CN105669792A - Preparation method of phenylpropanoid compound - Google Patents

Preparation method of phenylpropanoid compound Download PDF

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Publication number
CN105669792A
CN105669792A CN201610154195.4A CN201610154195A CN105669792A CN 105669792 A CN105669792 A CN 105669792A CN 201610154195 A CN201610154195 A CN 201610154195A CN 105669792 A CN105669792 A CN 105669792A
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preparation
eluent
phenylpropanoids
water
acid
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CN105669792B (en
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彭开锋
张鹏
伍实花
林丽美
夏博候
佘娜
白璐
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Zhuzhou Qianjin Pharmaceutical Co Ltd
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Zhuzhou Qianjin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to technical field of medicine, discloses a preparation method of a phenylpropanoid compound, and particularly relates to a phenylpropanoid compound obtained by being separated from dry roots of flemingia macrophylla. The phenylpropanoid compound is prepared through solution extraction, column chromatography separation and separation of a preparation liquid phase, and the phenylpropanoid compound obtained through the method is reported for the first time and high in purity. Experiments show that the obtained phenylpropanoid compound can suppress the expression effects of cell inflammatory factors TNF-alpha, IL-1beta and IL-6 and has a suppressing effect on (-OH) of hydroxyl radicals so that anti-inflammatory and anti-oxidant activity can be achieved, various inflammatory diseases such as cervicitis, endometritis, pelvic inflammation, mastitis, sphagitis and/or arthritis can be treated easily, and the compound can be developed into new drugs. The phenylpropanoid compound as shown in the structural formula (I) and pharmaceutically acceptable salt thereof are provided. Please see the structural formula (I) in the description.

Description

A kind of preparation method of phenylpropanoids
Technical field
The present invention relates to medical technical field, more specifically, relate to a kind of preparation method of new phenylpropanoids.
Background technology
The constituent structure that extraction separation obtains from natural drug is various, significantly active, and it is carried out to separation and purification, structureModify, transform and entirely synthesize, be a main thought of new drug development always.
TNF-α: be a kind of can direct killing tumour cell and to normal cell the cell factor without overt toxicity, be so farOne of bioactie agent that the direct killing function of tumor found till the present is the strongest, but its toxic and side effect is also very tightHeavy.
IL-1 β: collaborative APC and the T cell activation of stimulating in the time of local low concentration, promote B cell proliferation and secretory antibody, enterRow immunological regulation. When a large amount of generation, there is endocrine effect: induction liver acute phase protein is synthetic, causes heating and cachexia.
IL-6: mankind IL-6 gene is positioned on No. 7 chromosome; IL-6 molecular weight is between 21～30KD. Mainly by listCore macrophage, Th2 cell, vascular endothelial cell, fibroblast produce. Can stimulate activating B cell propagation, secretion is anti-Body; Stimulate T cell proliferation and CTL activation; Cell cultured supernatant synthesized acute phase albumen, participates in inflammatory reaction; Promote haemocyte to send outEducate.
IL-6 can be synthesized by various kinds of cell, comprise the T cell of activation and B cell, monocytes/macrophages, endothelial cell,Epithelial cell and fibroblast etc. The target cell of IL-6 effect is a lot, comprises that macrophage, liver cell, static T are thinB cell and the thick liquid cell etc. of born of the same parents, activation; Its biological effect is also very complicated.
OH is the reactive oxygen species of tool activity in biosystem, can cause DNA in cell and organism, protein and fatMatter oxidative damage.
Therefore, seek a kind of new preparation method, from natural plants, extract separation and obtain new compound, can suppress thinBorn of the same parents' inflammatory factor TNF-α, IL-1 β, the expressional function of IL-6, the activity of inhibition hydroxyl radical free radical (OH), is applied to struvite diseaseSick treatment, is necessary.
The very heavy medicinal material that pulls out is that pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania) plant is largeThe dry root that leaf is very heavy to be pulled out (Moghaniamacrophylla (Willd.) O.Kuntze), is mainly distributed in the southeast in ChinaArea. This plant Chinese Plants will (1995,41:313), Flora of Taiwan (1977,3:258), Hainan flora (1965,2:311), " Chinese Higher plant illustrated handbook " (1972,2:510), Chinese main plant figure say (1955, pp707) and Guangzhou plantIn will (1956, pp361), all include. Very heavyly pull out the genunie medicinal materials that medicinal material is Guangxi province, history is loaded in " Illustrated Book on Plants ",There is medication among the people basis widely. Its nature and flavor are sweet, micro-puckery, flat, have the effects such as removing damp-heat, are mainly used in treating rheumatic boneThe gynecological diseases such as bitterly, traumatic injury, chronic nephritis, dysmenorrhoea and leukorrhea be many. This medicinal material has recorded at present into version " middle traditional Chinese medicines in 2005Allusion quotation " annex.
Flemingia macrophylla pulls out the composition of having reported and mainly contains flavonoids, steroid class, terpene, Anthraquinones, volatile oil composition, all toolThere is certain pharmacologically active.
