CN105884841A - Preparation method of phenylpropanoid compound - Google Patents
Preparation method of phenylpropanoid compound Download PDFInfo
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- CN105884841A CN105884841A CN201610153958.3A CN201610153958A CN105884841A CN 105884841 A CN105884841 A CN 105884841A CN 201610153958 A CN201610153958 A CN 201610153958A CN 105884841 A CN105884841 A CN 105884841A
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Abstract
The invention relates to the technical field of medicines, discloses a preparation method of a phenylpropanoid compound, and particularly relates to a phenylpropanoid compound which is obtained by being separated from dried roots of moghania macrophylla (Willd.) O Ktze.. The phenylpropanoid compound is prepared through the steps of solvent extraction, column chromatographic separation and liquid phase preparation, separation and purification. The phenylpropanoid compound obtained through the method is reported for the first time and is high in purity. It is proved through experiments that the obtained novel phenylpropanoid compound can inhibit expression effects of cell inflammatory factors of TNF-alpha, IL-1 beta and IL-6, has an inhibiting effect on hydroxyl free radicals (-OH), has anti-inflammatory and antioxidant activities, is beneficial for treatment of various inflammatory diseases such as cervicitis, endometritis, pelvic inflammation, mastitis, faucitis and/or arthritis and can be developed into a novel drug. The compound is the phenylpropanoid compound with the structural formula as shown in a formula (I) and pharmaceutically acceptable salts thereof. Please see the formula (I) in the description.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly, to the preparation side of a kind of new phenylpropanoids
Method.
Background technology
The constituent structure extracting isolated from natural drug is various, active significantly, to its carry out isolated and purified,
Structural modification, transformation and complete synthesis, an always main thought of new drug development.
TNF-α: be a kind of can direct killing tumor cell and to normal cell without overt toxicity cell because of
Son, is one of bioactie agent that the direct killing function of tumor found up to now is the strongest, but it is malicious
Side effect is the most serious.
IL-1 β: collaborative APC and the T cell activation of stimulating, promotion B cell proliferation and secretion when local low concentration
Antibody, carries out immunomodulating.Endocrine effect is had: induced liver acute phase protein synthesizes, and draws during a large amount of generation
Play heating and cachexia.
IL-6: mankind's IL-6 gene is positioned on No. 7 chromosome；IL-6 molecular weight is between 21～30KD.Main
To be produced by mononuclear phagocyte, Th2 cell, vascular endothelial cell, fibroblast.Activation can be stimulated
B cell proliferation, secretory antibody；Stimulate T cell propagation and CTL activation；Cell cultured supernatant synthesized acute phase egg
In vain, inflammatory reaction is participated in；Promote blood cell development.
IL-6 can be synthesized by various kinds of cell, including T cell and B cell, monocytes/macrophages, the endothelium of activation
Cell, epithelial cell and fibroblast etc..The target cell of IL-6 effect is a lot, including macrophage, liver
Cell, static T cell, the B cell of activation and plasma cell etc.；Its biological effect is the most sufficiently complex.
OH is the reactive oxygen species of most activity in biosystem, can cause DNA in cell and organism, egg
White matter and lipid oxidation damage.
Therefore, seek a kind of new preparation method, from natural plants, extract the compound that isolated is new, energy
Suppression cellular inflammation factor TNF-α, the expressional function of IL-1 β, IL-6, suppression hydroxyl radical free radical (-OH)
Activity, is applied to the treatment of diseases associated with inflammation, is necessary.
Radix Flemingiae Philippinensis medical material is pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania)
The dry root of plant Flemingia macrophylla (Moghaniamacrophylla (Willd.) O.Kuntze), main in China
It is distributed in region of Southeast.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), China
Main plant figure is said in (1955, pp707) and Guangzhou flora (1956, pp361) and is all included.Very heavy
Pulling out the genuine medicinal materials that medical material is Guangxi province, history is loaded in " Zhiwu Mingshi Tukao ", has medication the most among the people
Basis.Its nature and flavor are sweet, micro-puckery, flat, have the effects such as removing damp-heat, are mainly used in treating rheumatic ostalgia, falling
Beat damage, chronic nephritis, dysmenorrhea and the gynaecopathia such as leucorrhea is many.This medical material the most recorded version in 2005 " in
State's pharmacopeia " annex.
The composition that Flemingia macrophylla has been reported mainly has flavonoid, steroid, terpenoid, Anthraquinones, volatile oil to become
Point, it is respectively provided with certain pharmacologically active.
Flemingia macrophylla pharmacologically active is various, reports the more neuroprotective that has, antiinflammatory, antioxidation,
The anthelmintic action of pathogenic microorganism, parahormone effect, cytotoxicity, antibacterial action and immunostimulant are made
With, antifatigue effect.
