excellent whitening effects and the like. On the other hand, it is unstable to light, heat, and oxidation, and its use in the cosmetic field has been hindered because of its insufficient stability over time. Therefore, various ascorbic acid derivatives or their salts have been proposed as those having improved stability over time compared to ascorbic acid, and their incorporation into topical skin preparations for whitening (Patent Documents 1 and 2) and their incorporation 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 there are problems such as a decrease in the pH in the formulation over time and decomposition proceeding under alkaline conditions. Also, the duration of activity in the living body cannot be said to be sufficient, and improvement is desired.

[0004] The present inventors have proposed an ascorbic acid derivative in which decomposition under alkaline conditions is suppressed in order to solve these problems (Patent Document 4). However, an ascorbic acid derivative having further improved stability over time under alkaline conditions and having high stability in a wide pH range is desired.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide an ascorbic acid derivative having excellent actions originally possessed by ascorbic acid such as a moisturizing action, high stability in a wide pH range, and further excellent physiological activity effects. Another object of the present invention is to provide a cosmetic and a drug containing the ascorbic acid derivative, which exhibit excellent moisturizing action and the like, have high stability in a wide pH range, and further exhibit excellent physiological activity effects.

Means for Solving the Problems

[0007] As a result of intensive studies in view of the above circumstances, the present inventors have found that novel ascorbic acid derivatives represented by the following formulas (1), (3) or (4) are excellent in actions such as a moisturizing action, have high stability in a wide pH range, and have excellent physiological activity effects such as a hyaluronic acid production promoting effect. And it has been found that cosmetics and drugs containing the ascorbic acid derivative represented by the following formula (1), (3) or (4) are excellent in moisturizing action and the like, are stable in a wide pH range, and further exhibit excellent physiological activity effects such as a hyaluronic acid production promoting effect. 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]

Chemical formula

[0010]

Chemical formula

[0011] [Chemical formula]

[0012] [In 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 where it is bonded to the O at the 2-position of the ascorbic ring), or a divalent group represented by the following formula (2), In formula (1), R 2 and R 3 are each 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, In formula (3), R 5 and R 6 are each hydrogen, a methyl group, or a phenyl group.]

[0013] [Chemical formula]

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

[0015] The ascorbic acid derivative represented by the general formula (1) has excellent stability over time in the neutral to weakly alkaline region (a region of about pH 6 to 10) compared to ascorbic acid and conventional ascorbic acid derivatives. In particular, even when stored for several weeks in a high-temperature environment of room temperature or higher, a high residual rate is maintained in a wide pH range, and problems such as odor generation and coloring are suppressed. Further, some of the ascorbic acid derivatives represented by the general formula (1), (3) or (4) have an excellent effect of promoting collagen production and an excellent effect of promoting hyaluronic acid production compared to conventional ascorbic acid derivatives such as glyceryl ascorbic acid.

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

[0017] The third aspect of the present invention is a preferred embodiment among the second aspect of the present invention, which is represented by the general formula (1), and in the general formula (1), R 1 is -(CH 2 ) 3 -*, -CH2 CH(OH)CH 2 -* (* represents the position bonded to the O at the 2-position of the ascorbic ring), or is a divalent group represented by the formula (2), R 2 and R 3 are each hydrogen, or R 1 is -(CH 2 ) 3 -*, R 2 is -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, and is an ascorbic acid derivative. These compounds are preferable in that they have particularly excellent effects of promoting collagen production and promoting hyaluronic acid production. Among them, R 1 is -(CH 2 ) 3 -*, or is a divalent group represented by the formula (2), R 2 and R 3 are hydrogen, or R 1 is -(CH 2 ) 3 -*, R 2 is -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, and the ascorbic acid derivative characterized by this is particularly excellent in the effect of promoting hyaluronic acid production and is preferable.

[0018] The ascorbic acid derivative of the present invention can be formulated in cosmetics. The fourth aspect of the present invention is a cosmetic characterized by containing the ascorbic acid derivatives of the first to third aspects of the present invention. The fourth cosmetic of the present invention is excellent in moisturizing action and the like, stable in a wide pH range, and further exhibits excellent physiological activity effects such as the effect of promoting collagen production and the effect of promoting hyaluronic acid production.

[0019] A fifth aspect of the present invention is a collagen production promoter characterized by containing the third ascorbic acid derivative of the present invention. The fifth collagen production promoter of the present invention is stable in a wide pH range, exhibits excellent physiological activity effects, and particularly excellent collagen production promoting effects, so it is suitably used as a collagen production promoter.

[0020] A sixth aspect of the present invention is a hyaluronic acid production promoter characterized by containing the first to third ascorbic acid derivatives of the present invention. The sixth hyaluronic acid production promoter of the present invention is stable in a wide pH range, exhibits excellent physiological activity effects, and excellent hyaluronic acid production promoting effects, so it is suitably used as a hyaluronic acid production promoter. Among the sixth hyaluronic acid production promoters of the present invention, those characterized by containing the third ascorbic acid derivative of the present invention are particularly excellent in hyaluronic acid production promoting effects, so they are more suitably used as hyaluronic acid production promoters.

Effects of the Invention

[0021] The ascorbic acid derivatives represented by the general formula (1), (3) or (4) of the present invention have excellent functions originally possessed by ascorbic acid such as a moisturizing effect, are stable even during long-term storage in a wide pH range, have less discoloration, off-odor, activity reduction, etc., and have high physiological activities such as a collagen production promoting effect and a hyaluronic acid production promoting effect. Therefore, by incorporating the ascorbic acid derivative represented by the general formula (1), (3) or (4) into cosmetics such as skin external preparations and hair cosmetics, cosmetics having excellent moisturizing effects and being stable even during long-term storage and having high physiological activities, such as moisturizing cosmetics, are provided. Furthermore, by incorporating the ascorbic acid derivative represented by the general formula (1), (3) or (4), a collagen production promoter having an excellent collagen production promoting effect and a hyaluronic acid production promoter having an excellent hyaluronic acid production promoting effect are provided.

