CN111303218B - Synthetic method and application of verbena glycoside - Google Patents
Synthetic method and application of verbena glycoside Download PDFInfo
- Publication number
- CN111303218B CN111303218B CN202010184492.XA CN202010184492A CN111303218B CN 111303218 B CN111303218 B CN 111303218B CN 202010184492 A CN202010184492 A CN 202010184492A CN 111303218 B CN111303218 B CN 111303218B
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesizing
- triphenylphosphine
- verbena
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 235000007212 Verbena X moechina Moldenke Nutrition 0.000 title claims abstract description 36
- 235000001594 Verbena polystachya Kunth Nutrition 0.000 title claims abstract description 36
- 235000007200 Verbena x perriana Moldenke Nutrition 0.000 title claims abstract description 36
- 235000002270 Verbena x stuprosa Moldenke Nutrition 0.000 title claims abstract description 36
- 229930182470 glycoside Natural products 0.000 title claims abstract description 29
- 150000002338 glycosides Chemical class 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title description 6
- 240000001519 Verbena officinalis Species 0.000 title 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 241001081203 Verbena Species 0.000 claims abstract description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000004440 column chromatography Methods 0.000 claims abstract description 19
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000000967 suction filtration Methods 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000605 extraction Methods 0.000 claims abstract description 13
- 238000000746 purification Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 claims abstract description 11
- 229940126062 Compound A Drugs 0.000 claims abstract description 10
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 10
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims abstract description 10
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003480 eluent Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- KDSWDGKIENPKLB-QJDQKFITSA-N verbascoside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC(=O)CCC=2C=C(O)C(O)=CC=2)[C@@H](CO)O[C@@H](OCCC=2C=C(O)C(O)=CC=2)[C@@H]1O KDSWDGKIENPKLB-QJDQKFITSA-N 0.000 claims description 12
- QFRYQWYZSQDFOS-UHFFFAOYSA-N verbascoside Natural products CC1OC(COC2C(O)C(COC3OC(C(O)C(O)C3O)C(=O)O)OC(Oc4cc(O)cc5OC(=CC(=O)c45)c6ccc(O)c(O)c6)C2O)C(O)C(O)C1O QFRYQWYZSQDFOS-UHFFFAOYSA-N 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 230000006837 decompression Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000001728 nano-filtration Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 206010000077 Abdominal mass Diseases 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Reproductive Health (AREA)
- Saccharide Compounds (AREA)
- Pharmacology & Pharmacy (AREA)
Abstract
The invention provides a method for synthesizing verbena glycoside and application thereof, wherein a compound A, a compound B, triphenylphosphine and anhydrous tetrahydrofuran are mixed and cooled to 0-10 ℃, diethyl azodicarboxylate is dripped, the room temperature is recovered, the pH value of a system is adjusted to 1 after reaction, the reaction is carried out at 40-50 ℃ for 5-10 h, suction filtration and purification are carried out to obtain a compound C, the compound C and anhydrous methanol are added into a reaction bottle, the temperature is reduced to 0-5 ℃, tris (triphenylphosphine) rhodium chloride is added, the reaction is carried out for 20-40 min and then is recovered to the room temperature, the reaction is continued for 2-6 h, filtration is carried out after decompression concentration, extraction and liquid separation are carried out, dichloromethane phase drying and column chromatography purification are carried out to obtain the verbena glycoside, the production amount of the verbena glycoside is greatly increased, the introduction of impurities, namely the verbena glycoside is avoided during the extraction process, the purity of the synthesized verbena glycoside is higher, the quality is better.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthetic method and application of verbena glycoside.
Background
The herba Verbenae is also called herba Verbenae, Plasmodium, herba Pteridis Multifidae, radix Aconiti Kusnezoffii, herba Schizonepetae. The whole herb contains verbascoside, tannin, volatile oil, stachyose in root and stem, and adenosine and B-carotene in leaf. Medicine property: bitter in taste and cold in nature, it enters liver and spleen meridians.
