A ceramide containing an omega-hydroxy fatty acid structure and a method for preparing the same

Abstract

The present application relates to the technical field of cosmetics, in particular to a ceramide containing omega-hydroxy fatty acid structure and a preparation method thereof, wherein omega-hydroxy fatty acid, a lower alcohol and concentrated sulfuric acid are mixed, esterification is carried out to obtain omega-hydroxy fatty acid ester; the omega-hydroxy fatty acid ester, a long-chain base and a reaction solvent are mixed, and an amine exchange reaction is carried out under alkaline conditions to obtain the ceramide containing omega-hydroxy fatty acid structure. The omega-hydroxy fatty acid raw material used in the present application is easy to obtain and has a low cost, and the ceramide prepared therefrom has excellent quality and low safety risk.

Description

Technical Field

[0001] This invention relates to the field of cosmetic technology, and in particular to a ceramide containing an ω-hydroxy fatty acid structure and its preparation method. Background Technology

[0002] Ceramides are the most abundant lipid component in the intercellular lipids of the stratum corneum of human skin, accounting for 40% to 50%. In the classic "brick wall model" of the skin barrier, ceramides act as "cement" filling the spaces between keratinocytes, forming a dense lipid bilayer structure in synergy with cholesterol and free fatty acids. This effectively prevents moisture evaporation from the skin and resists the invasion of external irritants and pathogens. In addition to its physical barrier function, ceramides also participate in regulating the proliferation, differentiation, and apoptosis of keratinocytes, playing an irreplaceable role in maintaining epidermal homeostasis and skin health. Furthermore, ceramides form the hydrophobic framework of sphingolipids, which are one of the main lipid components of cell membranes. Therefore, ceramides are important bioactive substances that play a vital and irreplaceable role in maintaining and regulating human skin function and normal metabolism.

[0003] From a chemical structure perspective, ceramides are lipid compounds composed of long-chain bases (LCBs) linked to fatty acids (FAs) via amide bonds. Common long-chain bases include phytosphingosine (P), dihydrosphingosine (DS), sphingosine (S), and 6-hydroxysphingosine (H). Based on the substitution position of the hydroxyl groups on the fatty acid chain, fatty acids can be classified into non-hydroxy fatty acids (N), α-hydroxy fatty acids (A), and ω-hydroxy fatty acids (O). The hydroxyl group at the end of ω-hydroxy fatty acids can further undergo esterification with another fatty acid molecule, thereby forming esterified ω-hydroxy fatty acids (EO). Various ceramides can be obtained by combining long-chain bases with different structures and the aforementioned fatty acids (including N, A, O, and EO). They are named according to the codes of the long-chain bases and fatty acids, such as ceramide NP (N+P), NS (N+S), AP (A+P), AS (A+S), EOP (EO+P), and EOS (EO+S). Currently, ceramides containing non-hydroxy or α-hydroxy fatty acids (such as NP and AP) and ceramides containing esterified ω-hydroxy fatty acids (such as EOP and EOS) are widely used in the cosmetics industry.

[0004] Omega-hydroxy fatty acids are a special class of fatty acids with free hydroxyl groups at the ends of their carbon chains. They possess the dual chemical properties of alcohols and carboxylic acids and play important roles in human physiological metabolism. On the one hand, they can participate in the synthesis of very long-chain fatty acid derivatives, playing a role in cell signaling, lipid metabolism, and membrane stability. On the other hand, they act as intermediate products of fatty acid ω-oxidation in tissues such as the liver, participating in metabolic regulation. Ceramides derived from ω-hydroxy fatty acids not only exhibit the moisturizing and water-locking effects of most ceramides but also exert certain physiological metabolic regulatory effects, showing significant research and application potential. However, ceramides containing unesterified ω-hydroxy fatty acids (i.e., with free terminal hydroxyl groups and no esterification modification), although also naturally present in the skin barrier structure, have not yet been widely used in the cosmetics industry. Structurally, their terminal hydroxyl groups can bind to water molecules through hydrogen bonds, theoretically endowing these ceramides with stronger hydrophilicity and water-retention capacity, while retaining the barrier repair function determined by their amide bonds. Based on these characteristics, ceramides containing ω-hydroxy fatty acid structures have potential advantages in improving skin hydration, enhancing moisturizing effects, and optimizing formula compatibility.

[0005] However, in existing technologies, ceramides containing ω-hydroxy fatty acid structures face numerous limitations in practical applications. From a natural perspective, these ceramides are mostly ultra-long-chain structures, with their fatty acid portions typically containing around C28 to C36 carbon atoms. These ultra-long-chain ω-hydroxy fatty acids are extremely rare in nature, and their preparation through chemical synthesis is difficult and costly, resulting in significant challenges in sourcing raw materials. Furthermore, commercially available products containing ω-hydroxy fatty acid structures are currently scarce, and no publicly reported preparation methods suitable for industrial-scale production have been found. This dual lack of readily available raw materials and advanced preparation processes makes it difficult for these ceramides to be used in cosmetic formulations as readily as other types of ceramides.

