High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid and topical compositions containing the same

Abstract

The present invention provides a highly purified pentylglyceryl ascorbic acid derivative that inhibits the generation of pro-oxidants and is highly safe, and a topical composition containing the same. [Solution] High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid and a topical composition containing the same, characterized in that the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and the total content of ascorbic acid is less than 3 mass% relative to the amount of 2-O-pentyl-3-O-glyceryl ascorbic acid and the total content of monopentyl ascorbic acid, monoglyceryl ascorbic acid, ascorbic acid, and other impurities.

Description

[Technical Field]

[0001] The present invention relates to high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid, which inhibits the generation of ascorbic acid radicals and is less likely to become a pro-oxidant, and to a topical composition containing said ascorbic acid derivative. [Background technology]

[0002] L-ascorbic acid is one of the important vitamins for humans. Humans, primates, and guinea pigs cannot synthesize vitamin C (L-ascorbic acid) in their bodies, making it an essential vitamin nutrient. For this reason, ascorbic acid and its derivatives are widely used as a vitamin C supplement in pharmaceuticals, quasi-drugs, cosmetics, and foods. Furthermore, ascorbic acid has a strong reducing effect, it is widely used as an antioxidant in chemical and industrial products.

[0003] On the other hand, most antioxidants are known to convert into substances that promote oxidation when they reduce their target. These substances are called prooxidants. Prooxidants are known to cause various disorders in the human body, including neurodegenerative disorders, peroxisomal disorders, Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpepecolic acidemia, punctate epiphyseal dysplasia, Zellweger-like syndrome, adrenoleukodystrophy, adrenal myeloneuropathy, acyl-COA oxidase deficiency, bifunctional protein deficiency, thiolase deficiency, type I hyperoxaluria, acatalaseemia, adult Refsum disease, Alzheimer's disease, Huntington's disease, schizophrenia, and diabetic neuropathy. Vitamin E derivatives with prooxidants are also known to exert toxic effects, killing cancer cells.

[0004] It is known that ascorbic acid acts as a pro-oxidant, generating free radicals such as ascorbic acid radicals (Non-Patent Document 1). It is also known that ascorbic acid radicals are a type of reactive oxygen and can be analyzed using an electron spin resonance (ESR) spectrometer (Non-Patent Document 2).

[0005] Furthermore, topical compositions such as cosmetics are often applied to the skin and exposed to the air or sunlight for long periods of time outdoors. When exposed to sunlight for extended periods, active oxygen is generated in the product. Even when not exposed to sunlight, some of the active oxygen is converted to active oxygen due to the influence of oxygen in the air. Therefore, conventional ascorbic acid and its derivatives are likely to generate ascorbic acid radicals, which can easily promote oxidation of the skin. For this reason, there has been a strong demand for the development of ascorbic acid derivatives that do not generate ascorbic acid radicals or whose generation is suppressed. The present inventors have been developing ascorbic acid derivatives that solve these problems (Patent Document 1). However, consumer demands are becoming more sophisticated, and there is a demand for the development of ascorbic acid derivatives that fully meet current consumer demands. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent Publication No. 2017-057146 [Non-patent literature]

[0007] [Non-Patent Document 1] Galley HF, Davies MJ, Webster NR.Free Radic Biol Med. 20(1):139-43,1996 [Non-patent document 2] Ito, et al.,Toxicology.30;240(1-2):96-110.2007 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention aims to provide an ascorbic acid derivative that suppresses the generation of ascorbic acid radicals induced by impurities, such as ascorbic acid, monopentyl ascorbic acid, and monoglyceryl ascorbic acid, present in conventional 2-O-pentyl-3-O-glyceryl ascorbic acid, or by reducing the concentrations of these impurities, thereby significantly reducing the adverse effects of active oxygen compared to conventional ascorbic acid derivatives, and to provide topical compositions, such as cosmetics, containing the derivative. [Means for solving the problem]