The verbena has the functions of clearing away heat and toxic materials, promoting blood circulation, removing blood stasis, inducing diuresis and relieving swelling. It can be used for treating fever, jaundice due to damp-heat pathogen, edema, dysentery, malaria, diphtheria, pharyngitis, gonorrhea, amenorrhea, abdominal mass, carbuncle, sore, and ulcerative gingivitis.
The verbena glycosides are used as main active ingredients in verbena and play a main promoting role in the treatment effect of the verbena, but at present, the verbena glycosides are mainly extracted from the verbena, and the artificial synthesis method is rarely reported.
Patent CN103232503A discloses a preparation method of verbenaside. The method comprises the following steps: 1) cutting herba Verbenae into segments, adding 10 times of water, heating and extracting, adding the extract into an ultrafiltration membrane for ultrafiltration, adding a nanofiltration membrane for nanofiltration, collecting the concentrated solution, adding an active carbon column for adsorption, carrying out gradient elution by using an ethanol solution, and concentrating the eluate under reduced pressure until no alcohol exists; 2) and (3) adding the concentrated solution into an alumina resin column for adsorption, eluting with an ethanol solution, concentrating the eluent, dissolving the eluent in an ethyl acetate solution in a refluxing manner, and refrigerating for crystallization to obtain the compound. The method has the advantages of simple production process, strong operability and high purity of the obtained product, and is suitable for industrial production.
The above patent only provides the extraction of verbena glycosides from verbena by an extraction method, and does not disclose a method for artificially synthesizing verbena glycosides.
Disclosure of Invention
Aiming at the existing problems, the invention provides a synthetic method and application of verbena glycoside, the production quantity of the verbena glycoside is greatly improved by utilizing a manual synthetic method, the introduction of impurities of the verbena glycoside with polarity close to that of the verbena glycoside can be greatly avoided in the extraction process of the verbena, and the synthesized verbena glycoside has higher purity and better quality.
In order to achieve the above object, the present invention adopts the following technical solutions:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A, a compound B, triphenylphosphine and anhydrous tetrahydrofuran into a reaction bottle under the protection of nitrogen, cooling to 0-10 ℃, dropwise adding diethyl azodicarboxylate within the temperature range, recovering to room temperature after dropwise adding, reacting for 3-10 h, adjusting the pH of a system to 1 by using hydrochloric acid, reacting for 5-10 h at 40-50 ℃, performing suction filtration, washing a filter cake by using anhydrous tetrahydrofuran, transferring the filter cake into the reaction bottle, adding water, stirring, dissolving, performing suction filtration, adjusting the pH of a filtrate to 10-12 by using a sodium hydroxide solution, adding dichloromethane for extraction, drying a dichloromethane phase by using anhydrous sodium sulfate, and performing column chromatography purification to obtain a compound C;
S2：
adding the compound C and absolute methanol into a reaction bottle under the protection of nitrogen, stirring for dissolving, cooling to 0-5 ℃, adding tris (triphenylphosphine) rhodium chloride, reacting for 20-40 min, recovering to room temperature, continuing to react for 2-6 h, filtering, concentrating under reduced pressure, adding dichloromethane and water, extracting, separating liquid, drying a dichloromethane phase with anhydrous sodium sulfate, and purifying by column chromatography to obtain the verbena glycoside.
Further, the mass ratio of the compound A, the compound B, triphenylphosphine and diethyl azodicarboxylate in S1 is 1: 1-1.05: 1-1.1: 1 to 1.1.
Furthermore, the mass concentration of the hydrochloric acid in the S1 is 8-12 mol/L.
Furthermore, the mass concentration of the sodium hydroxide solution in S1 is 0.1-1 mol/L.
Further, the eluent used for column chromatography purification in S1 was purified from ethyl acetate and methanol in a volume ratio of 5:1 are mixed.