It is various that flemingia macrophylla pulls out pharmacologically active, reports the more neuroprotection that has, and anti-inflammatory, antioxidation, to diseaseThe anthelmintic action of pathogenic microorganism, parahormone effect, CDCC, antibacterial action and immunological enhancement, antifatigue effect.
Very heavy pull out be widely used at present the type such as gynaecology, arthralgia due to wind-dampness Chinese patent drug produce, as FUKE QIANJIN PIAN, gynaecologyA thousand pieces of gold capsule, infusion of cherokee rose and spatholobus stem, JINJI JIAONANG etc., this type of Chinese patent drug is mainly used in gynaecological disease, and (dysmenorrhoea, cold uterus are infertile, uterusSagging, pelvic infecton, mastitis, leukorrhea are many, the postpartum deficiency of blood, arthralgia, postpartum waist and knee, hypogalactia and newborn sore etc.), weak anaemia(woman anemia, deficient qi and blood and the after being ill deficiency of vital energy etc.). What in recent years, clinical report was more is that FUKE QIANJIN PIAN is in treatment gynaecology inflammationThe effect of disease aspect.
At present, in the very heavy document pulling out, the document of report phenylpropanoids is few, finds a kind of new preparation sideMethod is isolated effective Phenylpropanoid Glycosides class noval chemical compound from natural plants, and it is carried out to separation and purification, structural modification and synthetic,Developing new drug, is applied to the treatment of diseases associated with inflammation, significant.
Summary of the invention
The object of the present invention is to provide the new Phenylpropanoid Glycosides of one that a kind of dry root pulling out from flemingia macrophylla, separation obtainsThe preparation method of compounds, is extracted and is separated the compound that obtains and can suppress cellular inflammation factor TNF-by this preparation methodα, IL-1 β, the expressional function of IL-6, has the inhibitory action of (OH) to hydroxyl radical free radical, and then has anti-inflammatory and anti-oxidantActivity, is of value to the treatment of various diseases associated with inflammation, this compound can be developed to new drug.
Particularly, the preparation method of phenylpropanoids of the present invention comprises the steps:
S1. getting the root that flemingia macrophylla pulls out is raw material, dry, and stripping and slicing is extracted through ethanolic solution, and extract is merged, denseBe reduced to without alcohol taste, obtain medicinal extract for subsequent use;
S2. gained medicinal extract in step S1 is dissolved in water, adopts large pore resin absorption column to carry out wash-out to it, eluant, eluent isEthanol-water system, collects the eluent of front 3 column volumes, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 reversed material ODS column chromatography of collecting in step S2 is carried out to wash-out, eluant, eluent is firstAlcohol-water system, 18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, collect 6 flow points in order,Called after MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16, for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, mobile phase is methanol-water-acetic acid systemSystem, collects eluent by peak sequence, collects altogether 4 flow points, called after MM-131 respectively, and MM-132, MM-133, MM-134,For subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, mobile phase is methanol-water-acetic acid systemSystem, collects eluent, obtains described phenylpropanoids after recrystallization. The purity of described phenylpropanoids is99.45%. The structural formula of described phenylpropanoids is suc as formula shown in (1):
Preferably, in step S1, the concentration of ethanolic solution is 50～80 volume %, more preferably ethanolic solution concentrationBe 60 volume %.
Preferably, in step S1, the extraction time of ethanolic solution is 2～4 times, extracts 1～3 hour at every turn, further excellentThe extraction time of electing ethanolic solution as is 3 times, each 2 hours.
Preferably, in step S2, macroporous absorbent resin adopts D101 macroporous absorbent resin.
Preferably, in step S2, the volume ratio of ethanol and water is 0:100～15:85.
Preferably, in step S3, the volume ratio of methyl alcohol and water is 20:80～30:70, more preferably 25:75.
Preferably, in step S4, the volume ratio of methanol-water-acetic acid is 10:90:0.01～35:65:0.01, further
Be preferably 15:85:0.01.
Preferably, in step S4, preparative liquid chromatography post is YMC, 20mm*250mm, and flow rate of mobile phase is 5～10ml/Min, more preferably flow velocity 5ml/min.
Preferably, in step S5, the volume ratio of methanol-water-acetic acid is 15:85:0.01.
Preferably, in step S5, preparative liquid chromatography post is YMC, 20mm*250mm, and flow rate of mobile phase is 5mL/min.
The invention provides the phenylpropanoids that described preparation method prepares.
And the phenylpropanoids preparing through chemical synthesis process taking described phenylpropanoids as raw materialSalt. The structure of described salt is suc as formula shown in (II) or formula (III):
Wherein, R is inorganic acid, R1Or R2For any one or any two kinds in sulfonate radical, alkali metal ion or ammonium root.
Preferably, described inorganic acid is hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid or breastAcid; Described sulfonate radical is the sulfonate radical with aryl; Described alkali metal ion be potassium ion, sodium ion, calcium ion, magnesium ion orLithium ion.
