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WO2023063466A1 - Procédé de préparation d'un composé de céramide - Google Patents

Procédé de préparation d'un composé de céramide Download PDF

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Publication number
WO2023063466A1
WO2023063466A1 PCT/KR2021/015416 KR2021015416W WO2023063466A1 WO 2023063466 A1 WO2023063466 A1 WO 2023063466A1 KR 2021015416 W KR2021015416 W KR 2021015416W WO 2023063466 A1 WO2023063466 A1 WO 2023063466A1
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WIPO (PCT)
Prior art keywords
formula
ceramide
substituted
unsubstituted
phytosphingosine
Prior art date
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Ceased
Application number
PCT/KR2021/015416
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English (en)
Korean (ko)
Inventor
조세현
엄현지
김선기
김나래
차경온
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Bjbiochem Co Ltd
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Bjbiochem Co Ltd
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Publication date
Application filed by Bjbiochem Co Ltd filed Critical Bjbiochem Co Ltd
Publication of WO2023063466A1 publication Critical patent/WO2023063466A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated

Definitions

  • the present invention relates to a method for preparing a ceramide compound.
  • Ceramide is a component that occupies a large portion of lipids between keratinocytes constituting the stratum corneum of the skin, and functions to suppress moisture evaporation and maintain the structure of the stratum corneum.
  • This stratum corneum acts as a barrier to protect harmful substances or microorganisms from the external environment from penetrating into the skin tissue.
  • Lipids between keratinocytes are composed of ceramide, cholesterol, free fatty acids, etc. It is known to play a central role in barrier function. It is known that when the content of ceramide in the stratum corneum is reduced, water evaporation increases and various skin diseases are aggravated.
  • natural ceramide was synthesized by refluxing stirring of fatty acid and phytosphingosine in an organic solvent under an acid catalyst, and was obtained in a low yield of about 30%.
  • activated ester intermediates are prepared using fatty acids, 1-hydroxybenzotriazol, and diisopropyl carbodiimide under a nitrogen atmosphere, and phytosphingosine Natural ceramides were prepared by combining.
  • the yield of natural ceramide is low, and expensive raw materials are used in an amount of 1 equivalent or more compared to phytosphingosine.
  • the present inventors of the present invention researched and developed a method for synthesizing natural ceramide without using a purification method using chromatography, and when using a cyclic amine base-based catalyst, high yield even under relatively mild conditions
  • the present invention was completed by finding that ceramide can be synthesized.
  • the present invention specifically aims to provide a method for synthesizing ceramide by reacting phytosphingosine as a starting material with a methyl ester-based compound represented by Formula 2 in the presence of a cyclic amine base-based catalyst.
  • the present invention provides a method for preparing ceramide represented by Chemical Formula 1 by reacting phytosphingosine with a methyl ester-based compound represented by Chemical Formula 2 in the presence of a cyclic amine base-based catalyst. .
  • ceramide in the method for preparing ceramide of the present invention, can be synthesized in high yield even under relatively mild conditions by reacting phytosphingosine as a starting material with a methyl ester-based compound represented by Formula 2 in the presence of a cyclic amine base-based catalyst. .
  • Ceramides synthesized in this way can be helpful for skin health, such as strengthening the skin barrier and moisturizing effect when applied to cosmetics.
  • Effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents to be described below.
  • Figure 1 shows the 1 H-NMR results of N-oleyl-phytosphingosine (ceramide NP) synthesized in Example 1.
  • Figure 2 shows the 1 H-NMR results of N-salicyloyl-phytosphingosine synthesized in Example 2.
  • Figure 3 shows the 1 H-NMR results of N-oleyl-phytosphingosine (ceramide NP) synthesized in Comparative Example 1.
  • Figure 4 shows the 1 H-NMR results of N-salicyloyl-phytosphingosine synthesized by Comparative Example 2.
  • the present invention provides a method for preparing ceramide represented by Chemical Formula 1 by reacting phytosphingosine with a methyl ester-based compound represented by Chemical Formula 2 in the presence of a cyclic amine base-based catalyst.
  • R is a substituted or unsubstituted C 8 to C 25 alkyl, a substituted or unsubstituted C 8 to C 25 alkenyl, a substituted or unsubstituted C 8 to C 25 alkynyl, a substituted or unsubstituted C 6 to C 12 aryl, or substituted or unsubstituted C 6 to C 12 heteroaryl.
  • the term "phytosphingosine” is a compound having the following structure and is used as a starting material for synthesizing ceramide.
