Derivatives of ascorbic acid or its salts, and cosmetics containing that substance.

Abstract

DEPCT68 Novel derivatives of ascorbic acid or salts of it, which have naturally occurring functions. Superior to ascorbic acid in aspects such as skin whitening effect and stimulating production. Collagen also plays a role in retaining moisture, maintaining its consistency even when stored. Leave it for a period of time, which will show changes in color, changes in smell, and a decrease in output. Due to its limited efficacy and similar properties, the present invention provides for derivatives of ascorbic acid. Or a salt of that substance in which one hydrogen atom from the hydroxyl group at the second and third positions is present. The ascorbic acid component is replaced by RO-CH2-CH(OH)-CH2-,RO-CH2-CH(CH2OH)-,R-. CH(CH2OH)-,R-CH(OH)-CH2-(R which is H, an alkyl group, an alkynyl group, or a phenyl group),HO- C(CH3)2-CH2-, or HO-CH2-C(CH3)2-. The current invention also provides for cosmetics that include: Derivatives of ascorbic acid or salts of it;

Description

Ascorbic acid derivatives or their salts and cosmetics containing them

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

[0002] Ascorbic acid is a safe and useful antioxidant and is known as a compound with excellent whitening effects, but its instability to light, heat, and oxidation has prevented its use in the field of cosmetics. 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 have problems such as discoloration and odor generation over time, and their stability over time is still insufficient. In addition, their activity in the body only lasts for a short period of time, and improvements in these areas are desired.

[0004] The present inventors have proposed an ascorbic acid derivative that solves these problems (Patent Document 4), but further improvements are desired.

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

[0006] The present invention addresses the problem of providing an ascorbic acid derivative or a salt thereof that has the excellent effects inherent to ascorbic acid, such as whitening and moisturizing effects, and that is highly stable with little discoloration, odor change, or activity decrease over time, and further has excellent physiologically active effects, as well as providing a cosmetic preparation containing the same.

[0007] The present inventors have conducted extensive research in light of the above-mentioned circumstances and have found that a novel ascorbic acid derivative or salt thereof represented by the following formula (I) has excellent effects such as whitening and moisturizing, is stable and suffers little discoloration, odor, or activity loss over time, and also has excellent physiological effects such as promoting hyaluronic acid production. The present invention has been completed based on these findings.

[0008] The present invention provides an ascorbic acid derivative or a salt thereof represented by the following general formula (I) (claim 1).

[0009]

[0010] [In the formula, R １ and R ２ represents H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, R ３ -CH(CH ２ OH)-, R ３ -CH(OH)-CH ２ -, HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R ３ is H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, or a phenyl group. １ and R ２ At least one of the following is HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - is.]

[0011] The salt of the ascorbic acid derivative is a compound represented by the formula (I) R １ or R ２is H, the H in the ascorbic acid derivative is replaced by a cation such as a metal ion or an ammonium ion, and such salts are also included in the present invention.

[0012] The ascorbic acid derivatives represented by general formula (I) or salts thereof have superior stability over time compared to ascorbic acid and conventional ascorbic acid derivatives, maintaining a high residual rate even when stored for several weeks in a high-temperature environment above room temperature, and suppressing odor generation and coloration problems. Furthermore, they have superior antioxidant effects compared to conventional ascorbic acid derivatives such as glyceryl ascorbate. Among these, ascorbic acid derivatives or salts thereof having a hydroxyisobutyl group at the 3-position are preferred.

[0013] An ascorbic acid derivative represented by general formula (I), wherein R １ or R ２ In the case where one of the hydroxyl groups is H, as described later, ascorbic acid is reacted with isobutylene oxide or halogenated tert-butyl alcohol, and only the 2- and / or 3-positions of the four hydroxyl groups at the 2-, 3-, 5-, and 6-positions of ascorbic acid are regiospecifically converted to HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - can be obtained by etherification with

[0014] In the reaction of ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol, depending on the reaction conditions for etherification, the hydroxyl group at the 2-position may be etherified mainly, or the hydroxyl group at the 3-position may be etherified mainly. When the hydroxyl group at the 2-position is etherified mainly, R １ But HO-C(CH ３ ) ２ -CH ２ - and HO-CH ２ -C(CH ３ ) ２ - may be produced, and when the hydroxyl group at the 3-position is mainly etherified, R ２ But HO-C(CH ３ ) ２ -CH２ - and HO-CH ２ -C(CH ３ ) ２ - and mixtures may occur.

[0015] Among the ascorbic acid derivatives represented by general formula (I), R １ is H and R ２ is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ Ascorbic acid derivatives having a value of - have superior melanin production inhibitory effects and collagen production promoting effects compared to conventional ascorbic acid derivatives such as glyceryl ascorbic acid.

[0016] In addition, among the ascorbic acid derivatives represented by general formula (I), R １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ -, and the other is an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, R ３ -CH(CH ２ OH)—, or R ３ -CH(OH)-CH ２ - and R １ , R ２ Both are HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２Ascorbic acid derivatives having a value of - have superior effects of inhibiting melanin production, promoting collagen production, and promoting hyaluronic acid production compared to conventional ascorbic acid derivatives such as glyceryl ascorbic acid.

[0017] Among the ascorbic acid derivatives represented by general formula (I), R １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ -, and the other is an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, R ３ -CH(CH ２ OH)—, or R ３ -CH(OH)-CH ２ - is an R 2 - obtained by reacting ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol. １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２- with glycidol, an alkyl glycidyl ether of a specific structure, alkenyl glycidyl ether, phenyl glycidyl ether, sulfate ester, alkylene oxide, alkenyl oxide, styrene oxide, alkyl halide, hydroxyalkyl halide, benzyl halide, alkenyl halide, hydroxyalkenyl halide, halogenated phenethyl alcohol, or the like; or １ or R ２ The compound obtained by reacting one of the above with isobutylene oxide or a halogenated tert-butyl alcohol can also be obtained.

[0018] The invention described in claim 2 is a compound represented by the general formula (I), wherein R １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ and the other is an alkyl group having 2 to 20 carbon atoms or a branched alkylglyceryl group having 6 to 20 carbon atoms.