Modes for Carrying Out the Invention

[0022] The following shows embodiments for carrying out the present invention, but the scope of the present invention is not limited to the embodiments shown below.

[0023] Specific examples of the ascorbic acid derivative represented by the 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, 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, 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 can be mentioned.

[0024] The ascorbic acid derivatives represented by the general formula (1), (3) or (4) can be produced by various methods. For example, by reacting dihaloalkanes, 2-halomethyloxiranes, bis-halomethyloxetanes, etc. with the hydroxyl groups at the 2- and 3-positions of ascorbic acid to form a cyclic structure from the hydroxyl groups, and then acylating, alkylating, benzylating, or acetalizing the oxygen atoms bonded to the 5- and 6-positions by known means, ascorbic acid derivatives represented by the general formula (1) or (3) can be obtained. Also, by acylating, alkylating, benzylating, or acetalizing the oxygen atoms bonded to the 5- and 6-positions of ascorbic acid by known means, and then forming a cyclic structure from the hydroxyl groups at the 2- and 3-positions using a dihaloalkane or the like, ascorbic acid derivatives represented by the general formula (1) or (3) may be obtained. The ascorbic acid derivative represented by the 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 treatment with a strong alkali and then a strong acid to cause an intramolecular reaction.

[0025] Examples of compounds that can react with the hydroxyl groups at the 2- and 3-positions of ascorbic acid to form a cyclic structure include, but are not particularly limited to, dihaloalkanes, 2-halomethyloxiranes, bis-halomethyloxetanes, 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 bis-halomethyloxetanes include bis-bromomethyloxetane, bis-chloromethyloxetane, etc.

[0026] In the synthesis of the ascorbic acid derivative represented by the general formula (1), (3) or (4), there is no particular limitation on the amount of the dihaloalkane, 2-halomethyloxirane, or bis(halomethyl)oxetane used to react with the hydroxyl groups at the 2- and 3-positions of ascorbic acid to form a cyclic structure, but it is preferably 0.5 to 2.0 moles, more preferably 1.0 to 1.5 moles, per mole of ascorbic acid.

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

[0028] Also, for the ascorbic acid derivative represented by the general formula (1), (3) or (4), where R 1 is -CH 2 CH(OH)CH 2 -*, or where R 1 is -CH 2 CH(CH 2 OH)-*, or -CH(CH 2 OH)CH 2 -*, it 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, for the ascorbic acid derivative represented by the general formula (1), (3) or (4), where R 1 is the divalent group represented by the general formula (2), it can be obtained by reacting ascorbic acid with bis(halomethyl)oxetane to form a cyclic structure from the hydroxyl groups at the 2- and 3-positions of ascorbic acid.

[0030] The above reaction for synthesizing the ascorbic acid derivative represented by the 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, isopropanol, etc., dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran (THF), N-methylpyrrolidone, acetonitrile, or a mixed solvent thereof, etc., and there is no particular limitation. The reaction temperature is not particularly limited, but the range of 30 to 100 °C is preferred, the range of 50 to 90 °C is more preferred, and the range of 60 °C to 90 °C is particularly preferred.

[0031] Examples of the pH adjuster 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 hydrogen carbonate, ammonium hydrogen carbonate, triethylamine, diazabicycloundecene, p-toluenesulfonic acid monohydrate, etc.

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

[0033] Also, an ascorbic acid derivative represented by the general formula (1), wherein R 1 is -(CH 2 ) n -* (n is an integer from 2 to 4), and R 2 and / or R 3 is -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), wherein R 1 is -(CH 2 ) n -* (n is an integer from 2 to 4), and R 5 and / or R6 Those in which R is a hydrogen, methyl group, or phenyl group, and which are ascorbic acid derivatives represented by the general formula (4), where R 1 is -(CH 2 ) n -*(n is an integer from 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 further carrying out various known methods. For example, an ascorbic acid derivative represented by the general formula (1) where R is -(CH 1 is -(CH 2 ) n -*(n is an integer from 2 to 4), and where R 2 and / or R 3 is -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. Also, an ascorbic acid derivative represented by the general formula (1) where R 1 is -(CH 2 ) n -*(n is an integer from 2 to 4), and where R 2 is a benzyl group, can be synthesized by synthesizing an ascorbic acid derivative represented by the general formula (3) where R 5 is a phenyl group and R 6 is hydrogen, and then ring-opening it using a reducing agent. Also, an ascorbic acid derivative represented by the general formula (3), where R 1 is -(CH 2 ) n -*(n is an integer from 2 to 4), and where R 5 and / or R 6 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 it with dialkoxyalkyl, α,α-dialkoxytoluene, etc. under strong acid conditions. An ascorbic acid derivative represented by the general formula (4), where R1 is -(CH 2 ) n -*(n is an integer from 2 to 4), after forming a cyclic structure from the 2nd and 3rd positions of ascorbic acid as described above, an intramolecular reaction occurs by using a strong alkali and then a strong acid, and it can be obtained.

[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, 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, isheptadecanoyl chloride, isononadecanoyl chloride, isoeicosanoyl chloride, isohenicosanoyl chloride, isodocosanoyl chloride, etc. can be used.

