CN115433151A - Preparation method of 6,7,8-trihydroxy coumarin - Google Patents
Preparation method of 6,7,8-trihydroxy coumarin Download PDFInfo
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- CN115433151A CN115433151A CN202211069017.3A CN202211069017A CN115433151A CN 115433151 A CN115433151 A CN 115433151A CN 202211069017 A CN202211069017 A CN 202211069017A CN 115433151 A CN115433151 A CN 115433151A
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- NSDVPAHANCHBFV-UHFFFAOYSA-N 6,7,8-trihydroxycoumarin Chemical compound C1=CC(=O)OC2=C1C=C(O)C(O)=C2O NSDVPAHANCHBFV-UHFFFAOYSA-N 0.000 title claims abstract description 70
- XALJYYXRQJOGCG-UHFFFAOYSA-N 6,7,8-trihydroxycoumarin Natural products O1C(=O)C=CC2=C1C=C(O)C(O)=C2O XALJYYXRQJOGCG-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 15
- PLXMOAALOJOTIY-FPTXNFDTSA-N Aesculin Natural products OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H]1Oc2cc3C=CC(=O)Oc3cc2O PLXMOAALOJOTIY-FPTXNFDTSA-N 0.000 claims abstract description 14
- XHCADAYNFIFUHF-TVKJYDDYSA-N esculin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C(=C1)O)=CC2=C1OC(=O)C=C2 XHCADAYNFIFUHF-TVKJYDDYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000000843 powder Substances 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 238000004262 preparative liquid chromatography Methods 0.000 claims abstract description 6
- 238000010791 quenching Methods 0.000 claims abstract description 6
- 230000000171 quenching effect Effects 0.000 claims abstract description 6
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 6
- 238000011068 loading method Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000003760 magnetic stirring Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000008589 Cortex Fraxini Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- CRSFLLTWRCYNNX-UHFFFAOYSA-N Fraxin Natural products OC=1C(OC)=CC=2C=CC(=O)OC=2C=1OC1OC(CO)C(O)C(O)C1O CRSFLLTWRCYNNX-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzo lactone ring compound Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- CRSFLLTWRCYNNX-QBNNUVSCSA-N fraxin Chemical compound OC=1C(OC)=CC=2C=CC(=O)OC=2C=1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O CRSFLLTWRCYNNX-QBNNUVSCSA-N 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of 6,7,8-trihydroxy coumarin, which comprises the following steps: putting 1 part of aesculin and 30-300 parts of solvent into a reaction vessel, adding 10-50 parts of boron tribromide as a catalyst under stirring, and reacting at room temperature for 10-30 h; quenching the reaction solution by using an alcohol solvent, and removing an organic reagent by rotary evaporation to obtain crude product powder; dissolving the crude product powder in methanol, and loading the solution to a preparative liquid chromatography for purification to obtain a high-purity product. The invention has simple synthesis process and is easy for industrialized production; less impurities in the synthesized product and easy purification.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a chemical synthesis process of 6,7,8-trihydroxy coumarin.
Background
The fraxins are coumarin compounds, are effective components of traditional Chinese medicine ash bark, are widely applied clinically, and have strong antibacterial and anti-inflammatory activities. Researches find that the metabolite in the cortex fraxini is 6,7,8-trihydroxy coumarin, has the drug effect activity of sterilization, anti-inflammation and hepatitis B treatment, and the reports of the preparation process are few. According to the characteristic that coumarin is a benzo lactone ring compound with high modifiability, brunoM.Bizzarri and the like [ Bizzarri, B.M.; botta, l.; capecchi, e.; celestino, i.; cherconi, p.; palamara, a.t.; nencioni, l.; saladino, R. registered IBX-Mediated Synthesis of Coumain Derivatives with antibiotic and Anti-antibiotic activity, J Nat Prod 2017,80 (12), 3247-3254. The product 6,7,8-trihydroxy Coumarin is produced by the reaction with aesculin as the raw material and 2-iodoxybenzoic acid as the oxidant, but the Synthesis method has more byproducts, is difficult to purify and the reaction end point is difficult to control. In the prior invention, CN110819665A adopts a biotransformation method, and takes aesculin or/and aesculin as starting raw materials, 6,7,8-trihydroxy coumarin is generated by using an intestinal flora metabolism mode, and the generated product 6,7,8-trihydroxy coumarin has stronger antioxidant activity, bacteriostasis, hepatitis B virus inhibition and liver protection effects and stronger pharmacological activity compared with aesculin or aesculin. But the method has lower conversion rate, and the conversion is only 1.2% after 24 hours of culture; because of the culture of intestinal flora and more metabolites, the byproducts are more complex and the subsequent purification is more difficult; the method belongs to biotransformation, and the mechanism is that enzyme produced by metabolism of certain intestinal flora catalyzes aesculin to convert the aesculin into 6,7,8-trihydroxy coumarin, the required reaction time is long, about 6-7 days, anaerobic culture is needed, the required culture solution is complex in reaction and high in cost, and the preparation and application of 6,7,8-trihydroxy coumarin are limited.