Further, the mass ratio of the compound C and the tris (triphenylphosphine) rhodium chloride in S2 is 1: 1.5-2.2.
Further, the eluent used for column chromatography purification in S2 was purified from ethyl acetate and methanol in a volume ratio of 10: 1 are mixed.
The verbena glycoside synthesized by the synthesis method is applied to treating female dysmenorrhea.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the S1 is mitsunobu reaction, the reaction condition is mild, the operation is easy, the yield is high, the configuration of a reactant is reversed, the obtained configuration accords with the configuration of the verbena glycoside, S2 is carbonyl extrusion reaction, carbonyl is directly removed under the catalysis of tris (triphenylphosphine) rhodium chloride, the reaction does not influence the configuration of an S1 product, the operation is easy, after the carbonyl is removed, the verbena glycoside can be obtained by directly forming ether bonds, the reaction route is short, the production quantity of the verbena glycoside is greatly improved by utilizing an artificial synthesis method, the introduction of an impurity of the verbena glycoside with the polarity close to that of the verbena glycoside in the extraction process of the verbena can be greatly avoided, the purity of the synthesized verbena glycoside is high, and the quality of the synthesized verbena glycoside is better.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
Example 1:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A (10g, 226.23g/mol, 44.2mg), a compound B (9.2g, 208.17g/mol, 44.2mg, 1eq), triphenylphosphine (11.59g, 262.3g/mol, 44.2mg, 1eq) and anhydrous tetrahydrofuran (100ml) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃, dropwise adding diethyl azodicarboxylate (7.7g, 174.15g/mol, 44.2mg, 1eq) in the temperature range, recovering to room temperature after the dropwise adding is finished, adjusting the pH of the system to 1 by hydrochloric acid with the mass concentration of 10mol/L after 5 hours of reaction, performing suction filtration after 8 hours of reaction at 40 ℃, washing a filter cake by anhydrous tetrahydrofuran (50ml multiplied by 3), transferring to the reaction bottle, adding water, stirring, dissolving and performing suction filtration, adjusting the pH of the filtrate to 10-12 by a sodium hydroxide solution with the mass concentration of 0.5mol/L, adding dichloromethane for extraction, drying a dichloromethane phase, column chromatography purification with ethyl acetate: methanol 5:1 as eluent, compound C (12.9g) MS (m/z): 416.38, respectively;
S2：
adding compound C (10g, 416.38g/mol, 24.02mg) and anhydrous methanol (100ml) into a reaction bottle under the protection of nitrogen, cooling to 5 ℃ after stirring and dissolving, adding tris (triphenylphosphine) rhodium chloride (33.33g, 925.21g/mol, 36.02mg, 1.5eq), recovering the room temperature after reacting for 30min, continuing to react for 5h, filtering, adding dichloromethane and water after decompression and concentration, extracting and separating liquid, drying a dichloromethane phase by using anhydrous sodium sulfate, purifying by column chromatography, and purifying by using ethyl acetate: methanol 10: 1 as eluent, to obtain verbascoside (5.15g) MS (m/z): 388.37.