[0035] In addition, when an acid halide derived from a branched fatty acid is used among the above acid halides, since commercially available products may contain acid halides with different branching points as a mixture, reaction products with fatty acids having different branching points may be obtained as by-products. For example, when using a commercially available product as 16-methylheptadecanoyl chloride, a compound in which 2-octyldecanoyl chloride with a different branching point reacts may also be produced as a by-product. In this case, the ascorbic acid derivative of the present invention includes such a by-product.

[0036] There is no particular limitation on the amount of the acid halide used. However, when mainly obtaining a product introduced into either the 5-position or 6-position hydroxyl group, it is preferably 0.5 to 2.0 mol, particularly preferably 0.8 to 1.5 mol, per 1 mol of the ascorbic acid derivative having a cyclic structure formed. When the amount of the acid halide used is 1.5 to 5.0 mol, preferably 1.5 to 3.0 mol, per 1 mol of the ascorbic acid derivative having a cyclic structure formed, a mixture of a product introduced into only one of them and a product introduced into both of them can be obtained. Further, after obtaining a product introduced into either the 5-position or 6-position hydroxyl group under the above conditions, a product introduced into both the 5-position and 6-position can be obtained by reacting an acid halide or the like.

[0037] As the dialkoxyalkyl and α,α-dialkoxytoluene used in the above reaction, dimethoxymethane, dimethoxypropane, α,α-dimethoxytoluene, etc. can be used. There is no particular limitation on the amount of the dialkoxyalkyl or α,α-dialkoxytoluene used. However, it is preferably 0.8 to 2.5 mol, particularly preferably 1.0 to 2.0 mol, per 1 mol of the ascorbic acid derivative having a cyclic structure formed.

[0038] The reactions with acid halides, dialkoxyalkyl, and α,α-dialkoxytoluene can be carried out by adjusting the solvent, reaction temperature, and pH similar to those for the reaction forming the cyclic structure, and by purification using means such as chromatography using silica gel, column chromatography using resins such as ion exchange resins, activated carbon treatment, extraction, distillation, crystallization, etc., an ascorbic acid derivative of the present invention having a desired structure can be obtained.

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

[0040] When the ascorbic acid derivative of the present invention is formulated into various cosmetics, the amount of formulation is preferably 1 to 20% by mass, particularly preferably in the range of 3 to 10% by mass, based on the total amount of the cosmetics. When it 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, when it exceeds 20% by mass, there is a risk of breaking the formulation system, and in many cases, even if the amount of formulation is increased, an improvement in the effect cannot be expected.

[0041] In addition to this essential component, the cosmetics of the present invention can be appropriately formulated with commonly used components, for example, oily raw materials, surfactants, moisturizers, high molecular compounds, antioxidants, whitening agents, drugs, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or their derivatives, amino acids or their derivatives, pH adjusters, preservatives, etc. Incidentally, although the ascorbic acid derivative of the present invention also exhibits an effect as a moisturizer, other moisturizers can also be appropriately formulated in the cosmetics of the present invention.

[0042] Examples of the oily raw materials, surfactants, other moisturizers, high molecular compounds, antioxidants, whitening agents, other drugs, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or their derivatives, amino acids or their derivatives, pH adjusters, preservatives, etc. can be the same as those described in WO2022 / 080287.

[0043] The formulation system of the cosmetic of the present invention is arbitrary, and any of a solution system, a solubilized system, an emulsion system, a gel system, a powder dispersion system, a water-oil two-layer system, etc. is possible, and according to the target product, the ascorbic acid derivative represented by the above general formula (1), (3) or (4) and the above optional compounding components can be compounded and produced.

Examples

[0044] Next, specific embodiments for carrying out the present invention will be specifically described by way of examples, but the scope of the present invention is not limited by the examples. Prior to the examples, a production example of the ascorbic acid derivative of the present invention used in the examples is shown as a synthesis example.

[0045] Synthesis Example 1 (Synthesis of 2,3-O-(1,2-ethanediyl)ascorbic acid) Into an eggplant flask, DMF (9.0 g), ascorbic acid (0.88 g), potassium carbonate (0.76 g), and dibromoethane (1.03 g) were added, and stirring was carried out at 80 °C for 3 hours. After allowing to cool, filtration was performed, and concentration was carried out under reduced pressure. The obtained residue (1.2 g) was subjected to silica gel chromatography and eluted with a mixed solution of chloroform / methanol / water = 20 / 3 / 0.3. Further, concentration was carried out under reduced pressure to obtain 2,3-O-(1,2-ethanediyl)ascorbic acid (0.505 g).

[0046] For the obtained product, mass spectrometry, 1 1H-NMR, 13 13C-NMR measurements were performed, and from these measurement results, it was confirmed that this product is 2,3-O-(1,2-ethanediyl)ascorbic acid represented by the following structural formula.

[0047] In addition, also in the synthesis examples shown below, for the obtained product, mass spectrometry, 1 1H-NMR, 1313C-NMR measurement was carried out, and from the measurement results, it was confirmed that the product is an ascorbic acid derivative represented by the structural formula or compound name shown in each synthesis example (including the case of two or more ascorbic acid derivatives), or mainly composed of the ascorbic acid derivative. For the products obtained in each synthesis example, mass spectrometry, 1 1H-NMR, 13 The measurement results of 13C-NMR are shown in Tables 1 to 9.