Radix Flemingiae Philippinensis be now widely used for the type such as gynecological, rheumatic arthralgia Chinese patent medicine produce, as FUKE QIANJIN PIAN,
FUKE QIANJIN JIAONANG, JINJI CHONGJI, JINJI JIAONANG etc., this type of Chinese patent medicine is mainly used in gynaecopathia (dysmenorrhea, son
Cold womb cold infertile, uterine prolapse, pelvic inflammatory disease, mastitis, leucorrhea are many, blood deficiency in puerperal, arthralgia, waist in puerperal
Gonalgia, hypogalactia and breast ulcer etc.), weak anemia (woman anemia, deficient qi and blood and the after being ill deficiency of vital energy etc.).In recent years,
What clinical report was more is FUKE QIANJIN PIAN effect in terms for the treatment of gynecological inflammation.
At present, in the document of Radix Flemingiae Philippinensis, the document of report phenylpropanoids is few, finds a kind of new
Preparation method, isolates effective Phenylpropanoid Glycosides class noval chemical compound from natural plants, to its carry out isolated and purified,
Structural modification and synthesis, developing new drug, it is applied to the treatment of diseases associated with inflammation, significant.
Summary of the invention
It is an object of the invention to provide a kind of a kind of phenylpropyl alcohol of isolated from the dry root of Flemingia macrophylla
The preparation method of chlorins compound, the compound being extracted isolated by this preparation method can suppress cell scorching
Inflammation factor TNF-α, the expressional function of IL-1 β, IL-6, the suppression with (-OH) to hydroxyl radical free radical is made
With, and then there is antiinflammatory and antioxidant activity, and it is of value to the treatment of various diseases associated with inflammation, can be by this chemical combination
Thing develops into new drug.
Specifically, the preparation method of phenylpropanoids of the present invention comprises the steps:
S1. the root taking Flemingia macrophylla is raw material, is dried, stripping and slicing, extracts through ethanol solution, by extracting solution
Merge, be concentrated into without alcohol taste, obtain extractum standby；
S2. gained extractum in step S1 is dissolved in water, uses macroporous adsorptive resins that it is carried out eluting, wash
De-agent is ethanol-water system, collects the eluent of front 3 column volumes, and named MM-1 is standby；
S3. the flow point MM-1 reversed material ODS column chromatography collected in step S2 is carried out eluting, eluant
For methanol-water system, 18 column volumes of eluting, collect the eluent of a flow point by every 3 column volumes, by suitable
Sequence collects 6 flow points, is respectively designated as MM-11, MM-12, MM-13, MM-14, MM-15, MM-16,
Standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, flowing is methanol-water-second mutually
Acid system, collects eluent by peak sequence, collects 4 flow points altogether, be respectively designated as MM-131, MM-132,
MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, flowing is methanol-water-second mutually
Acid system, collects eluent, obtains described phenylpropanoids after recrystallization.Described phenylpropanoids
Purity be 99.66%.Shown in the structural formula of described phenylpropanoids such as formula (1):
Preferably, in step S1, the concentration of ethanol solution is 50-80 volume %, and more preferably ethanol is molten
Liquid concentration is 60 volume %.
Preferably, in step S1, the extraction time of ethanol solution is 2～4 times, extracts 1～3 hour every time, enters
The extraction time of one step preferably ethanol solution is 3 times, each 2 hours.
Preferably, in step S2, macroporous adsorbent resin uses D101 macroporous adsorbent resin.
Preferably, in step S2, ethanol is 0:100～15:85 with the volume ratio of water.
Preferably, in step S3, methanol is 20:80～30:70, more preferably 25:75 with the volume ratio of water.
Preferably, in step S4, the volume ratio of methanol-water-acetic acid is 10:90:0.01～35:65:0.01, further
It is preferably 15:85:0.01.
Preferably, in step S4, preparative liquid chromatography post is YMC, 20mm*250mm, flow rate of mobile phase
It 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, flow rate of mobile phase
For 5mL/min.
The present invention provides the phenylpropanoids that described preparation method prepares.
And the Phenylpropanoid Glycosides class prepared for raw material through chemical synthesis process with described phenylpropanoids
Adduct salt.The structure of described salt is as shown in formula II or formula III:
Wherein, R is mineral acid, R1Or R2For any one in sulfonate radical, alkali metal ion or ammonium root or appoint
Anticipate two kinds.
Preferably, described mineral acid be hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid,
Phosphoric acid or lactic acid；Described sulfonate radical is the sulfonate radical with aryl；Described alkali metal ion be potassium ion, sodium from
Son, calcium ion, magnesium ion or lithium ion.
Preferably, the sulfonate radical described in aryl is benzenesulfonic acid root or p-methyl benzenesulfonic acid root.
Preferably, described pharmaceutically acceptable salt is ammonium salt.