[0019] Among the ascorbic acid derivatives according to claim 1, R １ or R ２ Either one of the following is HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２-, and the other is an alkyl group having 2 to 20 carbon atoms, preferably 6 to 16 carbon atoms, or a branched alkylglyceryl group having 6 to 20 carbon atoms, preferably 8 to 14 carbon atoms, is preferred because it has a particularly high effect of promoting hyaluronic acid production. Claim 2 corresponds to this particularly preferred embodiment.

[0020] The invention described in claim 3 is a compound represented by the general formula (I), wherein R １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ and the other is a benzyl group.

[0021] Among the ascorbic acid derivatives according to claim 1, R １ or R ２ Either one of the following is HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ The one in which the other is a benzyl group is preferred in that it exhibits high physiologically active effects such as the effect of promoting hyaluronic acid production and the effect of inhibiting melanin production. Claim 3 corresponds to this particularly preferred embodiment.

[0022] The invention described in claim 4 is a compound represented by the general formula (I), wherein R １ or R ２ One of them is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ The other is R ３ -O-CH ２ -CH(OH)-CH ２ - or R ３ -O-CH ２-CH(CH ２ 2. The ascorbic acid derivative or salt thereof according to claim 1, wherein the ascorbic acid derivative or salt thereof is a hydroxyl group.

[0023] The ascorbic acid derivatives described in claim 1 have superior stability over time compared to ascorbic acid. １ or R ２ Either one of the following is HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and the other is R ３ -O-CH ２ -CH(OH)-CH ２ - or R ３ -O-CH ２ -CH(CH ２ Among the ascorbic acid derivatives of the present invention, those having the formula (OH)- are preferred in that they have less odor. Claim 4 corresponds to this particularly preferred embodiment.

[0024] The invention described in claim 5 is a compound represented by the general formula (I), wherein R １ or R ２ One of the two is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ the other is H, alkyl or alkenyl, and R １ and R ２ The total number of carbon atoms in R is 8 or less, or １ or R ２ The other is R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３) ２ - and R ３ 2. The ascorbic acid derivative or salt thereof according to claim 1, wherein the number of carbon atoms is 4 or less.

[0025] The ascorbic acid derivatives described in claim 1 have superior stability over time compared to ascorbic acid. Among them, R １ or R ２ One of the two is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ the other is H, alkyl or alkenyl, and R １ and R ２ The total number of carbon atoms in R is 8 or less, or １ or R ２ The other is R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R ３ Those having 4 or less carbon atoms are preferred in that they have a high moisturizing effect when blended in cosmetics. Claim 5 corresponds to this particularly preferred embodiment.

[0026] The invention described in claim 6 is a compound represented by the general formula (I), wherein R １ or R ２ One of the two is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ The other is R ３-CH(CH ２ OH)—, or R ３ -CH(OH)-CH ２ - and R ３ is H, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or a phenyl group.

[0027] The ascorbic acid derivatives described in claim 1 have superior stability over time compared to ascorbic acid. Among them, R １ or R ２ One of the two is HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R １ or R ２ The other is R ３ -CH(CH ２ OH)—, or R ３ -CH(OH)-CH ２ - and R ３ Among the ascorbic acid derivatives of the present invention, those in which is H, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or a phenyl group are preferred in that coloration is suppressed. Claim 6 corresponds to this particularly preferred embodiment.

[0028] By incorporating the ascorbic acid derivative or salt thereof of the present invention into a cosmetic, it is possible to obtain a cosmetic that has excellent whitening and moisturizing effects, is stable even when stored for a long period of time, and has high physiological activity. Therefore, the present invention provides a cosmetic characterized by incorporating the ascorbic acid derivative or salt thereof of the present invention (claim 7). Furthermore, since the effects of the present invention are particularly exhibited when incorporated in a cosmetic at 1 to 20% by mass, the present invention further provides a cosmetic in which the ascorbic acid derivative or salt thereof of the present invention is incorporated in an amount of 1 to 20% by mass (claim 8).

[0029] The ascorbic acid or salt thereof represented by the general formula (I) of the present invention possesses the excellent functions inherent to ascorbic acid derivatives, such as whitening and moisturizing effects, and is stable even after long-term storage, exhibits little discoloration, odor, or loss of activity over time, and possesses high physiological activities, such as antioxidant effect, melanin production inhibitory effect, collagen production promotion effect, and hyaluronic acid production promotion effect. Therefore, by incorporating this compound into cosmetics, such as topical skin preparations and hair cosmetics, it is possible to obtain cosmetics that are excellent in whitening and moisturizing effects, stable even after long-term storage, and have high physiological activities. The cosmetics of the present invention are cosmetics (such as whitening cosmetics and moisturizing cosmetics) that are excellent in whitening and moisturizing effects, stable even after long-term storage, and have high physiological activities.

[0030] Below, HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ The symbol "-" represents a "hydroxyisobutyl group." Hydroxyisobutyl ascorbic acid refers to ascorbic acid in which a hydroxyisobutyl group is bonded to one or more oxygen atoms of each hydroxyl group. The ascorbic acid derivative of the present invention is hydroxyisobutyl ascorbic acid in which a hydroxyisobutyl group is bonded to the 2- and / or 3-position.

[0031] Specific examples of the ascorbic acid derivative represented by general formula (I) include the compounds shown below, but the scope of the present invention is not limited to these.

[0032] In the following examples, glyceryl refers to HOCH ２ -CH(OH)-CH ２ - or HOCH ２ -CH(CH ２ The alkylglyceryl group is R—O—CH ２ -CH(OH)CH ２ - or R-O-CH ２ -CH(CH ２OH)-(R represents an alkyl group), and a hydroxyalkyl group is R-CH(OH)-CH ２ - (R represents an alkyl group), and a hydroxyalkenyl group is represented by R-CH(OH)-CH ２ - (R represents an alkenyl group), the alkyl group represents a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, ethylhexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, behenyl group, etc., the alkenyl group represents a vinyl group, allyl group, butenyl group, isobutenyl group, crotyl group, octenyl group, decenyl group, dodecenyl group, etc.