The sulfonate radical preferably, with aryl is benzene sulfonic acid root or p-methyl benzenesulfonic acid root.
Preferably, described pharmaceutically acceptable salt is ammonium salt.
Beneficial effect of the present invention:
The present invention provides a kind of preparation method for new phenylpropanoids and pharmaceutically acceptable salt thereof, firstThe dry root pulling out from flemingia macrophylla, separate the new phenylpropanoids of one obtaining, the compound making can suppress cellInflammatory factor TNF-α, IL-1 β, the expressional function of IL-6, has the inhibitory action of (OH) to hydroxyl radical free radical, and then hasAnti-inflammatory and antioxidation activity, can be used as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or arthritisDeng the medicine of diseases associated with inflammation.
The object of the invention is from traditional prescriptions of traditional Chinese medicine, by the prescription from FUKE QIANJIN PIAN and ' Qianjin ' capsule to treat ganopathyIn, make a kind of new phenylpropanoids by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying, and by realChecking is real, and it can be applied to diseases associated with inflammation, as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or passThe treatment of the diseases such as joint is scorching.
Particularly, inventor is by from the prescription of FUKE QIANJIN PIAN, ' Qianjin ' capsule to treat ganopathy, and science is chosen flemingia macrophylla and pulled outDry root, by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying, obtain Phenylpropanoid Glycosides class chemical combination of the present inventionThing, then carries out test cell line to this compound, measures it to cellular inflammation factor TNF-α, IL-1 β, and the inhibition degree of IL-6,Experiment shows, this compound stimulates to LPS the Raw264.7 cell inflammation causing in concentration (7.50 – 13.50 μ g/mL) scopeInflammation factor TNF-alpha content has obvious inhibitory action (p < 0.05), and shows obvious dose-dependence; In concentrationIn (10.50 – 13.50 μ g/mL) scope, inflammatory factor IL-1 β and IL-6 content are had to obvious inhibitory action (p < 0.05), tableReveal obvious dose-dependence.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of phenylpropanoids of the present invention.
Fig. 2 is the carbon-13 nmr spectra figure of phenylpropanoids of the present invention.
Fig. 3 is the affect figure of phenylpropanoids of the present invention on cytoactive.
Fig. 4 is the inhibitory action figure of phenylpropanoids of the present invention to NO.
Fig. 5 is the inhibitory action figure of phenylpropanoids of the present invention to TNF-α.
Fig. 6 is the inhibitory action figure of phenylpropanoids of the present invention to IL-1 β.
Fig. 7 is the inhibitory action figure of phenylpropanoids of the present invention to IL-6.
Fig. 8 is the inhibitory action figure of phenylpropanoids of the present invention to OH.
Detailed description of the invention
Further illustrate the present invention below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present inventionLimit in any form. Unless stated otherwise, reagent, the method and apparatus that the present invention adopts is the conventional examination of the artAgent, method and apparatus. Unless stated otherwise, the present embodiment raw material used and equipment are conventional commercial former of the artMaterial and equipment.
Compound of the present invention is this change shown in the phenylpropanoids shown in described formula (I) and formula (II) or formula (III)Compound pharmaceutically acceptable salt. This compound can adopt the method for extracting into raw material of pulling out with flemingia macrophylla provided by the inventionPrepare, also can prepare in conjunction with the method such as chemical synthesis that adopts this area according to structural formula provided by the invention.
As the salt of phenylpropanoids of the present invention, as long as pharmaceutically acceptable salt, can be enumerated asThe inorganic acid salt forming with the inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid; WithThe sulfonate that sulfonic acid forms; The alkali metal salt that forms with the alkali-metal hydroxide such as potassium, sodium, calcium, magnesium, lithium, forms with ammoniumAmmonium salt etc.
Phenylpropanoids of the present invention can be used as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/Or the medicine of the diseases associated with inflammation such as arthritis.
The compounds of this invention can, as pharmaceutical composition together with the auxiliary material of pharmaceutically permission and/or carrier, also canIn the case of add pharmaceutically the auxiliary material that allows and/or carrier with cherokee rose root, one side pin, reticulate millettia, leatherleaf mahonia, Herba Andrographitis,One or more Chinese medicines in Radix Angelicae Sinensis, Radix Codonopsis or the combination of extract are as pharmaceutical composition, and the compounds of this invention is all rightBe used as pharmaceutical composition together with other pharmaceutically acceptable effective components.
As pharmaceutical composition, can be tablet, capsule, powder, granule, pill, solution, supensoid agent, syrupAgent, injection, ointment, suppository, spray etc.
Further, tablet can be in the case of adding the sugar-coat made the auxiliary material that pharmaceutically allows and/or carrierSheet, Film coated tablets, enteric coatings sheet or double-layer tablet, multilayer tablet.