Beneficial effects of the present invention:
The present invention is new phenylpropanoids and pharmaceutically acceptable salt provides a kind of preparation method,
A kind of new phenylpropanoids of isolated, prepared compound from the dry root of Flemingia macrophylla first
Cellular inflammation factor TNF-α, the expressional function of IL-1 β, IL-6 can be suppressed, have hydroxyl radical free radical
The inhibitory action of (-OH), and then there is antiinflammatory and antioxidant activity, can serve as such as cervicitis, intrauterine
The medicine of the diseases associated with inflammation such as film inflammation, pelvic inflammatory disease, mastitis, pharyngolaryngitis and/or arthritis.
It is an object of the invention to from traditional prescriptions of Chinese medicine, by from FUKE QIANJIN PIAN and FUKE QIANJIN JIAONANG
In prescription, prepare a kind of new Phenylpropanoid Glycosides class by solvent extraction, column chromatography for separation, preparation liquid phase separation, purification
Compound, and experiments prove that, it can apply to diseases associated with inflammation, as cervicitis, endometritis,
The treatment of the diseases such as pelvic inflammatory disease, mastitis, pharyngolaryngitis and/or arthritis.
Specifically, inventor by from FUKE QIANJIN PIAN, FUKE QIANJIN JIAONANG prescription, science chooses great Ye
The dry root of Radix Flemingiae Philippinensis, by solvent extraction, column chromatography for separation, preparation liquid phase separation, purification, obtains this
Bright described phenylpropanoids, then carries out test cell line to this compound, measures it to the cellular inflammation factor
TNF-α, the suppression degree of IL-1 β, IL-6, experiment shows, this compound is at concentration (10.50 13.50 μ g/mL) model
Enclose the interior Raw 264.7 cellular inflammation factor TNF-α content that LPS stimulation is caused and have obvious inhibitory action (p
＜ 0.05), and show obvious dose-dependence；To inflammation in the range of concentration (4.50 13.50 μ g/mL)
Inflammation factor IL-1 β content has obvious inhibitory action (p ＜ 0.05), shows obvious dose-dependence；?
In the range of concentration (7.50 13.50 μ g/mL), inflammatory factor IL-6 content is had obvious inhibitory action (p ＜ 0.05),
Show obvious dose-dependence.
Accompanying drawing explanation
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 that phenylpropanoids of the present invention affects figure to cytoactive.
Fig. 4 is the phenylpropanoids of the present invention inhibitory action figure to NO.
Fig. 5 is the phenylpropanoids of the present invention inhibitory action figure to TNF-α.
Fig. 6 is the phenylpropanoids of the present invention inhibitory action figure to IL-1 β.
Fig. 7 is the phenylpropanoids of the present invention inhibitory action figure to IL-6.
Fig. 8 is the phenylpropanoids of the present invention inhibitory action figure 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 the most right
The present invention limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus are this
Technical field conventional reagent, method and apparatus.Unless stated otherwise, raw material and equipment used by the present embodiment are equal
For the conventional commercial raw material of the art and equipment.
The compound of the present invention is the phenylpropanoids shown in described formula I and formula II or formula III
This compound pharmaceutically acceptable salt shown.This compound can use that the present invention provides with Flemingia macrophylla
The method extracted for raw material prepares, it is also possible to the structural formula provided according to the present invention combines and uses this area
The methods such as chemosynthesis prepare.
As the salt of phenylpropanoids of the present invention, as long as pharmaceutically acceptable salt, can
It is enumerated as and the nothing such as hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid
The inorganic acid salt that machine acid is formed；The sulfonate formed with sulfonic acid；Alkali-metal with potassium, sodium, calcium, magnesium, lithium etc.
The alkali metal salt that hydroxide is formed, the ammonium salt etc. formed with ammonium.
Phenylpropanoids of the present invention can be used as cervicitis, endometritis, pelvic inflammatory disease, mastitis,
The medicine of the diseases associated with inflammation such as pharyngolaryngitis and/or arthritis.
The compounds of this invention can be used as pharmaceutical composition, also together with the adjuvant pharmaceutically allowed and/or carrier
Can in the case of adding the adjuvant that pharmaceutically allows and/or carrier with Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi,
One or more Chinese crude drugs or the combination of extract in Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis are used as medicine group
Compound, the compounds of this invention can also be used as drug regimen together with other pharmaceutically acceptable active ingredient
Thing.
As pharmaceutical composition, can be tablet, capsule, powder, granule, pill, solution,
Suspensoid, syrup, injection, ointment, suppository, spray etc..
Further, tablet can be to make in the case of adding the adjuvant and/or carrier pharmaceutically allowed
Coated tablet, Film coated tablets, enteric coatings ply or two-ply, multilayer tablet.