[0006] Therefore, how to provide a ceramide containing an ω-hydroxy fatty acid structure that is suitable for industrial production and even more suitable for downstream formulation development has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a ceramide containing an ω-hydroxy fatty acid structure and its preparation method, so as to solve the problem that there is a lack of ceramides containing an ω-hydroxy fatty acid structure in the prior art that are both suitable for industrial production and easy for downstream formulation development.

[0008] To achieve the above and other related objectives, the present invention is obtained through the following technical solution.

[0009] A first aspect of the present invention is to provide a ceramide containing an ω-hydroxy fatty acid structure, the structure of which is shown in Formula 1:

[0010]

[0011] Formula 1

[0012] Where n is 5-19;

[0013] X is selected from , , or Any one of them.

[0014] A second aspect of the present invention provides a method for preparing a ceramide containing an ω-hydroxy fatty acid structure, the method comprising the following steps:

[0015] (1) Mix ω-hydroxy fatty acid, lower alcohol and concentrated sulfuric acid, and esterify to obtain ω-hydroxy fatty acid ester;

[0016] (2) The ω-hydroxy fatty acid ester, long-chain base and reaction solvent are mixed and subjected to urethane exchange reaction under alkaline conditions to obtain ceramide containing ω-hydroxy fatty acid structure.

[0017] A third aspect of the present invention is to provide a cosmetic comprising the ceramide containing an ω-hydroxy fatty acid structure as described above, and / or the ceramide containing an ω-hydroxy fatty acid structure prepared by the preparation method described above.

[0018] A fourth aspect of the present invention is to provide a ceramide containing an ω-hydroxy fatty acid structure prepared by the preparation method described above, and / or the use of the ceramide containing an ω-hydroxy fatty acid structure described above in the preparation of cosmetics.

[0019] As described above, the ceramide containing an ω-hydroxy fatty acid structure and its preparation method of the present invention have the following beneficial effects:

[0020] 1. This application provides a ceramide containing an ω-hydroxy fatty acid structure, wherein the ω-hydroxy fatty acid is a medium- to long-chain structure. Compared with the problems of difficult raw material sourcing, lack of preparation methods, and difficulty in large-scale production that are common in existing ceramides, the medium- to long-chain ω-hydroxy fatty acid raw materials used in this application are widely available and cost-controllable. The ceramide prepared from it retains the barrier repair function conferred by the amide bond, while having good hydrophilicity and moisturizing properties due to the presence of terminal hydroxyl groups. Moreover, the molecular chain length is moderate, and the solubility and compatibility with other cosmetic components are significantly improved, which is more conducive to downstream formulation development.

[0021] 2. This application also provides a method for preparing the ceramide. This method is simple to operate, has mild reaction conditions, produces high-purity products, and avoids the shortcomings of the prior art in preparing this type of ceramide, which is complex and difficult to scale up, making it suitable for industrial production.

[0022] 3. The ceramides in this invention enrich the types of ceramides, providing downstream customers with more options for developing ceramide raw material formulations, and can further broaden the market for ceramide applications. Detailed Implementation

[0023] To make the inventive objectives, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to embodiments. Those skilled in the art can easily understand other advantages and effects of this invention from the content disclosed in this specification.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] When using “including,” “having,” and “contains” as described herein, the intention is to cover non-exclusive inclusion, unless an explicit qualifying term such as “only,” “consisting of,” etc., is used, in which case another component may be added.

[0026] In this invention, the terms "preferredly," "more preferably," "better," and "even better" refer to embodiments of the invention that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of the invention. That is, in this invention, "preferredly," "more preferably," "better," and "even better" are merely descriptions of more effective implementations or examples, but do not constitute a limitation on the scope of protection of the invention.

[0027] In this invention, terms such as "further," "even more," and "particularly" are used for descriptive purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this invention.

[0028] In this invention, "at least one" means one or more, such as one, two, or more. "Multiple" or "several" means at least two, such as two, three, etc., and "multi-layered" means at least two layers, such as two layers, three layers, etc., unless otherwise explicitly specified. In the description of this invention, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.

[0029] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0030] Unless otherwise specified, all steps of this invention may be performed sequentially or randomly. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0031] Unless otherwise stated, a singular term may include a plural term and should not be understood as having a quantity of one.

[0032] In this invention, "above" or "below" both include the number itself. For example, "below 1" includes 1.