Auxiliary material of the present invention and/or carrier can be as follows:
Make solid pharmaceutical preparation, can use additive, for example sucrose, lactose, cellulose sugar, maltitol, glucose, shallow lakePowder class, agar, alginates, chitin, shitosan class, pectin class, gum arabic class, gelatin class, collagen class, junket eggAlbumin, calcium phosphate, D-sorbite, glycine, glycerine, polyethylene glycol, sodium acid carbonate, talcum etc. in vain.
Make semisolid preparation, can use of animal or plant nature grease (olive oil, corn oil, castor-oil plant wet goods), mineral oilFat (vaseline, albolene, solid paraffin etc.), wax class (jojoba oil, Brazil wax, beeswax etc.), part are synthesized or are completeSynthetic fatty acid glyceride (laurate, myristic acid, palmitic acid etc.) etc.
Make liquid preparation, can use additive, for example sodium chloride, glucose, D-sorbite, glycerine, olive oil, the third twoAlcohol, ethanol etc. Especially make in the situation of injection, can use aseptic aqueous solution, for example physiological saline, isotonic solution, oilinessLiquid, as sesame oil, soybean oil. In addition, can also be as required, and with suitable suspending agent, as sodium carboxymethylcellulose, nonionicSurfactant, cosolvent, as Ergol, phenmethylol etc.
The amount of the active ingredient of these preparations is 0.01～80 % by weight of preparation, is suitably 1～50 % by weight, dosageChange according to differences such as patient's symptom, body weight, ages.
The preparation of embodiment 1 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula (I), comprises the steps:
S1. get flemingia macrophylla and pull out 50kg, taking root as raw material, dry, be cut into small pieces. Through the alcohol reflux of 8 times of amounts 60%Extract 3 times, each 2 hours, extract is merged, be concentrated into without alcohol taste, obtain medicinal extract for subsequent use;
S2. the medicinal extract after concentrated in step S1 is dissolved in 10L water, adopts D101 large pore resin absorption column to wash itDe-, eluant, eluent is water, and 3 column volumes of wash-out are collected eluent, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 collecting in step S2 is carried out to wash-out with anti-phase ODS column chromatography, eluant, eluent is methanol-waterSystem, its volume ratio is 25:75,18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, in orderCollect 6 flow points, called after: MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16 is for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 25:75:0.01, collect eluent by peak sequence, collect altogether 4 flow points, called after MM-131 respectively, MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 15:85:0.01, collect eluent, after recrystallization, obtain described phenylpropanoids.
The preparation of embodiment 2 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula (I), comprises the steps:
S1. get flemingia macrophylla and pull out 40kg, taking root as raw material, dry, be cut into small pieces. Through the alcohol reflux of 6 times of amounts 50%Extract 2 times, each 1 hour, extract is merged, be concentrated into without alcohol taste, obtain medicinal extract for subsequent use;
S2. the medicinal extract after concentrated in step S1 is dissolved in 5L water, adopts D101 large pore resin absorption column to wash itDe-, eluant, eluent is that the volume ratio of ethanol and water is 15:85, and 3 column volumes of wash-out are collected eluent, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 collecting in step S2 is carried out to wash-out with anti-phase ODS column chromatography, eluant, eluent is methanol-waterSystem, its volume ratio is 20:80,18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, in orderCollect 6 flow points, called after: MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16 is for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 35:65:0.01, collects eluent by peak sequence, collects altogether 4 flow points, called after MM-131 respectively, MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 15:85:0.01, collect eluent, after recrystallization, obtain described phenylpropanoids.
The preparation of embodiment 3 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula (I), comprises the steps:
S1. get flemingia macrophylla and pull out 60kg, taking root as raw material, dry, be cut into small pieces. The alcohol reflux of 7 times of amounts 70% is carriedGet 4 times, each 3 hours, extract is merged, be concentrated into without alcohol taste, obtain medicinal extract for subsequent use;
S2. the medicinal extract after concentrated in step S1 is dissolved in 8L water, adopts D101 large pore resin absorption column to wash itDe-, eluant, eluent is that the volume ratio of ethanol and water is 10:90, and 3 column volumes of wash-out are collected eluent, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 collecting in step S2 is carried out to wash-out with anti-phase ODS column chromatography, eluant, eluent is methanol-waterSystem, its volume ratio is 30:70,18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, in orderCollect 6 flow points, called after: MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16 is for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 30:70:0.01, collects eluent by peak sequence, collects altogether 4 flow points, called after MM-131 respectively, MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 15:85:0.01, collect eluent, after recrystallization, obtain described phenylpropanoids.