Adjuvant and/or the carrier of the present invention can be such that
Make solid preparation, it is possible to use additive, such as sucrose, lactose, cellulose sugar, maltose alcohol,
Glucose, starch based, agar, alginates, chitin, chitosan class, pectin class, Radix Acaciae senegalis
Class, gelatin class, collagen class, casein, albumin, calcium phosphate, Sorbitol, glycine, glycerol, poly-
Ethylene glycol, sodium bicarbonate, Talcum etc..
Make semi-solid preparation, it is possible to use of animal or plant nature oils and fats (olive oil, Semen Maydis oil, Oleum Ricini etc.),
Mineral oils and fats (vaseline, white vaseline, solid paraffin etc.), wax class (Jojoba oil, Brazil wax,
Cera Flava etc.), partial synthesis or complete synthesis fatty acid glyceride (lauric acid, myristic acid, Palmic acid etc.)
Deng.
Make liquid preparation, can use additive, such as sodium chloride, glucose, Sorbitol, glycerol,
Olive oil, propylene glycol, ethanol etc..In the case of especially making injection, it is possible to use aseptic aqueous solution, example
Such as normal saline, isotonic solution, oiliness liquid, such as Oleum Sesami, soybean oil.Furthermore it is also possible to as required, and use
Suitable suspending agent, such as sodium carboxymethyl cellulose, nonionic surfactant, cosolvent, as benzyl benzoate,
Benzyl alcohol etc..
The amount of the effective ingredient of these preparations is 0.01～80 weight % of preparation, is suitably 1～50 weight %, is administered
Measure the differences such as the symptom according to patient, body weight, age and change.
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. take Flemingia macrophylla 50kg, with root as raw material, be dried, be cut into small pieces.Second through 8 times amount 60%
Alcohol reflux extracts 3 times, each 2 hours, is merged by extracting solution, is concentrated into without alcohol taste, obtains extractum standby；
S2. the extractum after concentrating in step S1 is dissolved in 10L water, uses D101 macroporous adsorptive resins to it
Carrying out eluting, eluant is water, 3 column volumes of eluting, collection eluent, and named MM-1 is standby；
S3. with anti-phase ODS column chromatography, the flow point MM-1 collected in step S2 being carried out eluting, eluant is first
Alcohol-water system, its volume ratio is 25:75,18 column volumes of eluting, collects a flow point by every 3 column volumes
Eluent, in order collect 6 flow points, be respectively designated as: MM-11, MM-12, MM-13, MM-14,
MM-15, MM-16 are standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 25:75:0.01, collects eluent by peak sequence, collects 4 flow points altogether, name respectively
For MM-131, MM-132, MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
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. take Flemingia macrophylla 40kg, with root as raw material, be dried, be cut into small pieces.Second through 6 times amount 50%
Alcohol reflux extracts 2 times, each 1 hour, is merged by extracting solution, is concentrated into without alcohol taste, obtains extractum standby；
S2. the extractum after concentrating in step S1 is dissolved in 5L water, uses D101 macroporous adsorptive resins to enter it
Row eluting, eluant is ethanol and the volume ratio of water is 15:85,3 column volumes of eluting, collects eluent, life
Entitled MM-1, standby；
S3. with anti-phase ODS column chromatography, the flow point MM-1 collected in step S2 being carried out eluting, eluant is first
Alcohol-water system, its volume ratio is 20:80,18 column volumes of eluting, collects a flow point by every 3 column volumes
Eluent, in order collect 6 flow points, be respectively designated as: MM-11, MM-12, MM-13, MM-14,
MM-15, MM-16 are standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 10ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 35:65:0.01, collects eluent by peak sequence, collects 4 flow points altogether, name respectively
For MM-131, MM-132, MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
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. take Flemingia macrophylla 60kg, with root as raw material, be dried, be cut into small pieces.The ethanol of 7 times amount 70%
Reflux, extract, 4 times, each 3 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby；
S2. the extractum after concentrating in step S1 is dissolved in 8L water, uses D101 macroporous adsorptive resins to enter it
Row eluting, eluant is ethanol and the volume ratio of water is 10:90,3 column volumes of eluting, collects eluent, life
Entitled MM-1, standby；
S3. with anti-phase ODS column chromatography, the flow point MM-1 collected in step S2 being carried out eluting, eluant is first
Alcohol-water system, its volume ratio is 30:70,18 column volumes of eluting, collects a flow point by every 3 column volumes
Eluent, in order collect 6 flow points, be respectively designated as: MM-11, MM-12, MM-13, MM-14,
MM-15, MM-16 are standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 10ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 30:70:0.01, collects eluent by peak sequence, collects 4 flow points altogether, name respectively