[0033] (1) 3-O-hydroxyisobutyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-alkyl ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-ethyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-butyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-hexyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-octyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-decyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-ethylhexyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-dodecyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-tetradecyl ascorbic acid, and 3-O-hydroxyisobutyl-2-O-hexadecylascorbic acid; 3-O-hydroxyisobutyl-2-O-alkenyl ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-allyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-octenyl ascorbic acid, and 3-O-hydroxyisobutyl-2-O-dodecenyl ascorbic acid; 3-O-hydroxyisobutyl-2-O-glyceryl ascorbic acid; 3-O-hydroxyisobutyl-2-O-alkyl glyceryl ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-butylglyceryl ascorbic acid, 3-O-hydroxyisobutyl-2-O-ethylhexylglyceryl ascorbic acid, and 3-O-hydroxyisobutyl-2-O-dodecylglyceryl ascorbic acid; 3-O-hydroxyisobutyl-2-O-alkenylglyceryl ascorbic acid, for example, 3-O-hydroxyisobutyl-2-O-dodecenylglyceryl ascorbic acid; 3-O-hydroxyisobutyl-2-O-phenylglyceryl ascorbic acid; 3-O-hydroxyisobutyl-2-O-benzyl ascorbic acid;3-O-hydroxyisobutyl-2-O-(2-hydroxyalkyl)ascorbic acids, for example, 3-O-hydroxyisobutyl-2-O-(2-hydroxypropyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxydecyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxyhexadecyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxyethylbenzene)ascorbic acid; 3-O-hydroxyisobutyl-2-O-(1-alkyl-2-hydroxyethyl)ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-(1-methyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(1-ethyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(1-octyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(1-tetradecyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(1-phenyl-2-hydroxyethyl)ascorbic acid;

[0034] (2) 2-O-hydroxyisobutyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-alkyl ascorbic acids, such as 2-O-hydroxyisobutyl-3-O-ethyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-butyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-hexyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-octyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-decyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-ethylhexyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-dodecyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-tetradecyl ascorbic acid, and 2-O-hydroxyisobutyl-3-O-hexadecylascorbic acid; 2-O-hydroxyisobutyl-3-O-alkenyl ascorbic acids, for example, 2-O-hydroxyisobutyl-3-O-allyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-octenyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-dodecenyl ascorbic acid; 2-O-hydroxyisobutyl-3-O-glyceryl ascorbic acid; 2-O-hydroxyisobutyl-3-O-alkyl glyceryl ascorbic acids, for example, 2-O-hydroxyisobutyl-3-O-butylglyceryl ascorbic acid, 2-O-hydroxyisobutyl-3-O-ethylhexylglyceryl ascorbic acid, 2-O-hydroxyisobutyl-3-O-dodecylglyceryl ascorbic acid; 2-O-Hydroxyisobutyl-3-O-alkenylglyceryl ascorbic acid, for example, 2-O-hydroxyisobutyl-3-O-dodecenylglyceryl ascorbic acid; 2-O-Hydroxyisobutyl-3-O-phenylglyceryl ascorbic acid; 2-O-Hydroxyisobutyl-3-O-benzyl ascorbic acid;2-O-hydroxyisobutyl-3-O-(2-hydroxyalkyl)ascorbic acids, for example, 2-O-hydroxyisobutyl-3-O-(2-hydroxypropyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxydecyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxyhexadecyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxyethylbenzene)ascorbic acid; 2-O-hydroxyisobutyl-3-O-(1-alkyl-2-hydroxyethyl)ascorbic acids, for example, 2-O-hydroxyisobutyl-3-O-(1-methyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(1-ethyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(1-octyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(1-tetradecyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(1-phenyl-2-hydroxyethyl)ascorbic acid;

[0035] (3) 2,3-di-O-hydroxyisobutyl ascorbic acid.

[0036] The ascorbic acid derivatives or salts thereof of the present invention can be produced by various methods. For example, ascorbic acid is reacted with isobutylene oxide or a halogenated tert-butyl alcohol to introduce a hydroxyisobutyl group into the oxygen atom bonded to the 2- or 3-position of ascorbic acid, thereby synthesizing 2-O- or 3-O-hydroxyisobutylascorbic acid. The other oxygen atom bonded to the 2- or 3-position is then alkylated or alkenylated by known means to obtain the ascorbic acid derivatives of the present invention. Alternatively, the oxygen atom bonded to the 2- or 3-position of ascorbic acid may first be alkylated or alkenylated, and then the compound of the present invention may be obtained by reacting the resulting product with isobutylene oxide or a halogenated tert-butyl alcohol.

[0037] Examples of the compound for introducing a hydroxyisobutyl group in the present invention include, but are not limited to, isobutylene oxide and halogenated tert-butyl alcohol. Examples of halogenated tert-butyl alcohol include fluorinated tert-butyl alcohol, chlorinated tert-butyl alcohol, and brominated tert-butyl alcohol.

[0038] In the reaction of ascorbic acid or hydroxyalkylated ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol, depending on the reaction conditions for etherification, the hydroxyl group at the 2-position may be etherified primarily, or the hydroxyl group at the 3-position may be etherified primarily. When the hydroxyl group at the 2-position is etherified primarily, R １ But HO-C(CH ３ ) ２ -CH ２ - and HO-CH ２ -C(CH ３ ) ２ - may be produced, and when the hydroxyl group at the 3-position is mainly etherified, R ２ But HO-C(CH ３ ) ２ -CH ２ - and HO-CH ２ -C(CH ３ ) ２ - and mixtures may occur.

[0039] The amount of isobutylene oxide or halogenated tert-butyl alcohol used in the present invention is not particularly limited, but is preferably 0.8 to 1.5 moles, more preferably 1.0 to 1.2 moles, per mole of ascorbic acid.

[0040] The reaction for introducing a hydroxyisobutyl group in the production of the present invention can be carried out in various solvents. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dioxane, tetrahydrofuran (THF), N-methylpyrrolidone, 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 50 to 90°C, and particularly preferably 60 to 90°C.

[0041] The pH of the reaction solvent is not particularly limited, but in the production of the ascorbic acid derivative or a salt thereof, when the ascorbic acid derivative or a salt thereof in which the 2-position of the ascorbic acid structure is H is produced, acidic conditions are preferred, with a pH of 2 to 6 being particularly preferred, and when the ascorbic acid derivative or a salt thereof in which the 3-position of the ascorbic acid structure is H is produced, alkaline conditions are preferred, with a pH of 8 to 11 being particularly preferred.