[0048]

Chemical formula

[0049] Synthesis Example 2 (Synthesis of 2,3-O-(1,3-propanediyl)ascorbic acid) Into a eggplant flask, DMF (35.0 g), ascorbic acid (3.50 g), potassium carbonate (3.0 g), and dibromopropane (4.4 g) were added, and the mixture was stirred at 80 °C for 16 hours. After cooling, filtration was carried out, and the filtrate was concentrated under reduced pressure. The obtained concentrate was dissolved in water. Extraction was carried out using isobutyl alcohol, and after recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and the filtrate was concentrated under reduced pressure. The obtained residue (4.2 g) was subjected to silica gel chromatography and eluted with a mixed solution of chloroform / methanol / water = 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.

[0050]

Chemical formula

[0051] Synthesis Example 3 (Synthesis of 2,3-O-(1,4-butanediyl)ascorbic acid) Into a eggplant flask, DMF (35.0 g), ascorbic acid (3.50 g), potassium carbonate (3.0 g), and dibromobutane (4.8 g) were added, and the mixture was stirred at 80 °C for 16 hours. After allowing it to cool, filtration was performed, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was carried out using isobutyl alcohol, and after recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue (3.8 g) was subjected to silica gel chromatography and eluted with a mixed solution 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]

Chemical formula

[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) Into a eggplant flask, DMF (13.6 g), water (6.3 g), ascorbic acid (3.5 g), triethylamine (2.0 g), and 2-chloromethyloxirane (2.2 g) were added, and the mixture was 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 carried out using isobutyl alcohol, and after recovering the organic layer, 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 and eluted with a mixed solution of chloroform / methanol / water = 15 / 3 / 0.3 to 10 / 3 / 0.3, and concentrated 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) represented by the following structural formula (Synthesis Example 4: the left structural formula below) and 2,3-O-(1-hydroxymethyl-1,2-ethanediyl)ascorbic acid (6.6 mg) (Synthesis Example 5: the right structural formula below).

[0054]

Chemical formula

[0055] Synthesis Example 6 (Synthesis of 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid) Into a eggplant flask, DMF (5.0 g), ascorbic acid (0.528 g), potassium carbonate (0.456 g), and 3,3-bis(bromomethyl)oxetane (0.805 g) were added, and the mixture was stirred at 80 °C for 7 hours. After cooling, filtration was performed, and the filtrate was concentrated under reduced pressure. The resulting concentrate was dissolved in water. Extraction was carried out using isobutyl alcohol, and after recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was performed, and the filtrate was concentrated under reduced pressure. The resulting residue (3.8 g) was subjected to silica gel chromatography and eluted with a mixed solution of chloroform / methanol / water = 20 / 3 / 0.3, and concentrated under reduced pressure to obtain 2,3-O-(3,3-dimethyleneoxetane)ascorbic acid (0.144 g).

[0056]

Chemical formula

[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 added to a recovery flask, and the mixture was stirred at 80° C. for 24 hours. After the reaction was completed, ion-exchanged water and isobutanol were added, and the mixture was separated. The isobutanol layer was collected and concentrated under reduced pressure. The resulting residue (0.60 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform / methanol = 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 (37.3 mg).

[0058] [ka]

[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. Into a eggplant flask, synthesized 3-O-(2-hydroxyisobutyl)ascorbic acid (4.21 g), THF (25 ml), and p-toluenesulfonic acid monohydrate (4.19 g) were added, and the mixture was stirred at 90 °C for 18 hours. After completion of the reaction, ion-exchanged water and ethyl acetate were added, and liquid separation operation was carried out. Ethyl acetate was recovered and concentrated under reduced pressure. The obtained residue (0.21 g) was subjected to silica gel chromatography, eluted with a mixed solution of chloroform / methanol = 10 / 0 to 9.5 / 0.5, and concentrated under reduced pressure to obtain 2,3-O-(1,1-dimethyl-1,2-ethanediyl)ascorbic acid (15.3 mg).

[0060] [Chemical formula]

[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)) Into a eggplant flask, 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 added. While stirring at 25 °C, butanoyl chloride (5.1 g) was added, and then the mixture was stirred at 25 °C for 5 hours and extracted with ethyl acetate. Washing with water was carried out 3 times. After recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out and concentration was carried out under reduced pressure. The obtained residue (2.5 g) was subjected to silica gel chromatography, eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentrated under reduced pressure to obtain 6-O-butanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (0.9 g) (Synthesis Example 9: the left structural formula below) and 5,6-O-dibutanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.4 g) (Synthesis Example 10: the right structural formula below).

[0062] [Chemical formula]

[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) Into a eggplant flask, 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 added, and octanoyl chloride (5.0 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 2 hours, and extraction was performed using ethyl acetate. Washing with water was carried out 3 times. After collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (5.1 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 5 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.4 g) represented by the following structural formula (Synthesis Example 11: the left structural formula below) and 5,6-O-dioctanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.6 g) (Synthesis Example 12: the right structural formula below).

[0064] [Chemical formula]

[0065] Synthesis Example 13 Synthesis of 6-O-lauroyl-2,3-O-(1,4-butanediyl)ascorbic acid Into an eggplant flask, 2,3-O-(1,4-butanediyl)ascorbic acid (3.0 g) obtained in Synthesis Example 3, N-methylpyrrolidone (30.0 g), and triethylamine (1.7 g) were added, and dodecanoyl chloride (3.4 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 4 hours, and extraction was performed using ethyl acetate. Washing with water was carried out 3 times. After recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (6.1 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 8 / 3 to 1 / 1, and concentration was carried out 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]

Chemical formula

[0067] Synthesis Example 14 Synthesis of 5,6-O-dilauroyl-2,3-O-(1,4-butanediyl)ascorbic acid Into an eggplant flask, 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 added, and stirring was carried out at 25°C for 4 hours. The obtained residue (3.2 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1, and concentration was carried out 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]

Chemical formula

[0069] Synthesis Example 15 Synthesis of 6-O-palmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid Into a eggplant flask, 2,3-O-(1,4-butanediyl)ascorbic acid (2.0 g) obtained in Synthesis Example 3, N-methylpyrrolidone (30.0 g), and triethylamine (1.1 g) were added, and hexadecanoyl chloride (2.6 g) was added while stirring at 0 °C. 25 The mixture was stirred at 25 °C for 5 hours and extracted with ethyl acetate. Washing with water was carried out twice, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was performed and concentration was carried out under reduced pressure. The obtained residue (4.7 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 5 / 1 to 1 / 1, and concentration was carried out 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.