[0033] In this invention, room temperature refers to 0~40°C, including but not limited to 10~40°C, or further to 20~30°C.

[0034] In this invention, ω-hydroxy fatty acids are fatty acids with a hydroxyl group at the end of the fatty acid (HOCH2(CH2)nCOOH).

[0035] In this invention, TLC monitoring is well known in the art and can be operated using methods known in the art.

[0036] The ceramide containing an ω-hydroxy fatty acid structure provided in this application uses readily available medium- to long-chain ω-hydroxy fatty acids as starting materials. It is prepared through esterification followed by aminotransfer reaction with long-chain bases. Unlike existing ceramides where the raw materials are difficult to obtain and thus cannot be widely applied, the ω-hydroxy fatty acids used in this application (such as 10-hydroxydecanoic acid or 15-hydroxypentadecanoic acid) can be prepared from natural oils through controlled chemical reaction steps. Specifically, 10-hydroxydecanoic acid can be obtained from natural castor oil through cracking and hydrolysis, and 15-hydroxypentadecanoic acid can be obtained from natural garlic fruit oil through oxidation. The above raw material routes, starting with renewable natural oils, are in line with the green and sustainable development strategy advocated by the state and industry.

[0037] Regarding the preparation method, the reaction route described in this application exhibits excellent reaction selectivity, effectively avoiding the formation of byproducts commonly found in traditional amidation reactions, thereby precisely controlling the purity and quality of the target ceramide. This characteristic significantly reduces the potential safety risks posed by impurities in the product, making the obtained ceramide more suitable for the high standards required in the cosmetics industry. Simultaneously, this preparation method is simple to operate, operates under mild conditions, and is easily scaled up industrially. The amine-ester exchange amidation reaction used in this application has significantly higher reaction specificity compared to conventional amidation methods (such as the carbodiimide condensing agent method, the mixed acid anhydride method, and the organophosphorus condensing agent method). This feature effectively avoids esterification side reactions of the hydroxyl groups on long-chain bases, thereby precisely controlling the purity of the ceramide product and improving its quality stability and safety in subsequent cosmetic formulations. Taking the reaction of 15-hydroxypentadecanoic acid with phytosphoin as an example, the reaction formula is as follows: .

[0038] When using the conventional condensation agent method described above for amidation, the esterification of plant sphingosine hydroxyl groups inevitably occurs as a byproduct; however, the amino-ester exchange method of the present invention can avoid the generation of such impurities from a mechanistic perspective.

[0039] In summary, this application solves the problems of difficulty in obtaining and uncontrollable quality of this type of ceramide in the prior art by optimizing the design of raw material sources and effectively controlling reaction selectivity, and provides a new type of ceramide raw material that is reliable, safe and compliant for cosmetic formulations.

[0040] This invention relates to a ceramide containing an ω-hydroxy fatty acid structure. Existing ceramides typically use ultra-long-chain ω-hydroxy fatty acids (e.g., C24 or higher), but these raw materials are limited in source, expensive, and commercially insufficient. Therefore, this invention selects medium- to long-chain ω-hydroxy fatty acids with 8 to 22 carbon atoms as the raw material, which is more widely available, commercially sufficient, and inexpensive.

[0041] After determining the raw materials, a suitable method for constructing the amide bond needs to be selected. This invention uses an aminotransfer reaction to synthesize ceramides, that is, through a nucleophilic substitution reaction between an ester and ammonia or an amine to generate an amide and an alcohol. This method does not require pre-activation of the carboxylic acid and has advantages such as high atom economy and few byproducts. In the aminotransfer reaction, an alkaline catalyst (such as sodium methoxide, sodium ethoxide, sodium hydroxide, or potassium hydroxide) needs to be added to lower the activation energy of the reaction by deprotonating ammonia, thereby accelerating the reaction.

[0042] However, using a strong base catalyst presents a problem: residual strong base may affect the safety and efficacy of the ceramide product in subsequent formulations. Therefore, this invention makes a key adjustment in the post-processing—using a weak acid to quench and neutralize the strong base catalyst in the reaction solution, and controlling the pH of the reaction solution to neutral (6-8), thereby effectively avoiding strong base residue and ensuring the quality of the finished product.

[0043] Furthermore, this invention simplifies the post-processing steps. The quenched reaction solution is directly replenished with a lower alcohol, and crystallization simultaneously removes the salts generated by the neutralization of the strong base, unreacted ω-hydroxy fatty acids, and any remaining traces of long-chain base materials. High-purity ceramides can be obtained simply through crystallization, pulping, and drying, eliminating the need for complex separation steps and making it more suitable for industrial-scale production. The selection of this post-crystallization post-processing method is based on a systematic consideration of the strong base quenching products, achieving an integrated operation of impurity removal and purification.