Therefore, it is necessary to propose a further solution to the above situation.
Disclosure of Invention
The invention aims to provide a preparation method of 6,7,8-trihydroxy coumarin, which is simple and convenient to operate.
The technical scheme of the invention is as follows:
a preparation method of 6,7,8-trihydroxy coumarin comprises the following steps:
(1) Putting the aesculin and a solvent into a reaction vessel, adding boron tribromide as a catalyst under a magnetic stirring state, and reacting at room temperature to obtain a reaction solution;
(2) Quenching the reaction solution by using an alcohol solvent, and removing the organic solvent by rotary evaporation to obtain crude product powder;
(3) And dissolving the crude product powder in methanol, and loading the product into a preparative liquid chromatography for purification to obtain the high-purity 6,7,8-trihydroxy coumarin.
Further, in the step (1), the solvent is selected from any one of chloroform, dichloromethane, ethyl acetate and n-hexane.
Further, in the step (1), the weight ratio of the fraxins, the solvent and the boron tribromide is 1:30 to 300 parts by weight: 10 to 50.
Further, in the step (1), the room temperature reaction time is 10-30 h.
Further, in the step (2), the alcohol solvent is selected from methanol or ethanol.
Further, in the step (3), the type of the chromatographic column in the preparative liquid chromatography is any one of silica gel, a C8 column or a C18 column.
The invention provides a preparation method of 6,7,8-trihydroxy coumarin, which has the main advantages that:
(1) The synthesis process is simple, and the industrial production is easy to realize;
(2) The synthesized product has less impurities and is easy to purify.
Drawings
FIG. 1 is a schematic diagram of the synthesis of 6,7,8-trihydroxy coumarin according to the present invention;
FIG. 2 is a schematic diagram showing the results of the preparation of 6,7,8-trihydroxy coumarin, a liquid-phase purified product of the preparation method of 6,7,8-trihydroxy coumarin, in which 1 is aesculin and 2 is 6,7,8-trihydroxy coumarin, according to the present invention, in example 2;
fig. 3 is a schematic diagram of a reaction result of the preparation method of 6,7,8-trihydroxy coumarin in the invention, which is monitored by HPLC in example 1, wherein 1 is fraxin, and 2 is 6,7,8-trihydroxy coumarin.
Detailed Description
The invention provides a preparation method of 6,7,8-trihydroxy coumarin, which comprises the following steps:
1) Putting 1 part of aesculin and 30-300 parts of solvent into a reaction vessel, adding 10-50 parts of boron tribromide as a catalyst under the magnetic stirring state, and reacting at room temperature for 10-30 h, wherein the solvent is any one of chloroform, dichloromethane, ethyl acetate and n-hexane;
2) Quenching the reaction solution by using an alcohol solvent, and removing the organic solvent by rotary evaporation to obtain a crude product powder, wherein the alcohol solvent is methanol or ethanol;
3) Dissolving the crude product powder in methanol, and loading the product into a preparative liquid chromatography for purification to obtain a high-purity product, wherein the type of the chromatographic column is any one of silica gel, a C8 column or a C18 column.
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, embodiments accompanying the present invention are further described below. The invention is not limited to the embodiments listed but also comprises any other known variations within the scope of the invention as claimed.
First, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Example 1
The embodiment shows a preparation method of 6,7,8-trihydroxy coumarin according to the following steps:
accurately weighing 1 part of aesculin, adding 180 parts of dichloromethane reagent, and placing in a reaction container under the protection of nitrogen; adding 45 parts of boron tribromide as a catalyst by using an injector, reacting at low temperature for 20min, finally reacting at room temperature for 24h, quenching by using methanol, removing an organic reagent by rotary evaporation to obtain crude product powder, dissolving the crude product powder in the methanol, loading the crude product powder into a preparative liquid chromatogram for purification to obtain a high-purity product, wherein the purity of the purified 6,7,8-trihydroxy coumarin is 97%, and the liquid chromatogram thereof is shown in fig. 2; dissolving the obtained high-purity product 6,7,8-trihydroxy coumarin 1mg in 1mL of methanol, wherein the maximum absorption wavelength of the product is 334nm, and performing LC-MS analysis; 6mg of the product was dissolved in 0.6mL of DMSO-d6,1H-NMR (400 MHz), 13C-NMR (400 MHz) for analysis; the results are as follows: ESI-MS: m/z:193.0145;1H-NMR (400MHz, dmso), delta: 7.84 (1H, d, J =9.42, 3H), 6.55 (1H, s, 5H), 6.15 (1H, d, J =9.42, 4H); 13C-NMR (400MHz, dmso), delta: 161.12 (C, C-2), 145.48 (C, C-4), 143.39 (C, C-6), 139.38 (C, C-7), 138.53 (C, C-8 a), 133.32 (C, C-8), 112.07 (C, C-3), 110.33 (C, C-4 a), 103.66 (C, C-5); the conversion product can be determined to be 6,7,8-trihydroxy coumarin by the information.