[0070]

Chemical formula

[0071] Synthesis Example 16 Synthesis of 5,6-O-dipalmitoyl-2,3-O-(1,4-butanediyl)ascorbic acid Into an eggplant flask, 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 added, and the mixture was stirred at 60 °C for 4 hours, and then stirred at 25 °C for 16 hours. Thereafter, extraction was carried out using hexane / ethyl acetate = 1:1, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was performed and concentration was carried out under reduced pressure. The obtained residue (3.3 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1, and concentration was carried out 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]

Chemical formula

[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 eggplant flask, 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 added. While stirring at 25°C, isostearoyl chloride (9.4 g) was added, and then stirring was carried out at 25°C for 3 hours. Extraction was performed using ethyl acetate. Washing with water was carried out twice. After recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (9.8 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid (2.5 g) (Synthesis Example 17: the upper structural formula below) and 5,6-O-diisostearoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.8 g) (Synthesis Example 18: the lower structural formula below) represented by the following structural formula.

[0074]

Chemical formula

[0075] Synthesis Example 19 Synthesis of 5-O-butanoyl-6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid Into a eggplant flask, 6-O-octanoyl-2,3-O-(1,4-butanediyl)ascorbic acid (1.0 g) obtained in Synthesis Example 11, acetonitrile (5.0 g), and triethylamine (0.6 g) were added, and butanoyl chloride (0.5 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 2 hours, and extraction was performed using ethyl acetate. Washing with water was carried out twice, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (1.5 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 3 / 1, and concentration was carried out 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] [Chemical formula]

[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 eggplant flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g) obtained in Synthesis Example 2, N-methylpyrrolidone (22.0 g), and triethylamine (5.0 g) were added, and butanoyl chloride (2.6 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 2 hours, and extraction was performed using ethyl acetate. Washing with water was carried out 4 times, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (4.2 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 3 / 1 to 2 / 3, and concentration was carried out under reduced pressure to obtain 6-O-butanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.7 g) (Synthesis Example 20: the left structural formula below) and 5,6-O-dibutanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.9 g) (Synthesis Example 21: the right structural formula below).

[0078]

Chem.

[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 eggplant flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g) obtained in Synthesis Example 2, N-methylpyrrolidone (22.0 g), and triethylamine (5.0 g) were added, and octanoyl chloride (6.0 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 3 hours, and extraction was performed using ethyl acetate. Washing with water was carried out 4 times, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (7.6 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-octanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) represented by the following structural formula (Synthesis Example 22: the left structural formula below) and 5,6-O-dioctanoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.3 g) (Synthesis Example 23: the right structural formula below).

[0080]

Chem.

[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 eggplant flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g) obtained in Synthesis Example 2, N-methylpyrrolidone (22.0 g), and triethylamine (11.0 g) were added, and dodecanoyl chloride (7.8 g) was added while stirring at room temperature. Stirring was carried out at 25 °C for 3 hours, and extraction was carried out using ethyl acetate. Washing with water was carried out 3 times, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (6.6 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-lauroyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) represented by the following structural formula (Synthesis Example 24: the upper structural formula below) and 5,6-O-dilauroyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.3 g) (Synthesis Example 25: the lower structural formula below).

[0082] [Chemical formula]

[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 eggplant flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.2 g) obtained in Synthesis Example 2, N-methylpyrrolidone (22.0 g), and triethylamine (3.9 g) were added, and hexadecanoyl chloride (9.9 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 3 hours, and extraction was performed using ethyl acetate. Washing with water was carried out twice. After collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (13.4 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 6 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (1.3 g) (Synthesis Example 26: the upper structural formula below) and 5,6-O-dipalmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (2.6 g) (Synthesis Example 27: the lower structural formula below) represented by the following structural formula.

[0084]

Chemical formula

[0085] Synthesis Example 28 Synthesis of 6-O-isostearoyl-2,3-O-(1,3-propanediyl)ascorbic acid Into a eggplant flask, 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) were added, and isostearoyl chloride (5.0 g) was added while stirring. Stirring was carried out at 25°C for 4 hours, and extraction was performed using ethyl acetate. Washing with water was carried out three times. After collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (8.6 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentration was carried out 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]

Chemical formula

[0087] Synthesis Example 29 Synthesis of 5,6-O-Diisostearoyl-2,3-O-(1,3-propanediyl)ascorbic Acid Into a eggplant flask, 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. Further, N-methylpyrrolidone (14.0 g) was added, and the mixture was stirred at 25°C for 7 hours and concentrated under reduced pressure. The obtained residue (3.8 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1, 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] [Chemical formula]

[0089] Synthesis Example 30 Synthesis of 5-Butanoyl-6-O-palmitoyl-2,3-O-(1,3-propanediyl)ascorbic Acid Into a eggplant flask, 6-O-Palmitoyl-2,3-O-(1,3-propanediyl)ascorbic acid (0.8 g), acetonitrile (4.0 g), and triethylamine (0.36 g) obtained in Synthesis Example 26 were added, 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. Washing with water was performed twice, and after collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was performed and concentrated under reduced pressure. The obtained residue (0.9 g) was subjected to silica gel chromatography and eluted with a mixed solution 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] [Chemical formula]