[0009] The first aspect of the present invention is a highly purified 2-O-pentyl-3-O-glyceryl ascorbic acid, characterized in that the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and the ascorbic acid content is less than 3% by mass. By removing or reducing the concentrations of ascorbic acid, monopentyl ascorbic acid, and monoglyceryl ascorbic acid present as impurities in conventional 2-O-pentyl-3-O-glyceryl ascorbic acid, the adverse effects of active oxygen can be significantly reduced compared to conventional ascorbic acid derivatives such as conventional 2-O-pentyl-3-O-glyceryl ascorbic acid. In this specification, "high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid" refers to 2-O-pentyl-3-O-glyceryl ascorbic acid that is primarily composed of 2-O-pentyl-3-O-glyceryl ascorbic acid and that contains less than 3% by mass of either monopentyl ascorbic acid or monoglyceryl ascorbic acid plus ascorbic acid. 2-O-pentyl-3-O-glyceryl ascorbic acid that contains 3% or more of the aforementioned components in total, such as conventional 2-O-pentyl-3-O-glyceryl ascorbic acid disclosed in publicly known literature, is hereinafter referred to as "pure 2-O-pentyl-3-O-glyceryl ascorbic acid." Furthermore, the term "2-O-pentyl-3-O-glyceryl ascorbic acid" refers to the 2-O-pentyl-3-O-glyceryl ascorbic acid compound itself, or 2-O-pentyl-3-O-glyceryl ascorbic acid in which no impurities are detected by measurement or in which the impurities are less than 0.1% by mass of the total.

[0010] Monopentyl ascorbic acid is a compound in which a pentyl group, an alkyl group having 5 carbon atoms, is added to any of the 2-, 3-, 5-, or 6-positions of ascorbic acid, and examples include 2-O-pentyl ascorbic acid, 3-O-pentyl ascorbic acid, 5-O-pentyl ascorbic acid, and 6-O-pentyl ascorbic acid.

[0011] Monoglyceryl ascorbic acid is a compound in which a glyceryl group is added to any of the 2-, 3-, 5-, or 6-positions of ascorbic acid, and examples include 2-O-glyceryl ascorbic acid, 3-O-glyceryl ascorbic acid, 5-O-glyceryl ascorbic acid, and 6-O-glyceryl ascorbic acid.

[0012] The second aspect of the present invention is the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the first aspect of the present invention, characterized in that, in peak areas measured by automatic integration of liquid chromatograms (a method based on the General Rules for High-Performance Liquid Chromatography (JIS K0124:2011)), the area of ​​peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid is less than 5% of the total area of ​​the peak for 2-O-pentyl-3-O-glyceryl ascorbic acid and the area of ​​peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid. A peak area ratio of less than 5% is preferred because it further suppresses the generation of ascorbic acid radicals.

[0013] Furthermore, the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention can be contained in externally applied compositions such as cosmetics, and by including it, the externally applied composition can be made to have reduced generation of pro-oxidants. The third aspect of the present invention is this externally applied composition (claim 3).

[0014] The composition for external use of the present invention may be, for example, a cosmetic. The fourth aspect of the present invention is this cosmetic (claim 4). [Effects of the Invention]

[0015] The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention suppresses the generation of pro-oxidants, which is a problem with conventional ascorbic acid derivatives, and reduces the production of toxic ascorbic acid radicals. Therefore, an ascorbic acid derivative that is superior in safety (in which the adverse effects of reactive oxygen are suppressed) compared to conventional ascorbic acid derivatives is provided. Furthermore, by incorporating the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention, it is possible to provide an externally applied composition, particularly a cosmetic, that is even safer. DETAILED DESCRIPTION OF THE INVENTION

[0016] The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention is a high-purity pentylglyceryl ascorbic acid characterized in that the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and the ascorbic acid content is less than 3 mass%.

[0017] Furthermore, when the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and ascorbic acid is less than 1% by mass, the highly toxic hydroxyl radical and superoxide, which are usually detected along with an increase in ascorbic acid radical, are not detected, which is more preferable because a stronger antioxidant effect can be expected.

[0018] The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention can be produced by various methods, for example, by producing pure 2-O-pentyl-3-O-glyceryl ascorbic acid (conventional 2-O-pentyl-3-O-glyceryl ascorbic acid) and purifying the product. 2-O-pentyl-3-O-glyceryl ascorbic acid can be produced by reacting 5,6-isopropylidene ascorbic acid with a pentyl halide, followed by acid treatment to produce 2-O-pentylascorbic acid, followed by introducing a glyceryl group into the 3-hydroxyl group by a known method using glycidol or the like.

[0019] 2-O-pentyl-3-O-glyceryl ascorbic acid may be produced by reacting 5,6-isopropylidene ascorbic acid with a pentyl halide and glycidol, followed by acid treatment.

[0020] Alternatively, 2-O-pentyl-3-O-glyceryl ascorbic acid can be produced by introducing a glyceryl group into the hydroxyl group at the 3-position by a known method using glycidol or the like, followed by reaction with a pentyl halide and acid treatment.