[0044] A first aspect of the present invention is to provide a ceramide containing an ω-hydroxy fatty acid structure, the structure of which is shown in Formula 1:

[0045]

[0046] Formula 1

[0047] Where n is 5-19;

[0048] X is selected from , , or Any one of them.

[0049] The structure of the ceramide is selected from any one of Formula 2, Formula 3, Formula 4, and Formula 5, and the structural formulas of Formula 2, Formula 3, Formula 4, and Formula 5 are shown below:

[0050] .

[0051] A second aspect of the present invention provides a method for preparing a ceramide containing an ω-hydroxy fatty acid structure, the method comprising the following steps:

[0052] (1) Mix ω-hydroxy fatty acid, lower alcohol and concentrated sulfuric acid, and esterify to obtain ω-hydroxy fatty acid ester;

[0053] (2) The ω-hydroxy fatty acid ester, long-chain base and reaction solvent are mixed and subjected to urethane exchange reaction under alkaline conditions to obtain ceramide containing ω-hydroxy fatty acid structure.

[0054] The reaction formula is as follows:

[0055] .

[0056] To address the practical limitations of existing ceramides containing ω-hydroxy fatty acid structures due to the scarcity of raw materials, this invention selects readily available medium- to long-chain ω-hydroxy fatty acids as starting materials, thus overcoming the bottleneck of raw material acquisition. Simultaneously, to resolve the issues of side reactions such as long-chain base hydroxyl esterification that easily occur in conventional amidation reactions (e.g., carbodiimide condensation methods, mixed anhydride methods, organophosphorus condensation methods, etc.), leading to low product purity and high safety risks, this invention first esterifies the ω-hydroxy fatty acid and then constructs an amide bond through an aminotransfer reaction under alkaline conditions. This reaction route is highly specific, mechanistically avoiding the generation of over-reaction impurities, effectively improving the quality of the target product and the safety of subsequent cosmetic formulations. Furthermore, to overcome the problems of cumbersome, time-consuming, and unsuitable for industrial-scale production by traditional purification methods (e.g., liquid-liquid chromatography and column chromatography), this invention directly uses lower alcohols for crystallization after the reaction to obtain high-purity ceramides. The operation is simple, product quality is controllable, and no complex post-processing steps are required. Through the above technical solution, this invention achieves the efficient preparation of ceramides containing ω-hydroxy fatty acid structures using readily available raw materials, highly selective reactions, and a simple crystallization and purification process. The resulting product has high purity and good safety, and the process is suitable for industrial production, providing a new and reliable functional raw material for the cosmetics field.

[0057] In some embodiments of the present invention, in step (1), the ω-hydroxy fatty acid is a C8-C22 fatty acid; preferably, the ω-hydroxy fatty acid is selected from one or more of 8-hydroxyoctadecanoic acid, 9-hydroxynonadecanoic acid, 10-hydroxydecanoic acid, 11-hydroxyundecanoic acid, 12-hydroxydodecanoic acid, 13-hydroxytridecanoic acid, 15-hydroxypentadecanoic acid, 16-hydroxyhexadecanoic acid, 17-hydroxyheptadecanoic acid, 18-hydroxyoctadecanoic acid, 19-hydroxynonadecanoic acid, 20-hydroxyeicosanoic acid, 21-hydroxyeicosanoic acid, or 22-hydroxyeicosanoic acid.

[0058] In some embodiments of the present invention, in step (1), the lower alcohol is selected from one or more of ethanol, methanol, n-propanol or isopropanol;

[0059] In some embodiments of the present invention, in step (1), the weight ratio of the ω-hydroxy fatty acid to concentrated sulfuric acid is 1:0.05-0.2; for example, 1:0.05-0.10, 1:0.10-0.15, 1:0.15-0.20.

[0060] In some embodiments of the present invention, in step (1), the esterification temperature is 50-70°C, for example, 50-55°C, 55-60°C, 60-65°C, or 65-70°C; and the esterification time is 6-12h, for example, 6-8h, 8-10h, or 10-12h.

[0061] In some embodiments of the present invention, in step (1), the weight ratio of the ω-hydroxy fatty acid to the lower alcohol is 1:3-6. For example, it is 1:3-4, 1:4-5, or 1:5-6.

[0062] In some embodiments of the present invention, in step (1), the ω-hydroxy fatty acid ester is one or more of the following: C8-C22 ω-hydroxy fatty acid methyl ester, C8-C22 ω-hydroxy fatty acid ethyl ester, C8-C22 ω-hydroxy fatty acid n-propyl ester or C8-C22 ω-hydroxy fatty acid isopropyl ester.

