WO2023063466A1 - Method for preparing ceramide compound - Google Patents

Abstract

Disclosed is a method for preparing a ceramide compound. Specifically, provided is a method for synthesizing ceramide by reaction of phytosphingosine and a methyl ester-based compound represented by chemical formula 2, as starting materials, in the presence of a cyclic amine base-based catalyst. The use of the cyclic amine base-based catalyst enables the synthesis of ceramide at high yield even under relatively mild conditions.

Description

Manufacturing method of ceramide compound

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.

In addition, it is known that when the aging of the skin progresses or the ceramide content in the stratum corneum decreases due to external stimulation, the skin can be restored to a normal state by replenishing ceramide from the outside.

Therefore, in order to obtain ceramide from nature, studies on various animals and plants containing ceramide have been conducted.

Conventionally, 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%.

In addition, as another method, 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.

In the case of the above reactions, the yield of natural ceramide is low, and expensive raw materials are used in an amount of 1 equivalent or more compared to phytosphingosine.

Accordingly, research is being conducted on similar ceramides that compensate for the disadvantages of natural ceramides, mimic commercially available natural ceramides, have more improved physical properties and properties, and can be mass-produced.

However, there is a problem in that the production yield is very low because purification using chromatography must be performed.

Therefore, it is necessary to research and develop a method for synthesizing natural ceramide in an economical way.

Accordingly, 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.

Accordingly, 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.

In order to achieve the above object, 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. .

In the method for preparing ceramide of the present invention, ceramide 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.

Hereinafter, the present specification will be described in more detail.

A detailed description of this is as follows. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.

Expressions such as “comprising” used in this specification are understood as open-ended terms that include the possibility of including other embodiments, unless specifically stated otherwise in a phrase or sentence in which the expression is included. It should be.

The terms or words used in the description and claims of the present invention should not be construed as being limited to ordinary or dictionary meanings, and the inventors use the concept of terms appropriately in order to explain their invention in the best way. Based on the principle that it can be defined, it should be interpreted as meaning and concept consistent with the technical spirit of the present invention.

Manufacturing method of ceramide

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.

[Formula 1]

[Formula 2]

In Formulas 1 and 2,

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 specific reaction mechanism for the ceramide production method of the present invention is as described in Reaction Scheme 1 below.

[Scheme 1]

In the present invention, the term "phytosphingosine" is a compound having the following structure and is used as a starting material for synthesizing ceramide.

In the present invention, the term "substituted" means that one or more hydrogen atoms are replaced with an atom other than hydrogen, that is, a substituent. Preferred 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.

In the present invention, the term "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.

In the present invention, the term "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. do. Specifically, 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-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}, more preferably 1,5,7-triazabicyclo[4,4,0]dec-5-ene {1,5,7-Triazabicyclo[4.4.0]dec-5-ene; TBD}, but is not limited thereto.

In the present invention, 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.

In the present invention, in Formulas 1 and 2, 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.

In the present invention, in Formulas 1 and 2, 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.)

In the present invention, 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.

[Formula 2-1]

[Formula 2-2]

[Formula 2-3]

[Formula 2-4]

[Formula 2-5]

Specifically, 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, and 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, and the methyl ester-based compound represented by Formula 2-5 is It is methyl salicylate.

In the present invention, the method for preparing ceramide may be performed at 40 to 80 ° C. for 16 to 32 hours, but is not limited thereto.

Specifically, 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.

In the present invention, 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.

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

Specifically, the ceramide represented by Formula 1-1 is N-Lauroyl Phytosphingosine, and the ceramide represented by Formula 1-2 is N-palmitoyl-phytosphingosine (N-Lauroyl Phytosphingosine). -Palmitoyl Phytosphingosine), ceramide represented by Formula 1-3 is N-Stearoyl-phytosphingosine, and ceramide represented by Formula 1-4 is N-oleyl-phytosine. It is phingosine (N-Oleayl-phytosphingosine, ceramide NP), and the ceramide represented by Formula 1-5 is N-salicyloyl-phytosphingosine.

In the present invention, 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.

When phytosphingosine and the methyl ester-based compound represented by Formula 2 are reacted within the above weight ratio range, there is an advantage in reducing washing and obtaining high-purity ceramide.

In the present invention, 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.

Within the above content range, when the cyclic amine base-based catalyst is less than 3.5% by weight, the reaction time is increased, and when it is greater than 10% by weight, the reaction time is shortened, but the cost of the catalyst is high, which affects the economics of the compound.

In the present invention, 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.

Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention may be embodied in many different forms and is not limited to the examples described below.

