CN112174846A - Method for synthesizing ceramide without solvation - Google Patents

Method for synthesizing ceramide without solvation Download PDF

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CN112174846A
CN112174846A CN202011215411.4A CN202011215411A CN112174846A CN 112174846 A CN112174846 A CN 112174846A CN 202011215411 A CN202011215411 A CN 202011215411A CN 112174846 A CN112174846 A CN 112174846A
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reaction
ceramide
synthesis
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李新华
叶云飞
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Shanghai Lisheng Shengte Enterprise Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention relates to a method for synthesizing ceramide without solvation, which comprises three steps of etherification of alcohol and halogenated hydrocarbon, ring opening of ethanolamine and epoxy, condensation, utilization of cheap raw materials, no utilization of additional solvent for participating in the reaction except for reaction reagents, and synthesis of a plurality of ceramides and analogues by utilizing the method. The invention has the advantages of cheap raw materials, no need of additional solvent, greenness, safety, environmental protection, high efficiency and suitability for industrial production.

Description

Method for synthesizing ceramide without solvation
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing ceramide by three-step reaction of alcohol and halogenated hydrocarbon etherification, ethanolamine and epoxy ring opening and condensation, wherein cheap raw materials are used, no extra solvent is used for participating in the reaction except for a reaction reagent, and the method for synthesizing ceramide by solvent-free synthesis is developed.
Background
In the conventional synthesis process of organic compounds, organic solvents are the most common media, which can disperse reactants into the same phase, reduce viscosity and promote reaction, but the toxicity of the solvents and the recovery of reagents have adverse effects on the environment. In recent years, green synthesis has emerged, which has led to a number of green chemical processes replacing traditional organic solvents, among which the solventless organic reactions are one of them, and the chemical reactions are carried out without or with a small amount of added solvent.
In recent years, the results of skin studies have shown that the presence of intercellular lipids with corneocytes contributes greatly to the maintenance of healthy skin, of which Ceramide (Ceramide) is the most important component for skin protection, and has a barrier action, an adhesive action, a moisturizing action, an anti-aging action and an antiallergic action in the horny layer of the epidermis, which can maintain the integrity of the barrier structure well and have the greatest effect on the restoration of impaired water retention. Ceramide is a main component of hair lipid, can reduce the adhesive force of fur cells, reduce the damage to hair caused by light and the like and decorate the surface of the hair, is a novel bioactive substance, and has wide development prospect in the application of skin care and hair care.
CN102351730A discloses a method for preparing ceramide from konjac flying powder, which is to extract the konjac flying powder as a raw material by using an ethanol solution with the volume fraction of 95%, then extract the konjac flying powder by using petroleum ether, purify the konjac flying powder by using a silica gel column chromatography, and finally purify the konjac flying powder by using a medium-pressure C18 bonded silica gel ODS column chromatography to obtain the ceramide with the purity of more than 95%. However, the ethanol with the volume fraction of 95% adopted in the crude extraction stage of the process is not suitable for industrial production, and the subsequent purification and separation adopts a silica gel chromatographic column and a medium-pressure C18 bonded silica gel ODS column chromatography series connection, so that the production cost is high.
CN102093244A discloses a method for extracting ceramide, which comprises using sea anemone as raw material, extracting with 95% ethanol solution by volume fraction, extracting with ethyl acetate, purifying with macroporous resin chromatographic column, and crystallizing to obtain ceramide. However, ethanol with a volume fraction of 95% is not suitable for industrial production in the crude extraction stage of the process, and the subsequent purification and crystallization methods have low yield, generally 0.015-0.03%, and high production cost.
