CN113845501B - Preparation method of senkyunolide J - Google Patents
Preparation method of senkyunolide J Download PDFInfo
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- CN113845501B CN113845501B CN202111238098.0A CN202111238098A CN113845501B CN 113845501 B CN113845501 B CN 113845501B CN 202111238098 A CN202111238098 A CN 202111238098A CN 113845501 B CN113845501 B CN 113845501B
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- AXRIHSJZHOTGAE-UHFFFAOYSA-N 3-butyl-6,7-dihydroxy-4,5,6,7-tetrahydro-3h-2-benzofuran-1-one Chemical compound C1CC(O)C(O)C2=C1C(CCCC)OC2=O AXRIHSJZHOTGAE-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 potassium hydrogen peroxymonosulfate compound salt Chemical class 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 9
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 8
- 238000013375 chromatographic separation Methods 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZPIKVDODKLJKIN-NSHDSACASA-N Senkyunolide Chemical compound C1CC=CC2=C1[C@H](CCCC)OC2=O ZPIKVDODKLJKIN-NSHDSACASA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012266 salt solution Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 241000244365 Ligusticum sinense Species 0.000 claims description 4
- 238000000622 liquid--liquid extraction Methods 0.000 claims description 3
- 238000000638 solvent extraction Methods 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims 1
- 241000112528 Ligusticum striatum Species 0.000 abstract description 9
- 239000000284 extract Substances 0.000 abstract description 8
- 238000011160 research Methods 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 2
- 229940126680 traditional chinese medicines Drugs 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002994 raw material Substances 0.000 description 13
- IQVQXVFMNOFTMU-FLIBITNWSA-N (Z)-ligustilide Chemical compound C1CC=CC2=C1C(=C/CCC)/OC2=O IQVQXVFMNOFTMU-FLIBITNWSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- IQVQXVFMNOFTMU-DHZHZOJOSA-N Z-ligustilide Natural products C1CC=CC2=C1C(=C/CCC)\OC2=O IQVQXVFMNOFTMU-DHZHZOJOSA-N 0.000 description 10
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- DQNGMIQSXNGHOA-UMEXKXKESA-N (3e,6s,7s)-3-butylidene-6,7-dihydroxy-4,5,6,7-tetrahydro-2-benzofuran-1-one Chemical compound C1([C@@H]([C@@H](O)CC2)O)=C2C(=C/CCC)\OC1=O DQNGMIQSXNGHOA-UMEXKXKESA-N 0.000 description 2
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010059109 Cerebral vasoconstriction Diseases 0.000 description 1
- 241000212948 Cnidium Species 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 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
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- DQNGMIQSXNGHOA-UHFFFAOYSA-N senkyunolide-H Natural products C1CC(O)C(O)C2=C1C(=CCCC)OC2=O DQNGMIQSXNGHOA-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of senkyunolide J, which belongs to the technical field of preparation of chemical components of traditional Chinese medicines, and comprises the steps of extracting ligusticum wallichii oil by an aqueous solvent, adding potassium hydrogen peroxymonosulfate compound salt into an extract for reaction, and treating the product after the reaction is finished by steps of filtering, concentrating, liquid-liquid extracting, chromatographic separation and the like to obtain a pure senkyunolide J product; the invention provides a simple and easy method for preparing a large amount of high-purity senkyunolide J, thereby providing possibility and convenience for the research of the drug effect of the senkyunolide J and the large-scale application.
Description
Technical Field
The invention relates to the technical field of preparation of chemical components of traditional Chinese medicines, in particular to a preparation method of senkyunolide J.
Background
Senkyunolide J (senkyunolide J) is light yellow viscous oil, and is a phthalide active ingredient (Molecules 2012, 17, 10614-10651) contained in rhizoma Ligustici Chuanxiong. Senkyunolide J is reported to have suitable lipophilicity and good water solubility, and is rapidly absorbed orally and is able to enter blood and cerebrospinal fluid; animal experiment results show that senkyunolide J has the pharmacological action of resisting cerebral ischemia, can obviously improve cerebral blood flow of rats subjected to cerebral ischemia/reperfusion, can also resist cerebral blood flow reduction caused by local cerebral vasoconstriction of rats induced by potassium chloride, and has the potential of being developed into a medicament for preventing and treating cerebral apoplexy and relevant treatment in the convalescence (application of senkyunolide J in preparing medicaments for resisting cerebral apoplexy, chinese patent CN 102144997B).