[0042] 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, and triethylamine.

[0043] The ascorbic acid derivative or a salt thereof of the present invention produced as described above can be purified by means of 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.

[0044] The ascorbic acid derivative represented by the general formula (I) is １ or R ２In a compound where R is H, the hydrogen ion dissociated from H can be substituted with a cation such as a metal ion or an ammonium ion to form a salt, and such salts are also included within the scope of the present invention. Examples of such salts include inorganic salts and organic salts. Examples of inorganic salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and ammonium salts, while examples of organic salts include diethanolamine salts, triethanolamine salts, and basic amino acid salts. The formation of a salt is achieved by the reaction of R １ or R ２ This can be carried out by a method similar to that for forming a known salt, such as a method of neutralizing an aqueous solution of an ascorbic acid derivative in which is H with a basic substance.

[0045] The hydroxyisobutylascorbic acid synthesized as described above can be alkylated, alkenylated, benzylated, hydroxyalkylated, or the like with glycidol, alkyl glycidyl ethers of specific structures, alkenyl glycidyl ethers, phenyl glycidyl ethers, sulfates, alkylene oxides, alkenyl oxides, styrene oxides, alkyl halides, hydroxyalkyl halides, halogenated benzyl alcohols, halogenated alkenyls, halogenated hydroxyalkenyls, halogenated phenethyl alcohols, or the like to obtain the ascorbic acid derivatives of claims 2, 3, 4, or 6.

[0046] The amount of glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, or the like used in alkylation, alkenylation, benzylation, phenylation, or the like is not particularly limited, but is preferably 0.8 to 2.0 moles per mole of hydroxyisobutylascorbic acid.

[0047] The reaction with glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, etc. can be carried out in the same solvent, reaction temperature, and pH as in the reaction for introducing a hydroxyisobutylene group, and the ascorbic acid derivative of the present invention can be synthesized by purifying the product by means of column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, etc. Note that even when first reacting glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, etc. with the oxygen atom bonded to the 2- or 3-position of ascorbic acid and then introducing a hydroxyisobutyl group into the other oxygen atom, each reaction can be carried out under the same conditions as above.

[0048] The ascorbic acid derivative or salt thereof of the present invention can be suitably used as a component of various cosmetics such as external preparations for skin and hair cosmetics, and can also be used as a food additive, animal feed, etc.

[0049] When the ascorbic acid derivative or salt thereof of the present invention is blended into various cosmetics, the blending amount is preferably 1% to 20% by weight, and particularly preferably 3% to 10% by weight. If the blending amount is less than 1% by weight, the effects of the ascorbic acid derivative or salt thereof of the present invention, such as the whitening effect and the hyaluronic acid production promoting effect, are often not fully exhibited. On the other hand, if the blending amount exceeds 20% by weight, the effects commensurate with the blending amount are often not expected, and there is also a risk of damaging the formulation system.

[0050] 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 or salt thereof 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.

[0051] Examples of oily raw materials, surfactants, other moisturizers, polymeric compounds, antioxidants, other 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 JP 2022-028125 A.

[0052] 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 (I) or a salt thereof with the above-mentioned optional ingredients according to the desired product.

[0053] 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, production examples of the ascorbic acid derivatives of the present invention used in the Examples and Comparative Examples will be shown as Synthesis Examples.

[0054] Synthesis Example 1 Synthesis of 2-O-(2-hydroxyisobutyl)ascorbic acid Water (10.5 mL), DMF (5 mL), ascorbic acid (10.0 g), sodium hydroxide (2.50 g), and isobutylene oxide (4.50 g) were placed in a recovery flask and stirred at 60°C for 4 hours. After completion of the reaction, 5 mol / L hydrochloric acid was added to adjust the pH to acidic. The mixture was concentrated under reduced pressure, and isopropanol was added, followed by filtration and further concentration under reduced pressure. The resulting residue (10.1 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform / methanol = 10 / 0 to 6 / 4, and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)ascorbic acid (8.83 g).

[0055] The resulting product was analyzed by mass spectrometry. 1 H-NMR, １３ C-NMR measurement was carried out, and the results confirmed that the product was 2-O-(2-hydroxyisobutyl)ascorbic acid represented by the following structural formula.

[0056]

[0057] In this structural formula, carbon atoms and hydrogen atoms bonded to the carbon atoms are omitted. For example, in this formula, positions 1, 2, 4, 6, and 7 are carbon atoms, and position 5 is CH ３ group, and positions 3 and 9 are CH ２ The 8th position is a CH group. In the structural formulae below, hydrogen atoms and carbon atoms are omitted in the same manner as in this formula.

[0058] In the synthesis examples shown below, the products obtained were analyzed by mass spectrometry, 1 H-NMR, and １３ C-NMR measurements were carried out, and the results confirmed that each product was an ascorbic acid derivative represented by the structural formula or compound name shown in each synthesis example. 1 H-NMR and １３ The results of C-NMR measurements are shown in Tables 1 to 8.

[0059] Synthesis Example 2 Synthesis of 3-O-(2-hydroxyisobutyl)ascorbic acid The title 3-O-(2-hydroxyisobutyl)ascorbic acid (7.42 g) was obtained in the same manner as in Synthesis Example 1, except that water and DMF (50 mL) were used instead of DMF, and triethylamine (1.72 g) was used instead of sodium hydroxide.

[0060]

[0061] Synthesis Example 3: Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-ethylascorbic acid 2-O-(2-hydroxyisobutyl)ascorbic acid (1.50 g) obtained in Synthesis Example 1, DMF (6 mL), triethylamine (1.22 g), and diethyl sulfate (1.86 g) were placed in a recovery flask and stirred at 70°C for 4 hours. After completion of the reaction, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (1.16 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol (10 / 0 to 7 / 3), and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)-3-O-ethylascorbic acid (148.5 mg) represented by the following structural formula:

[0062]

[0063] Synthesis Example 4 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-butylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-butylascorbic acid (710.3 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.27 g) was used instead of triethylamine and butyl bromide (1.08 g) was used instead of diethyl sulfate.