example 2:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A (10g, 226.23g/mol, 44.2mg), a compound B (9.66g, 208.17g/mol, 46.42mg, 1.05eq), triphenylphosphine (12.75g, 262.3g/mol, 48.62mg, 1.1eq) and anhydrous tetrahydrofuran (100ml) into a reaction bottle under the protection of nitrogen, cooling to 5 ℃, dropwise adding diethyl azodicarboxylate (8.47g, 174.15g/mol, 48.62mg, 1.1eq) in the temperature range, recovering to room temperature after dropwise adding, adjusting the pH of the system to 1 by hydrochloric acid with the mass concentration of 12mol/L after reaction for 3 hours, performing suction filtration after reaction for 10 hours at 45 ℃, washing a filter cake by the anhydrous tetrahydrofuran (50ml multiplied by 3), transferring to the reaction bottle, adding water, stirring, dissolving and performing suction filtration, adjusting the filtrate to 10-12 by a sodium hydroxide solution with the mass concentration of 0.2mol/L, adding dichloromethane for extraction, drying a dichloromethane phase, column chromatography purification with ethyl acetate: methanol 5:1 as eluent, compound C (12.31g) MS (m/z): 416.38, respectively;
S2：
adding compound C (10g, 416.38g/mol, 24.02mg) and anhydrous methanol (100ml) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃ after stirring and dissolving, adding tris (triphenylphosphine) rhodium chloride (48.88g, 925.21g/mol, 52.84mg, 2.2eq), recovering to room temperature after reacting for 20min, continuing to react for 6h, filtering, adding dichloromethane and water after decompression and concentration, extracting and separating liquid, drying a dichloromethane phase by using anhydrous sodium sulfate, purifying by column chromatography, and purifying by using ethyl acetate: methanol 10: 1 as eluent, to obtain verbascoside (5.12g) MS (m/z): 388.37.
example 3:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A (10g, 226.23g/mol, 44.2mg), a compound B (9.2g, 208.17g/mol, 44.2mg, 1eq), triphenylphosphine (11.59g, 262.3g/mol, 44.2mg, 1eq) and anhydrous tetrahydrofuran (100ml) into a reaction bottle under the protection of nitrogen, cooling to 5 ℃, dropwise adding diethyl azodicarboxylate (7.7g, 174.15g/mol, 44.2mg, 1eq) in the temperature range, recovering to room temperature after the dropwise adding is finished, adjusting the pH of the system to 1 by hydrochloric acid with the mass concentration of 12mol/L after 8 hours of reaction, performing suction filtration after 10 hours of reaction at 45 ℃, washing a filter cake by anhydrous tetrahydrofuran (50ml multiplied by 3), transferring to the reaction bottle, adding water, stirring, dissolving and performing suction filtration, adjusting the pH of the filtrate to 10-12 by a sodium hydroxide solution with the mass concentration of 0.1mol/L, adding dichloromethane for extraction, drying a dichloromethane phase, column chromatography purification with ethyl acetate: methanol 5:1 as eluent, compound C (12.85g) MS (m/z): 416.38, respectively;
S2：
adding compound C (10g, 416.38g/mol, 24.02mg) and anhydrous methanol (100ml) into a reaction bottle under the protection of nitrogen, cooling to 5 ℃ after stirring and dissolving, adding tris (triphenylphosphine) rhodium chloride (33.33g, 925.21g/mol, 36.02mg, 1.5eq), recovering the room temperature after reacting for 20min, continuing to react for 4h, filtering, adding dichloromethane and water after decompression and concentration, extracting and separating liquid, drying a dichloromethane phase by using anhydrous sodium sulfate, purifying by column chromatography, and purifying by using ethyl acetate: methanol 10: 1 as eluent, to obtain verbascoside (5.21g) MS (m/z): 388.37.