However, there is still a considerable lack of research on the efficacy of Guan Yang ligustilide J. This is mainly limited by the low content of senkyunolide J in Ligusticum chuanxiong Hort, and it is difficult to prepare a large amount of high purity compounds for related research.
The inventors of the present application have made a great deal of study in the art. Earlier studies by the inventors show that ligustilide I can be obtained by chemical conversion of ligustilide with high content in ligustilide oil (a preparation method of ligustilide I, chinese patent, CN 107619401A). Considering that senkyunolide J is structurally similar to senkyunolide I, the inventors originally intended the same approach to be followed, namely: directly taking ligusticum wallichii oil as a raw material, heating the ligusticum wallichii oil and potassium hydrogen persulfate compound salt in an alkaline aqueous solvent to be more than 30 ℃ for reaction, and preparing the senkyunolide J by converting the senkyunolide A with high content in the ligusticum wallichii oil, and surprisingly, the result shows that the generation of the senkyunolide J is not detected by the method.
Disclosure of Invention
The invention aims to provide a simple and efficient method for preparing senkyunolide J, which aims to solve the problem that senkyunolide J is difficult to prepare in large quantities.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the method comprises the steps of taking ligustilide A-containing ligusticum wallichii oil as a raw material, adding an aqueous solvent, fully mixing, standing for layering, removing insoluble oily matters, and concentrating a solvent extract to obtain a reaction raw material; adding potassium hydrogen peroxymonosulfate compound salt solution into the reaction raw materials, stirring at a proper reaction temperature for reaction, monitoring the reaction progress by liquid chromatography until the senkyunolide J in the reaction liquid is not increased, filtering the product, concentrating, extracting by liquid-liquid extraction and separating by chromatography to obtain the senkyunolide J.
The potassium hydrogen peroxymonosulfate compound salt is also called potassium hydrogen peroxymonosulfate compound salt, and has a chemical formula of 2KHSO 5 ·KHSO 4 ·K 2 SO 4 。
The conversion process is as follows:
the inventors of the present application confirmed by a large number of experiments: the conversion reaction can be smoothly performed only by pre-treating the ligustilide A-containing ligustilide oil to remove impurities and under neutral to weakly acidic conditions at room temperature (less than or equal to 28 ℃) without heating.
It is to be noted that the pH of the potassium hydrogen peroxymonosulfate complex salt solution may be varied between 1 and 10 by adjusting the amount of sodium carbonate added, as known to those skilled in the art.
As a preferable technical scheme: the aqueous solvent is selected from one of water-methanol and water-ethanol.
As a preferable technical scheme: the volume ratio of water in the aqueous solvent is 10-50%.
As a preferable technical scheme: the pH value of the potassium hydrogen peroxymonosulfate compound salt solution is 4-7.
As a preferable technical scheme: the temperature of the reaction is 10-28 ℃.
As a preferable technical scheme: the solvent used for liquid-liquid extraction is selected from one of ethyl acetate, butyl acetate and diethyl ether.
As a preferable technical scheme: the stuffing for chromatographic separation is one of normal phase column chromatographic silica gel and reversed phase C18 silica gel.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the advantages that: compared with the method for directly separating and purifying the ligustilide J from the ligusticum chuanxiong hort extract, the method provided by the invention is simple and easy to implement, high in yield and low in cost, so that the method provides possibility and convenience for the drug effect research and large-scale application of the ligustilide J.
Drawings
FIG. 1 UPLC chromatograms of Ligusticum chuanxiong oil before and after reaction.
FIG. 2 shows a nuclear magnetic resonance hydrogen spectrum of senkyunolide J.