[0064]

[0065] Synthesis Example 5 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-hexylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-hexylascorbic acid (473.7 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.27 g) was used instead of triethylamine and hexyl bromide (1.30 g) was used instead of diethyl sulfate.

[0066]

[0067] Synthesis Example 6 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-octylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-octylascorbic acid (148.5 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.52 g) was used instead of triethylamine and octyl bromide (1.75 g) was used instead of diethyl sulfate.

[0068]

[0069] Synthesis Example 7 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-decyl ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-decyl ascorbic acid (371.2 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (1.27 g) was used instead of triethylamine and decyl bromide (1.74 g) was used instead of diethyl sulfate.

[0070]

[0071] Synthesis Example 8 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-dodecyl ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-dodecyl ascorbic acid (358.8 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (1.27 g) was used instead of triethylamine and dodecyl bromide (1.96 g) was used instead of diethyl sulfate.

[0072]

[0073] Synthesis Example 9 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-tetradecyl ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-tetradecyl ascorbic acid (328.8 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (1.27 g) was used instead of triethylamine and tetradecyl bromide (2.18 g) was used instead of diethyl sulfate.

[0074]

[0075] Synthesis Example 10 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-hexadecylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-hexadecylascorbic acid (258.0 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.27 g) was used instead of triethylamine and cetyl bromide (1.85 g) was used instead of diethyl sulfate.

[0076]

[0077] Synthesis Example 11 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-allylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-allylascorbic acid (366.4 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.52 g) was used instead of triethylamine and allyl bromide (1.10 g) was used instead of diethyl sulfate.

[0078]

[0079] Synthesis Example 12 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-benzyl ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-benzyl ascorbic acid (602.2 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (1.52 g) was used instead of triethylamine and benzyl bromide (1.55 g) was used instead of diethyl sulfate.

[0080]

[0081] Synthesis Example 13: Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-glyceryl ascorbic acid. 3-O-Glyceryl ascorbic acid (3.00 g), DMF (12 mL), triethylamine (0.24 g), and isobutylene oxide (1.04 g) were placed in a recovery flask and stirred at 85°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 layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (1.12 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol (9.5 / 0.5 to 7 / 3), followed by concentration under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)-3-O-glyceryl ascorbic acid (178.6 mg) represented by the following structural formula:

[0082]

[0083] Synthesis Example 14 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-butyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-butyl)ascorbic acid (216.6 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (0.20 g) was used instead of triethylamine and butyl glycidyl ether (1.89 g) was used instead of diethyl sulfate.

[0084]

[0085] Synthesis Example 15 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-ethylhexyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-ethylhexyl)ascorbic acid (375.9 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (0.20 g) was used instead of triethylamine and ethylhexyl glycidyl ether (2.70 g) was used instead of diethyl sulfate.

[0086]

[0087] Synthesis Example 16: Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-dodecyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxy-3-O-dodecyl)ascorbic acid (450.3 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogen carbonate (0.20 g) was used instead of triethylamine and lauryl glycidyl ether (3.52 g) was used instead of diethyl sulfate.

[0088]

[0089] Synthesis Example 17 Synthesis of 2,3-di-O-(2-hydroxyisobutyl)ascorbic acid The title 2,3-di-O-(2-hydroxyisobutyl)ascorbic acid (500.9 mg) was obtained in the same manner as in Synthesis Example 3, except that isobutylene oxide (1.05 g) was used instead of diethyl sulfate.

[0090]

[0091] Synthesis Example 18: Synthesis of 2-O-ethyl-3-O-(2-hydroxyisobutyl)ascorbic acid Into a recovery flask were added 3.00 g of 3-O-(2-hydroxyisobutyl)ascorbic acid obtained in Synthesis Example 2, DMF (12 mL), triethylamine (1.35 g), and diethyl sulfate (2.42 g), followed by stirring at 80°C for 5 hours. After completion of the reaction, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (2.41 g) was subjected to silica gel chromatography, eluting with a chloroform / methanol mixture (10 / 0 to 9 / 1), followed by concentration under reduced pressure to obtain 2-O-ethyl-3-O-(2-hydroxyisobutyl)ascorbic acid (443.0 mg) represented by the following structural formula:

[0092]

[0093] Synthesis Example 19: Synthesis of 2-O-butyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-butyl-3-O-(2-hydroxyisobutyl)ascorbic acid (464.8 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and butyl bromide (0.99 g) was used instead of diethyl sulfate.

[0094]

[0095] Synthesis Example 20 Synthesis of 2-O-hexyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-hexyl-3-O-(2-hydroxyisobutyl)ascorbic acid (617.8 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and hexyl bromide (1.20 g) was used instead of diethyl sulfate.

[0096]

[0097] Synthesis Example 21 Synthesis of 2-O-octyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-octyl-3-O-(2-hydroxyisobutyl)ascorbic acid (1.05 g) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (1.12 g) was used instead of triethylamine and octyl bromide (2.80 g) was used instead of diethyl sulfate.

[0098]

[0099] Synthesis Example 22 Synthesis of 2-O-decyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-decyl-3-O-(2-hydroxyisobutyl)ascorbic acid (216.7 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and decyl bromide (1.60 g) was used instead of diethyl sulfate.

[0100]

[0101] Synthesis Example 23 Synthesis of 2-O-dodecyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-dodecyl-3-O-(2-hydroxyisobutyl)ascorbic acid (248.9 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and dodecyl bromide (1.81 g) was used instead of diethyl sulfate.

[0102]

[0103] Synthesis Example 24 Synthesis of 2-O-tetradecyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-tetradecyl-3-O-(2-hydroxyisobutyl)ascorbic acid (383.9 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and tetradecyl bromide (2.01 g) was used instead of diethyl sulfate.

[0104]

[0105] Synthesis Example 25 Synthesis of 2-O-hexadecyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-hexadecyl-3-O-(2-hydroxyisobutyl)ascorbic acid (234.5 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and cetyl bromide (2.21 g) was used instead of diethyl sulfate.

[0106]

[0107] Synthesis Example 26 Synthesis of 2-O-allyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-allyl-3-O-(2-hydroxyisobutyl)ascorbic acid (276.0 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.70 g) was used instead of triethylamine and allyl bromide (0.88 g) was used instead of diethyl sulfate.