Example

[ingredient]

Raw materials used in the following Examples and Comparative Examples were purchased from Sigma-Aldrich Korea and TCI.

[ ¹ H-NMR]

¹ H-NMR was performed using a Bruker Advance III HD 400.

Example 1. Synthesis of N-Oleayl-phytosphingosine (ceramide NP)

Phytosphingosine 20 g, Methyl oleate 25 g, 1,5,7-triazabicyclo[4,4,0]dec-5-ene (1,5,7-Triazabicyclo[ After 2.6 g of 4.4.0]dec-5-ene; TBD) was added to the reactor, dichloromethane (DCM, 50 mL) as a solvent was added. After stirring under reflux for 24 hours at 40 ° C., dichloromethane as a solvent was removed under reduced pressure at the end of the reaction. A methanol/water mixed solution (9/1 (v/v), 700 mL) was added to the concentrated reaction mixture, and the resulting white precipitate was filtered and dried to obtain N-oleyl-phytosphingosine (N- Oleayl-phytosphingosine, ceramide NP) was obtained (30 g, yield: 85%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.51 (1H, m, -NH-), 5.36 (2H, m, -CH ₂ -CH = CH -CH ₂ -), 4.41 (1H, s , -CHOH- CH OH-CH-), 4.01 (1H, br, -OH ), 3.88 (1H, m, -CHOH- CH -CH ₂ -), 3.72 (1H, m, -CH ₂ - C H OH-CHOH-), 3.61 (2H, m, -CH-C H ₂ -OH), 2.23 (2H, t, -CH ₂ -C H ₂ -CO-), 2.02 (4H, -C H ₂ -CH=CH-C H ₂ -), 1.63 (2H, m, -CH ₂ -C H ₂ -CH ₂ -CO-), 1.50 (2H, m, -CH ₂ -C H ₂ -CHOH-), 1.27 (44H, br, CH ₃ -(CH 2 ) ₁₂ -CH ₂ - _, CH ₃ -(CH 2 ) _{6 -CH 2} -CH=, =CH-CH ₂ -( CH ₂ ) ₄ -CH ₂ -), 0.89 (6H, t, C H ₃ -). (See Figure 1 description).

[Scheme 2]

Example 2. Synthesis of N-Salicyloyl-phytosphingosine

Phytosphingosine 20 g, Methyl salicylate 14 g, 1,5,7-triazabicyclo[4,4,0]dec-5-ene (1,5,7-Triazabicyclo After adding 2.7 g of [4.4.0]dec-5-ene; TBD) to the reactor, the reaction was maintained at 80 °C for 24 hours under solvent free condition (S.F.C.). Thereafter, methanol, a by-product produced by concentration under reduced pressure, was removed, and a dichloromethane/hexane mixed solution (dichloromethane: hexane = 3: 5 weight ratio, 500 mL) was added, and the resulting white precipitate was filtered and dried to obtain N, an example of ceramide. -Salicyloyl-phytosphingosine (N-Salicyloyl-phytosphingosine) was obtained (19 g, yield: 69%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.07 (1H, s, -NH-), 7.46 (2H, m, Ar), 7.01 (1H, d, Ar), 6.89 (1H, t, Ar) , 4.40 (1H, s, -CHOH- CH OH-CH-), 4.10 (1H, d, -CHOH- CH -CH ₂ -), 3.89 (1H, m, -CH ₂ -CH OH-CHOH -), 3.74 (2H, s, -CH- CH ₂ -OH), 1.81 (1H, s, -CH ₂ -CH 2 _-CHOH- ), 1.54 (1H, s, -CH ₂ -CH ₂ -CHOH-), 1.27 (24H, br, CH ₃ -( CH ₂ ) ₁₂ -CH ₂ -), 0.90 (3H, t, CH 3 _- ). (See Figure 2 description).

[Scheme 3]

comparative example

Comparative Example 1. N-oleyl-phytosphingosine (N-Oleayl-phytosphingosine, ceramide NP) synthesis