[0021] After producing the pure 2-O-pentyl-3-O-glyceryl ascorbic acid, the product is purified by various methods to remove the impurities ascorbic acid, monopentyl ascorbic acid, and monoglyceryl ascorbic acid, and the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and the ascorbic acid content is less than 3 mass%, thereby producing the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention.

[0022] The pentyl halide used in the above reaction may be pentyl bromide, etc., but other pentyl halides may also be used. There is no particular limitation on the amount used, but when reacting 5,6-isopropylideneascorbic acid with a pentyl halide, the amount used is preferably 0.8 to 1.5 mol, more preferably 1.0 to 1.25 mol, relative to the 5,6-isopropylideneascorbic acid. On the other hand, when a pentyl halide is reacted after introducing a glyceryl group at the 3-position, the amount is also preferably 0.8 to 1.5 mol, more preferably 1.0 to 1.25 mol, relative to 3-O-glyceryl ascorbic acid.

[0023] There are no particular restrictions on the amount of glycidol or the like used to introduce a glyceryl group into the hydroxyl group at the 3-position, but it is preferably 0.8 to 1.5 mol, more preferably 1.0 to 1.25 mol, relative to 2-O-pentyl ascorbic acid. First, when a glyceryl group is introduced into the hydroxyl group at the 3-position, the amount is also preferably 0.8 to 1.5 mol, more preferably 1.0 to 1.25 mol, relative to 5,6-isopropylideneascorbic acid.

[0024] Examples of solvents used in the reaction include water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, tetrahydrofuran, methanol, ethanol, etc. The reaction temperature is preferably 20°C to 90°C, and more preferably 30°C to 80°C.

[0025] When reacting a pentyl halide with the hydroxyl group at the 2-position, the pH of the reaction system is basic, preferably pH 8.0 to 12.0, more preferably pH 9.0 to 11.0. On the other hand, when introducing a glyceryl group into the hydroxyl group at the 3-position, the pH of the reaction system is acidic, preferably pH 3.0 to 6.0, more preferably pH 3.5 to 5.5.

[0026] 2-O-Pentylascorbic acid can be produced by reacting 5,6-isopropylideneascorbic acid with a pentyl halide and then performing an acid treatment. The pH when performing the acid treatment is preferably 0.5 to 3.0, more preferably 1.0 to 2.0.

[0027] Examples of pH adjusters used in the step of reacting with pentyl halide or glycidol or in the acid treatment include, but are not particularly limited to, lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, gluconic acid, sulfuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, ammonium hydrogencarbonate, triethylamine, and diazabicycloundecene.

[0028] Examples of the solvent used in the acid treatment include water, DMF, DMSO, and N-methylpyrrolidone, and the reaction is preferably carried out at a temperature of 0 to 50°C, more preferably 10 to 40°C.

[0029] The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention can be obtained by purifying the crude 2-O-pentyl-3-O-glyceryl ascorbic acid synthesized by the above method. As the purification method, known methods can be used, such as column chromatography separation and extraction, solvent extraction, etc.

[0030] Examples of column packing materials that can be used in column chromatography separation and extraction include chelating resins, synthetic adsorbents, small particle size particles for chromatographic separation, gel filtration columns, silica gel, and ion exchange resins. However, there are no particular limitations on the packing materials, as long as they can separate impurities other than monopentyl ascorbic acid, monoglyceryl ascorbic acid, ascorbic acid, and 2-O-pentyl-3-O-glyceryl ascorbic acid from 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0031] When using silica gel column chromatography, the adsorption force is related to the electrostatic bonding force between the charge within the molecule and the hydroxyl groups of the silica gel. The greater the imbalance in the charge within the molecule and the higher the polarity, the higher the adsorption force. In this column, more polar substances are eluted later, which improves the separation performance between the target 2-O-pentyl-3-O-glyceryl ascorbic acid and impurities, allowing for the production of higher-purity 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0032] Examples of solvents that can be used in the solvent extraction method include ethyl acetate, chloroform, methanol, and mixtures of these with water. However, there are no particular limitations on the solvent, as long as it can separate impurities other than monopentyl ascorbic acid, monoglyceryl ascorbic acid, ascorbic acid, and 2-O-pentyl-3-O-glyceryl ascorbic acid from 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0033] The composition of the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention can be determined using a liquid chromatographic analyzer such as a liquid chromatograph (HPLC) or a liquid chromatographic mass spectrometer. The liquid chromatographic analyzer is not particularly limited as long as it has a liquid chromatogram that can separate and quantify the peaks of 2-O-pentyl-3-O-glyceryl ascorbic acid, monopentyl ascorbic acid, monoglyceryl ascorbic acid, ascorbic acid, and impurities other than 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0034] Examples of measurement conditions using an HPLC analyzer are described below, but the present invention is not limited to these. High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid or pure 2-O-pentyl-3-O-glyceryl ascorbic acid (0.01 g) was dissolved in 100 mL of water to prepare the test solution. Using a polyhydroxymethacrylate resin-packed column, 10 μL of the test solution was measured under the following conditions: detector: 265 nm, eluent: 0.03 mol / L dipotassium hydrogen phosphate aqueous solution, column temperature: 65°C, flow rate: 1.2 mL / min. The peak area A of 2-O-pentyl-3-O-glyceryl ascorbic acid and the peak area B of peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid were calculated using automatic integration, and the average of 10 measurements was obtained.