[0108]

[0109] Synthesis Example 27 Synthesis of 2-O-benzyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-benzyl-3-O-(2-hydroxyisobutyl)ascorbic acid (511.5 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (1.12 g) was used instead of triethylamine and benzyl bromide (2.07 g) was used instead of diethyl sulfate.

[0110]

[0111] Synthesis Example 28: Synthesis of 2-O-glyceryl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-glyceryl-3-O-(2-hydroxyisobutyl)ascorbic acid (243.7 mg) was obtained in the same manner as in Synthesis Example 13, except that 2-O-glyceryl ascorbic acid (3.0 g) was used instead of 3-O-glyceryl ascorbic acid.

[0112]

[0113] Synthesis Example 29: Synthesis of 2-O-(2-hydroxy-3-O-butyl)-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-(2-hydroxy-3-O-butyl)-3-O-(2-hydroxyisobutyl)ascorbic acid (579.4 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.20 g) was used instead of triethylamine and butyl glycidyl ether (1.89 g) was used instead of diethyl sulfate.

[0114]

[0115] Synthesis Example 30 Synthesis of 2-O-(2-hydroxy-3-O-ethylhexyl)-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-(2-hydroxy-3-O-ethylhexyl)-3-O-(2-hydroxyisobutyl)ascorbic acid (358.8 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogencarbonate (0.20 g) was used instead of triethylamine and ethylhexyl glycidyl ether (2.70 g) was used instead of diethyl sulfate.

[0116]

[0117] Synthesis Example 31 Synthesis of 2-O-(2-hydroxy-3-O-dodecyl)-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-(2-hydroxy-3-O-dodecyl)-3-O-(2-hydroxyisobutyl)ascorbic acid (458.0 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.10 g) was used instead of triethylamine and lauryl glycidyl ether (1.76 g) was used instead of diethyl sulfate.

[0118]

[0119] Synthesis Example 32 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-propylascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-butylascorbic acid (642.7 mg) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (1.27 g) was used instead of triethylamine and propyl bromide (0.97 g) was used instead of diethyl sulfate.

[0120]

[0121] Synthesis Example 33 Synthesis of 2-O-propyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-propyl-3-O-(2-hydroxyisobutyl)ascorbic acid (423.7 mg) was obtained in the same manner as in Synthesis Example 18, except that sodium hydrogen carbonate (0.56 g) was used instead of triethylamine and propyl bromide (1.26 g) was used instead of diethyl sulfate.

[0122]

[0123] Synthesis Example 34 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxypropyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxypropyl)ascorbic acid (0.17 g) was obtained in the same manner as in Synthesis Example 3, except that epoxypropane (0.64 g) was used instead of diethyl sulfate.

[0124]

[0125] Synthesis Example 35 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxybutyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxybutyl)ascorbic acid (0.18 g) was obtained in the same manner as in Synthesis Example 3, except that epoxybutane (0.80 g) was used instead of diethyl sulfate.

[0126]

[0127] Synthesis Example 36 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxydecyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxydecyl)ascorbic acid (0.11 g) was obtained in the same manner as in Synthesis Example 3, except that sodium hydrogencarbonate (0.14 g), tetrabutylammonium bromide (0.77 g), and epoxydecane (1.63 g) were used instead of triethylamine and diethyl sulfate, respectively.

[0128]

[0129] Synthesis Example 37 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxyhexadecyl)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxyhexadecyl)ascorbic acid (0.55 g) was obtained in the same manner as in Synthesis Example 3, except that epoxyhexadecane (2.65 g) was used instead of diethyl sulfate.

[0130]

[0131] Synthesis Example 38 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxyethylbenzene)ascorbic acid The title 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxyethylbenzene)ascorbic acid (0.65 g) was obtained in the same manner as in Synthesis Example 3, except that styrene oxide (1.32 g) was used instead of diethyl sulfate.

[0132]

[0133] Synthesis Example 39 Synthesis of 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxypropyl)ascorbic acid The title 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxypropyl)ascorbic acid (0.38 g) was obtained in the same manner as in Synthesis Example 18, except that diazabicycloundecene (0.15 g) was used instead of DMF, DMAc (5.0 mL) was used instead of triethylamine, and epoxypropane (0.35 g) was used instead of diethyl sulfate.

[0134]

[0135] Synthesis Example 40 Synthesis of 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxybutyl)ascorbic acid The title 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxybutyl)ascorbic acid (0.27 g) was obtained in the same manner as in Synthesis Example 18, except that diazabicycloundecene (0.15 g) was used instead of DMF, DMAc (5.0 mL) was used instead of triethylamine, and epoxybutane (0.43 g) was used instead of diethyl sulfate.

[0136]

[0137] Synthesis Example 41 Synthesis of 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxydecyl)ascorbic acid The title 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxydecyl)ascorbic acid (0.30 g) was obtained in the same manner as in Synthesis Example 18, except that diazabicycloundecene (0.15 g) was used instead of DMF, DMAc (5.0 mL) was used instead of triethylamine, and epoxydecane (0.94 g) was used instead of diethyl sulfate.

[0138]

[0139] Synthesis Example 42 Synthesis of 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxyhexadecyl)ascorbic acid The title 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxyhexadecyl)ascorbic acid (0.30 g) was obtained in the same manner as in Synthesis Example 18, except that diazabicycloundecene (0.15 g) was used instead of DMF, DMAc (5.0 mL) was used instead of triethylamine, and epoxyhexadecane (1.44 g) was used instead of diethyl sulfate.

[0140]

[0141] Synthesis Example 43 Synthesis of 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxyethylbenzene)ascorbic acid The title 3-O-(2-hydroxyisobutyl)-2-O-(2-hydroxyethylbenzene)ascorbic acid (0.48 g) was obtained in the same manner as in Synthesis Example 18, except that diazabicycloundecene (0.15 g) was used instead of DMF, DMAc (5.0 mL) was used instead of triethylamine, and styrene oxide (0.74 g) was used instead of diethyl sulfate.

[0142]

[0143] Mass spectrometry of the products obtained in Synthesis Examples 1 to 43 was carried out using an LCMS-2020 (manufactured by Shimadzu Corporation). The measurement results are shown in Table 1.

