CN113087618A - Method for preparing andrographolide derivatives by using industrial chromatography - Google Patents
Method for preparing andrographolide derivatives by using industrial chromatography Download PDFInfo
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000004587 chromatography analysis Methods 0.000 title abstract description 7
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011347 resin Substances 0.000 claims abstract description 14
- 229920005989 resin Polymers 0.000 claims abstract description 14
- 238000001179 sorption measurement Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 238000000926 separation method Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000011734 sodium Substances 0.000 claims description 29
- 229910052708 sodium Inorganic materials 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 7
- 238000011068 loading method Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 5
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 239000003463 adsorbent Substances 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract 1
- 150000003871 sulfonates Chemical class 0.000 abstract 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- -1 labdane diterpenoid compound Chemical class 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000207965 Acanthaceae Species 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical class [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- QJQRNDGUWQVAEV-AAFSJPGBSA-M sodium bisulfite adduct Chemical compound [Na+].[O-]S(=O)(=O)C([C@H]1N(C(C2=C3)=O)C=C(C1)/C=C/C(=O)N(C)C)NC2=CC1=C3OCO1 QJQRNDGUWQVAEV-AAFSJPGBSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for preparing andrographolide derivatives by using industrial chromatography, which comprises the steps of purifying andrographolide total sulfonates by macroporous adsorption resin column chromatography and industrial chromatography column; the method can realize real-time online monitoring of the separation process, has good process reproducibility, simple operation, short preparation time and small organic solvent consumption, and can be used for large-scale industrial production.
Description
Technical Field
The invention discloses a method for preparing andrographolide derivatives by using industrial chromatography, and particularly relates to a method for preparing sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate by using industrial chromatography.
Background
Andrographolide is a labdane diterpenoid compound extracted from the whole herb of Andrographis paniculata (Burm.F.) Nees of Acanthaceae, has the effects of resisting bacteria, diminishing inflammation, detoxifying and the like, and is an important active natural product. Andrographolide is poorly soluble and almost insoluble in water. In order to increase water solubility, facilitate use and improve clinical efficacy, it is usually formulated into water-soluble derivatives such as sodium bisulfite adduct, succinic acid half ester monopotassium/potassium sodium salt, sulfate ester, and the like. The andrographolide related product Xiyanping injection which is most widely clinically applied at present is a traditional Chinese medicine injection prepared by taking andrographolide total sulfonate (prepared by sulfonation reaction of andrographolide and sulfuric acid) as a raw material, has broad-spectrum antibacterial and antiviral effects, and has obvious effects on resisting bacteria and viral infection, quickly reducing fever and the like. In recent years, there have been more and more researches on the chemical components, pharmacological activities and clinical applications of Xiyanping injection solution (scholarly, Wang Gong Fu, Hanfei, etc.. isolation and characterization of four new derivatives in andrographolide sulfation reaction system [ J ]. chemical bulletin, 2009,67(3): 261-265.).
Shaojun and the like (Shaojun, Chenweikang, Zhengdongkin and the like, research on in vitro metabolic rate and metabolic products of 17-hydro-9-dehydroandrographolide, Chinese traditional medicine J2015, 40(5): 971-. Incubating the 17-hydro-9-dehydroandrographolide and rat liver microsome added with NADPH together, determining the residual concentration by adopting ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS), investigating the liver microsome metabolic rate of the 17-hydro-9-dehydroandrographolide, and identifying the metabolite of the 17-hydro-9-dehydroandrographolide in an incubation system by adopting ultra-high performance liquid chromatography tandem flight time mass spectrometry (UPLC-TOF-MSE). Wherein the molecular ion peak of the compound M3 is M/z367, which is consistent with the molecular ion peak of the compound 17-hydrogen-9-dehydrogenation-andrographolide-16-sodium carboxylate separated from andrographolide total sulfonate; but at present, no process suitable for industrial production exists.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides the method for preparing the andrographolide derivative by using industrial chromatography, and the method is suitable for industrial production and has high purity.
The invention provides a preparation method of a compound shown in a formula (I),
the method comprises the following steps:
(1) macroporous adsorption resin column chromatography: dissolving andrographolide sulfonate in solvent 1, loading onto macroporous adsorbent resin column, eluting with mixed solvent system 1, mixing eluates, and concentrating to obtain 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate (formula I) crude product;
(2) purifying by an industrial chromatographic column: dissolving a crude product of 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate (formula I) by using a proper amount of solvent 2, loading the crude product into an industrial chromatographic column, eluting by using a mixed solvent system 2, detecting the separation condition by using a dual-wavelength ultraviolet online detector, determining the start and stop time of eluent collection according to the peak-out time and the chromatographic peak height, combining the eluents containing the 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate, and concentrating under reduced pressure.
Preferably, in the step (1), the macroporous adsorption resin is styrene type macroporous adsorption resin; D101S macroporous adsorbent resin is preferred.
Preferably, in step (1), the solvent 1 is water; purified water is preferred.
Preferably, in the step (1), the mixed solvent system 1 is a mixed solution of short-chain alcohol and water; more preferably 0 to 40% (V/V) methanol aqueous solution or 0 to 40% (V/V) ethanol aqueous solution.