For MM-131, MM-132, MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
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. take Flemingia macrophylla 50kg, with root as raw material, be dried, be cut into small pieces.The ethanol of 8 times amount 60%
Reflux, extract, 2 times, each 1.5 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby；
S2. the extractum after concentrating in step S1 is dissolved in 6L water, uses D101 macroporous adsorptive resins to enter it
Row eluting, eluant is ethanol and the volume ratio of water is 5:95,3 column volumes of eluting, collects eluent, life
Entitled MM-1, standby；
S3. with anti-phase ODS column chromatography, the flow point MM-1 collected in step S2 being carried out eluting, eluant is first
Alcohol-water system, its volume ratio is 25:75,18 column volumes of eluting, collects a flow point by every 3 column volumes
Eluent, in order collect 6 flow points, be respectively designated as: MM-11, MM-12, MM-13, MM-14,
MM-15, MM-16 are standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 10ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 25:75:0.01, collects eluent by peak sequence, collects 4 flow points altogether, name respectively
For MM-131, MM-132, MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
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. take Flemingia macrophylla 50kg, with root as raw material, be dried, be cut into small pieces.The ethanol of 8 times amount 80%
Reflux, extract, 2 times, each 1.5 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby；
S2. the extractum after concentrating in step S1 is dissolved in 6L water, uses D101 macroporous adsorptive resins to enter it
Row eluting, eluant is ethanol and the volume ratio of water is 10:90,3 column volumes of eluting, collects eluent, life
Entitled MM-1, standby；
S3. with anti-phase ODS column chromatography, the flow point MM-1 collected in step S2 being carried out eluting, eluant is first
Alcohol-water system, its volume ratio is 28:72,18 column volumes of eluting, collects a flow point by every 3 column volumes
Eluent, in order collect 6 flow points, be respectively designated as: MM-11, MM-12, MM-13, MM-14,
MM-15, MM-16 are standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 10ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 10:90:0.01, collects eluent by peak sequence, collects 4 flow points altogether, name respectively
For MM-131, MM-132, MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, preparative liquid chromatography post is:
YMC, 20mm*250mm, flow velocity: 5ml/min, flowing is methanol-water-acetic acid system mutually, methanol: water:
The volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
Compound embodiment 1 to embodiment 5 prepared carries out mass spectrum, proton nmr spectra, nuclear magnetic resonance, NMR
The detection of carbon spectrum, result proves that gained compound is: 3 '-hydroxyl-4 ' glucosyl group-3-hydroxybutyrate methyl ester.Its
Structural formula is as shown in formula I:
Its mass spectrum, proton nmr spectra, carbon-13 nmr spectra spectral data as follows:
HR-ESIMS shows [M+Na]+for m/z 397.1267, and in conjunction with nuclear-magnetism feature, can obtain molecular formula is
C16H22O10, degree of unsaturation is 6.
1H-NMR(600MHz,CD3OD):7.43(dd,1H),7.12(dd,1H),6.81(dd,1H),4.84(d,1H),4.
12(t,2H),3.56(m,1H),1.14(s,3H)。
13C-NMR(150MHz,CD3OD):179.3(C-1),168.8(C-5'),150.1(C-1'),144.7(C-3'),129.
9(C-2'),116.4(C-4'),114.8(C-6'),103.6(C-1”),76.6-61.4(C2”-6”),42.9(C-2),21.8(C-3),
17.0(-CH3)。
The preparation of embodiment 6 phenylpropanoids salt
The preparation of phenylpropanoids hydrochlorate:
By this Phenylpropanoid Glycosides compound methanol solution dripping saturated hydrochloric acid to pH value 2-3 under stirring, stir lower
Add acetonitrile, sucking filtration, be dried to obtain white powder solid, be the hydrochlorate of Phenylpropanoid Glycosides compound.
The preparation of phenylpropanoids sulfonate:
Reaction system containing this phenylpropanoids, solvent, sulfonic acid, neutral oil and accelerator adds
Alkali-metal hydroxide, adds solvent, lower alcohol and kicker, is passed through carbon dioxide, and isolated is white
Color powder solid, is the sulfonate of Phenylpropanoid Glycosides compound.
Phenylpropanoids potassium salt or the preparation of sodium salt:
KOH or NaOH being dissolved in ethanol is added in this Phenylpropanoid Glycosides compound, be heated to reflux anti-under stirring
Should, cold room temperature processed, drip acetonitrile, sucking filtration under stirring, be dried to obtain white solid, be this Phenylpropanoid Glycosides compound
Potassium salt or sodium salt.
The preparation of phenylpropanoids ammonium salt:
To pH value 9-11, stirring, second is dripped by this Phenylpropanoid Glycosides compound methanol solution drips saturated ammonia under stirring
Nitrile, sucking filtration, it is dried to obtain white solid, is the ammonium salt of phenylpropanoids.