20 g of phytosphingosine, 20 g of oleic acid, and 1.2 g of p-toluenesulfonic acid were added to the reactor, and an organic solvent, toluene (100 mL) was added. Thereafter, the mixture was refluxed and stirred at 110° C. for 10 hours under a nitrogen (N ₂ ) atmosphere, and after the reaction was completed, toluene, an organic solvent, was removed under reduced pressure. A white precipitate produced by adding methanol/water mixture solution (9/1 (v/v), 700 mL) was filtered and dried to obtain N-Oleayl-phytosphingosine, an example of ceramide. NP) was obtained (9 g, yield: 24%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.42 (1H, m, -NH-), 5.36 (2H, m, -CH ₂ -CH = CH -CH ₂ -), 4.16 (1H, m , -CHOH-C H OH-CH-), 3.91 (3H, br, -O H , -CHOH-C H -CH ₂ -), 3.73 (1H, m, -CH ₂ -C H OH-CHOH-) , 3.61 (2H, m, -CH- CH ₂ -OH), 3.11 (1H, br, -OH), 2.24 (2H _, t, -CH ₂ -CH 2 -CO-), 2.02 (4H, - C H ₂ -CH=CH-C H ₂ -), 1.64 (2H, m, -CH ₂ -C H ₂ -CH ₂ -CO-), 1.51 (2H, m, -CH ₂ -C H ₂ -CHOH -), 1.27 (44H _, br, CH ₃ -(CH 2 _{) 12} -CH ₂ -, CH ₃ -(CH 2 ) ₆ -CH ₂ -CH=, =CH-CH ₂ -( CH ₂ ) ₄ -CH ₂ -), 0.90 (6H, t, CH ₃ -). (See FIG. 3 description).

Comparative Example 2. Synthesis of N-Salicyloyl-phytosphingosine

20 g of phytosphingosine, 10 g of salicylic acid, and 1.2 g of p-toluenesulfonic acid were added to the reactor, and an organic solvent, toluene (80 mL) was added. Thereafter, the mixture was refluxed and stirred at 110 °C for 24 hours under a nitrogen (N ₂ ) atmosphere, and then toluene, an organic solvent, was removed under reduced pressure. A white precipitate produced by adding a dichloromethane/hexane mixed solution (dichloromethane:hexane = 3:5 weight ratio, 500 mL) was filtered and dried to obtain N-salicyloyl-phytosphingosine (N-salicyloyl-phytosphingosine, an example of ceramide). Salicyloyl-phytosphingosine) was obtained (4 g, yield: 15%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ 12.05 (1H, s, -NH-), 7.46 (2H, m, Ar), 7.01 (1H, d, Ar), 6.89 (1H, t, Ar) , 4.40 (1H, s, -CHOH- CH OH-CH-), 4.10 (1H, m, -CHOH- CH -CH ₂ -), 3.89 (1H, m, -CH ₂ -CH OH-CHOH -), 3.74 (2H, s, -CH- CH ₂ -OH), 2.42 (4H, br, -OH), 1.81 (1H, s, -CH ₂ -CH ₂ -CHOH-), 1.54 (1H , s, -CH ₂ -CH ₂ -CHOH-), 1.27 (24H, br, CH ₃ -(CH 2 _{) 12} -CH ₂ -), 0.90 (3H, t, CH ₃ -). (See FIG. 4 description).

When synthesizing natural ceramide, 1,5,7-triazabicyclo[4,4,0]dec-5-ene (1,5,7-Triazabicyclo[4.4.0]dec-5- ene; TBD), it can be confirmed that ceramide can be obtained in a high yield under mild conditions compared to ceramides synthesized by conventional synthesis methods (Comparative Examples 1 and 2).

Claims (9)

1. 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:

   [Formula 1]

   

   [Formula 2]

   

   In Formulas 1 and 2,

   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.
2. According to claim 1,

   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} method characterized in that any one or more selected from the group consisting of.
3. According to claim 1,

   In Formulas 1 and 2,

   Wherein R is any one of 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.
4. According to claim 1,

   In Formulas 1 and 2,

   Wherein R is any one of 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.
5. According to claim 1,

   A method characterized in that the methyl ester-based compound represented by Formula 2 is at least one of the compounds represented by Formulas 2-1 to 2-5 below:

   [Formula 2-1]

   

   [Formula 2-2]

   

   [Formula 2-3]

   

   [Formula 2-4]

   

   [Formula 2-5]

   
6. According to claim 1,

   The method is carried out at 40 to 80 ℃ for 16 to 32 hours.
7. According to claim 1,

   A method characterized in that the ceramide represented by Formula 1 is any one or more of the compounds represented by Formulas 1-1 to 1-5 below:

   [Formula 1-1]

   

   [Formula 1-2]

   

   [Formula 1-3]

   

   [Formula 1-4]

   

   [Formula 1-5]

   
8. According to claim 1,

   A method characterized by reacting phytosphingosine with a methyl ester-based compound represented by Formula 2 at a weight ratio of 1:0.5 to 1.5.
9. According to claim 1,

   The cyclic amine base-based catalyst is characterized in that 3.5 to 10% by weight is added based on the total sum of phytosphingosine and the methyl ester-based compound represented by Formula 2.

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