example 4:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A (10g, 226.23g/mol, 44.2mg), a compound B (9.2g, 208.17g/mol, 44.2mg, 1eq), triphenylphosphine (11.59g, 262.3g/mol, 44.2mg, 1eq) and anhydrous tetrahydrofuran (100ml) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃, dropwise adding diethyl azodicarboxylate (7.7g, 174.15g/mol, 44.2mg, 1eq) in the temperature range, recovering to room temperature after the dropwise adding is finished, adjusting the pH of the system to 1 by hydrochloric acid with the mass concentration of 8mol/L after 3 hours of reaction, performing suction filtration after 5 hours of reaction at 40 ℃, washing a filter cake by anhydrous tetrahydrofuran (50ml multiplied by 3), transferring to the reaction bottle, adding water, stirring, dissolving and performing suction filtration, adjusting the pH of the filtrate to 10-12 by a sodium hydroxide solution with the mass concentration of 0.1mol/L, adding dichloromethane for extraction, drying a dichloromethane phase, column chromatography purification with ethyl acetate: methanol 5:1 as eluent, compound C (13.53g) MS (m/z): 416.38, respectively;
S2：
adding compound C (10g, 416.38g/mol, 24.02mg) and anhydrous methanol (100ml) into a reaction bottle under the protection of nitrogen, cooling to 0 ℃ after stirring and dissolving, adding tris (triphenylphosphine) rhodium chloride (33.33g, 925.21g/mol, 36.02mg, 1.5eq), recovering to room temperature after reacting for 20min, continuing to react for 2h, filtering, adding dichloromethane and water after decompression and concentration, extracting and separating liquid, drying a dichloromethane phase by using anhydrous sodium sulfate, purifying by column chromatography, and purifying by using ethyl acetate: methanol 10: 1 as eluent, to obtain verbascoside (4.98g) MS (m/z): 388.37.
example 5:
a method for synthesizing verbenaside comprises the following steps:
S1：
adding a compound A (10g, 226.23g/mol, 44.2mg), a compound B (9.2g, 208.17g/mol, 44.2mg, 1eq), triphenylphosphine (11.59g, 262.3g/mol, 44.2mg, 1eq) and anhydrous tetrahydrofuran (100ml) into a reaction bottle under the protection of nitrogen, cooling to 10 ℃, dropwise adding diethyl azodicarboxylate (7.7g, 174.15g/mol, 44.2mg, 1eq) in the temperature range, recovering to room temperature after the dropwise adding is finished, adjusting the pH of the system to 1 by hydrochloric acid with the mass concentration of 12mol/L after 10 hours of reaction, performing suction filtration at 50 ℃ for 10 hours, washing a filter cake by the anhydrous tetrahydrofuran (50ml multiplied by 3), transferring to the reaction bottle, adding water, stirring, dissolving and performing suction filtration, adjusting the pH of the filtrate to 10-12 by a sodium hydroxide solution with the mass concentration of 1mol/L, adding dichloromethane for extraction, drying a dichloromethane phase by anhydrous sodium sulfate, column chromatography purification with ethyl acetate: methanol 5:1 as eluent, compound C (13.32g) MS (m/z): 416.38, respectively;
S2：
adding compound C (10g, 416.38g/mol, 24.02mg) and anhydrous methanol (100ml) into a reaction bottle under the protection of nitrogen, cooling to 5 ℃ after stirring and dissolving, adding tris (triphenylphosphine) rhodium chloride (33.33g, 925.21g/mol, 36.02mg, 1.5eq), recovering the room temperature after reacting for 40min, continuing to react for 6h, filtering, adding dichloromethane and water after decompression and concentration, extracting and separating liquid, drying a dichloromethane phase by using anhydrous sodium sulfate, purifying by column chromatography, and purifying by using ethyl acetate: methanol 10: 1 as eluent, to obtain verbascoside (5.05g) MS (m/z): 388.37.
table 1 below shows the reaction yield and product purity statistics in examples 1-5 of the present invention.