[0035] Standards of 2-O-pentyl-3-O-glyceryl ascorbic acid, monopentyl ascorbic acid, and monoglyceryl ascorbic acid to be used in HPLC analysis can be prepared, for example, by the following method.

[0036] The standard of 2-O-pentyl-3-O-glyceryl ascorbic acid was prepared by fractionating the raw 2-O-pentyl-3-O-glyceryl ascorbic acid (conventional 2-O-pentyl-3-O-glyceryl ascorbic acid) produced according to the method described in Patent No. 4681670 by preparative HPLC, and separating the various fractionated components. 1 The structure can be identified by H-NMR measurement, and the fraction corresponding to 2-O-pentyl-3-O-glyceryl ascorbic acid can be identified. The fraction can then be concentrated under reduced pressure to prepare the desired product. The preparative HPLC conditions used for fractionation were: a shim-pack Scepter C18-120 / 5 μm column manufactured by Shimadzu GLC Corporation; detector: 240 nm; eluent: methanol: 0.1% formic acid aqueous solution = 4:6; column temperature: 30°C; flow rate: 5 ml / min.

[0037] A standard monopentyl ascorbic acid can be prepared, for example, by reacting commercially available 5,6-isopropylidene ascorbic acid with pentyl bromide, treating with acid, and further purifying by column chromatography.

[0038] A standard sample of monoglyceryl ascorbic acid can be prepared, for example, using a commercially available 3-O-glyceryl ascorbic acid product (iVC 3GA, manufactured by Seiwa Kasei Co., Ltd.) in a manner similar to that used for the above-mentioned standard sample of 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0039] Standards of monopentyl ascorbic acid and monoglyceryl ascorbic acid can be selected from those that show no impurity peaks whose peak areas can be measured when analyzed by HPLC.

[0040] The standard ascorbic acid may be ascorbic acid from the Japanese Pharmacopoeia, but it must have a purity of 99.9% or higher.

[0041] The products of the above reaction may contain impurities such as ascorbic acid derivatives with free 2- and / or 3-positions, such as 6-O-pentyl monoglyceryl ascorbate, 5-O-pentyl monoglyceryl ascorbate, 5,6-O-dipentyl monoglyceryl ascorbate, 6-O-glyceryl monopentyl ascorbate, 5-O-glyceryl monopentyl ascorbate, and 5,6-O-diglyceryl monopentyl ascorbate. Because standard products cannot be produced, qualitative analysis by HPLC is impossible, and individual identification is not possible; however, it is possible to integrate the areas of these impurity peaks. Therefore, it is possible to measure the peak area of ​​2-O-pentyl-3-O-glyceryl ascorbic acid and the peak area of ​​peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid by automatic integration, and it is also possible to calculate the ratio of the peak area other than 2-O-pentyl-3-O-glyceryl ascorbic acid to the total peak area.

[0042] In the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention, the peak area of ​​peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid is preferably less than 5% of the total peak area, more preferably less than 3%, and most preferably less than 1%, from the viewpoint of further suppressing the generation of free radicals.

[0043] These impurity ascorbic acid derivatives have free 2- and / or 3-positions of ascorbic acid. Therefore, when reacted under acidic conditions, they are more easily decomposed into water-soluble ascorbic acid than the target product, 2-O-pentyl-3-O-glyceryl ascorbic acid, in which both positions are blocked by chemical modification. Furthermore, some of the resulting ascorbic acid is decomposed into smaller water-soluble substances, such as ketogulonic acid. In other words, reactions under acidic conditions can selectively decompose impurities into smaller water-soluble molecules. This allows for easier purification of the target product, high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid, in the final purification step, such as separation by silica gel chromatography, and also contributes to further increasing its purity.