Preferably, in step (1), the elution is a gradient elution, such as elution with 0%, 10%, 20%, 40% (V/V) methanol aqueous solution in that order.
Preferably, in the step (1), the concentration temperature is 40-60 ℃; more preferably 45 to 50 ℃.
Preferably, in step (2), the industrial chromatographic column employs a reverse direction C18Filling a filler; more preferably, the reverse direction C18The filler is selected from XAqua and ODS-A, ODS-AQ.
Preferably, in step (2), the industrial chromatographic column is a dynamic axial compression industrial chromatographic column system.
Preferably, in the step (2), the wavelength is 200-300 nm; more preferably: 225nm and 254 nm.
Preferably, in the step (2), the solvent 2 is a methanol aqueous solution or an acetonitrile aqueous solution; more preferably 10-30% aqueous methanol or 10-30% aqueous acetonitrile.
Preferably, in the step (2), the mixed solvent system 2 is a mixed solution of methanol and water or a mixed solution of acetonitrile and water; more preferably 20 to 30% (V/V) methanol aqueous solution or 20 to 30% (V/V) acetonitrile aqueous solution.
Preferably, in step (2), the elution is a gradient elution; such as: sequentially eluting with 20% and 30% (V/V) acetonitrile-water solution; alternatively, elution was carried out with 20%, 25%, and 30% (V/V) methanol aqueous solution in this order.
Preferably, in the step (2), the concentration temperature is 40 to 60 ℃, and more preferably 45 to 50 ℃.
The invention provides a novel andrographolide derivative, which is shown in a formula (I):
the invention has the beneficial technical effects that:
1. the invention provides a compound with potential antibacterial, anti-inflammatory and antipyretic activities, which is shown in formula (I).
2. The preparation method of the sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate, disclosed by the invention, is convenient to operate, high in yield, high in purity up to more than 98%, and suitable for industrial production.
3. The filler used in the macroporous adsorption resin column chromatography and industrial chromatographic purification process of the preparation method disclosed by the invention is easy to regenerate, can be repeatedly used, has long normal service life and can obviously reduce the cost; good process reproducibility, simple operation, short preparation time and small organic solvent consumption.
Drawings
FIG. 1: HPLC chromatogram of sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate obtained in example 2;
FIG. 2: a 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate nuclear magnetic resonance hydrogen spectrogram;
FIG. 3: a nuclear magnetic resonance carbon spectrum of 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate.
Detailed Description
The chemical structure of sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate referred to in the examples below (the arabic number in the structure is the index position of the carbon atom in the chemical structure):
example 1: preparation of andrographolide general sulfonate
Taking 50L of absolute ethyl alcohol, placing the absolute ethyl alcohol in a reaction kettle, slowly adding 20L of concentrated sulfuric acid, stirring uniformly, adding 50.00kg of andrographolide, stirring, and standing at normal temperature for 72 hours. Controlling temperature, adding 50L 95% ethanol, stirring, adding 50% sodium hydroxide solution, adjusting pH to 7.0, adding ethanol until the alcohol content is 85%, standing for 24 hr, filtering, recovering ethanol from filtrate, concentrating into soft extract, and vacuum drying to obtain andrographolide total sulfonate.
Example 2: preparation of sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate
Taking 10.03kg of andrographolide total sulfonate, adding a proper amount of purified water to dissolve, loading the andrographolide total sulfonate on a D101S macroporous adsorption resin column, sequentially eluting with 0%, 10%, 20% and 40% ethanol-water solution by volume ratio, combining elution fractions containing 17-hydrogen-9-dehydrogenation-andrographolide-16-sodium carboxylate, and concentrating and drying at 45 ℃ under reduced pressure to obtain a 17-hydrogen-9-dehydrogenation-andrographolide-16-sodium carboxylate crude product; dissolving the crude product of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate with a proper amount of 10% methanol-water solution, purifying the crude product by an industrial chromatographic system (DAC-HB150 dynamic axial compression column, 5kg of ODS-AQ50 mu m filler), eluting the crude product by 20%, 25% and 30% methanol-water solution in sequence, receiving fractions according to the absorption peak height and peak shape under the detection conditions of 225nm and 254nm wavelengths, combining the eluents with the purity of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate being more than 98%, and concentrating and drying the eluents under reduced pressure at 45 ℃ to obtain 97.62g of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate with the HPLC purity of 98.10% (see figure 1).