CN102058727A discloses a ceramide-containing tea seed extract and a preparation method thereof, wherein the extraction is continued by water or low carbon alcohol. However, the extracting solution has more impurities, which increases the difficulty of subsequent purification treatment, increases the purification link and prolongs the production period.
Disclosure of Invention
The invention aims to develop a solvent-free reaction method, and particularly relates to three steps of etherification of alcohol and halogenated hydrocarbon, ring opening of ethanolamine and epoxy, and condensation, wherein cheap raw materials are used, no extra solvent is used for participating in the reaction except for reaction reagents, and synthesis of a plurality of ceramides and analogues is realized.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for the solventless synthesis of ceramide, comprising the steps of:
1) etherification of alcohols with halogenated hydrocarbons: adding a catalyst into long-chain fatty alcohol, and reacting with halogenated hydrocarbon to obtain long-chain glycidyl ether;
2) and (3) performing ring opening reaction of ethanolamine and epoxy: adding the long-chain glycidyl ether obtained in the step 1) into an ethanolamine solution for reaction to obtain an intermediate;
3) condensation reaction: mixing the intermediate obtained in the step 2) with an alkaline substance, heating, adding fatty acid methyl ester for reaction, and crystallizing the product after the reaction is finished to obtain the ceramide and the analogue thereof.
In the technical scheme, the reaction route of the invention is as follows:
Figure BDA0002760205850000021
R＝C12H25，C14H29，C16H33，C18H37，R1＝C12H25，C14H29，C16H33，C18H37。
the first step of etherification reaction has the following reaction equation:
Figure BDA0002760205850000022
wherein R is C12H25，C14H29，C16H33，C18H37
Adding a catalyst into the long-chain fatty alcohol, reacting for 0.5-2h at 20-50 ℃, adding epoxy chloropropane for reacting for 2-20h at 20-80 ℃, and distilling the epoxy chloropropane and the long-chain glycidyl ether after the reaction is finished.
The second step of ring-opening reaction has the following reaction equation:
Figure BDA0002760205850000023
wherein R is C12H25，C14H29，C16H33，C18H37，Dripping long-chain glycidyl ether into ethanolamine solution, reacting at 20-80 deg.C for 3-20h, distilling excessive ethanolamine out of the product after reaction, recovering, and crystallizing the mother liquor with ethanol to obtain white intermediate.
The third step of reaction condensation, the reaction equation is as follows:
Figure BDA0002760205850000031
wherein R is C12H25，C14H29，C16H33，C18H37，R1Is C12H25，C14H29，C16H33，C18H37，
Mixing the intermediate with alkaline substance, heating the system to 20-80 deg.C, reacting for 3-20h, and crystallizing the product with ethanol to obtain ceramide and its analog.
Preferably, in step 1), the long-chain fatty alcohol comprises a C12-C16 fatty alcohol.
Preferably, in step 1), the halogenated hydrocarbon is epichlorohydrin; the catalyst comprises NaOH, KOH and K2CO3，Na2CO3One or more of sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, pyridine and triethylamine.
Preferably, in the step 1), the mass ratio of the long-chain aliphatic alcohol to the halogenated hydrocarbon is 1:1-1:2, and the preferred mass ratio is 1: 1.5.
Preferably, in the step 1), the reaction temperature is 20-80 ℃, the reaction time is 2-20h, the preferred reaction temperature is 50 ℃, and the preferred reaction time is 12 h.
Preferably, in step 2), the volume ratio of the long-chain glycidyl ether to the ethanolamine is 1:1 to 1:10, and the preferred volume ratio is 1: 6.
Preferably, in the step 2), the reaction temperature is 20-80 ℃, the reaction time is 3-20h, the preferred reaction temperature is 60 ℃, and the preferred reaction time is 8 h.
Preferably, in step 3), the mass ratio of the intermediate to the fatty acid methyl ester is 1:1 to 1:2, and the preferred mass ratio of the intermediate to the fatty acid methyl ester is 1: 1.5.
Preferably, in step 3), the reaction temperature is 20-80 ℃ and the reaction time is 3-20h, preferably the reaction temperature is 50 ℃ and the reaction time is 6 h.
Preferably, in step 3), the alkaline substance comprises NaOH, KOH and K2CO3，Na2CO3One or more of sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, pyridine and triethylamine.
Compared with the prior art, the invention has the beneficial effects that:
aiming at the technical characteristics and the defects of the prior art, the invention develops a set of reaction system without solvent, utilizes cheap raw materials, removes reaction reagents, and does not utilize extra solvent to participate in the reaction, thereby reducing the consumption and the waste of materials, simultaneously reducing the subsequent post-treatment process, saving time and labor, being green and environment-friendly, and efficiently completing the synthesis of ceramide and analogues thereof.