FIG. 3 shows a nuclear magnetic resonance carbon spectrum of senkyunolide J.
FIG. 4 mass spectrum of senkyunolide J.
Detailed Description
The invention will be further described with reference to the accompanying drawings.
Instrument: b11-3 magnetic stirrer (Shanghai Sele instruments Co., ltd.); PX224ZH electronic balance (ohus instruments limited); r-100 rotary evaporator (BUCHI, switzerland); c-620 medium pressure preparative chromatograph (BUCHI, switzerland); the acquisition UPLC (WATERS Co., USA); milli-Q integrate-3 ultra-pure water machine (Merck Mibo Co., U.S.A.).
Raw materials and reagents: supercritical extraction of rhizoma Ligustici Chuanxiong oil from Jiangxi all around ball perfumery company; potassium hydrogen persulfate complex salts were purchased from hadamard reagent company; methanol, ethanol, formic acid, ethyl acetate, petroleum ether and sodium bicarbonate are all analytically pure and are purchased from Chengdu Kelong chemical reagent factories; chromatographic acetonitrile is a product of Fisher corporation, USA.
Example 1
A preparation method of senkyunolide J comprises the following steps:
(1) Pretreatment: 30g of ligusticum wallichii oil (purchased from Jiangxi Huangzhou natural perfume Co., ltd., senkyunolide A content 7.5%, w/w), 600ml of 85% methanol with volume percentage concentration, intense shaking for 5 minutes, standing and layering; discarding the lower deep red oily matter, concentrating the upper solution under reduced pressure, and removing the solvent to obtain a reaction raw material;
(2) The reaction: transferring the prepared reaction raw materials into a 1000ml round-bottom flask, adding 150ml of ethanol, and stirring to fully dissolve the reaction raw materials; 60g of potassium hydrogen peroxymonosulfate compound salt is dissolved in 230ml of water, sodium carbonate is added to adjust the pH value of the solution to 5, then the solution is slowly added into a reaction system, the reaction temperature is maintained at 20-25 ℃, the reaction progress is monitored by liquid chromatography, and the reaction is finished after 10 hours;
(3) And (3) detection: waters Acquity UPLC chromatograph; column Waters BEH C18 (2.1 mm. Times.50 mm, 1.7 μm); acetonitrile (a) -0.1% formic acid water (B) as mobile phase; gradient elution is carried out for 0 to 0.5min (20 percent A), 0.5 to 3.0min (20 percent A to 70 percent A), 3.0 to 3.5min (70 percent A to 100 percent A), 3.5 to 4.0min (100 percent A), 4.0 to 4.01min (100 percent A to 20 percent A) and 4.01 to 5.0min (20 percent A); the flow rate is 0.4ml/min; column temperature is 35 ℃; a detection wavelength of 216nm; the chromatograms at the beginning and end of the reaction are shown in FIG. 1;
(4) Separating: the reaction system was filtered to remove insoluble matters, the filtrate was concentrated under reduced pressure, the remaining aqueous solution was extracted with ethyl acetate (100 ml. Times.2), the ethyl acetate extracts were combined, concentrated under reduced pressure, and the extract was separated by reversed phase C18 silica gel column chromatography (phi 49 mm. Times.460 mm, packing YMC ODS-AQ 50 μm) and eluted with a 30% -40% ethanol (v/v) gradient. Collecting target fractions, combining the target fractions after UPLC detection, and evaporating the solvent under reduced pressure to obtain 0.93g of light yellow oily substance, wherein the yield is 35.2%, and the UPLC purity is 94.7%; the results of NMR and MS analysis prove that the senkyunolide J is shown in the figures 2, 3 and 4;
spectral data of the obtained senkyunolide J: UV (ultraviolet) light λmax :216nm; ESI-MS display criteriaMolecular ion [ M+H ]] + A kind of electronic devicem/zIs 227, [ M+Na ]] + A kind of electronic devicem/z249; 1 H NMR (600 MHz, DMSO-d 6 )δ: 0.87 (3H, t), 1.20～1.25 (2H, m), 1.27～1.33 (2H, m),1.38～1.45 (1H, m), 1.72～1.86 (3H, m), 2.19～2.31 (2H, m), 3.76 (1H, m), 3.93 (1H, dd, j = 2.4,4.2 Hz), 4.98(1H, dd)； 13 C-NMR (150 MHz, DMSO-d 6 )δ: 172.8, 167.5, 125.6, 82.2, 69.1, 63.3, 31.6, 26.7, 23.9, 22.2, 19.2, 14.3。