[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 eggplant flask, 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) were added, and isostearoyl chloride (6.8 g) was added while stirring at 25°C. Stirring was carried out at 25°C for 3 hours, and extraction was performed using ethyl acetate. Washing with water was carried out 4 times, and after recovering the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (9.2 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 4 / 1 to 1 / 1, and concentration was carried out under reduced pressure to obtain 6-O-isostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid (1.0 g) represented by the following structural formula (Synthesis Example 31: the upper structural formula below) and 5,6-O-diisostearoyl-2,3-O-(1,2-ethanediyl)ascorbic acid (1.0 g) (Synthesis Example 32: the lower structural formula below).

[0092] [Chemical formula]

[0093] Synthesis Example 33 4-Hydroxy-2,6,9,14-tetraoxatricyclo[6.6.0.0 1.5 tetradecan-7-one synthesis Into an eggplant flask, 2,3-O-(1,4-butanediyl)ascorbic acid (1.3 g) obtained in Synthesis Example 3, water (8.0 g), and isopropyl alcohol (2.0 g) were added. While stirring at 25 °C, a 10% aqueous sodium hydroxide solution (4.5 g) was added, and then stirring was carried out at 25 °C for 30 minutes. Thereafter, a 17% aqueous hydrochloric acid solution (2.4 g) was added, and the mixture was allowed to stand at 25 °C for 16 hours. Ethyl acetate was added for extraction. Washing with water was performed three times. After collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was performed under reduced pressure. The obtained residue (0.4 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 3 / 1 to 1 / 1, and concentration was performed under reduced pressure. 4-Hydroxy-2,6,9,14-tetraoxatricyclo[6.6.0.0 1.5 tetradecan-7-one (125 mg) was obtained.

[0094]

Chemical formula

[0095] Synthesis Example 34 Synthesis of 4-hydroxy-2,6,9,13-tetraoxatricyclo[6.5.0.0 1.5 tridecan-7-one Into an eggplant flask, 2,3-O-(1,3-propanediyl)ascorbic acid (2.5 g) obtained in Synthesis Example 2, water (16.0 g), and isopropyl alcohol (4.0 g) were added. While stirring at 25 °C, a 10% aqueous sodium hydroxide solution (9.0 g) was added, and then stirring was carried out at 25 °C for 8 hours. Thereafter, a 17% aqueous hydrochloric acid solution (7.5 g) was added, and the mixture was allowed to stand at 25 °C for 16 hours. Ethyl acetate was added for extraction. Washing with water was performed three times. After collecting the organic layer, magnesium sulfate was added. Subsequently, filtration was carried out, and concentration was performed under reduced pressure. The obtained residue (1.7 g) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 1 / 1, and concentration was performed under reduced pressure. 4-Hydroxy-2,6,9,13-tetraoxatricyclo[6.5.0.0 1.5 tridecan-7-one (464 mg) was obtained.

[0096] [Chemical formula]

[0097] Synthesis Example 35 Synthesis of 5,6-O-Isopropylidene-2,3-O-(1,4-butanediyl)ascorbic Acid Into a eggplant flask, 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 in sequence, and the mixture was stirred at 25 °C for 2 hours. Neutralization was carried out using triethylamine, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained concentrate for extraction. Washing with water was performed once, and washing with saturated brine was performed twice. Magnesium sulfate was added to the recovered organic layer. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (1.1 g) was dissolved by heating in a mixed solution of hexane / ethyl acetate = 5 / 3, allowed to cool, and then left standing at room temperature overnight. The precipitated solid was collected by filtration, washed with hexane, and dried under vacuum to obtain 5,6-O-isopropylidene-2,3-O-(1,4-butanediyl)ascorbic acid (619 mg) represented by the following structural formula.

[0098] [Chemical formula]

[0099] Synthesis Example 36 Synthesis of 5,6-O-Isopropylidene-2,3-O-(1,3-propanediyl)ascorbic Acid Into a eggplant flask, 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 in order, and the mixture was stirred at 25 °C for 2.5 hours. Neutralization was carried out using an aqueous sodium hydroxide solution, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained concentrate for extraction. Washing with water was performed once, and washing with saturated brine was performed twice. Magnesium sulfate was added to the recovered organic layer. Subsequently, filtration was carried out, and concentration was carried out under reduced pressure. The obtained residue (750 mg) was dissolved by heating in a mixed solution of isopropanol / methanol = 3 / 2, allowed to cool, and then allowed to stand overnight at room temperature. The precipitated solid was collected by filtration, washed with isopropanol, and dried under vacuum to obtain 5,6-O-isopropylidene-2,3-O-(1,3-propanediyl)ascorbic acid (303 mg) represented by the following structural formula.

[0100]

Chemical formula

[0101] Synthesis Example 37 Synthesis of 5,6-O-(phenylmethylene)-2,3-O-(1,4-butanediyl)ascorbic acid Into a eggplant flask, 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 in order, and the mixture was stirred at 25 °C for 19 hours. Neutralization was carried out using triethylamine, and the mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained concentrate in order for washing. The solid was recovered by filtration and dried under vacuum to obtain 5,6-O-(phenylmethylene)-2,3-O-(1,4-butanediyl)ascorbic acid (226 mg) represented by the following structural formula.