  • substituted means that one or more hydrogen atoms are replaced with an atom other than hydrogen, that is, a substituent.
  • substituents include, but are not limited to, halogen, nitro, amino, azido, oxo, hydroxyl, thiol, carboxy, carboxy ester, carboxamide, alkylamino, alkyldithio, alkylthio, alkoxy, acylamido, acyl It may be oxy or acylthio, but is not limited thereto.
  • aryl refers to an aromatic ring compound having 6 to 12 carbon atoms, and specifically may be phenyl, naphthyl, or anthracenyl, but is not limited thereto.
  • cyclic amine base-based catalyst is in the form of a bulky, fused ring, and includes at least one nitrogen atom (N) to serve as a base catalyst.
  • cyclic amine base-based catalysts include 1,8-diazabicyclo[5,4,0]undec-7-ene; DBU ⁇ , 1,5-Diazabicyclo[4,3,0]non-5-ene; DBN ⁇ , 1,5,7-Triazabicyclo[4,4,0]dec-5-ene ⁇ 1,5,7-Triazabicyclo[4.4.0]dec-5-ene; TBD ⁇ and 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5-ene ⁇ 1,5,7-Triazabicyclo[4.4.0]dec-5-ene; MTBD ⁇ may be any one or more selected from the group consisting of, preferably 1,5,7-triazabicyclo[4,4,0]dec-5-ene ⁇ 1,5,7-Triaza
  • the cyclic amine base-based catalyst combines with an ester compound during ceramide synthesis to generate an activated intermediate and converts it to ceramide, so that reaction by-products are minimized in ceramide synthesis and relatively mild reaction conditions It has the advantage of being able to generate ceramide.
  • R is substituted or unsubstituted C 8 to C 25 alkyl, substituted or unsubstituted C 8 to C 25 alkenyl, or substituted or unsubstituted C 6 to C 12 aryl It may be any one of, but is not limited thereto.
  • R is substituted or unsubstituted C 8 to C 17 alkyl, substituted or unsubstituted C 8 to C 17 alkenyl, or substituted or unsubstituted C 6 to C 8 aryl It may be any one of, specifically R is , , , or It may be, but is not limited thereto. (as shown in the R substituent above means the part to be joined.)
  • the methyl ester-based compound represented by Chemical Formula 2 may be any one or more of the compounds represented by Chemical Formulas 2-1 to 2-5 below, but is not limited thereto.
  • the methyl ester-based compound represented by Chemical Formula 2-1 is methyl laurate
  • the methyl ester-based compound represented by Chemical Formula 2-2 is methyl palmitate
  • Chemical Formula 2-3 The methyl ester-based compound represented by is methyl stearate
  • the methyl ester-based compound represented by Formula 2-4 is methyl oleate
  • the methyl ester-based compound represented by Formula 2-5 is It is methyl salicylate.
  • the method for preparing ceramide may be performed at 40 to 80 ° C. for 16 to 32 hours, but is not limited thereto.
  • the temperature range as described above is a mild condition, and when using a cyclic amine base-based catalyst, there is an advantage in synthesizing ceramide with a high yield even if the reaction temperature is progressed under mild conditions.
  • the ceramide represented by Chemical Formula 1 may be any one or more of the compounds represented by Chemical Formulas 1-1 to 1-5 below, but is not limited thereto.
  • the ceramide represented by Formula 1-1 is N-Lauroyl Phytosphingosine
  • the ceramide represented by Formula 1-2 is N-palmitoyl-phytosphingosine (N-Lauroyl Phytosphingosine).
  • ceramide represented by Formula 1-3 is N-Stearoyl-phytosphingosine
  • ceramide represented by Formula 1-4 is N-oleyl-phytosine.
  • It is phingosine (N-Oleayl-phytosphingosine, ceramide NP)
  • the ceramide represented by Formula 1-5 is N-salicyloyl-phytosphingosine.
  • phytosphingosine and the methyl ester-based compound represented by Formula 2 may be reacted in a weight ratio of 1: 0.5 to 1.5, specifically 1: 0.7 to 1.25. It is not limited.
  • the cyclic amine base-based catalyst may be added in an amount of 3.5 to 10% by weight based on the total sum of phytosphingosine and the methyl ester-based compound represented by Formula 2, specifically 5 to 8% by weight % can be added, but is not limited thereto.
  • the method may be carried out under dichloromethane solvent or solventless conditions, but is not limited thereto.
  • the ceramide synthesized according to the present invention is applied to the skin when applied to cosmetics, and effects such as moisturizing power, elasticity, and wrinkle whitening can be expected.
  • N-oleyl-phytosphingosine N- Oleayl-phytosphingosine, ceramide NP was obtained (30 g, yield: 85%).
  • N-salicyloyl-phytosphingosine N-salicyloyl-phytosphingosine, an example of ceramide. Salicyloyl-phytosphingosine was obtained (4 g, yield: 15%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé de céramide. En particulier, l'invention concerne un procédé de synthèse de céramide par réaction de phytosphingosine et d'un composé à base d'ester méthylique représenté par la formule chimique 2, en tant que matières premières, en présence d'un catalyseur à base d'une base d'amine cyclique. L'utilisation du catalyseur à base d'une base d'amine cyclique permet la synthèse de céramide à un rendement élevé même dans des conditions relativement douces.
PCT/KR2021/015416 2021-10-14 2021-10-29 Procédé de préparation d'un composé de céramide Ceased WO2023063466A1 (fr)