example 2
A preparation method of senkyunolide J comprises the following steps:
(1) Pretreatment: 6g of ligusticum wallichii oil (the content of senkyunolide A is 7.5 percent, w/w), 100ml of 65 percent ethanol is added, the mixture is vigorously shaken for 5 minutes, and the mixture is stood for layering; discarding the lower deep red oily matter, concentrating the upper solution under reduced pressure, and removing the solvent to obtain a reaction raw material;
(2) The reaction: transferring the prepared reaction raw materials into a 250ml round-bottom flask, adding 50ml of ethanol, and stirring to fully dissolve the reaction raw materials; 12g of potassium hydrogen peroxymonosulfate compound salt is dissolved in 75ml of water, sodium carbonate is added to adjust the pH value of the solution to 6, then the solution is slowly added into a reaction system, the reaction temperature is maintained at 10-15 ℃, the reaction progress is monitored by liquid chromatography, and the reaction is finished after 24 hours;
(3) Separating: after the reaction is finished, insoluble substances are removed by suction filtration, the filtrate is concentrated under reduced pressure, the residual water solution is extracted by ethyl acetate (20 ml multiplied by 2 times), the extracts are combined and concentrated, and the extract is separated by reversed phase C18 silica gel column chromatography (phi 26 mm multiplied by 460 mm, packing YMC ODS-AQ 50 μm) and is eluted by 40% -60% methanol (v/v) gradient. The target fractions were collected, combined after UPLC detection, and the solvent was distilled off under reduced pressure to give 0.21g of pale yellow oil in 39.7% yield with a UPLC purity of 96.3%.
Example 3
A preparation method of senkyunolide J comprises the following steps:
(1) Pretreatment: 60g of ligusticum wallichii oil (the content of senkyunolide A is 7.5 percent, w/w), 800ml of 65 percent ethanol is added, the mixture is vigorously shaken for 5 minutes, and the mixture is stood for layering; discarding the lower deep red oily matter, concentrating the upper solution under reduced pressure, and removing the solvent to obtain a reaction raw material;
(2) The reaction: transferring the prepared reaction raw materials into a 2500ml round-bottom flask, adding 800ml of methanol, and stirring to fully dissolve; 120g of potassium hydrogen peroxymonosulfate compound salt is dissolved in 800ml of water, sodium carbonate is added to adjust the pH value of the solution to 5, then the solution is slowly added into a reaction system, the reaction temperature is maintained at 15-20 ℃, the reaction progress is monitored by liquid chromatography, and the reaction is finished after 16 hours;
(3) Separating: after the reaction, insoluble substances are removed by suction filtration, the filtrate is concentrated under reduced pressure, the remaining water solution is extracted by ethyl acetate (200 ml multiplied by 3 times), the extracts are combined and concentrated, the extract is separated by normal phase silica gel column chromatography (phi 50mm multiplied by 500 mm, packing 200-300 mesh column chromatography silica gel), and petroleum ether-ethyl acetate (1:1, v/v) is eluted in a gradient way. The target fractions were collected, combined after detection by UPLC, and the solvent was distilled off under reduced pressure to give 1.85g of a pale yellow oil with a yield of 34.9% and a UPLC purity of 91.3%.
Comparative example 1
This comparative example was based on the foregoing example 1, in which the ligustilide J was obtained in a yield of only 1.9% in about 0.05g without leaving the ligustilide J unchanged by directly using the ligusticum wallichii oil for the reaction without any pretreatment.