The preparation of embodiment 4 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula (I), comprises the steps:
S1. get flemingia macrophylla and pull out 50kg, taking root as raw material, dry, be cut into small pieces. The alcohol reflux of 8 times of amounts 60% is carriedGet 2 times, each 1.5 hours, extract is merged, be concentrated into without alcohol taste, obtain medicinal extract for subsequent use;
S2. the medicinal extract after concentrated in step S1 is dissolved in 6L water, adopts D101 large pore resin absorption column to wash itDe-, eluant, eluent is that the volume ratio of ethanol and water is 5:95, and 3 column volumes of wash-out are collected eluent, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 collecting in step S2 is carried out to wash-out with anti-phase ODS column chromatography, eluant, eluent is methanol-waterSystem, its volume ratio is 25:75,18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, in orderCollect 6 flow points, called after: MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16 is for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 25:75:0.01, collects eluent by peak sequence, collects altogether 4 flow points, called after MM-131 respectively, MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 15:85:0.01, collect eluent, after recrystallization, obtain described phenylpropanoids.
The preparation of embodiment 5 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula (I), comprises the steps:
S1. get flemingia macrophylla and pull out 50kg, taking root as raw material, dry, be cut into small pieces. The alcohol reflux of 8 times of amounts 80% is carriedGet 2 times, each 1.5 hours, extract is merged, be concentrated into without alcohol taste, obtain medicinal extract for subsequent use;
S2. the medicinal extract after concentrated in step S1 is dissolved in 6L water, adopts D101 large pore resin absorption column to wash itDe-, eluant, eluent is that the volume ratio of ethanol and water is 10:90, and 3 column volumes of wash-out are collected eluent, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 collecting in step S2 is carried out to wash-out with anti-phase ODS column chromatography, eluant, eluent is methanol-waterSystem, its volume ratio is 28:72,18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, in orderCollect 6 flow points, called after: MM-11 respectively, MM-12, MM-13, MM-14, MM-15, MM-16 is for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 10:90:0.01, collects eluent by peak sequence, collects altogether 4 flow points, called after MM-131 respectively, MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, preparative liquid chromatography post is: YMC,20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methyl alcohol: water: the volume ratio of acetic acid is 15:85:0.01, collect eluent, after recrystallization, obtain described phenylpropanoids.
The compound that embodiment 1 to embodiment 5 is prepared carries out mass spectrum, proton nmr spectra, carbon-13 nmr spectraDetection, result proves that gained compound is: 3-hydroxyl-4-methoxyl group-5-glucosyl group-9,9-dimethyl benzene propyl alcohol. Its knotStructure formula is suc as formula shown in (I):
The spectral data of its mass spectrum, proton nmr spectra, carbon-13 nmr spectra is as follows:
HR-ESIMS demonstration [M+Na]+be m/z411.1713, in conjunction with nuclear-magnetism feature, can obtain molecular formula is C18H28O9, noSaturation degree is 5.
1H-NMR(600MHz,CD3OD):6.97(d,1H),6.29(d,1H),4.89(d,1H),3.80(s,3H),3.56(m,2H),3.12-3.89(5H,glc-H),3.03(m,2H),1.34(s,3H),1.18(s,3H)。
13C-NMR(150MHz,CD3OD):158.2(C-5),155.6(C-4),131.4(C-3),130.0(C-2),129.5(C-1),117.5(C-6),102.2(C-1'),61.0-72.4(C2'-6'),68.7(C-9),58.1(-OCH3),48.5(C-7),43.9(C-8),27.8(-CH3),21.0(-CH3)。
The preparation of embodiment 6 phenylpropanoids salt
The preparation of phenylpropanoids hydrochloride:
Under stirring, will in this phenylpropanoids methanol solution, drip saturated hydrochloric acid to pH value 2-3, stir the lower second that dripsNitrile, suction filtration, is dried and obtains white powder solid, is the hydrochloride of phenylpropanoids.
The preparation of phenylpropanoids sulfonate:
In the reaction system that contains this phenylpropanoids, solvent, sulfonic acid, neutral oil and promoter, add alkali metalHydroxide, add solvent, lower alcohol and kicker, pass into carbon dioxide, separate obtain white powder solid, be benzeneThe sulfonate of the third chlorins compound.
The preparation of phenylpropanoids sylvite or sodium salt:
The KOH or the NaOH that are dissolved in ethanol are added in this phenylpropanoids, stir lower heating reflux reaction, cold systemRoom temperature, stirs the lower acetonitrile that drips, and suction filtration, is dried to obtain white solid, is sylvite or the sodium salt of this phenylpropanoids.
The preparation of phenylpropanoids ammonium salt:
Under stirring, will in this phenylpropanoids methanol solution, drip saturated ammoniacal liquor to pH value 9-11, stir the lower second that dripsNitrile, suction filtration, is dried and obtains white solid, is the ammonium salt of phenylpropanoids.