Drawings
FIG. 1 is a hydrogen spectrum of example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
This example provides a method for the solventless synthesis of ceramide comprising the steps of:
1) etherification of alcohols with halogenated hydrocarbons:
Figure BDA0002760205850000041
in the presence of 640mg of tetrabutylammonium bromide (TBAB), 48.4g of hexadecanol was placed in a round-bottom flask, the temperature was then raised to 50 ℃ to dissolve, 16.2g of sodium methoxide was added, stirring was carried out for 20 minutes, 28g of epichlorohydrin was added dropwise with vigorous stirring, the reaction was monitored by Thin Layer Chromatography (TLC), and when the amount of the product remained unchanged, the reaction mixture was quenched with water by cooling to room temperature, the separated liquid was washed directly with water twice, the organic phase was dried over anhydrous sodium sulfate, and then unreacted epichlorohydrin and glycidyl ether were evaporated under vacuum to give 54g of glycidyl ether liquid.
2) And (3) performing ring opening reaction of ethanolamine and epoxy:
Figure BDA0002760205850000042
adding 310g of ethanolamine into a four-neck flask, mechanically stirring, dropwise adding 50g of hexadecyl glycidyl ether obtained in the step 1) at 50 ℃, finishing dropwise adding within 2h, reacting for 2h, distilling out the ethanolamine after the reaction is finished, and crystallizing the product with ethanol to obtain an intermediate 44g with a melting point of 64-65 ℃.
3) Condensation reaction:
Figure BDA0002760205850000043
42g of intermediate obtained in the step 2) and 11.2g of potassium methoxide are added into a four-neck flask, 43g of methyl palmitate is dropwise added after the mixture is heated to 50 ℃ for 1 hour, the mixture is kept for reacting for 1 hour, and after the reaction is completed, solid obtained by treatment is crystallized by ethanol to obtain 68g of off-white solid ceramide.
The measurement was carried out on the off-white solid ceramide obtained in example 1, and the results are shown in FIG. 1 and Table 1.
TABLE 1 NMR spectra assignment
Figure BDA0002760205850000051
As shown in table 1 and fig. 1, the white-like solid prepared in this example corresponds to the expected structure, which indicates that the present invention obtains ceramide through solventless synthesis, and the present invention utilizes cheap raw materials, does not utilize additional solvent to participate in the reaction except for the reaction reagent, reduces the consumption and waste of materials, simultaneously reduces the subsequent post-treatment process, saves time and labor, is green and environment-friendly, and efficiently completes the synthesis of ceramide and its analogues.
Example 2
This example provides a method for the solventless synthesis of a ceramide analogue, comprising the steps of:
1) etherification of alcohols with halogenated hydrocarbons:
in the presence of 640mg of tetrabutylammonium bromide (TBAB), 42.8g of tetradecanol is placed in a round-bottom flask, the temperature is then raised to 50 ℃ to dissolve, 16.2g of sodium methoxide is added, stirring is carried out for 20 minutes, 28g of epichlorohydrin is added dropwise with vigorous stirring, the reaction is monitored by thin-layer chromatography (TLC), when the amount of the product remains unchanged, the reaction mixture is cooled to room temperature and quenched with water, the separated liquid is washed directly with water twice, the organic phase is dried over anhydrous sodium sulfate, the unreacted epichlorohydrin and glycidyl ether are evaporated under vacuum, and finally 48g of glycidyl ether liquid is obtained.
2) And (3) performing ring opening reaction of ethanolamine and epoxy:
adding 240g of ethanolamine into a four-neck flask, mechanically stirring, dropwise adding 40g of tetradecyl glycidyl ether obtained in the step 1) at 50 ℃, finishing dropwise adding within 2h, reacting for 2h, distilling out the ethanolamine after the reaction is finished, and crystallizing the product with ethanol to obtain 37g of an intermediate with a melting point of 64-65 ℃.
3) Condensation reaction:
adding 36g of intermediate obtained in the step 2) and 10g of potassium methoxide into a four-neck flask, heating to 50 ℃, dropwise adding 37g of methyl myristate for 1h, continuing to perform heat preservation reaction for 1h, and after the reaction is completed, crystallizing the obtained solid with ethanol to obtain 58g of off-white solid ceramide.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes in the embodiments and/or modifications of the invention can be made, and equivalents and modifications of some features of the invention can be made without departing from the spirit and scope of the invention.