[0063] In some embodiments of the present invention, in step (2), the long-chain base is selected from one or more of phytosphingosine, dihydrosphingosine, neurosphingosine, or 6-hydroxysphingosine; specifically as follows:

[0064]

[0065] Phytosphingosine dihydrosphingosine

[0066]

[0067] 6-Hydroxysphingosine

[0068] In some embodiments of the present invention, in step (2), the reaction solvent is isopropanol;

[0069] In some embodiments of the present invention, in step (2), after the urethane exchange reaction, quenching and crystallization are performed to obtain a ceramide containing an ω-hydroxy fatty acid structure; specifically:

[0070] In some embodiments of the present invention, the quenching step is carried out using an acid; preferably, the acid is selected from one or more of citric acid, formic acid, or glacial acetic acid; more preferably, the molar ratio of the long-chain base to the acid is 1:0.5-1.5; for example, 1:0.5-0.83, 1:0.83-1.17, or 1:1.17-1.5.

[0071] In some embodiments of the present invention, the quenching temperature is 40-50°C; for example, 40-43°C, 43-46°C, or 46-50°C.

[0072] In some embodiments of the present invention, the crystallization temperature is 0-20°C. For example, 0-5°C, 5-10°C, 10-15°C, or 15-20°C.

[0073] In some embodiments of the present invention, in step (2), the alkali used under alkaline conditions is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, or potassium hydroxide;

[0074] In some embodiments of the present invention, in step (2), the molar ratio of the long-chain base and the ω-hydroxy fatty acid ester is 1:1-2; for example, 1:1-1.33, 1:1.33-1.67, 1:1.67-2;

[0075] In some embodiments of the present invention, in step (2), the molar ratio of the long-chain base to the base used under alkaline conditions is 1:0.5-1.5; for example, 1:0.5-0.83, 1:0.83-1.17, 1:1.17-1.5;

[0076] In some embodiments of the present invention, in step (2), the weight ratio of the long-chain base to the reaction solvent is 1:2-10; for example, 1:2-4, 1:4-6, 1:6-8, 1:8-10;

[0077] In some embodiments of the present invention, in step (2), the reaction temperature is 30-70°C; for example, 30-40°C, 40-50°C, 50-60°C, or 60-70°C; and the reaction time is 3-9 hours; for example, 3-5 hours, 5-7 hours, or 7-9 hours.

[0078] A third aspect of the present invention is to provide a cosmetic comprising the ceramide containing an ω-hydroxy fatty acid structure as described above, and / or the ceramide containing an ω-hydroxy fatty acid structure prepared by the preparation method described above.

[0079] In some embodiments of the present invention, the cosmetics include at least daily chemical industrial products that are applied to any part of the human body surface (skin, hair, nails, lips, etc.) by rubbing, spraying or similar methods to achieve the purposes of cleaning, removing unpleasant odors, skin care, beautification and decoration. Specifically, they may include, but are not limited to, lotions and creams, such as hand cream, face cream, skin lotion, etc.

[0080] In some embodiments of the present invention, the cosmetic may further include other ingredients, such as thickeners, emulsifiers, preservatives, moisturizers (e.g., hyaluronic acid, sodium hyaluronate, propylene glycol, butylene glycol, panthenol, etc.), antioxidants (e.g., vitamin E, vitamin C), preservatives (e.g., parabens), active ingredients (e.g., retinol, nicotinamide), occlusive agents (e.g., petrolatum, lanolin, cetyl alcohol, mineral oil, siloxane derivatives, etc.), soothing agents (e.g., allantoin, urea, various plant extracts (e.g., asiaticoside, purslane, bisabolol, dipotassium glycyrrhizate), whitening ingredients (e.g., niacinamide, arbutin, vitamin C, phenylethyl resorcinol, tranexamic acid, glutathione, kojic acid, etc.), anti-aging ingredients (e.g., retinol), and acne-fighting ingredients (e.g., azelaic acid, salicylic acid, fruit acids, etc.). Those skilled in the art can select appropriate ingredients according to actual needs.

[0081] In some embodiments of the present invention, the cosmetic can be prepared by mixing the ceramide provided by the present invention with other ingredients in the cosmetic.

[0082] A fourth aspect of the present invention is to provide a ceramide containing an ω-hydroxy fatty acid structure prepared by the preparation method described above, and / or the use of the ceramide containing an ω-hydroxy fatty acid structure described above in the preparation of cosmetics.

[0083] The present invention will be further illustrated by the following examples, but these examples do not limit the scope of the invention.

[0084] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. All reagents or instruments whose manufacturers are not specified are conventional products that can be purchased commercially. In addition to the specific methods, equipment, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, equipment, and materials similar to or equivalent to those described, used, and materials in the embodiments of this invention may be used to implement this invention.