[0044] The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention can be used in external compositions such as cosmetics, and by blending it into the external composition of the present invention, this external composition can further contain any ingredients commonly used in cosmetics depending on its intended use, as long as the ingredients do not impair its stability.

[0045] Examples of ingredients commonly used in cosmetics include oily ingredients, polymeric compounds such as surfactants, emulsifiers, and thickeners, whitening agents, texture improvers, pharmaceuticals, ultraviolet absorbers, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, antioxidants, sequestering agents, pH adjusters, preservatives, moisturizers, pigments, colorants, and fragrances, and these can be blended as appropriate.

[0046] Examples of oily components, polymeric compounds such as surfactants, emulsifiers, and thickeners, whitening agents, texture improvers, drugs, ultraviolet absorbers, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, antioxidants, sequestering agents, pH adjusters, preservatives, moisturizers, pigments, colorants, and fragrances include those similar to those described in WO2022 / 080287, and these can be used alone or in combination of two or more.

[0047] Typical stability tests for cosmetics require minimal changes in color, odor, viscosity, and other problematic aspects during accelerated testing at long-term, high-temperature conditions of 40°C ± 2°C and 75% RH ± 5% RH for six months. However, conventional ascorbic acid and its derivatives have not adequately resolved this issue, making its solution a major challenge. The topical composition of the present invention, which contains the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention and suppresses the generation of ascorbic acid radicals, can solve this problem.

[0048] Furthermore, viscosity changes over time have often been a problem with conventional topical compositions. Because viscosity changes over time significantly impair product value, antioxidants such as ascorbic acid and its derivatives, tocopherol, dibutylhydroxytoluene (BHT), and butylhydroxyanisole (BHA) have been added. However, conventional ascorbic acid and its derivatives generate ascorbic acid radicals, which make it difficult to adequately suppress viscosity changes over time. Furthermore, tocopherol and its derivatives, BHT, BHA, and other compounds generate pro-oxidants, which also make these compounds ineffective.

[0049] On the other hand, by containing the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention, the generation of ascorbic acid radicals is suppressed and furthermore, pro-oxidants are not generated, so that the viscosity change over time, which was a conventional problem, can be suppressed and the product life can be extended.

[0050] The topical composition of the present invention may be formulated in any system, including a solution system, solubilized system, emulsion system, gel system, powder dispersion system, or water-oil two-phase system, and can be manufactured by blending high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid with the above-mentioned optional ingredients according to the desired product. [Example]

[0051] The present invention will be specifically described with reference to examples, but the scope of the present invention is not limited to these examples.

[0052] Example 1: Synthesis of high purity 2-O-pentyl-3-O-glyceryl ascorbate Under an argon atmosphere, 5,6-isopropylidene ascorbic acid (100.0 g) and potassium carbonate (95.9 g: 1.5 equivalents relative to 5,6-isopropylidene ascorbic acid) were added to 100 mL of DMSO and stirred at room temperature for 30 minutes. Pentyl bromide (76.9 g: 1.1 equivalents relative to 5,6-isopropylidene ascorbic acid) was then added. The mixture was heated to 50°C and stirred for 24 hours, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 5000 mL of methanol and 1000 mL of hydrochloric acid were added to the resulting residue and stirred at room temperature for 24 hours. The pH was adjusted to 3 or higher with aqueous sodium hydroxide, and the mixture was concentrated under reduced pressure. The resulting residue (120.8 g) was subjected to silica gel column chromatography. The mixture was eluted with a chloroform / methanol = 8 / 2 mixture and concentrated under reduced pressure to obtain 2-O-pentyl ascorbic acid (63.5 g). Further, under an argon atmosphere, 150 mL of DMSO was added to 2-O-pentylascorbic acid (63.5 g) and stirred. Sodium hydroxide (2.0 g: 0.2 equivalents relative to 2-O-pentylascorbic acid) and glycidol (22.9 g: 1.2 equivalents relative to 2-O-pentylascorbic acid) were added, the mixture was heated to 80°C, stirred for 18 hours, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 80.3 g of the resulting concentrate was divided into two, concentrate α and concentrate β, and concentrate β was used in the production of Comparative Example 1. To the concentrate α, 600 mL of 10% aqueous sulfuric acid solution was added, and the mixture was stirred under reflux for 2 hours, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The mixture was eluted with a mixture of chloroform / methanol / water (20 / 3 / 0.4) and concentrated under reduced pressure to obtain product α (9.3 g).