[0102]

Chemical formula

[0103] Synthesis Example 38 Synthesis of 5,6-O-(phenylmethylene)-2,3-O-(1,3-propanediyl)ascorbic acid Into an eggplant flask, 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 in order, and the mixture was stirred at 25 °C for 5 hours. Neutralization was carried out using triethylamine, and the mixture was concentrated under reduced pressure. Water and hexane / ethyl acetate = 5 / 1 were added to the obtained concentrate in this order for washing. The solid was recovered by filtration and vacuum dried to obtain 5,6-O-(phenylmethylene)-2,3-O-(1,3-propanediyl)ascorbic acid (303 mg) represented by the following structural formula.

[0104]

Chemical formula

[0105] Synthesis Example 39 Synthesis of 6-O-benzyl-2,3-O-(1,4-butanediyl)ascorbic acid Into an eggplant flask, 2,3-O-(1,4-butanediyl)ascorbic acid (318 mg) obtained in Synthesis Example 3 and DMF (5.0 mL) were placed, cooled in an ice bath, 2-picolyl borane (1000 mg) and trimethylsilyl chloride (543 mg) were added, and the mixture was stirred in a 50 °C water bath for 1 hour. Ice water was added, and the mixture was further stirred for 1 hour. Ethyl acetate (10 mL) was added for liquid separation, and after the organic layer was recovered, the aqueous layer was extracted with ethyl acetate (50 mL), and the recovered organic layer was washed twice with saturated brine (50 mL). After adding magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The obtained residue (750 mg) was subjected to silica gel chromatography and eluted with a mixed solution of hexane / ethyl acetate = 1 / 1 to 1 / 2, and concentrated under reduced pressure to obtain 6-O-benzyl-2,3-O-(1,4-butanediyl)ascorbic acid (90 mg).

[0106]

Chemical formula

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

[0108]

Table 1

[0109]

Table 2

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

[0111]

Table 3

[0112]

Table 4

[0113]

Table 5

[0114]

Table 6

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

[0116]

Table 7

[0117]

Table 8

[0118]

Table 9

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

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

[0121] Odor: Evaluated by 10 panelists according to the following criteria. 3: Almost odorless. 2: Slight off-odor can be felt. 1: Strong off-odor can be felt. Based on this evaluation result, it was classified as follows. ○: The total score of 10 people is 25 or more △: The total score of 10 people is 16 - 24 ×: The total score of 10 people is 15 or less

[0122] Coloring: Evaluated by 10 panelists according to the following criteria. 3: Almost no change compared to immediately after preparation. 2: Color it as compared with immediately after preparation. 1: Color strongly as compared with immediately after preparation. Based on this evaluation result, it was classified as follows. ○: The total score of 10 people is 25 or more △: The total score of 10 people is 16 - 24 ×: The total score of 10 people is 15 or less

[0123]

Table 10

[0124]

Table 11

[0125] Test Example 2 [Stability Test - 2] Regarding the samples of Synthesis Examples 9 - 32, (a) and (b) described in Table 12 were heated and mixed respectively. After cooling, a cream with pH 7 or 9 was prepared by adding (c). It 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. Also, the odor and degree of coloring were evaluated based on the same methods and criteria as in Test Example 1. The results regarding the residual rate are shown in Tables 13 - 14, and the results regarding the odor and degree of coloring are shown in Tables 15 - 16.

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

[0127]

Table 12

[0128]

Table 13

[0129]

Table 14

[0130]

Table 15

[0131]

Table 16

[0132] The results of the above test examples show that the ascorbic acid derivative represented by the general formula (1) of the present invention has a residual rate when stored at 50°C that does not decrease compared to ascorbic acid and conventional ascorbic acid derivatives, has excellent stability over time, and shows almost no generation of odor or coloring. In Test Example 1, in the neutral to weakly alkaline region of pH 7 to 9, the residual rate of ascorbic acid and conventional ascorbic acid derivatives decreased to less than 30% after 2 weeks, while the ascorbic acid derivative represented by the general formula (1) of the present invention had a residual rate of 50% or more after 2 weeks, and even after 4 weeks, the residual rate was much higher than that of ascorbic acid and conventional ascorbic acid derivatives. Also, similarly in Test Example 2, it was clarified that the ascorbic acid derivative represented by the general formula (1) of the present invention has higher stability than ascorbyl tetrahexyldecanoate, which is a conventional ascorbic acid derivative, in the neutral to weakly alkaline region of pH 7 to 9. The ascorbic acid derivative represented by the general formula (1) of the present invention has the excellent properties originally possessed by ascorbic acid, and the results shown in Tables 10, 11, 13 to 16 further indicate that the stability over time, which was a problem of conventional ascorbic acid derivatives, has been improved, showing that it is more suitable as a blending material for cosmetics.

[0133] Test Example 3 [Collagen Production Promoting Effect] Normal human dermal fibroblasts were treated with 2.5×10 4After preparation with D-MEM containing 5% (v / v) fetal bovine serum to achieve a cell density of cells / well, pre-incubation was performed on a 96-well plate for 24 hours. After removing the medium, samples prepared at a predetermined concentration with D-MEM containing 5% (v / v) fetal bovine serum were then 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 the ELISA method. The measurement was performed with N = 3.

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

[0135]

Table 17

[0136] From the results in Table 17, it is clear that the ascorbic acid derivative represented by the general formula (1) of the present invention has a collagen production promoting effect equal to or higher than that of known ascorbic acid derivatives, namely, 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 4 prepared with D-MEM containing 5% (v / v) fetal bovine serum to achieve a cell density of cells / well, and pre-incubation was performed on a 96-well plate for 24 hours. After removing the medium, samples prepared with serum-free D-MEM were then 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 the ELISA method. The measurement was performed with N = 3.