[0085] The CAS number of the plant sphingosine of this invention is 554-62-1; the manufacturer is Chongqing Zhihe Biomedical Co., Ltd.

[0086] The CAS number of the dihydrosphingosine of this invention is 764-22-7; the manufacturer is Chongqing Zhihe Biomedical Co., Ltd.

[0087] The CAS number of the sphingosine of this invention is 123-78-4; the manufacturer is Chongqing Zhihe Biomedical Co., Ltd.

[0088] The CAS number of the 6-hydroxysphingosine of this invention is 566203-07-4; the manufacturer is Chongqing Zhihe Biomedical Co., Ltd.

[0089] Example of preparation of ω-hydroxy fatty acid esters

[0090] Preparation Example 1 (Methyl 12-hydroxydodecanoate)

[0091]

[0092] This preparation example provides a method for preparing ω-hydroxy fatty acid esters, including the following steps:

[0093] 20.0 g of 12-hydroxydodecanoic acid (CAS: 505-95-3), 2.0 g of concentrated sulfuric acid, and 60.0 g of methanol were added to a reactor, and the mixture was heated to 45-48 °C and reacted for 10 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 10:1 + two drops of acetic acid) until completion. Methanol was removed by vacuum distillation at 50 °C. 100 g of tetrahydrofuran was added to the residue, dissolved, and washed twice with 100 g of 1% sodium bicarbonate each time. The residue was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure at 50 °C to obtain methyl 12-hydroxydodecanoate. No separation was performed in this step, and the yield was assumed to be 100%. The colorimetric reagent was 10% phosphomolybdic acid, and the colorimetric method was hot air gun heating. The monitored substance was 12-hydroxydodecanoic acid.

[0094] Preparation Example 2 (Ethyl 10-hydroxydecanoate)

[0095]

[0096] This preparation example provides a method for preparing ω-hydroxy fatty acid esters, which differs from Preparation Example 1 in that it includes the following steps:

[0097] 26.0 g of 10-hydroxydecanoic acid, 1.3 g of concentrated sulfuric acid, and 78.0 g of ethanol were added to a reactor, and the mixture was heated to 50-53 °C and reacted for 7 h. The reaction was monitored by TLC until completion (petroleum ether: ethyl acetate = 10:1 + two drops of acetic acid). Ethanol was removed by vacuum distillation at 55 °C. 80 g of tetrahydrofuran was added to the residue, and after dissolution, the residue was washed twice with 80 g of 1% sodium bicarbonate each time. The residue was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure at 55 °C to obtain ethyl 10-hydroxydecanoic acid. No separation was performed in this step, and the yield was assumed to be 100%.

[0098] Preparation Example 3 (Isopropyl 15-hydroxypentadecanoate)

[0099]

[0100] This preparation example provides a method for preparing ω-hydroxy fatty acid esters, which differs from Preparation Example 1 in that it includes the following steps:

[0101] 18.0 g of 15-hydroxypentadecanoic acid, 2.2 g of concentrated sulfuric acid, and 72.0 g of isopropanol were added to a reactor and the mixture was heated to 52-55 °C and reacted for 8 h. The reaction was monitored by TLC until completion (petroleum ether:ethyl acetate = 10:1 + two drops of acetic acid). Isopropanol was removed by vacuum distillation at 60 °C. Tetrahydrofuran (120 g) was added to the residue, dissolved, and washed twice with 1% sodium bicarbonate (120 g each time). The residue was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure at 60 °C to obtain isopropyl 15-hydroxypentadecanoate. No separation was performed in this step, and the yield was assumed to be 100%.

[0102] Ceramide Examples

[0103] Example 1 (Ceramide Formula 6)

[0104] This embodiment provides a method for preparing ω-hydroxy fatty acid esters, including the following steps:

[0105]

[0106] Phytosphingosine (10.0 g), isopropyl 15-hydroxypentadecanoate (11.4 g) prepared in Preparation Example 3, isopropanol (40.0 g), and sodium methoxide (2.0 g) were added to a reactor, and the mixture was heated to 55-58 °C and reacted for 4 h. The reaction of phytosphingosine (dichloromethane:methanol = 4:1 + 3 drops of ammonia) was monitored by TLC until completion. The mixture was then cooled to 44 °C, and glacial acetic acid (2.2 g) was added to quench the reaction. Methanol (60.0 g) was then added and stirred to induce crystallization. The mixture was cooled to 0-3 °C and allowed to crystallize for 1.5 h. The crystals were filtered, washed, and dried at 50-53 °C to obtain 13.3 g of the target product with a purity of 93.4% and a yield of 76.0%. The molecular formula is C0. 33 H 67 NO5, MS[M+H] + 558.61. Among them, the monitored object is phytosphingosine; the colorimetric agent is 10% phosphomolybdic acid, and the colorimetric method is hot air gun heating colorimetric development.