[0053] The obtained product α was analyzed by HPLC. 1 H-NMR, 13 The results of C-NMR and IR (infrared absorption spectroscopy) measurements are shown in Examples 2 and 3. As a result, it was confirmed that product α was the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention.

[0054] Comparative Example 1: The concentrate β obtained during the production process in Example 1 was subjected to silica gel chromatography. Elution was performed with a mixture of chloroform / methanol / water (20 / 3 / 0.4), followed by concentration under reduced pressure to obtain product β (7.3 g).

[0055] Comparative Example 2: Conventional synthesis of high-purity 2-O-glyceryl-3-O-octyl ascorbic acid Based on Example 1 of Patent Document 1, high-purity 2-O-glyceryl-3-O-octylascorbic acid (11.3 g) defined in Patent Document 1 was obtained.

[0056] Example 2: HPLC analysis 0.6 g (precisely weighed value WA1) of the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid (product α) produced in Example 1 and 1.0 g (precisely weighed value WM1) of maleic acid as an internal standard were accurately weighed and dissolved in water to make 200 mL. This was used as a test solution and measured by HPLC under the operating conditions below, and the peak area (SA1) of the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid and the peak area (SM1) of maleic acid were calculated. In addition, the same procedure was performed in advance using 0.6 g (precisely weighed value WA2) of a standard sample of 2-O-pentyl-3-O-glyceryl ascorbic acid and 1.0 g (precisely weighed value WM2) of maleic acid, and the respective peak areas SA2 and SM2 were calculated. The content (composition ratio) of 2-O-pentyl-3-O-glyceryl ascorbic acid in product α was calculated using the following formula, and the same procedure was performed 10 times to obtain the average value. Furthermore, using the same method as above, the product β (Comparative Product 1) produced in Comparative Example 1, the high-purity 2-O-glyceryl-3-O-octyl ascorbic acid (Comparative Product 2) produced in Comparative Example 2, and the impurities ascorbic acid, monopentyl ascorbic acid, and monooctyl ascorbic acid were also quantified, and the results are summarized in Table 1.

[0057] Quantitative value (wt%) = (SA1 / WA1) x (WM1 / SM1) x (WA2 / WM2) x (SM2 / SA2) x 100

[0058] Operating conditions: A polyhydroxymethacrylate resin-packed column, Shodex SB-802 HQ (manufactured by Resonac), was used; detection wavelength: 265 nm; eluent: 0.03 mol / l potassium dihydrogen phosphate solution (adjusted to pH 6 with dipotassium hydrogen phosphate solution); column temperature: 65°C; flow rate: 1.2 ml / min

[0059] (Creating standard products) 30 g of the product prepared as described in Comparative Example 1 was fractionated by HPLC. The operating conditions were as follows. 1 The fraction corresponding to 2-O-pentyl-3-O-glyceryl ascorbic acid was identified by H-NMR measurement, and the fraction was concentrated under reduced pressure to obtain a standard sample of 2-O-pentyl-3-O-glyceryl ascorbic acid.

[0060] Operating conditions: Shim-pack Scepter C18-120 / 5 μm column manufactured by Shimadzu GLC Corporation was used, detection wavelength: 240 nm, eluent: methanol: 0.1% formic acid aqueous solution = 4:6, column temperature: 30°C, flow rate: 5 ml / min

[0061] The monopentyl ascorbic acid standard was prepared in the same manner as the 2-O-pentyl-3-O-glyceryl ascorbic acid standard described above, using 2-O-pentyl ascorbic acid obtained in the production process of 2-O-pentyl-3-O-glyceryl ascorbic acid in Example 1.

[0062] The standard ascorbic acid used was ascorbic acid from the Japanese Pharmacopoeia.

[0063] Furthermore, based on the method described in Patent Document 1, standard preparations of 2-O-glyceryl-3-O-octylascorbic acid and monooctylascorbic acid were prepared by carrying out the same procedures as above using commercially available 2-O-glyceryl-3-O-octylascorbic acid (GO-VC 10W, manufactured by Seiwa Kasei Co., Ltd.) and 3-O-octylascorbic acid obtained in the production process of 2-O-glyceryl-3-O-octylascorbic acid.

[0064] [Table 1]

[0065] The results in Table 1 indicate that Comparative Product 1 (Product β) contained 3.8 mass% of monopentyl ascorbic acid and ascorbic acid, and was 2-O-pentyl-3-O-glyceryl ascorbic acid. Furthermore, the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention has a reduced content of monopentyl ascorbic acid and ascorbic acid contained as impurities compared to the pure 2-O-pentyl-3-O-glyceryl ascorbic acid produced in Comparative Example 1, and it has also been shown that the content is reduced to the same extent as that of high-purity glyceryl octyl ascorbic acid, a conventional high-purity ascorbic acid derivative.