Table 1:
| example 1 | Example 2 | Example 3 | Example 4 | Example 5 | |
| S1 yield/%) | 70.1 | 66.9 | 69.8 | 73.5 | 72.4 |
| S2 yield/%) | 55.2 | 54.9 | 55.8 | 53.4 | 54.1 |
| Purity of the product /) | 99.4 | 99.6 | 99.8 | 99.5 | 99.5 |
As can be seen from the table above, the purity of the verbena glycosides prepared by the synthetic method of the invention can reach more than 99%, the quality is good, and the pharmaceutical requirements can be completely met.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in a process, method, article, or apparatus that comprises the element.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (7)
1. A method for synthesizing verbena glycoside is characterized in that: the method comprises the following steps:
S1：
adding a compound A, a compound B, triphenylphosphine and anhydrous tetrahydrofuran into a reaction bottle under the protection of nitrogen, cooling to 0-10 ℃, dropwise adding diethyl azodicarboxylate within the temperature range, recovering to room temperature after dropwise adding, reacting for 3-10 h, adjusting the pH of a system to 1 by using hydrochloric acid, reacting for 5-10 h at 40-50 ℃, performing suction filtration, washing a filter cake by using anhydrous tetrahydrofuran, transferring the filter cake into the reaction bottle, adding water, stirring, dissolving, performing suction filtration, adjusting the pH of a filtrate to 10-12 by using a sodium hydroxide solution, adding dichloromethane for extraction, drying a dichloromethane phase by using anhydrous sodium sulfate, and performing column chromatography purification to obtain a compound C;
S2：
adding the compound C and absolute methanol into a reaction bottle under the protection of nitrogen, stirring for dissolving, cooling to 0-5 ℃, adding tris (triphenylphosphine) rhodium chloride, reacting for 20-40 min, recovering to room temperature, continuing to react for 2-6 h, filtering, concentrating under reduced pressure, adding dichloromethane and water, extracting, separating liquid, drying a dichloromethane phase with anhydrous sodium sulfate, and purifying by column chromatography to obtain the verbena glycoside.
2. A method of synthesizing verbascoside as in claim 1, wherein: the mass ratio of the compound A to the compound B to the triphenylphosphine to the diethyl azodicarboxylate in S1 is 1: 1-1.05: 1-1.1: 1 to 1.1.
3. A method of synthesizing verbascoside as in claim 1, wherein: the mass concentration of the hydrochloric acid in the S1 is 8-12 mol/L.
4. A method of synthesizing verbascoside as in claim 1, wherein: the mass concentration of the sodium hydroxide solution in S1 is 0.1-1 mol/L.
5. A method of synthesizing verbascoside as in claim 1, wherein: eluent used for column chromatography purification in S1 is prepared from ethyl acetate and methanol according to the volume ratio of 5:1 are mixed.
6. A method of synthesizing verbascoside as in claim 1, wherein: the mass ratio of the compound C and the tris (triphenylphosphine) rhodium chloride in S2 is 1: 1.5-2.2.
7. A method of synthesizing verbascoside as in claim 1, wherein: eluent used for column chromatography purification in S2 is prepared from ethyl acetate and methanol according to the volume ratio of 10: 1 are mixed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010184492.XA CN111303218B (en) | 2020-03-17 | 2020-03-17 | Synthetic method and application of verbena glycoside |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010184492.XA CN111303218B (en) | 2020-03-17 | 2020-03-17 | Synthetic method and application of verbena glycoside |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111303218A CN111303218A (en) | 2020-06-19 |
| CN111303218B true CN111303218B (en) | 2021-03-30 |
Family
ID=71155309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010184492.XA Active CN111303218B (en) | 2020-03-17 | 2020-03-17 | Synthetic method and application of verbena glycoside |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111303218B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006052886A1 (en) * | 2004-11-05 | 2006-05-18 | Wyeth | Metabolites of certain [1,4]diazepino[6,7,1-ij]quinoline derivatives and methods of preparation and use thereof |