[0138] When the hyaluronic acid production amount when measuring the sample at a concentration of 10 mM or less was compared with the Control group, the results (% values when the Control group was set to 100%) are shown in Tables 18 to 20 based on the following criteria. <100% :± 100 - 120%:+ 120%< :++

[0139]

Table 18

[0140]

Table 19

[0141]

Table 20

[0142] From the results of Tables 18 to 20, it is clear that the ascorbic acid derivative of the present invention has a higher hyaluronic acid production promoting effect than ascorbic acid and known ascorbic acid derivatives.

[0143] Test Example 5 [Antioxidant effect] Normal human epidermal keratinocytes were seeded into a 96-well plate using KG2 medium so that the cell density became 2.0×10 4 cells / well. After performing 24-hour pre-incubation, samples adjusted to a predetermined concentration with KG2 medium were added to each well. After culturing for 24 hours, the medium was removed, washed with HBSS(-), and the ROS-reactive fluorescent probe DCFHDA was allowed to be incorporated for 30 minutes. After washing again with HBSS(-), 0.2 mM of H 2 O 2It was processed and cultured for 2 hours. The fluorescence intensity was measured, and the amount of ROS produced per unit protein was calculated by describing the fluorescence intensity in terms of the protein amount quantified by the BCA method, which was taken as Analytical Value 1. Also, without adding the sample adjusted to a predetermined concentration by the above test method, the calculated ROS production amount was taken as Analytical Value 2, and without adding the sample and 0.2 mM H 2 O 2 the calculated ROS production amount was taken as Analytical Value 3, and the ROS production inhibition rate was calculated by the following formula. These results are shown in Table 21. It can be evaluated that the higher the ROS production inhibition rate, the higher the antioxidant effect. ROS production inhibition rate (%) = [(Analytical Value 2) - (Analytical Value 1)] / [(Analytical Value 2) - (Analytical Value 3)] × 100

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

[0145]

Table 21

[0146] From the results in Table 21, it is shown that the ascorbic acid derivative of the present invention has an antioxidant effect equivalent to or higher than that of known ascorbic acid derivatives.

[0147] Example 122 Cream The raw materials of the oil phase part of (1) to (5) and the raw materials of the water phase part of (6) to (10) with the compositions shown in Table 22 were each heated to 70°C and dissolved to prepare the oil phase and the water phase, respectively. Then, the oil phase was added to the water phase for preliminary emulsification, homogenized with a homomixer, and cooled to room temperature while stirring well to prepare the cream. In the tables after Table 22, the blending amounts are represented by parts by mass.

[0148]

Table 22

[0149] Example 123 Emulsion The raw materials of the oil phase part of (1) to (9) and the raw materials of the water phase part of (10) to (13) in the composition shown in Table 23 were each heated to 70°C and dissolved to prepare the oil phase and the water phase, respectively. Then, the oil phase was added to the water phase for preliminary emulsification, and after uniformly emulsifying with a homomixer, the emulsion was prepared by cooling to room temperature while stirring well.

[0150]

Table 23

[0151] Example 124 Emulsion The raw materials of the oil phase part of (5) to (10) and the raw materials of the water phase part of (1) to (4), (11) to (12) in the composition shown in Table 24 were each heated to 70°C and dissolved to prepare the oil phase and the water phase, respectively. Then, the oil phase was added to the water phase for preliminary emulsification, and after uniformly emulsifying with a homomixer, the emulsion can be prepared by cooling to room temperature while stirring well.

[0152]

Table 24

[0153] Example 125 Cream The raw materials of the oil phase part of (1) to (2) and the raw materials of the water phase part of (3) to (10) in the composition shown in Table 25 were each heated to 70°C and dissolved to prepare the oil phase and the water phase, respectively. After that, the oil phase was added to the water phase for preliminary emulsification, and after uniformly emulsifying with a homomixer, the cream can be prepared by cooling to room temperature while stirring well.

[0154]

Table 25

[0155] Example 126 Lotion A lotion can be prepared by mixing the raw materials (1) to (6) having the composition shown in Table 26 while stirring well.

[0156]

Table 26

[0157] Example 127 Cream The components (1) to (6) of the composition shown in Table 27 and the components (7) to (10) are each heated to 70 °C for dissolution. The oil phase is added to the aqueous phase for preliminary emulsification, and then emulsified with a homomixer. Subsequently, it is cooled to room temperature while stirring well to prepare a cream.

[0158]

Table 27

[0159] Example 128 Cream The raw materials of the oil phase part of the components (1) to (5) and the raw materials of the aqueous phase part of the components (6) to (10) of the composition shown in Table 28 are each heated to 70 °C for dissolution to prepare the oil phase and the aqueous phase, respectively. Subsequently, the oil phase is added to the aqueous phase for preliminary emulsification, uniformly emulsified with a homomixer, and then cooled to room temperature while stirring well to prepare a cream.

[0160]

Table 28

[0161] Example 129 Cream The raw materials of the oil phase part of the components (1) to (2) and the raw materials of the aqueous phase part of the components (3) to (10) of the composition shown in Table 29 are each heated to 70 °C for dissolution to prepare the oil phase and the aqueous phase, respectively. After that, the oil phase is added to the aqueous phase for preliminary emulsification, uniformly emulsified with a homomixer, and then cooled to room temperature while stirring well to prepare a cream.

[0162]

Table 29

Claims

1. An ascorbic acid derivative represented by the following general formula (1), (3) or (4): 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 [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. 【Chemistry 4】

2. The ascorbic acid derivative represented by the general formula (1) is 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 comprising 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 comprising an ascorbic acid derivative according to any one of claims 1 to 3.

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