CN117567311A - Method for efficiently preparing alpha-hydroxy fatty acid ceramide - Google Patents
Method for efficiently preparing alpha-hydroxy fatty acid ceramide Download PDFInfo
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- CN117567311A CN117567311A CN202311599245.6A CN202311599245A CN117567311A CN 117567311 A CN117567311 A CN 117567311A CN 202311599245 A CN202311599245 A CN 202311599245A CN 117567311 A CN117567311 A CN 117567311A
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- fatty acid
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- 229940106189 ceramide Drugs 0.000 title claims abstract description 48
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 47
- 239000000194 fatty acid Substances 0.000 title claims abstract description 47
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 47
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 title claims abstract description 45
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 title claims abstract description 45
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 title claims abstract description 45
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 229940061720 alpha hydroxy acid Drugs 0.000 claims abstract description 25
- 150000001280 alpha hydroxy acids Chemical class 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011574 phosphorus Substances 0.000 claims abstract description 12
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 8
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 7
- 239000000376 reactant Substances 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 230000001105 regulatory effect Effects 0.000 claims abstract description 5
- 230000026030 halogenation Effects 0.000 claims abstract description 4
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 claims description 13
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 description 10
- KIHBGTRZFAVZRV-UHFFFAOYSA-N 2-hydroxyoctadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)C(O)=O KIHBGTRZFAVZRV-UHFFFAOYSA-N 0.000 description 8
- 238000007112 amidation reaction Methods 0.000 description 5
- KRBFFJIZAKABSA-UHFFFAOYSA-N 2-bromooctadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(Br)C(O)=O KRBFFJIZAKABSA-UHFFFAOYSA-N 0.000 description 3
- -1 alpha-hydroxy acid ester Chemical class 0.000 description 3
- 150000001783 ceramides Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AERBNCYCJBRYDG-UHFFFAOYSA-N D-ribo-phytosphingosine Natural products CCCCCCCCCCCCCCC(O)C(O)C(N)CO AERBNCYCJBRYDG-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- QOQZSVKKTPUAJM-UHFFFAOYSA-N ethyl 2-hydroxyoctadecanoate Chemical compound CCCCCCCCCCCCCCCCC(O)C(=O)OCC QOQZSVKKTPUAJM-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- AERBNCYCJBRYDG-KSZLIROESA-N phytosphingosine Chemical compound CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO AERBNCYCJBRYDG-KSZLIROESA-N 0.000 description 2
- 229940033329 phytosphingosine Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000010468 Hell-Volhard-Zelinsky reaction Methods 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- IUHFWCGCSVTMPG-UHFFFAOYSA-N [C].[C] Chemical class [C].[C] IUHFWCGCSVTMPG-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
Classifications
-
- 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for efficiently preparing alpha-hydroxy fatty acid ceramide, which comprises the following steps: s1, preparation of alpha-halogenated acid: the classical Heler-Wu Erha-Zelinsky reaction is adopted, fatty acid and a phosphorus-containing catalyst are put into a reactor, the temperature is raised to 90-100 ℃, halogen simple substance is added dropwise, and the halogen is taken as a reaction reagent to carry out halogenation of alpha carbon atoms; s2, preparation of alpha-hydroxy acid: dropwise adding an inorganic alkali reagent into the reactant in the previous step, heating to 80-85 ℃ for reaction, and regulating the pH to 1-3 by concentrated hydrochloric acid after the reaction is finished; s3, preparation of alpha-hydroxy acid esterified compound: adding alpha-hydroxy acid, lower alcohol and inorganic acid into a reactor, heating to 50-65 ℃ for reaction; s4, preparing alpha-hydroxy fatty acid ceramide. The invention provides a novel and feasible preparation process for preparing alpha-hydroxy fatty acid ceramide, which has low cost and controllable quality.
Description
Technical Field
The invention relates to the technical field of ceramide preparation, in particular to a method for efficiently preparing alpha-hydroxy fatty acid ceramide.
Background
Ceramides (ceramides) are a class of biologically active substances consisting of bases on sphingosine and different fatty acids, and can be composed into ceramides of different chemical structures and biological activities due to the difference in the structures of sphingosine and fatty acids.
Research shows that ceramide has been applied to different degrees in the daily chemical field, the medical field, the food field and the like, and especially the daily chemical field, the application of ceramide is very wide and is widely accepted in the market.
The ceramide has very strong effects on skin, such as moisturizing effect, skin barrier effect, adhesive effect, anti-aging effect and the like, and the following main ways of obtaining the ceramide are adopted at present:
1. the natural extraction method is used for extracting the ceramide from animals and plants, and is limited by animal and plant sources, growth cycle and the like, so that the yield is low and the cost is high; 2. the chemical synthesis method has long synthesis steps, the chemical three-dimensional configuration is not easy to control, and the quality of the ceramide is difficult to ensure; 3. the microbial fermentation method mostly uses yeast to ferment to obtain acetylated sphingosine, and then the acetylated sphingosine is subjected to deacetylation to obtain sphingosine, and the sphingosine reacts with different fatty acids to obtain ceramide.