It can be seen that the low polarity substances insoluble in aqueous methanol or aqueous ethanol in the cnidium oil prevent the conversion of senkyunolide A to senkyunolide J, which must be removed in the pretreatment step.
Comparative example 2
This comparative example was based on the aforementioned example 2, in which 12g of potassium hydrogen peroxymonosulfate complex salt was dissolved in 50ml of water, and sodium carbonate was added to adjust the pH of the solution to 8, and the remainder was unchanged, so that the formation of senkyunolide J was not detected.
It can be seen that the acid-base nature of the potassium hydrogen peroxymonosulfate complex salt solution is a key factor affecting the production of senkyunolide J.
Comparative example 3
The comparative example was based on the above-mentioned example 1, in which the reaction temperature was maintained at 35 to 40℃by heating in the reaction in the step (2), and the remainder was unchanged, and as a result, about 0.259g of senkyunolide J was obtained, with a yield of only 9.8%.
It can be seen that heating impedes the conversion of senkyunolide A to senkyunolide J, significantly reducing the yield of senkyunolide J, and thus it is necessary to maintain the reaction at room temperature (28 ℃ C.).
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (5)
1. A preparation method of senkyunolide J is characterized by comprising the following steps: the method comprises extracting Ligusticum chuanxiong oil containing senkyunolide A with aqueous solvent to remove insoluble oily substance, adding potassium hydrogen peroxymonosulfate compound salt solution to react, and making into final product
Filtering, concentrating, liquid-liquid extracting, and separating by chromatography to obtain senkyunolide J; wherein the pH value of the potassium hydrogen peroxymonosulfate compound salt solution is 4-7, and the reaction temperature is 10-28 ℃.
2. The method according to claim 1, characterized in that: the aqueous solvent is selected from one of water-methanol and water-ethanol.
3. The method according to claim 2, characterized in that: the volume ratio of water in the aqueous solvent is 10-50%.
4. The method according to claim 1, characterized in that: the solvent used for liquid-liquid extraction is selected from one of ethyl acetate, butyl acetate and diethyl ether.
5. The method according to claim 1, characterized in that: the stuffing for chromatographic separation is one of normal phase column chromatographic silica gel and reversed phase C18 silica gel.
Priority Applications (1)
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| JPH01207233A (en) * | 1988-02-12 | 1989-08-21 | Tsumura & Co | Antiarteriosclerotic |
| JPH05247022A (en) * | 1990-07-10 | 1993-09-24 | Tsumura & Co | New phthalide and brain function improver containing the same as active ingredient |
| CN103896892A (en) * | 2012-12-26 | 2014-07-02 | 上海张江中药现代制剂技术工程研究中心 | Preparation of senkyunolide I and senkyunolide H from ligusticum wallichii extract via high-speed countercurrent chromatography |
| CN104003963A (en) * | 2014-05-30 | 2014-08-27 | 长沙高新技术产业开发区博海生物科技有限公司 | Separation and preparation method of ligustilide |
| CN107619401A (en) * | 2017-11-07 | 2018-01-23 | 四川省中医药科学院 | A kind of preparation method of senkyunolide Ⅰ |
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| JPH01207233A (en) * | 1988-02-12 | 1989-08-21 | Tsumura & Co | Antiarteriosclerotic |
| JPH05247022A (en) * | 1990-07-10 | 1993-09-24 | Tsumura & Co | New phthalide and brain function improver containing the same as active ingredient |
| CN103896892A (en) * | 2012-12-26 | 2014-07-02 | 上海张江中药现代制剂技术工程研究中心 | Preparation of senkyunolide I and senkyunolide H from ligusticum wallichii extract via high-speed countercurrent chromatography |
| CN104003963A (en) * | 2014-05-30 | 2014-08-27 | 长沙高新技术产业开发区博海生物科技有限公司 | Separation and preparation method of ligustilide |
| CN107619401A (en) * | 2017-11-07 | 2018-01-23 | 四川省中医药科学院 | A kind of preparation method of senkyunolide Ⅰ |
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