[0144]

[0145] The products obtained in Synthesis Examples 1 to 43 1 H-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Tables 2 to 5.

[0146]

[0147]

[0148]

[0149]

[0150] The products obtained in Synthesis Examples 1 to 43 1３C-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Tables 6 to 8.

[0151]

[0152]

[0153]

[0154] Test Example 1 [Melanin Production Inhibitory Effect] As a test for whitening effect, the ascorbic acid derivatives of the present invention were evaluated for their effect on theophylline-induced melanin production in B16 melanoma 4A5 cells according to the following procedure. A similar evaluation was also performed on a known ascorbic acid derivative for comparison. The results are shown in Tables 9 to 11.

[0155] (1) B16 mouse melanoma 4A5 cells were cultured at 8.0 × 10 ３Cells were seeded onto 48-well plates at a cell density of 1000 cells / well. (2) After 24 hours of culture in Dulbecco's modified Eagle's medium (Sigma, hereafter abbreviated as D-MEM) containing 10% fetal bovine serum, the medium was replaced with D-MEM containing 10% fetal bovine serum containing theophylline (final concentration 1 mmol / L) and a specified concentration of the sample. (3) After 3 days of culture in the presence of the sample, the medium was removed using an aspirator, distilled water was added, and the cells were disrupted by sonication. (4) Subsequently, protein content was quantified using a BCA protein assay kit (PIERCE), and melanin production was measured by alkaline solubilization. Sodium hydroxide was added to the cell lysate to a final concentration of 1 mol / L, and the mixture was heated to dissolution (60°C, 30 minutes), after which the absorbance at 405 nm was measured using a microplate reader. The amount of melanin was calculated from a calibration curve prepared using synthetic melanin (SIGMA) as a standard. The amount of melanin per unit protein was calculated by dividing the amount of melanin by the amount of protein. (5) The melanin production inhibition rate was calculated using the following formula: Melanin production inhibition rate (%) = [1 - (A - B) / (C - B)] x 100 (where A is the amount of melanin per unit protein (g / g) when the sample was added, B is the amount of melanin per unit protein (g / g) in the normal group, and C is the amount of melanin per unit protein (g / g) in the control group.)

[0156] The melanin production inhibition rate when the sample was measured at a concentration of 10 mM or less was expressed as follows. Note that the measurement was performed with N=4. <20%: ± 20-40%: + 40-60%: ++ 60-100%: +++

[0157]

[0158]

[0159]

[0160] The results in Tables 9 to 11 show that the ascorbic acid derivatives of the present invention have whitening effects equal to or greater than those of known ascorbic acid derivatives, namely, 2-O-glyceryl ascorbic acid and 3-O-glyceryl ascorbic acid.

[0161] Test Example 2 [Stability Test] A 1% aqueous solution of each test sample was adjusted to pH 6 with a dilute potassium hydroxide aqueous solution, placed in a 50 mL screw tube, sealed, and stored at 50°C for 4 weeks. HPLC measurement (using a liquid chromatograph manufactured by Shimadzu Corporation) was performed, and the residual rate was calculated from the peak area. The residual rate, odor, and coloration were evaluated according to the following methods and criteria, and the results are shown in Tables 12 and 13.

[0162] Residual rate: ◎: 90% or more ○: 80% or more, less than 90% △: 60% or more, less than 80% ×: 20% or more, less than 60% XX: Less than 20%

[0163] 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 odors were classified as follows: ◎: Total score of 25 or more by 10 panelists ○: Total score of 20-24 by 10 panelists △: Total score of 16-19 by 10 panelists ×: Total score of 15 or less by 10 panelists

[0164] 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

[0165]

[0166]

[0167] The ascorbic acid derivatives of the present invention have superior stability over time when stored at 50° C. compared to ascorbic acid, and show almost no odor or coloration. That is, the results shown in Tables 12 and 13 indicate that the ascorbic acid derivatives of the present invention have the excellent properties inherent to ascorbic acid, such as excellent whitening effect, and also have improved stability over time, which was a problem with conventional ascorbic acid derivatives, making them more suitable as ingredients for use in cosmetics.

[0168] Test Example 3 [Antioxidation Test] Normal human epidermal keratinocytes were cultured at 2.0 × 10 ４ The 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 cells were treated with HCl and cultured for 2 hours. Fluorescence intensity was measured, and the amount of ROS produced per unit protein was calculated by dividing the fluorescence intensity by the amount of protein quantified by the BCA method. The results are shown in Table 14.

[0169] The antioxidant effect when the sample was measured at a concentration of 10 mM or less was expressed as follows. Note that the measurement was performed with N=4. <20%: ± 20-40%: + 40-70%: ++ 70-100%: +++

[0170]

[0171] The results in Table 14 show that the ascorbic acid derivatives of the present invention have a superior antioxidant effect to known ascorbic acid derivatives or salts thereof, i.e., 2-O-glyceryl ascorbic acid and 3-O-glyceryl ascorbic acid.

[0172] Test Example 4 [Collagen production promoting effect] Normal human skin fibroblasts were cultured at 2.5 × 10 ４ The cells were adjusted to a cell density of 100 cells / well with D-MEM containing 5% (v / v) fetal bovine serum, and then pre-incubated on a 96-well plate for 24 hours. After removing the medium, samples adjusted to the desired concentration with D-MEM containing 5% (v / v) fetal bovine serum were added to each well and cultured for 48 hours. After incubation, the amount of free collagen in the supernatant was quantified by ELISA. Measurements were performed in triplicate.

[0173] The amount of collagen produced when the samples were measured at a concentration of 10 mmol / L or less was compared with that of the control group, and the results (% values ​​when the control group was set to 100%) are shown in Tables 15 to 17 based on the following criteria: <100%: ± 100-120%: + 120%<: ++

[0174]

[0175]

[0176]

[0177] The results in Tables 15 to 17 clearly show that the ascorbic acid derivatives of the present invention have a collagen production-promoting effect equal to or greater than that of known ascorbic acid derivatives or salts thereof, i.e., 2-O-glyceryl ascorbic acid and 3-O-glyceryl ascorbic acid.