[0107] Example 2 (Ceramide Formula 7)

[0108]

[0109] This embodiment provides a method for preparing ceramide, which differs from Example 1 in that it includes the following steps:

[0110] Dihydrosphingosine (15.0 g), ethyl 10-hydroxydecanoate (11.0 g) prepared in Example 2, isopropanol (60.0 g), and sodium ethoxide (1.7 g) were added to a reactor, and the mixture was heated to 50-53 °C and reacted for 6 h. The reaction of dihydrosphingosine (dichloromethane:methanol = 4:1 + 3 drops of ammonia) was monitored by TLC until completion. The mixture was then cooled to 41 °C, and glacial acetic acid (1.7 g) was added to quench the reaction. Ethanol (40.0 g) was then added for crystallization, and the mixture was cooled to 2-5 °C for 2 h to allow crystallization. The crystals were filtered, washed, and dried at 50-60 °C to obtain 19.2 g of the target product with a purity of 95.4% and a yield of 82.0%. The molecular formula is C2. 28 H 57 NO4, MS[M+H] + 472.57.

[0111] Example 3 (Ceramide Formula 8)

[0112]

[0113] This embodiment provides a method for preparing ceramide, which differs from Example 1 in that it includes the following steps:

[0114] Sphingosine (12.0 g), methyl 12-hydroxydodecanoate (10.1 g) prepared in Preparation Example 1, isopropanol (35.0 g), and sodium methoxide (1.6 g) were added to a reactor, and the mixture was heated to 50-53 °C and reacted for 7 h. The reaction of sphingosine (dichloromethane:methanol = 8:1 + 3 drops of ammonia) was monitored by TLC until completion. The mixture was then cooled to 43 °C, and glacial acetic acid (1.8 g) was added to quench the reaction. Methanol (30.0 g) was then added for crystallization, and the mixture was cooled to 0-3 °C for 1.5 h to allow crystallization. The crystals were filtered, washed, and dried at 50-53 °C to obtain 16.9 g of the target product with a purity of 96.1% and a yield of 85.0%. The molecular formula is C0. 30 H 59 NO4, MS[M+H] + 498.36.

[0115] Example 4 (Ceramide Formula 9)

[0116]

[0117] This embodiment provides a method for preparing ceramide, which differs from Example 1 in that it includes the following steps:

[0118] 20.0 g of 6-hydroxysphingosine, 14.0 g of methyl 10-hydroxydecanoate prepared in Example 2, 50.0 g of isopropanol, and 1.8 g of potassium hydroxide were added to a reactor, and the mixture was heated to 52-55 °C and reacted for 8 h. The reaction of dihydrosphingosine was monitored by TLC until completion (dichloromethane:methanol = 4:1 + 3 drops of ammonia). The mixture was then cooled to 45 °C, and 2.0 g of glacial acetic acid was added to quench the reaction. Then, 40.0 g of methanol was added for crystallization, and the mixture was cooled to 2-5 °C for 2 h to allow crystallization. The crystals were filtered, washed, and dried at 57-60 °C to obtain 22.7 g of the target product with a purity of 94.7% and a yield of 74.0%. The molecular formula is C2. 28 H 55 NO5, MS[M+H] + 486.63.

[0119] Comparative Example

[0120] Comparative Example 1

[0121] This embodiment provides a method for preparing ceramide, which differs from Example 1 in that glacial acetic acid was not used for quenching, resulting in sodium methoxide residue in the finished product. Since sodium methoxide is a strong alkaline substance, even small or trace amounts of residue can affect subsequent research on formulations using this ceramide, directly impacting the pH value of the formulation and indirectly affecting its stability and even efficacy.

[0122] Phytosphingosine (10.0 g), isopropyl 15-hydroxypentadecanoate (12.6 g) prepared in Example 3, isopropanol (40.0 g), and sodium methoxide (2.0 g) were added to a reactor, and the mixture was heated to 55-58 °C and reacted for 5 h. The reaction of phytosphingosine (dichloromethane:methanol = 4:1 + 3 drops of ammonia) was monitored by TLC until completion. The mixture was then cooled to 31 °C, and methanol (60.0 g) was added and stirred to induce crystallization. The mixture was then cooled to 0-3 °C and allowed to crystallize for 1.5 h. The crystals were filtered, washed, and dried at 50-53 °C to obtain 14.5 g of the target product with a purity of 94.1%.