The spectral data of above-claimed cpd salt:
Phenylpropanoids hydrochlorate: ESIMS shows m/z 410.62, nuclear-magnetism feature1H-NMR(600
MHz,CD3OD):7.40(dd,1H),7.07(dd,1H),6.77(dd,1H),4.64(d,1H),4.02(t,2H),
3.46(m,1H),1.11(s,3H)。
Phenylpropanoids sulfonate: ESIMS is shown as m/z 438.22, nuclear-magnetism feature1H-NMR(600
MHz,CD3OD):7.54(dd,1H),7.13(dd,1H),6.80(dd,1H),4.83(d,1H),4.10(t,2H),
3.54(m,1H),1.13(s,3H)。
Phenylpropanoids potassium salt or sodium salt:
Potassium salt: ESIMS shows m/z 412.42, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):7.55(dd,1H),7.11(dd,1H),6.86(dd,1H),4.83(d,1H),4.11(t,2H),3.56(m,1H),1.1
4(s,3H)。
Sodium salt: ESIMS display m/z 396.54,7.51 (dd, 1H), 7.10 (dd, 1H), 6.87 (dd, 1H),
4.85(d,1H),4.12(t,2H),3.57(m,1H),1.14(s,3H)。
Phenylpropanoids ammonium salt: ESIMS shows m/z 389.26, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):7.46(dd,1H),7.17(dd,1H),6.80(dd,1H),4.84(d,1H),4.13(t,2H),3.51(m,1H),1.1
1(s,3H)。
Shown in the structural formula such as formula IV of above-mentioned Phenylpropanoid Glycosides compound salt～formula (VIII).
Wherein, formula IV is the phenylpropanoids hydrochlorate prepared, and formula (V) is for preparing
The one of which sulfonate of phenylpropanoids, formula VI is the phenylpropanoids prepared
One of which potassium salt, formula (VII) is the one of which sodium salt of the phenylpropanoids prepared, formula (VIII)
The one of which ammonium salt of the phenylpropanoids for preparing.
Experimental example 7 application test
RAW 264.7 oxidative macrophage that LPS is induced by compound of the present invention and salt stress be with inflammation
The impact of disease.(in order in experimentation, record is convenient, below by phenylpropanoids mark of the present invention
Number it is: medicine MM-133, the most heretofore described medicine MM-133 i.e. refer to formula I of the present invention institute
Show phenylpropanoids or its pharmaceutically acceptable salt.)
1 materials and methods
1.1 medicines and instrument
Lipopolysaccharide (lipopolysaccharide, LPS), MTT is purchased from Sigma company；Mouse macrophage Raw
264.7 are purchased from the refined cell bank in Hunan；PBS；DMEM high glucose medium, hyclone, penicillin and streptomycin；
Full-automatic microplate reader；Constant temperature CO2 incubator.
Mice IL-1β (IL-1-β) ELISA detection kit, lot number: 2014/06 (96T)；Mice is situated between in vain
Element 6 (IL-6) ELISA detection kit, lot number: 2014/06 (96T)；Murine tumor necrosis factor
-α (TNF-α) ELISA detection kit, lot number: 2014/06 (96T)；Mouse nitrous oxide (NO) ELISA
Detection kit, lot number: 2014/10 (96T)；Mice hydroxyl radical free radical (OH) ELISA detection kit, batch
Number: 2014/10 (96T).
Prepared by 1.2 medicines
First dissolve with a small amount of DMSO, be then diluted to certain concentration with DMEM, make in final concentration
DMSO content is less than 1 ‰.
1.3 cells are cultivated
Mouse macrophage Raw 264.7 is incubated at the hyclone containing 10% heat inactivation (56 DEG C, 30min)
(FBS), in the DMEM culture medium of 10U/mL penicillin sodium, 100 μ g/mL streptomycins, 37 DEG C, 5%CO2
Constant incubator is hatched growth.
1.4 cell viabilities measure
Cell viability is measured by mtt assay.Cell is made cell suspension inoculation in 96 orifice plates (1 × 104
Individual/hole) hatch 24h, resynchronization 24h, then the medicine of variable concentrations is acted on cell 2h, the most again
Adding LPS (30 μ g/mL) and stimulate 24h, inhale and abandon former culture medium, every hole adds the MTT (0.5mg/mL) of 100 μ L
Continuing to hatch 4h, inhale and abandon culture medium, every hole adds the DMSO of 150 μ L, and shaking table shaking 10min, at 490nm
Place measures absorbance.
1.5 NO assays
Raw 264.7 cell is inoculated in 96 orifice plate 24h, resynchronization 24h, then by the medicine of variable concentrations
Acting on cell 2h, then adding LPS (30 μ g/mL) stimulates 24h, finally collects supernatant, and in
10000rpm is centrifuged 5min, and subpackage supernatant is placed in-80 DEG C and saves backup.By mice NO kit measurement
NO content.