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KR10-2021-0136720 2021-10-14
KR1020210136720A KR20230053777A (ko) 2021-10-14 2021-10-14 세라마이드 화합물의 제조방법

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567310A (zh) * 2023-11-28 2024-02-20 重庆智合生物医药有限公司 一种神经酰胺np1的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150022A2 (fr) * 2008-06-13 2009-12-17 Evonik Goldschmidt Gmbh Synthèse enzymatique de sphingolipides
KR20140060505A (ko) * 2011-09-13 2014-05-20 카오카부시키가이샤 N-아실아미노트리올의 제조법
WO2019224356A1 (fr) * 2018-05-24 2019-11-28 Universiteit Gent Amidation de polymères contenant des chaînes latérales ester à l'aide d'amines fonctionnalisées

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100539965B1 (ko) 2002-08-29 2006-01-10 주식회사 코리아나화장품 신규한 유사 세라마이드를 포함하는 아토피 피부염 예방및 완화용 화장료 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150022A2 (fr) * 2008-06-13 2009-12-17 Evonik Goldschmidt Gmbh Synthèse enzymatique de sphingolipides
KR20140060505A (ko) * 2011-09-13 2014-05-20 카오카부시키가이샤 N-아실아미노트리올의 제조법
WO2019224356A1 (fr) * 2018-05-24 2019-11-28 Universiteit Gent Amidation de polymères contenant des chaînes latérales ester à l'aide d'amines fonctionnalisées

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SABOT, C. KUMAR, K.A. MEUNIER, S. MIOSKOWSKI, C.: "A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 48, no. 22, 3 May 2007 (2007-05-03), Amsterdam , NL , pages 3863 - 3866, XP022058997, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2007.03.146 *
WEIBERTH FRANZ J., YU YONG, SUBOTKOWSKI WITOLD, PEMBERTON CLIVE: "Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient Amidation of an Unactivated Methyl Ester", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 16, no. 12, 21 December 2012 (2012-12-21), US , pages 1967 - 1969, XP093058738, ISSN: 1083-6160, DOI: 10.1021/op300210j *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567310A (zh) * 2023-11-28 2024-02-20 重庆智合生物医药有限公司 一种神经酰胺np1的合成方法

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