| CN103232503A (en) * | 2013-05-17 | 2013-08-07 | 南京泽朗医药科技有限公司 | Method for preparing verbenalin |
-
2020
- 2020-03-17 CN CN202010184492.XA patent/CN111303218B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006052886A1 (en) * | 2004-11-05 | 2006-05-18 | Wyeth | Metabolites of certain [1,4]diazepino[6,7,1-ij]quinoline derivatives and methods of preparation and use thereof |
| CN103232503A (en) * | 2013-05-17 | 2013-08-07 | 南京泽朗医药科技有限公司 | Method for preparing verbenalin |
Non-Patent Citations (2)
| Title |
|---|
| A General Synthetic Approach to Optically Active Iridoid Aglycones. The Total Syntheses ofβ-Ethyl Descarbomethoxyverbenalol, Ethyl Catalpol, and (-)-Specionin+;Byeang Hyean Kim et al.;《Tetrahedron》;19881231;第44卷(第11期);第3079-3092页 * |
| 对马鞭草中环烯醚萜苷类生物合成路径的探讨;张涛等;《江汉大学学报(医学版)》;20020930;第30卷(第3期);第16-17，32页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111303218A (en) | 2020-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109593034A (en) | A method of it is extracted in waste liquid from ginkgo leaf and prepares shikimic acid | |
| CN111303218B (en) | Synthetic method and application of verbena glycoside | |
| CN112266399B (en) | High-purity separation and extraction method of epimedium extract | |
| CN106831930B (en) | A kind of extractant and extracting method for ursolic acid extraction | |
| CN111056941B (en) | Method for preparing high-purity shikimic acid by utilizing ginkgo leaf extract chromatography waste liquid | |
| CN111018819B (en) | Preparation method of luteolin | |
| CN113754626B (en) | Method for preparing fisetin by enzyme method | |
| CN108586440A (en) | The purification process of Puerarin | |
| CN115536590A (en) | Preparation method of ergothioneine | |
| CN105481809B (en) | A kind of isolation and purification method of tanshin polyphenolic acid B and the preparation method of B magnesium tanphenolate | |
| CN110606863B (en) | Preparation method of N-acetylneuraminic acid dihydrate | |
| CN112920043A (en) | Preparation method of carnosic acid with content of more than 99% | |
| CN1513869A (en) | Malonyl ginseng saponin structure modification, enriched ginseng saponin Rb1 technology | |
| CN110862429A (en) | Preparation method of sodium aescinate | |
| CN106316797A (en) | Method for preparing hydroxytyrosol by using immobilized enzymic method coupled film technique | |
| CN113416182B (en) | Mangiferin and preparation method thereof | |
| CN109096275A (en) | A kind of hyoscine supercritical extraction process | |
| CN109336943A (en) | A kind of Bolbostemma paniculatum glucoside A purification process | |
| CN109320566B (en) | Separation and purification preparation method for extracting ganglioside from pig brain marrow | |
| CN114014900B (en) | Method for extracting and separating linarin from chrysanthemum indicum stems | |
| CN112920249B (en) | Industrial method for preparing stigmasterol | |
| CN114031499B (en) | Method for obtaining high-purity isochlorogenic acid from stevia rebaudiana and application | |
| CN117534644A (en) | Preparation method of alpinetin | |
| CN116396251A (en) | Method for extracting and purifying salvianolic acid B from red sage root | |
| CN116178466A (en) | Preparation method of momordica grosvenori leaf extract |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231213 Address after: 410000 room b5053, unit B, building 1, green food city, Agricultural Expo Center, Zhongyi 1st Road, Yuhua District, Changsha City, Hunan Province Patentee after: Hunan Tianhua Medical Biological Technology Co.,Ltd. Address before: Room 12-1, floor 1, building 1, sunrise Oriental II, No.1 Jin'an East Road, Fengcheng Town, Lianjiang county, Fuzhou City, Fujian Province, 350599 Patentee before: Lianjiang Renze Biotechnology Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20240515 Address after: 410205 Xianglu International Garden Phase II Hotel and apartment 511, No. 61, Lufeng Road, high tech Development Zone, Changsha, Hunan Patentee after: Hunan Dali Technology Consulting Co.,Ltd. Country or region after: China Address before: 410000 room b5053, unit B, building 1, green food city, Agricultural Expo Center, Zhongyi 1st Road, Yuhua District, Changsha City, Hunan Province Patentee before: Hunan Tianhua Medical Biological Technology Co.,Ltd. Country or region before: China |