The alpha-hydroxyceramide is prepared from sphingosine and alpha-hydroxy fatty acid through amidation, and no report on efficient preparation of the substance exists at home and abroad at present, so that the development of an efficient, easily-amplified, low-cost and high-quality alpha-hydroxyceramide preparation process is urgent for solving the supply problem of the alpha-hydroxyfatty acid ceramide.
Disclosure of Invention
The invention aims to provide a method for efficiently preparing alpha-hydroxy fatty acid ceramide, which aims to solve the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions: a method for efficiently preparing alpha-hydroxy fatty acid ceramide, comprising the following steps:
s1, preparation of alpha-halogenated acid:
the classical Heler-Wu Erha-Zelinsky reaction is adopted, fatty acid and a phosphorus-containing catalyst are put into a reactor, the temperature is raised to 90-100 ℃, halogen simple substance is added dropwise, and the halogen is taken as a reaction reagent to carry out halogenation of alpha carbon atoms;
s2, preparation of alpha-hydroxy acid:
dropwise adding an inorganic alkali reagent into the reactant in the previous step, heating to 80-85 ℃ for reaction, and regulating the pH to 1-3 by concentrated hydrochloric acid after the reaction is finished;
s3, preparation of alpha-hydroxy acid esterified compound:
adding alpha-hydroxy acid, lower alcohol and inorganic acid into a reactor, heating to 50-65 ℃ for reaction;
s4, preparation of alpha-hydroxy fatty acid ceramide:
adding the alpha-hydroxy acid esterified product, sphingosine, lower alcohol and organic base into a reactor, and carrying out reflux reaction.
Preferably, the phosphorus-containing catalyst may be elemental phosphorus, phosphorus tribromide or phosphorus trichloride.
Preferably, the inorganic alkali agent in S2 may be sodium hydroxide, potassium hydroxide or calcium hydroxide; the inorganic acid in the step S3 can be concentrated sulfuric acid or hydrochloric acid; the organic base in the step S4 can be sodium methoxide, sodium ethoxide or potassium tert-butoxide; the lower alcohol in S3 and S4 may be methanol, ethanol or isopropanol.
Preferably, the post-treatment step of the alpha-hydroxy acid in the S2 comprises the following steps:
extracting with tetrahydrofuran, concentrating the organic phase under reduced pressure, rectifying with n-hexane, crystallizing at 0-5 deg.c, filtering and drying to obtain alpha-hydroxy acid.
Preferably, the post-treatment step of the alpha-hydroxy acid ester in the S3 comprises the following steps:
after the reaction is finished, cooling and crystallizing, centrifuging, pulping, filtering and drying to obtain the alpha-hydroxy acid esterified substance.
Preferably, the post-treatment step of the alpha-hydroxy fatty acid ceramide in the S4 comprises the following steps:
and after the reaction is finished, adding glacial acetic acid for quenching, cooling for crystallization, and recrystallizing and drying the wet crystallization product to obtain the alpha-hydroxy fatty acid ceramide.
The invention has at least the following beneficial effects:
(1) The method for efficiently preparing the alpha-hydroxy fatty acid ceramide provided by the invention provides a novel and feasible preparation process for preparing the alpha-hydroxy fatty acid ceramide, and the process has low cost and controllable quality;
(2) The method for efficiently preparing the alpha-hydroxy fatty acid ceramide creatively designs a synthetic route of the alpha-hydroxy fatty acid ester intermediate, and aims to improve the activity of amidation reaction;
(3) According to the method for efficiently preparing the alpha-hydroxy fatty acid ceramide, provided by the invention, after the reaction of the finished product steps, the finished product is obtained only by cooling, crystallization and drying, so that the post-treatment steps are reduced, and the yield is improved;
(4) The method for efficiently preparing the alpha-hydroxy fatty acid ceramide provided by the invention has the advantages that the prepared alpha-hydroxy fatty acid ceramide has stable quality, commercial production is realized, and the market acceptance is high.