[0178] Test Example 5 [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.

[0179] The amount of hyaluronic acid produced when the samples were measured at a concentration of 10 mmol / L 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%: + 120-150%: ++ 150%<: +++

[0180]

[0181]

[0182]

[0183] The results in Tables 18 to 20 clearly show that the ascorbic acid derivatives of the present invention have a hyaluronic acid production promoting effect equal to or greater than that of known ascorbic acid derivatives such as 2-O-glyceryl ascorbic acid.

[0184] Example 131 Cream The oil phase ingredients (1) to (5) and the aqueous phase ingredients (6) to (10) of the composition shown in Table 21 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 with excellent whitening effects. In Table 22 and subsequent tables, the blend amounts are in parts by mass.

[0185]

[0186] Example 132 Emulsion The oil phase ingredients (1) to (9) and the aqueous phase ingredients (10) to (13) in 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 well to prepare an emulsion with excellent whitening effect.

[0187]

[0188] Example 133 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 23 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. After that, the mixture was cooled to room temperature while stirring well, thereby preparing an emulsion with excellent whitening effect.

[0189]

[0190] Example 134 Cream The oil phase ingredients (1) and (2) and the aqueous phase ingredients (3) to (10) shown in Table 24 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 with thorough stirring to prepare a cream. This cream is used as a skin cosmetic with excellent whitening effects.

[0191]

[0192] Example 135: Lotion A lotion can be prepared by thoroughly mixing the raw materials (1) to (6) shown in Table 25. This lotion contains 7% by weight of 2,3-di-O-(2-hydroxyisobutyl)ascorbic acid and therefore has an excellent whitening effect.

[0193]

[0194] Example 136 Cream The oil phases (1) to (6) and the aqueous phases (7) to (10) shown in Table 26 are each heated to 70°C and dissolved. The oil phase is added to the aqueous phase and pre-emulsified. The mixture is then emulsified using a homomixer and cooled to room temperature with thorough stirring to prepare a cream. This cream contains 3% by weight of 3-O-(2-hydroxyisobutyl)ascorbic acid, and can be used as a skin cosmetic with excellent melanin production inhibitory effect and excellent whitening effect.

[0195]

[0196] Example 137 Cream The oil phase ingredients (1) to (5) and the aqueous phase ingredients (6) to (10) in the compositions shown in Table 27 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 with excellent whitening effects.

[0197]

[0198] Example 138 Emulsion The oil phase ingredients (1) to (9) and the aqueous phase ingredients (10) to (13) 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 with thorough stirring to prepare an emulsion with excellent whitening effect.

[0199]

[0200] Example 139 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 29 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 with excellent whitening effect.

[0201]

[0202] Example 140 Cream The oil phase ingredients (1) and (2) and the aqueous phase ingredients (3) to (10) shown in Table 30 are each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase is then added to the aqueous phase and pre-emulsified, and the mixture is homogeneously emulsified using a homomixer. The mixture is then cooled to room temperature with thorough stirring to prepare a cream. This cream is used as a skin cosmetic with excellent whitening effects.

[0203]

[0204] Example 141: Lotion A lotion is prepared by thoroughly mixing the raw materials (1) to (6) shown in Table 31. This lotion contains 7% by mass of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxybutyl) ascorbic acid and therefore has an excellent whitening effect.

[0205]

[0206] Example 142 Cream The oil phase components (1) to (6) and the aqueous phase components (7) to (10) shown in Table 32 were each heated to 70°C and dissolved. The oil phase component was added to the aqueous phase component and pre-emulsified. The mixture was then emulsified using a homomixer and cooled to room temperature with thorough stirring to prepare a cream. This cream contains 3% by mass of 2-O-(2-hydroxyisobutyl)-3-O-(2-hydroxydecyl)ascorbic acid, and can therefore be used as a skin cosmetic with excellent melanin production inhibitory effect and excellent whitening effect.

[0207]

Claims

DEPCT681. A derivative of ascorbic acid or its salts which is characterized by being represented by the following general formula (I) [Chemical Formula 1](Chemical Formula)(I) [where R1 and R2 are H, an alkyl group with 1 to 22 carbon atoms, an alkenyl group with 2 to 22 carbon atoms, a benzyl group, R3-O-CH2-CH(OH)-CH2-, R3-O-CH2-CH(CH2OH)-, R3-CH(CH2OH)-, R3-CH(OH)-CH2-, HO-C(CH3)2-CH2-, or HO-CH2-C(CH3)2- and R3 is H, an alkyl group with 1 to 22 carbon atoms, an alkenyl group with 2 to 22 carbon atoms or a phenyl group, provided that at least one of R1 and R2 are H.

1. A derivative of ascorbic acid or its salts according to claim 1 in which, in the general formula (I), one of R1 and R2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the other of R1 and R2 is an alkyl group of 2 to 20 carbon atoms or an alkylglyceryl branched chain group of 6 to 20 carbon atoms.

3. A derivative of ascorbic acid or its salts according to claim 1 in which, in the general formula (I), one of R1 and R2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the other of R1 and R2 is a benzyl group. 4.Derivatives of ascorbic acid or salts of it according to claim 1, in which the general formula (I) one of R1 and R2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the other of R1 and R2 is R3-O-CH2-CH(OH)-CH2- or R3-O-CH2-CH(CH2OH)-.

5. Derivatives of ascorbic acid or salts of it according to claim 1, in which the general formula (I) one of R1 and R2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the other of R1 and R2 is H, alkyl or alkenyl, and the total number of carbon atoms in R1 and R2 is 8 or less. One or another of R1 and R2 is R3-O-CH2-CH(OH)-CH2-, R3-O-CH2-CH(CH2OH)-, HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the number of carbon atoms in R3 is 4 or less than 6. Derivatives of ascorbic acid or salts of it according to claim 1 in which in general formula(I) one of R1 and R2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2- and the other of R1 and R2 is R3-CH(CH2OH)- or R3-CH(OH)-CH2-.

7. Cosmetics which contain derivatives of ascorbic acid or salts of it according to any of claims 1-6. 8.Cosmetics in which derivatives of ascorbic acid or salts of it, as per any of claims 1-6, are included in an amount of 1 to 20% by mass;