[0066] (HPLC analysis conditions using the area method) 0.01 g of each of the ascorbic acid derivatives of the present invention and comparative products 1 and 2 was dissolved in 100 mL of purified water to prepare a test solution. Using a polyhydroxymethacrylate resin-packed column, 10 μL of each test solution was measured under the following conditions: detection wavelength: 265 nm, eluent: 0.03 mol / L dipotassium hydrogen phosphate solution, column temperature: 65°C, and flow rate: 1.2 mL / min. The peak area A of 2-O-pentyl-3-O-glyceryl ascorbic acid or 2-O-glyceryl-3-O-octyl ascorbic acid The peak areas B of the compounds other than 2-O-pentyl-3-O-glyceryl ascorbic acid and 2-O-glyceryl-3-O-octyl ascorbic acid were measured by automatic integration, and the average values ​​are shown in Table 2.

[0067] [Table 2]

[0068] As can be seen from the results in Table 2, the peak areas of all the components other than 2-O-pentyl-3-O-glyceryl ascorbic acid were 5% or more in Comparative Product 1, whereas the peak areas of the high-purity ascorbic acid derivatives of the present invention and Comparative Product 2 were very small and almost undetectable. These results clearly show that the ascorbic acid derivatives of the present invention and comparative product 2 are highly pure ascorbic acid derivatives with extremely reduced content of ascorbic acid or its derivatives with free 2- and / or 3-positions, and are ascorbic acid derivatives that are less likely to become pro-oxidants.

[0069] Example 3: IR and NMR analysis results The IR analysis results of the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention were as follows: Measurement was performed using an IR Prestige 21 (manufactured by Shimadzu Corporation) by the ATR method.

[0070] ATR: 3500-3250cm -1 , 2930cm -1 , 2870cm-1 , 1750cm -1 , 1670cm -1 , 1325cm -1 , 1165cm -1 , 1115cm -1 , 1035cm -1

[0071] The NMR (nuclear magnetic resonance) analysis results of the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention were as follows: A 400 MHz NMR ECZL400S (manufactured by JEOL Ltd.) was used for the measurement.

[0072] 1 H-NMR (400 MHz, CD3OD) δ ppm 0.91(3H, t), 1.33-1.41(4H, m), 1.69(2H, tt), 3.58(2H, d), 3.62-3.65(2H, m), 3.86-3. 92(2H, m), 3.97-4.02(2H, m), 4.43-4.48(1H, m), 4.54-4.59(1H, dd), 4.84-4.85(1H, m)

[0073] 13 C-NMR (100 MHz, CD3OD) δ ppm 14.4, 23.5, 29.1, 30.5, 63.2, 63.6, 70.5, 71.6, 74.0, 74.1, 76.7, 123.3, 159.3, 172.3

[0074] Example 4: Test of changes in color and odor over time Pure 2-O-pentyl-3-O-glyceryl ascorbic acid (Comparative Sample 1), conventional high-purity 2-O-glyceryl-3-O-octyl ascorbic acid (Comparative Sample 2), sodium ascorbyl 2-phosphate (Comparative Sample 3), trisodium ascorbyl palmitate phosphate (Comparative Sample 4), a standard ascorbic acid from the Japanese Pharmacopoeia (Comparative Sample 5), and the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention (Invention Product) were each dissolved at a concentration of 10 mmol in a solution of sodium chloride (137 mmol), potassium chloride (2.7 mmol), disodium hydrogen phosphate (10 mmol), and potassium dihydrogen phosphate (1.7 mmol) in purified water. Each solution was placed in a 20 mL screw bottle and stored at 40°C ± 2°C and 75% ± 5% RH for 6 months. After storage, the color and odor changes were measured using the following measurement methods.

[0075] To measure color change, a 20 mL screw bottle was photographed with a digital camera under uniform lighting with a white screen in the background, and the image was automatically processed by a computer to calculate the L value, which is the brightness of the center of the screw bottle. Since the L value is an index of brightness, it decreases as the color of the solution turns brown. The brightness after 6 months was calculated, with the initial brightness set to 100%, and the results are summarized in Table 3.

[0076] The odor was evaluated by 10 panelists using a sensory evaluation system and scored on a 5-point scale based on the following criteria. No odor: 4 points, faint odor: 3 points, slight odor: 2 points, moderate odor: 1 point, severe odor: 0 points. The results were calculated by adding up the scores of 10 people, with the starting score being 100% and the condition after 6 months is summarized in Table 3.