Drawings
FIG. 1 is a scheme of the synthesis of alpha-hydroxyceramide in the present invention;
FIG. 2 is a route for the preparation of α -bromostearic acid in example 1;
FIG. 3 is a route for the preparation of α -hydroxystearic acid of example 1;
FIG. 4 is a route for the preparation of ethyl alpha-hydroxystearate in example 1;
FIG. 5 is a route for the preparation of α -hydroxystearic acid ceramide in example 1;
FIG. 6 is an HPLC chart of α -hydroxystearic acid ceramide in example 1.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a method for efficiently preparing alpha-hydroxy fatty acid ceramide, which comprises the following steps:
s1, preparation of alpha-halogenated acid:
the classical Heler-Wu Erha-Zelinsky reaction is adopted, fatty acid and a phosphorus-containing catalyst are put into a reactor, the temperature is raised to 90-100 ℃, halogen simple substance is added dropwise, and the halogen is taken as a reaction reagent to carry out halogenation of alpha carbon atoms;
s2, preparation of alpha-hydroxy acid:
dropwise adding an inorganic alkali reagent into the reactant in the previous step, heating to 80-85 ℃ for reaction, and regulating the pH to 1-3 by concentrated hydrochloric acid after the reaction is finished;
extracting with tetrahydrofuran, concentrating the organic phase under reduced pressure, rectifying with n-hexane, crystallizing at 0-5 deg.c, filtering and drying to obtain alpha-hydroxy acid;
s3, preparation of alpha-hydroxy acid esterified compound:
adding alpha-hydroxy acid, lower alcohol and inorganic acid into a reactor, heating to 50-65 ℃ for reaction;
cooling and crystallizing after the reaction is finished, pulping, filtering and drying after centrifugation to obtain an alpha-hydroxy acid esterified substance;
s4, preparation of alpha-hydroxy fatty acid ceramide:
adding the alpha-hydroxy acid esterified product, sphingosine, lower alcohol and organic base into a reactor, and carrying out reflux reaction;
and after the reaction is finished, adding glacial acetic acid for quenching, cooling for crystallization, and recrystallizing and drying the wet crystallization product to obtain the white-like powder alpha-hydroxy fatty acid ceramide.
As shown in figure 1, the alpha-hydroxy fatty acid ceramide is prepared by taking long-chain fatty acid as a substrate through halogenation reaction, hydrolysis reaction, esterification reaction and amidation reaction. Wherein, the halogenation reaction adopts classical Hell-Wu Erha-Zelinsky reaction (Hell-Volhard-Zelinsky reaction), and the fatty acid is catalyzed by phosphorus reagent such as phosphorus simple substance and halogenated phosphorus, and halogen simple substance is used as a reaction reagent to carry out the halogenation reaction of alpha carbon atoms. In order to improve the reactivity and simplify the post-treatment of the finished product preparation step, the invention prepares the alpha-hydroxy fatty acid, and then reacts with lower alcohol to obtain the alpha-hydroxy fatty acid ester. The esterified substance can be subjected to amidation reaction with sphingosine in the presence of inorganic or organic alkali, and after the reaction is finished, the alpha-hydroxy fatty acid ceramide can be obtained only by cooling and crystallizing without complex post-treatment.
In fig. 1, R1 is a saturated or unsaturated carbon-carbon straight chain; r2 is a carbon-carbon straight chain, and R2 can be provided with hydroxyl or unsaturated bond according to the difference of sphingosine structures; r3 is methyl, ethyl or isopropyl; x is a halogen atom.
First step halogenation reaction: the fatty acid can be saturated or unsaturated fatty acid, and the number of carbon atoms of the fatty acid is 10-30 at most; the selected catalyst is a phosphorus-containing catalyst, and can be specifically phosphorus simple substance, phosphorus tribromide and phosphorus trichloride.
And a second step of hydrolysis reaction: the hydrolysis reagent is an inorganic alkali reagent, and can be specifically common inorganic alkali such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
And thirdly, esterification reaction: the esterifying reagent is inorganic acid, and can be concretely concentrated sulfuric acid and hydrochloric acid; the esterified lower alcohol can be selected from lower alcohols such as methanol, ethanol, isopropanol, etc.
Fourth step amidation reaction: the acylating reagent base is an organic base, and can be specifically sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.
In the invention, alpha-hydroxy fatty acid ceramide with different structures can be prepared due to different structures of fatty acid and sphingosine. For better understanding by the skilled artisan, the process of the present invention is described using stearic acid and phytosphingosine as raw materials in example 1 below:
example 1
1. Preparation of alpha-bromostearic acid (as shown in figure 2):
150g of stearic acid and 187g of phosphorus tribromide are put into a reactor, the temperature is raised to 90-100 ℃, and 177g of bromine is added dropwise. After the reaction is completed, the alpha-bromostearic acid reactant is obtained. The reactant can be put into the next reaction without purification.
2. Preparation of alpha-hydroxystearic acid (as shown in figure 3):
slowly adding 30% sodium hydroxide solution into the reactant in the previous step, and heating to 80-85 ℃ for reaction. After the reaction is finished, the pH is regulated to 1-3 by concentrated hydrochloric acid.