The spectral data of above-claimed cpd salt:
Phenylpropanoids hydrochloride: ESIMS shows m/z424.67, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.40(d,1H),6.19(d,1H),5.09(d,1H),3.90(s,3H),3.34(m,2H),3.13(m,2H),1.44(s,3H),1.28(s,3H)。
Phenylpropanoids sulfonate: ESIMS is shown as m/z452.17, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.28(d,1H),6.25(d,1H),4.87(d,1H),3.84(s,3H),3.51(m,2H),3.00(m,2H),1.24(s,3H),1.11(s,3H)。
Phenylpropanoids sylvite or sodium salt:
Sylvite: ESIMS shows m/z426.87, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.23(d,1H),6.20(d,1H),4.41(d,1H),3.57(s,3H),3.41(m,2H),3.01(m,2H),1.15(s,3H),1.02(s,3H)。
Sodium salt: ESIMS shows m/z411.17, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.25(d,1H),6.21(d,1H),4.47(d,1H),3.58(s,3H),3.44(m,2H),3.01(m,2H),1.17(s,3H),1.08(s,3H)。
Phenylpropanoids ammonium salt: ESIMS shows m/z403.47, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.22(d,1H),6.21(d,1H),4.97(d,1H),3.80(s,3H),3.51(m,2H),3.03(m,2H),1.44(s,3H),1.38(s,3H)。
The structural formula of above-mentioned phenylpropanoids salt is suc as formula shown in (IV)～formula (VIII).
Wherein, the phenylpropanoids hydrochloride of formula (IV) for preparing, the Phenylpropanoid Glycosides of formula (V) for preparingWherein a kind of sulfonate of compounds, wherein a kind of sylvite that formula (VI) is the phenylpropanoids for preparing, formulaWherein a kind of sodium salt that (VII) is the phenylpropanoids for preparing, the phenylpropanoids of formula (VIII) for preparingWherein a kind of ammonium salt.
Experimental example 7 application tests
The RAW264.7 oxidative macrophage of compound of the present invention and salt pair LPS induction stress with the shadow of inflammationRing. (convenient for record in experimentation, below by phenylpropanoids label of the present invention be: medicine MM-132,Be that the medicine MM-132 described in the present invention refers to phenylpropanoids shown in formula of the present invention (I) or it is pharmaceutically acceptableSalt. )
1 materials and methods
1.1 medicines and instrument
Lipopolysaccharides (lipopolysaccharide, LPS), MTT is purchased from Sigma company; Mouse macrophage Raw264.7Purchased from the refined cell bank in Hunan; PBS; DMEM high glucose medium, hyclone, penicillin and streptomysin; Full-automatic ELIASA; Constant temperatureCO2 incubator.
Mouse IL-1β (IL-1-β) ELISA detection kit, lot number: 2014/06 (96T); Little mIL6(IL-6) ELISA detection kit, lot number: 2014/06 (96T); Mouse tumor necrosis factor-alpha (TNF-α) ELISA detects examinationAgent box, lot number: 2014/06 (96T); Mouse nitrous oxide (NO) ELISA detection kit, lot number: 2014/10 (96T); MouseHydroxyl radical free radical (OH) ELISA detection kit, lot number: 2014/10 (96T).
1.2 medicine preparations
First dissolve with a small amount of DMSO, be then diluted to certain concentration with DMEM, DMSO content in final concentration is less than1‰。
1.3 cells are cultivated
Mouse macrophage Raw264.7 be incubated at containing the hyclone (FBS) of 10% hot deactivation (56 DEG C, 30min),In the DMEM culture medium of 10U/mL Benzylpenicillin sodium salt, 100 μ g/mL streptomysins, 37 DEG C, 5%CO2In constant incubator, hatch growth.
1.4 cell viabilities are measured
Cell viability is measured by mtt assay. Cell is made to cell suspension inoculation incubates in 96 orifice plates (1 × 104/hole)Educate 24h, resynchronization 24h, then by the drug effect of variable concentrations in cell 2h, and then add LPS (30 μ g/mL) stimulate24h, inhales and abandons former culture medium, and every hole adds the MTT (0.5mg/mL) of 100 μ L to continue to hatch 4h, inhales and abandons culture medium, and every hole addsThe DMSO of 150 μ L, shaking table jolting 10min, measures absorbance at 490nm place.
1.5NO assay
Raw264.7 cell is inoculated in 96 orifice plate 24h, resynchronization 24h, then by the drug effect of variable concentrations in carefullyBorn of the same parents 2h, and then add LPS (30 μ g/mL) to stimulate 24h, finally collect supernatant, and in the centrifugal 5min of 10000rpm, divide and load ontoClear and be placed in-80 DEG C and save backup. By mouse NO kit measurement NO content.
1.6 inflammatory factor TNF-α, IL-1 β, IL-6 measures
Sample is got 1.5 samples that prepare and is measured for follow-up inflammatory factor. Cell produces TNF-α, IL-1 β, IL-6'sAmount is passed through mouse TNF-α, IL-1 β, and IL-6 kit is measured.
1.7OH assay
Sample is got 1.5 samples that prepare for OH factor determination. By OH kit measurement content.
1.8 statistical analysis
Adopt SPSS17.0 software, experimental data is so that (x ± s represents; The data obtained is by with one-way analysis of variance, squarePoor homogeneous is checked with LSD, and heterogeneity of variance is checked with DunnettT3.