[0077] [Table 3]

[0078] The results in Table 3 show that the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention dramatically improves color and odor changes compared to ascorbic acid (Comparative Product 5) and conventional ascorbic acid derivatives, such as sodium ascorbyl 2-phosphate (Comparative Product 3) and trisodium ascorbyl palmitate phosphate (Comparative Product 4). Furthermore, a clear improvement was confirmed compared to the conventional pure 2-O-pentyl-3-O-glyceryl ascorbic acid (Comparative Product 1), and an improvement was also observed compared to the conventional high-purity 2-O-glyceryl-3-O-octyl ascorbic acid (Comparative Product 2).

[0079] Example 5: Test for improving feel when applied Ascorbic acid from the Japanese Pharmacopoeia as a standard product, conventional high-purity 2-O-glyceryl-3-O-octyl ascorbic acid (Comparative Product 2), and high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention (Product of the present invention) were each diluted with purified water to a concentration of 3% of the essential components. Each sample was subjected to a sensory evaluation by 10 panelists regarding the ease of application to the skin, ease of spread, lack of squeaking, and tingling sensation. The results are summarized in Table 4.

[0080] The evaluation was based on the following criteria, with the result of the standard ascorbic acid being the standard (0 points), and the comparative product 2 and the product of the present invention being evaluated on a 5-point scale. The results are shown as the total points of the 10 panelists, with higher points indicating better results.

[0081] [Evaluation criteria] 2 points: Much better than standard 1 point: Better than standard 0 points: same as standard product -1 point: slightly worse than standard product - 2 points: Worse than standard product

[0082] [Table 4]

[0083] The results in Table 4 show that the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention received favorable ratings in all categories, including ease of application, ease of spreading, lack of squeaking, and stinging sensation, compared to standard ascorbic acid. Furthermore, a clear improvement was confirmed compared to high-purity 2-O-glyceryl-3-O-octyl ascorbic acid (Comparative Product 2), a conventional ascorbic acid derivative.

[0084] Examples of formulations incorporating the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention are shown below, but the scope of the present invention is not limited to these formulation examples.

[0085] Example 6: Gel High purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention: 1.0%, glycerin: 1.5%, polyacrylate crosspolymer-6: 2.0%, phenoxyethanol: 0.3%, purified water: balance.

[0086] Example 7: Gel Cream High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention: 1.0%, (hydroxyethyl acrylate / sodium acryloyldimethyl taurate) copolymer: 0.35%, squalane: 5.0%, 1,3-butylene glycol: 5.0%, phenoxyethanol: 0.5%, (acrylates / C10-30 alkyl acrylate) crosspolymer: 0.5%, glycerin: 1.5%, potassium hydroxide: appropriate amount, pH adjuster: appropriate amount, purified water: balance.

[0087] Example 8: Emulsion composition High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid of the present invention: 1.0%, glyceryl stearate: 2.5%, PEG-40 stearate: 1.5%, cetearyl alcohol: 4.0%, olive squalane: 8.0%, dimethicone: 2.0%, sodium stearoyl methyl taurate: 1.0%, 1,3-butylene glycol: 5.0%, glycerin: 1.5%, pH adjuster: 0.1%, phenoxyethanol: 0.45%, ethylhexylglycerin: 0.05%, purified water: balance.

Claims

1. High-purity 2-O-pentyl-3-O-glyceryl ascorbic acid, characterized in that the total content of either monopentyl ascorbic acid or monoglyceryl ascorbic acid and the total content of ascorbic acid is less than 3 mass% based on the total amount of 2-O-pentyl-3-O-glyceryl ascorbic acid and the total contents of monopentyl ascorbic acid, monoglyceryl ascorbic acid, ascorbic acid, and other impurities.

2. The high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid according to claim 1, wherein when the peak area of ​​2-O-pentyl-3-O-glyceryl ascorbic acid and the peak areas of peaks other than 2-O-pentyl-3-O-glyceryl ascorbic acid are measured by an automatic integration method for liquid chromatograms, the peak area other than 2-O-pentyl-3-O-glyceryl ascorbic acid accounts for less than 5% of the total peak area.

3. A composition for external use, comprising the high-purity 2-O-pentyl-3-O-glyceryl ascorbic acid according to claim 1 or 2.

4. 4. The composition for external use according to claim 3, which is a cosmetic.

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