1.6 inflammatory factor TNF-α, IL-1 β, IL-6 measure
Sample takes 1.5 samples prepared for subsequent inflammation factor determination.Cell generation TNF-α, IL-1 β,
The amount of IL-6 passes through mice TNF-α, and IL-1 β, IL-6 test kit measures.
1.7 OH assays
Sample takes 1.5 samples prepared for OH factor determination.By OH kit measurement content.
1.8 statistical analysis
Using SPSS17.0 software, experimental data is so that (x ± s represents；The data obtained is by dividing by single factor test variance
Analysis, homogeneity of variance LSD checks, and heterogeneity of variance Dunnett T3 checks.
2 experimental results
2.1 cell viability
The impact of cell viability is evaluated by medicine by mtt assay.As it is shown on figure 3, medicine MM-133 exists
In 1.50-13.50 μ g/mL concentration range, Raw 264.7 cell viability is had no significant effect；Therefore at this model
Enclosing the drug level under concentration is suitable for subsequent experimental.
The generation of 2.2 Drug inhibition NO
As shown in Figure 4, stimulating Raw 264.7 cell by LPS, it produces NO (65.81 ± 2.93IU/mL)
Content significantly raised compared with normal group NO (33.61 ± 2.19IU/mL) (p ＜ 0.01).Medicine MM-133 is at this
The NO content under concentration caused LPS raises does not has obvious inhibitory action.
2.3 Drug inhibition TNF-α, the generation of IL-1 β, IL-6
As shown in Figures 5 to 7, by LPS stimulate Raw 264.7 cell, Raw 264.7 cellular inflammation because of
Sub-TNF-α (132.16 ± 5.28pg/mL), IL-1 β (358.80 ± 24.64pg/mL), IL-6
(198.39 ± 5.97pg/mL) content and normal 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 significantly raised (p ＜ 0.01)；
Illustrate that LPS can stimulate Raw 264.7 cell to produce a large amount of inflammatory factors.
Medicine MM-133 stimulates the Raw 264.7 caused in the range of concentration (10.50-13.50 μ g/mL) to LPS
Cellular inflammation factor TNF-α content has an obvious inhibitory action (p ＜ 0.05), and shows obvious dosage and depend on
The relation of relying；In the range of concentration (4.50-13.50 μ g/mL), inflammatory factor IL-1 β content is had and significantly suppress to make
With (p ＜ 0.05), show obvious dose-dependence；To inflammation in the range of concentration (7.50-13.50 μ g/mL)
Inflammation factor IL-6 content has obvious inhibitory action (p ＜ 0.05), shows obvious dose-dependence.
The generation of 2.4 Drug inhibition OH
As shown in Figure 8, stimulating Raw 264.7 cell by LPS, it produces OH (113.58 ± 6.03ng/mL)
Content significantly raised compared with normal group OH (63.40 ± 1.19ng/mL) (p ＜ 0.01).
The OH changes of contents that LPS is caused in (7.50-13.50 μ g/mL) concentration range by medicine MM-133 has
Significantly inhibitory action (p ＜ 0.05), and show dose-dependence.
This experiment, through In vitro culture, have studied medicine MM-133 to mouse macrophage NO, TNF-α, IL-1 β,
The impact that IL-6, OH generate.
Medicine MM-133 is to factor NO unrestraint activity, at higher concentration to cellular inflammation factor TNF-α
There is obvious inhibitory activity, relatively strong to IL-1 β, IL-6 inhibitory activity, illustrate that it is by the generation suppressing TNF-α
After, the content of IL-1 β, IL-6 being created impact, illustrates that its anti-inflammatory activity is preferable, it is table when middle and high concentration
Reveal certain antioxidant activity.
Embodiment 8
The preparation of tablet: first prepare the phenylpropanoids shown in formula I as embodiment 1 method, and
Utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid,
Phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (as potassium hydroxide, sodium hydroxide, calcium hydroxide,
Magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, by this compound or its any one salt and excipient weight
Excipient, pelletizing press sheet is added than the ratio for 1:10.
Embodiment 9
The preparation of powder: first prepare the phenylpropanoids shown in formula I as embodiment 1 method, and
Utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid,
Phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (as potassium hydroxide, sodium hydroxide, calcium hydroxide,
Magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, powder preparation method makes powder routinely.
Embodiment 10
Capsule or the preparation of granule: first prepare the Phenylpropanoid Glycosides class shown in formula I as embodiment 1 method
Compound, and utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid,
Nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (as potassium hydroxide, sodium hydroxide,
Calcium hydroxide, magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, by this compound or its any one salt with
Excipient weight adds excipient than the ratio for 1:10, makes capsule or granule.