Claims (10)

1. A method for the solventless synthesis of ceramide, comprising the steps of:
1) etherification of alcohols with halogenated hydrocarbons: adding a catalyst into long-chain fatty alcohol, and reacting with halogenated hydrocarbon to obtain long-chain glycidyl ether;
2) and (3) performing ring opening reaction of ethanolamine and epoxy: adding the long-chain glycidyl ether obtained in the step 1) into an ethanolamine solution for reaction to obtain an intermediate;
3) condensation reaction: mixing the intermediate obtained in the step 2) with an alkaline substance, heating, adding fatty acid methyl ester for reaction, and crystallizing the product after the reaction is finished to obtain the ceramide and the analogue thereof.
2. The method for the solventless synthesis of ceramide as claimed in claim 1, wherein, in step 1), the long-chain fatty alcohol comprises a C12-C16 fatty alcohol.
3. The solvent-free composition of claim 1The method for synthesizing ceramide by chemical agent is characterized in that in the step 1), the halogenated hydrocarbon is epichlorohydrin; the catalyst comprises NaOH, KOH and K2CO3，Na2CO3One or more of sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, pyridine and triethylamine.
4. The method for the solventless synthesis of ceramide according to claim 1, wherein in step 1), the ratio of the amounts of the long-chain aliphatic alcohol and the halogenated hydrocarbon is 1:1-1: 2.
5. The method for the solventless synthesis of ceramide according to claim 1, wherein in step 1), the reaction temperature is 20-80 ℃ and the reaction time is 2-20 h.
6. The method for synthesizing ceramide according to claim 1, wherein in the step 2), the volume ratio of the long-chain glycidyl ether to the ethanolamine is 1:1-1: 10.
7. The method for the solventless synthesis of ceramide according to claim 1, wherein in step 2), the reaction temperature is 20-80 ℃ and the reaction time is 3-20 h.
8. The method for the solventless synthesis of ceramide according to claim 1, wherein in step 3), the ratio of the amount of the intermediate to the amount of fatty acid methyl ester in the fatty acid methyl ester is 1:1 to 1: 2.
9. The method for the solventless synthesis of ceramide according to claim 1, wherein in step 3), the reaction temperature is 20-80 ℃ and the reaction time is 3-20 h.
10. The method for the unsolvated synthesis of ceramide according to claim 1The method is characterized in that in the step 3), the alkaline substances comprise NaOH, KOH and K2CO3，Na2CO3One or more of sodium methoxide, potassium ethoxide, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, pyridine and triethylamine.
CN202011215411.4A 2020-11-04 2020-11-04 Method for synthesizing ceramide without solvation Pending CN112174846A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567311A (en) * 2023-11-28 2024-02-20 重庆智合生物医药有限公司 Method for efficiently preparing alpha-hydroxy fatty acid ceramide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117567311A (en) * 2023-11-28 2024-02-20 重庆智合生物医药有限公司 Method for efficiently preparing alpha-hydroxy fatty acid ceramide

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