Example 3: preparation of sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate
Taking 15.00kg of andrographolide total sulfonate, adding a proper amount of purified water to dissolve, then loading the andrographolide total sulfonate on a D101S macroporous adsorption resin column, sequentially eluting with methanol-water solution with the volume ratio of 0%, 10%, 20% and 40%, combining elution fractions containing 17-hydrogen-9-dehydrogenation-andrographolide-16-sodium carboxylate, and concentrating and drying the elution fractions at 50 ℃ under reduced pressure to obtain a 17-hydrogen-9-dehydrogenation-andrographolide-16-sodium carboxylate crude product; dissolving the crude product of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate by using a proper amount of 10% acetonitrile-water solution, then purifying the crude product by using an industrial chromatographic system (DAC-HB150 dynamic axial compression column, 5kg of ODS-AQ50 mu m filler), eluting the crude product by using 20% acetonitrile-water solution and 30% acetonitrile-water solution in sequence according to the volume ratio, absorbing peak height and peak type receiving flow under the detection conditions of 225nm and 254nm wavelengths, combining eluent with the purity of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate being more than 98%, and concentrating and drying the eluent at 50 ℃ under reduced pressure to obtain 142.93g of the 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate with the HPLC purity of 98.54%.
The chemical structure of the compound sodium 17-hydro-9-dehydro-andrographolide-16-carboxylate obtained in the example is identified by modern spectral techniques such as NMR, ESI-MS and the like, and the physicochemical properties are as follows:
white powder with molecular formula of C20H31O6Na；
High resolution mass spectrum ESI MS M/z367.2084[ M-Na ]]–(cald.for.C20H31O6,367.2121). Hydrogen spectrum of nuclear magnetic resonance1H-NMR(400MHZ) And nuclear magnetic resonance carbon spectrum13C-NMR(100MHZ) See fig. 2 and 3, respectively, and the data is shown in table 1.
TABLE 117 Hydrogen and carbon Spectroscopy data (400/100MHz, DMSO) for sodium hydro-9-dehydro-andrographolide-16-carboxylate
Claims (8)
1. A method for preparing a compound shown in a formula (I),
the method comprises the following steps:
(1) macroporous adsorption resin column chromatography: dissolving andrographolide sulfonate in solvent 1, loading onto macroporous adsorbent resin column, eluting with mixed solvent system 1, mixing eluates, and concentrating to obtain 17-hydrogen-9-dehydro-andrographolide-16-sodium carboxylate (formula I) crude product;
(2) purifying by an industrial chromatographic column: dissolving a crude product of 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate (formula I) by using a proper amount of solvent 2, loading the crude product into an industrial chromatographic column, eluting by using a mixed solvent system 2, detecting the separation condition by using a dual-wavelength ultraviolet online detector, determining the start and stop time of eluent collection according to the peak-out time and the chromatographic peak height, combining the eluents containing the 17-hydro-9-dehydro-andrographolide-16-sodium carboxylate, and concentrating under reduced pressure.
2. The preparation method according to claim 1, wherein in the step (1), the macroporous adsorption resin is styrene type macroporous adsorption resin, preferably D101S macroporous adsorption resin.
3. The production method according to claim 1, wherein in step (1),
the solvent 1 is water; preferably purified water;
and/or the mixed solvent system 1 is a mixed solution of short-chain alcohol and water, preferably 0-40% (V/V) methanol aqueous solution or 0-40% (V/V) ethanol aqueous solution;
and/or, the elution is gradient elution, such as elution sequentially with 0%, 10%, 20%, 40% (V/V) methanol water solution;
and/or the concentration temperature is 40-60 ℃, preferably 45-50 ℃.
4. The method according to claim 1, wherein in step (2), the industrial chromatographic column is reversed-phase C18Filling a filler; further preferably, reverse direction C18The filler is selected from XAqua and ODS-A, ODS-AQ.
5. The method of claim 1, wherein in step (2), the industrial chromatographic column is a dynamic axial compression industrial chromatographic column system.
6. The method according to claim 1, wherein in the step (2), the wavelength is 200 to 300nm, preferably 225nm and 254 nm.
7. The production method according to claim 1, wherein in the step (2),
the solvent 2 is methanol aqueous solution or acetonitrile aqueous solution, more preferably 10-30% methanol aqueous solution or 10-30% acetonitrile aqueous solution;
and/or the mixed solvent system 2 is a mixed solution of methanol and water or a mixed solution of acetonitrile and water, and more preferably a 20-30% (V/V) methanol aqueous solution or a 20-30% (V/V) acetonitrile aqueous solution;
and/or, the elution is a gradient elution; such as: sequentially eluting with 20%, 30% (V/V) acetonitrile-water solution or sequentially eluting with 20%, 25%, 30% (V/V) methanol-water solution;
and/or the concentration temperature is 40-60 ℃, preferably 45-50 ℃.
8. A compound shown in the formula (I),
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| CN201911337322.4A Pending CN113087618A (en) | 2019-12-23 | 2019-12-23 | Method for preparing andrographolide derivatives by using industrial chromatography |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687049A (en) * | 2005-03-25 | 2005-10-26 | 唐春山 | Sulfonated derivative of andrographolide and combination of medication |
| CN108392478A (en) * | 2017-02-07 | 2018-08-14 | 江西青峰药业有限公司 | Application of the andrographolide class compound in terms of preparing for radioactive damage drug |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1687049A (en) * | 2005-03-25 | 2005-10-26 | 唐春山 | Sulfonated derivative of andrographolide and combination of medication |
| CN108392478A (en) * | 2017-02-07 | 2018-08-14 | 江西青峰药业有限公司 | Application of the andrographolide class compound in terms of preparing for radioactive damage drug |
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