2 experimental results
2.1 cell viability
Medicine is evaluated by mtt assay the impact of cell viability. As shown in Figure 3, medicine MM-132 is at 1.50-13.50 μIn g/mL concentration range, Raw264.7 cell viability is had no significant effect; Therefore the drug concentration pair under this scope concentrationSuitable in subsequent experimental.
2.2 medicines suppress the generation of NO
As shown in Figure 4, stimulate Raw264.7 cell by LPS, its produce NO (65.81 ± 2.93IU/mL) content with justNormal group NO (33.61 ± 2.19IU/mL) compares obvious rising (p < 0.01). Medicine MM-132 causes LPS under this concentrationNO content raises does not have obvious inhibitory action.
2.3 medicines suppress TNF-α, IL-1 β, the generation of IL-6
As shown in Figures 5 to 7, stimulate Raw264.7 cell by LPS, Raw264.7 cellular inflammation factor TNF-α(132.16 ± 5.28pg/mL), IL-1 β (358.80 ± 24.64pg/mL), IL-6 (198.39 ± 5.97pg/mL) content with justNormal group TNF-α (65.41 ± 6.29pg/mL), IL-1 β (172.67 ± 10.06pg/mL), IL-6 (103.34 ± 2.88pg/mL)Compare content obviously raise (p < 0.01); Illustrate that LPS can stimulate Raw264.7 cell to produce a large amount of inflammatory factors.
Medicine MM-132 stimulates to LPS the Raw264.7 cell inflammation causing in concentration (7.50-13.50 μ g/mL) scopeInflammation factor TNF-alpha content has obvious inhibitory action (p < 0.05), and shows obvious dose-dependence; In concentrationIn (10.50-13.50 μ g/mL) scope, inflammatory factor IL-1 β and IL-6 content are all had to obvious inhibitory action (p < 0.05),Show obvious dose-dependence.
2.4 medicines suppress the generation of OH
As shown in Figure 8, stimulate Raw264.7 cell by LPS, its produce OH (113.58 ± 6.03ng/mL) content withNormal group OH (63.40 ± 1.19ng/mL) compares obvious rising (p < 0.01).
The OH content that medicine MM-132 causes LPS in (4.50-13.50 μ g/mL) concentration range has significantlyInhibitory action (p < 0.05), and show dose-dependence.
This experiment, through in vitro culture, has been studied medicine MM-132 to mouse macrophage NO, TNF-α, IL-1 β, IL-6, OHThe impact generating.
Medicine MM-132 to the generation of factor NO without obvious inhibitory action, to cellular inflammation factor TNF-α, IL-1 β, IL-6Content shows and suppresses active at middle and high concentration, illustrates that its performance anti-inflammatory activity needs higher drug concentration to realize; It is to OH'sSuppress obviously active, certain antioxidation activity is described.
Embodiment 8
The preparation of tablet: first make the phenylpropanoids shown in formula (I) by embodiment 1 method, and utilize this changeCompound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkaliThe hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) of metal or the salt that ammonium is made, pressThe ratio that this compound or its any one salt and excipient weight ratio are 1:10 adds excipient, pelletizing press sheet.
Embodiment 9
The preparation of powder: first make the phenylpropanoids shown in formula (I) by embodiment 1 method, and utilize this changeCompound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkaliThe hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) of metal or the salt that ammonium is made, pressConventional powder method for making is made powder.
Embodiment 10
The preparation of capsule or granule: first make the phenylpropanoids shown in formula (I) by embodiment 1 method, withAnd utilize this compound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid)Or sulfonic acid or alkali-metal hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammoniumThe salt of making, the ratio that is 1:10 in this compound or its any one salt and excipient weight ratio adds excipient, makes glueWafer or granule.
Embodiment 11
The preparation of injection: first make the phenylpropanoids shown in formula (I) by embodiment 1 method, and utilization shouldCompound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid orThe salt that alkali-metal hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium are made,Water for injection routinely, essence filter, injection is made in embedding sterilizing.
Embodiment 12
A kind of pharmaceutical composition, contains embodiment 1 method and makes the phenylpropanoids shown in formula (I), and utilizesThis compound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acidOr alkali-metal hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium are madeSalt, and the powder made of cherokee rose root, one side pin, reticulate millettia, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis, and auxiliary material.
Embodiment 13
A kind of pharmaceutical composition, contains embodiment 1 method and makes the phenylpropanoids shown in formula (I), and golden cherryThe powder that root, one side pin, reticulate millettia, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis are made, and auxiliary material.
Embodiment 14
A kind of pharmaceutical composition, contains embodiment 1 method and makes the phenylpropanoids shown in formula (I), and golden cherryThe extract of root, one side pin, reticulate millettia, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis, and auxiliary material. Extract is by patent announcement numberCN1078079C、CN1170549C、CN1158087C、CN1330335C、CN1296071C、CN1321631C、CN1296072C、In any one or several the patent documents of CN1296073C, extracting method prepares.