[0123] The target product in Comparative Example 1 was prepared into a 10% suspension, and its pH value was found to be greater than 8.5. The target product in Example 1, which was measured using the same method, had a pH value of 7.4.

[0124] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A ceramide containing an ω-hydroxy fatty acid structure, characterized in that, The structure of the ceramide is shown in Formula 1: Formula 1 Where n is 5-19; X is selected from , , or Any one of them.

2. The ceramide according to claim 1, characterized in that: The structure of the ceramide is selected from any one of Formula 2, Formula 3, Formula 4, and Formula 5, and the structural formulas of Formula 2, Formula 3, Formula 4, and Formula 5 are shown below: 。 3. A method for preparing a ceramide containing an ω-hydroxy fatty acid structure as described in any one of claims 1-2, characterized in that: The preparation method includes the following steps: (1) Mix ω-hydroxy fatty acid, lower alcohol and concentrated sulfuric acid, and esterify to obtain ω-hydroxy fatty acid ester; (2) The ω-hydroxy fatty acid ester, long-chain base and reaction solvent are mixed and subjected to urethane exchange reaction under alkaline conditions to obtain ceramide containing ω-hydroxy fatty acid structure.

4. The preparation method according to claim 3, characterized in that: It also includes one or more of the following features: 11) In step (1), the ω-hydroxy fatty acid is a C8-C22 fatty acid; 12) In step (1), the lower alcohol is selected from one or more of ethanol, methanol, n-propanol or isopropanol; 13) In step (1), the weight ratio of the ω-hydroxy fatty acid to concentrated sulfuric acid is 1:0.05-0.2; 14) In step (1), the esterification temperature is 50-70℃ and the esterification time is 6-12h; 15) In step (1), the weight ratio of the ω-hydroxy fatty acid to the lower alcohol is 1:3-6.

5. The preparation method according to claim 3, characterized in that: In feature 11), the ω-hydroxy fatty acid is selected from one or more of 8-hydroxyoctadecanoic acid, 9-hydroxynonadecanoic acid, 10-hydroxydecanoic acid, 11-hydroxyundecanoic acid, 12-hydroxydodecanoic acid, 13-hydroxytridecanoic acid, 15-hydroxypentadecanoic acid, 16-hydroxyhexadecanoic acid, 17-hydroxyheptadecanoic acid, 18-hydroxyoctadecanoic acid, 19-hydroxynonadecanoic acid, 20-hydroxyeicosanoic acid, 21-hydroxyeicosanoic acid, or 22-hydroxyeicosanoic acid.

6. The preparation method according to claim 3, characterized in that: It also includes one or more of the following features: 21) In step (2), the long-chain base is selected from one or more of phytosphingosine, dihydrosphingosine, neurosphingosine, or 6-hydroxysphingosine; 22) In step (2), the reaction solvent is isopropanol; 23) In step (2), after the urethane exchange reaction, quenching and crystallization are performed to obtain ceramide containing ω-hydroxy fatty acid structure; 24) In step (2), the alkali used under alkaline conditions is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, or potassium hydroxide; 25) In step (2), the molar ratio of the long-chain base and the ω-hydroxy fatty acid ester is 1:1-2; 26) In step (2), the molar ratio of the long-chain base to the base used under alkaline conditions is 1:0.5-1.5; 27) In step (2), the weight ratio of the long-chain base to the reaction solvent is 1:2-10; 28) In step (2), the reaction temperature is 30-70℃; the reaction time is 3-9h.

7. The preparation method according to claim 3, characterized in that: In step (1), the ω-hydroxy fatty acid ester is one or more of the following: C8-C22 ω-hydroxy fatty acid methyl ester, C8-C22 ω-hydroxy fatty acid ethyl ester, C8-C22 ω-hydroxy fatty acid n-propyl ester or C8-C22 ω-hydroxy fatty acid isopropyl ester.

8. The preparation method according to claim 7, characterized in that: It also includes one or more of the following features: 231) In feature 23), the quenching step is carried out using an acid; preferably, the acid is selected from one or more of citric acid, formic acid or glacial acetic acid; more preferably, the molar ratio of the long-chain base to the acid is 1:0.5-1.5; 232) In feature 23), the quenching temperature is 40-50℃; 233) In feature 23), the crystallization temperature is 0-20℃.

9. A cosmetic product, characterized in that: Includes ceramides containing an ω-hydroxy fatty acid structure as described in any one of claims 1-2, and / or ceramides containing an ω-hydroxy fatty acid structure prepared by the preparation method described in any one of claims 3-8.

10. The use of ceramides containing ω-hydroxy fatty acid structures prepared by the preparation method according to any one of claims 3-8, and / or the use of ceramides containing ω-hydroxy fatty acid structures according to claims 1-2 in the preparation of cosmetics.

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