Embodiment 11
The preparation of injection: first prepare the phenylpropanoids shown in formula I as embodiment 1 method, with
And utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic
Acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, hydroxide
Calcium, magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, water for injection routinely, fine straining, embedding sterilizing system
Become injection.
Embodiment 12
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method,
And utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid,
Carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, hydrogen-oxygen
Change calcium, magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, and Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, merit
The powder that Lao Mu, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis are made, and adjuvant.
Embodiment 13
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method,
And the powder that Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis are made, and auxiliary
Material.
Embodiment 14
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method,
And Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, the extract of Radix Codonopsis, and adjuvant.
Extract be by patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C,
Any one of CN1296071C, CN1321631C, CN1296072C, CN1296073C or several specially
In profit file, extracting method prepares.
Embodiment 15
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method,
And utilize this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid,
Carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, hydrogen-oxygen
Change calcium, magnesium hydroxide, Lithium hydrate) or the salt made of ammonium, and Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, merit
Lao Mu, Herba Andrographis, Radix Angelicae Sinensis, the extract of Radix Codonopsis, and adjuvant.Extract be by patent announcement CN1078079C,
CN1170549C、CN1158087C、CN1330335C、CN1296071C、CN1321631C、
In any one of CN1296072C, CN1296073C or several patent documents, extracting method prepares.
The ultimate principle of the present invention and principal character and the advantage of the present invention have more than been shown and described.This area
Skilled person will appreciate that, the present invention is not restricted to the described embodiments, described in above-described embodiment and description
The principle that the present invention is simply described, without departing from the spirit and scope of the present invention, the present invention also has
Various changes and modifications, this will be apparent to those skilled in the art, and these changes and improvements all fall
Enter in scope of the claimed invention.Claimed scope is by appending claims and equivalence thereof
Thing defines.
Claims (10)
1. the preparation method of a phenylpropanoids, it is characterised in that the knot of described phenylpropanoids
Structure formula as shown in formula I,
Described preparation method comprises the steps:
S1. the root taking Flemingia macrophylla is raw material, is dried, stripping and slicing, extracts through ethanol solution, by extracting solution
Merge, be concentrated into without alcohol taste, obtain extractum standby；
S2. gained extractum in step S1 is dissolved in water, uses macroporous adsorptive resins that it is carried out eluting, wash
De-agent is ethanol-water system, collects the eluent of front 3 column volumes, and named MM-1 is standby；
S3. the flow point MM-1 reversed material ODS column chromatography collected in step S2 is carried out eluting, eluant
For methanol-water system, 18 column volumes of eluting, collect the eluent of a flow point by every 3 column volumes, by suitable
Sequence collects 6 flow points, is respectively designated as MM-11, MM-12, MM-13, MM-14, MM-15, MM-16,
Standby；
S4. by the flow point MM-13 collected in step S3 with preparing liquid phase separation, flowing is methanol-water-second mutually
Acid system, collects eluent by peak sequence, collects 4 flow points altogether, be respectively designated as MM-131, MM-132,
MM-133, MM-134, standby；
S5. being purified with preparing liquid phase by the flow point MM-133 collected in step S4, flowing is methanol-water-second mutually
Acid system, collects eluent, obtains described phenylpropanoids after recrystallization.
Preparation method the most according to claim 1, it is characterised in that: in step S1, ethanol solution dense
Degree be 50～80 volume %, preferably ethanol solution concentration be 60 volume %.
Preparation method the most according to claim 1, it is characterised in that: in step S1, carrying of ethanol solution
Taking number of times is 2～4 times, extracts 1-3 hour every time, and the preferably extraction time of ethanol solution is 3 times, each 2
Hour.
Preparation method the most according to claim 1, it is characterised in that: in step S2, macroporous adsorbent resin
Use D101 macroporous adsorbent resin.
Preparation method the most according to claim 1, it is characterised in that: in step S2, ethanol and the body of water
Long-pending ratio is 0:100～15:85.
Preparation method the most according to claim 1, it is characterised in that: in step S3, eluant methanol with
The volume ratio of water is 20:80～30:70, preferably 25:75.
Preparation method the most according to claim 1, it is characterised in that: in step S4, methanol-water-acetic acid
Volume ratio be 10:90:0.01～35:65:0.01, preferably 15:85:0.01.
Preparation method the most according to claim 1, it is characterised in that: in step S4, the color of preparation liquid phase
Spectrum post is YMC, 20mm*250mm, and flow rate of mobile phase is 5～10mL/min, preferably flow velocity 5mL/min.
Preparation method the most according to claim 1, it is characterised in that in step S5, methanol-water-acetic acid
Volume ratio is 15:85:0.01.
Preparation method the most according to claim 1, it is characterised in that: in step S5, preparation liquid phase
Chromatographic column is YMC, 20mm*250mm, and flow rate of mobile phase is 5mL/min.
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| 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 |
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| 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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| 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 |
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