Extracting with 750g tetrahydrofuran, concentrating the organic phase under reduced pressure, rectifying with n-hexane, crystallizing at 0-5 deg.C, filtering, and drying to obtain alpha-hydroxystearic acid with purity of 96.2% and yield of 85.1%.
3. Preparation of ethyl alpha-hydroxystearate (as shown in figure 4):
135g of alpha-hydroxystearic acid, 400g of absolute ethyl alcohol and concentrated sulfuric acid are added into a reactor, and the temperature is raised to 50 to 65 ℃ for reaction. After the reaction is finished, cooling and crystallizing, pulping, filtering and drying after centrifuging to obtain 112g of alpha-hydroxystearic acid ethyl ester, wherein the GC purity is 98.3%, and the yield is 76.8%.
4. Preparation of alpha-hydroxystearic acid ceramide (as shown in figure 5):
135g of alpha-ethyl hydroxystearate, 95g of phytosphingosine, 475g of absolute ethyl alcohol and 20g of sodium methoxide are added into a reactor, and the temperature is raised and the reaction is carried out under reflux. And adding glacial acetic acid for quenching after the reaction is finished, and cooling and crystallizing. The wet product is recrystallized and dried to obtain 146g of white powder alpha-hydroxystearic acid ceramide with purity of 96.5% and yield of 84.2%.
HPLC testing was performed on the product prepared in example 1 above, as shown in fig. 6.
While the fundamental principles, principal features, and advantages of the present invention have been shown and described, it will be apparent to those skilled in the art that the present invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A method for efficiently preparing alpha-hydroxy fatty acid ceramide, which is characterized by comprising the following steps:
s1, preparation of alpha-halogenated acid:
the classical Heler-Wu Erha-Zelinsky reaction is adopted, fatty acid and a phosphorus-containing catalyst are put into a reactor, the temperature is raised to 90-100 ℃, halogen simple substance is added dropwise, and the halogen is taken as a reaction reagent to carry out halogenation of alpha carbon atoms;
s2, preparation of alpha-hydroxy acid:
dropwise adding an inorganic alkali reagent into the reactant in the previous step, heating to 80-85 ℃ for reaction, and regulating the pH to 1-3 by concentrated hydrochloric acid after the reaction is finished;
s3, preparation of alpha-hydroxy acid esterified compound:
adding alpha-hydroxy acid, lower alcohol and inorganic acid into a reactor, heating to 50-65 ℃ for reaction;
s4, preparation of alpha-hydroxy fatty acid ceramide:
adding the alpha-hydroxy acid esterified product, sphingosine, lower alcohol and organic base into a reactor, and carrying out reflux reaction.
2. The method for efficiently preparing alpha-hydroxy fatty acid ceramide according to claim 1, wherein: the phosphorus-containing catalyst can be phosphorus simple substance, phosphorus tribromide or phosphorus trichloride.
3. The method for efficiently preparing alpha-hydroxy fatty acid ceramide according to claim 1, wherein: the inorganic alkali reagent in the step S2 can be sodium hydroxide, potassium hydroxide or calcium hydroxide; the inorganic acid in the step S3 can be concentrated sulfuric acid or hydrochloric acid; the organic base in the step S4 can be sodium methoxide, sodium ethoxide or potassium tert-butoxide; the lower alcohol in S3 and S4 may be methanol, ethanol or isopropanol.
4. The method for efficiently preparing alpha-hydroxy fatty acid ceramide according to claim 1, wherein: the post-treatment steps of the alpha-hydroxy acid in the S2 are as follows:
extracting with tetrahydrofuran, concentrating the organic phase under reduced pressure, rectifying with n-hexane, crystallizing at 0-5 deg.c, filtering and drying to obtain alpha-hydroxy acid.
5. The method for efficiently preparing alpha-hydroxy fatty acid ceramide according to claim 1, wherein: the post-treatment steps of the alpha-hydroxy acid esterified compound in the S3 are as follows:
after the reaction is finished, cooling and crystallizing, centrifuging, pulping, filtering and drying to obtain the alpha-hydroxy acid esterified substance.
6. The method for efficiently preparing alpha-hydroxy fatty acid ceramide according to claim 1, wherein: the post-treatment steps of the alpha-hydroxy fatty acid ceramide in the S4 are as follows:
and after the reaction is finished, adding glacial acetic acid for quenching, cooling for crystallization, and recrystallizing and drying the wet crystallization product to obtain the alpha-hydroxy fatty acid ceramide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114563505A (en) * | 2022-03-16 | 2022-05-31 | 上海大学 | Alpha-hydroxyceramide detection method based on ultra-high performance liquid chromatography-mass spectrometry combined technology |
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