Example 2
The embodiment shows a preparation method of 6,7,8-trihydroxy coumarin according to the following steps:
accurately weighing 1 part of aesculin, adding 200 parts of dichloromethane reagent, and placing in a reaction container under the protection of nitrogen; adding 50 parts of boron tribromide serving as a catalyst into an injector, reacting at a low temperature for 20min, finally reacting at room temperature for 30h, quenching methanol, removing an organic reagent by rotary evaporation to obtain crude product powder, monitoring the reaction by using HPLC, dissolving 1mg of the crude product powder in 1mL of methanol, performing HPLC analysis on the product, wherein the maximum absorption wavelength of the product is 334nm, and the result is shown in figure 3, and the conversion rate of the reaction is more than 85%.
Comparing the present invention with other prior inventions, the results are shown in table 1 below:
TABLE 1
Compared with the prior art, the invention has the beneficial effects that: the preparation method of 6,7,8-trihydroxy coumarin solves the problems of complex process, long consumed time, low yield, high cost and the like of the conventional process for synthesizing 6,7,8-trihydroxy coumarin; the method has the advantages of simple operation steps, high yield which can reach more than 85 percent, short time consumption, low cost, easy industrial production and the like. .
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (6)
1. A preparation method of 6,7,8-trihydroxy coumarin is characterized by comprising the following steps:
(1) Putting the aesculin and a solvent into a reaction vessel, adding boron tribromide as a catalyst under a magnetic stirring state, and reacting at room temperature to obtain a reaction solution;
(2) Quenching the reaction solution by using an alcohol solvent, and removing the organic solvent by rotary evaporation to obtain crude product powder;
(3) And dissolving the crude product powder in methanol, and loading the product powder to a preparative liquid chromatography for purification to obtain the high-purity 6,7,8-trihydroxy coumarin.
2. The preparation method of 6,7,8-trihydroxy coumarin according to claim 1, wherein the method comprises the following steps: in the step (1), the solvent is selected from any one of chloroform, dichloromethane, ethyl acetate and n-hexane.
3. The method for preparing 6,7,8-trihydroxy coumarin according to claim 1, wherein said method comprises the steps of: in the step (1), the weight ratio of the fraxins, the solvent and the boron tribromide is 1:30 to 300 parts by weight: 10 to 50.
4. The preparation method of 6,7,8-trihydroxy coumarin according to claim 1, wherein the method comprises the following steps: in the step (1), the room temperature reaction time is 10-30 h.
5. The preparation method of 6,7,8-trihydroxy coumarin according to claim 1, wherein the method comprises the following steps: in the step (2), the alcohol solvent is selected from methanol or ethanol.
6. The preparation method of 6,7,8-trihydroxy coumarin according to claim 1, wherein the method comprises the following steps: in the step (3), the type of the chromatographic column in the preparative liquid chromatography is any one of silica gel, a C8 column or a C18 column.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150036224A (en) * | 2012-06-27 | 2015-04-07 | 아마젠티스 에스에이 | Enhancing autophagy or increasing longevity by administration of urolithins or precursors thereof |
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| CN110819665A (en) * | 2019-10-21 | 2020-02-21 | 苏州大学 | Preparation method of 6, 7, 8-trihydroxy coumarin |
| CN113214282A (en) * | 2021-05-27 | 2021-08-06 | 中国人民解放军北部战区总医院 | AChE/BACE1/GSK3 beta three-target inhibitor, preparation method thereof and application thereof in resisting Alzheimer disease |
| CN114315733A (en) * | 2020-09-30 | 2022-04-12 | 中国科学院上海药物研究所 | Photoinduced cell covalent labeling fluorescent molecule, preparation method and application thereof |
-
2022
- 2022-09-02 CN CN202211069017.3A patent/CN115433151A/en active Pending
Patent Citations (5)
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| Title |
|---|
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| ZUBIA EVA等, 《 TETRAHEDRON 》/AN EFFICIENT SYNTHESIS OF FURANOCOUMARINS, vol. 48, no. 20, 31 December 1992 (1992-12-31) * |
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