Embodiment 15
A kind of pharmaceutical composition, contains embodiment 1 method and makes the phenylpropanoids shown in formula (I), and utilizesThis compound and inorganic acid (example hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acidOr alkali-metal hydroxide (as potassium hydroxide, NaOH, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium are madeSalt, and the extract of cherokee rose root, one side pin, reticulate millettia, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis, and auxiliary material. Extract be byPatent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C,In any one or several the patent documents of CN1296072C, CN1296073C, extracting method prepares.
More than show and described general principle of the present invention and principal character and advantage of the present invention. The technology of this areaPersonnel should understand, and the present invention is not restricted to the described embodiments, and the just explanation of describing in above-described embodiment and description originallyThe principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, and this is to thisThose skilled in the art are apparent, and these changes and improvements all fall in the claimed scope of the invention. ThisBright claimed scope is defined by appending claims and equivalent thereof.

Claims (10)

1. a preparation method for phenylpropanoids, is characterized in that, the structural formula of described phenylpropanoids suc as formulaShown in (I),
Described preparation method comprises the steps:
S1. getting the root that flemingia macrophylla pulls out is raw material, dry, and stripping and slicing is extracted through ethanolic solution, and extract is merged, and is concentrated intoWithout alcohol taste, obtain medicinal extract for subsequent use;
S2. gained medicinal extract in step S1 is dissolved in water, adopts large pore resin absorption column to carry out wash-out to it, eluant, eluent is secondAlcohol-water system, collects the eluent of front 3 column volumes, and called after MM-1 is for subsequent use;
S3. the flow point MM-1 reversed material ODS column chromatography of collecting in step S2 is carried out to wash-out, eluant, eluent is methanol-waterSystem, 18 column volumes of wash-out, by the eluent of a flow point of every 3 column volumes collection, collect 6 flow points, respectively in orderCalled after MM-11, MM-12, MM-13, MM-14, MM-15, MM-16, for subsequent use;
S4. by preparation liquid phase separation for the flow point MM-13 collecting in step S3, mobile phase is methanol-water-acetic acid system, pressesPeak sequence is collected eluent, collects altogether 4 flow points, called after MM-131 respectively, and MM-132, MM-133, MM-134, for subsequent use;
S5. the flow point MM-132 collecting in step S4 is purified by preparation liquid phase, mobile phase is methanol-water-acetic acid system, receivesCollection eluent, obtains described phenylpropanoids after recrystallization.
2. preparation method according to claim 1, is characterized in that: in step S1, the concentration of ethanolic solution is 50～80Volume %, being preferably ethanolic solution concentration is 60 volume %.
3. preparation method according to claim 1, is characterized in that: in step S1, the extraction time of ethanol is 2～4 times,Each extraction 1～3 hour, the extraction time that is preferably ethanol is 3 times, each 2 hours.
4. preparation method according to claim 1, is characterized in that: in step S2, macroporous absorbent resin adopts D101 largeMacroporous adsorbent resin.
5. preparation method according to claim 1, is characterized in that: in step S2, the volume ratio of ethanol and water is 0:100～15:85。
6. preparation method according to claim 1, is characterized in that: in step S3, and the volume ratio of eluant, eluent methyl alcohol and waterFor 20:80～30:70, be preferably 25:75.
7. preparation method according to claim 1, is characterized in that: in step S4, the volume ratio of methanol-water-acetic acid is10:90:0.01～35:65:0.01, is preferably 15:85:0.01.
8. preparation method according to claim 1, is characterized in that: in step S4, the chromatographic column of preparation liquid phase is YMC,20mm*250mm, flow rate of mobile phase is 5～10mL/min, is preferably flow velocity 5mL/min.
9. preparation method according to claim 1, is characterized in that, in step S5, the volume ratio of methanol-water-acetic acid is15:85:0.01。
10. preparation method according to claim 1, is characterized in that: in step S5, the chromatographic column of preparation liquid phase is YMC,20mm*250mm, flow rate of mobile phase is 5mL/min.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102274341A (en) * 2010-06-10 2011-12-14 上海中医药大学 Extracting and refining process for medicinal components of figwort root
CN102631390A (en) * 2012-04-12 2012-08-15 贵州师范大学 Preparation method of periploca forrestii schltr extract as well as product and application of periploca forrestii schltr extract
CN104529984A (en) * 2014-12-25 2015-04-22 株洲千金药业股份有限公司 Method for extracting genistin from largeleaf flemingia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102274341A (en) * 2010-06-10 2011-12-14 上海中医药大学 Extracting and refining process for medicinal components of figwort root
CN102631390A (en) * 2012-04-12 2012-08-15 贵州师范大学 Preparation method of periploca forrestii schltr extract as well as product and application of periploca forrestii schltr extract
CN104529984A (en) * 2014-12-25 2015-04-22 株洲千金药业股份有限公司 Method for extracting genistin from largeleaf flemingia

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