CN105732736B - A kind of preparation method of phenylpropanoids - Google Patents
A kind of preparation method of phenylpropanoids Download PDFInfo
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Abstract
The present invention relates to pharmaceutical technology fields, disclose a kind of preparation method of phenylpropanoids, more particularly to isolated a kind of phenylpropanoids from the dry root of Flemingia macrophylla, the phenylpropanoids isolate and purify obtained through solvent extraction, column chromatography for separation, preparation liquid phase, the phenylpropanoids obtained through the method for the present invention are to report for the first time, purity is high.It is demonstrated experimentally that obtained new phenylpropanoids can inhibit the content of cellular inflammation factor NO and the expressional function of cellular inflammation factor TNF-α, have to hydroxyl radical free radical（-OH）Inhibiting effect, and then have anti-inflammatory and antioxidant activity, be beneficial to the treatment of the various diseases associated with inflammation such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or arthritis, can by the compound develop at new drug.Heretofore described structural formula of compound is formula（Ⅰ）Shown in phenylpropanoids and its pharmaceutically acceptable salt.（Ⅰ）.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly, to a kind of preparation method of phenylpropanoids.
Background technique
It is significant that isolated constituent structure multiplicity, activity are extracted from natural drug, it are isolated and purified, structure
Modification, transformation and it is fully synthetic, be always a main thought of new drug development.
TNF-α：Be it is a kind of can direct killing tumour cell and the cell factor to normal cell without overt toxicity, be so far
One of strongest bioactie agent of direct killing function of tumor found until the present, however its toxic side effect is also very tight
Weight.
IL-1β：In local low concentration, collaboration stimulation APC and T cell activation, promote B cell proliferation and secretory antibody, into
Row immunological regulation.There is endocrine effect when a large amount of generations：The synthesis of induced liver acute phase protein, causes fever and cachexia.
IL-6：Mankind's IL-6 gene is located on No. 7 chromosome；IL-6 molecular weight is between 21~30KD.Mainly by list
Core macrophage, Th2 cell, vascular endothelial cell, fibroblast generate.Activating B cell can be stimulated to be proliferated, secretion is anti-
Body；Stimulate T cell proliferation and CTL activation；Cell cultured supernatant synthesized acute phase albumen participates in inflammatory reaction；Promote haemocyte hair
It educates.
IL-6 can be synthesized by various kinds of cell, T cell and B cell, monocytes/macrophages, endothelial cell including activation,
Epithelial cell and fibroblast etc..There are many target cell of IL-6 effect, thin including macrophage, liver cell, static T
Born of the same parents, the B cell of activation and thick liquid cell etc.；Its biological effect is also sufficiently complex.
OH is most active reactive oxygen species in biosystem, can lead to DNA in cell and organism, protein and rouge
Matter oxidative damage.
Macrophage can generate inflammation medium and participate in inflammatory reaction, wherein NO is the important cellular inflammation factor, NO
A variety of pathological processes are participated in, excessive NO can promote the generation and development of diseases associated with inflammation, and also can induce other inflammation
The factor.
Therefore, seek a kind of new preparation method, isolate new compound, from natural plants to inhibit cellular inflammation
The content of factor NO and the expressional function of cellular inflammation factor TNF-α inhibit the activity of hydroxyl radical free radical (- OH), are applied to inflammation
The treatment of disease property disease, is necessary.
Philippine flemingia root medicinal material is that pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania) plant is big
The dry root of leaf philippine flemingia root (Moghania macrophylla (Willd.) O.Kuntze), is distributed mainly on the southeast in China
Area.The plant is in 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 says (1955, pp707) and Guangzhou plant
Will is included in (1956, pp361).Philippine flemingia root medicinal material is the genunie medicinal materials of Guangxi province, and history is loaded in《The Illustrated Book on Plants》,
There is extensive civil medication basis.Its nature and flavor is sweet, micro-puckery, puts down, and has removing damp-heat and other effects, is mainly used for treating rheumatic bone
Bitterly, the gynecological diseases such as more than traumatic injury, chronic nephritis, dysmenorrhea and leukorrhea.The medicinal material has been recorded at present into version in 2005《Middle traditional Chinese medicines
Allusion quotation》Annex.
The reported ingredient of Flemingia macrophylla mainly has flavonoids, steroid, terpene, Anthraquinones, volatile oil component, has
There is certain pharmacological activity.
Flemingia macrophylla pharmacological activity multiplicity, reports the more neuroprotection that has, anti-inflammatory, antioxidation, to disease
The anthelmintic action of pathogenic microorganism, parahormone effect, cytotoxicity, antibacterial action and immunological enhancement, antifatigue effect.
Philippine flemingia root is now widely used for the Chinese patent drug production of the types such as gynaecology, rheumatic arthralgia, such as FUKE QIANJIN PIAN, gynaecology
A thousand pieces of gold capsule, infusion of cherokee rose and spatholobus stem, JINJI JIAONANG etc., such Chinese patent drug is mainly used for gynaecological disease, and (dysmenorrhea, cold uterus be infertile, uterus
Sagging, pelvic inflammatory disease, mazoitis, leukorrhea be more, the postpartum deficiency of blood, arthralgia, postpartum waist and knee, hypogalactia and newborn sore etc.), weak anaemia
(woman anemia, deficient qi and blood and after being ill deficiency of vital energy etc.).In recent years, what clinical report was more is that FUKE QIANJIN PIAN is scorching in treatment gynaecology
Effect in terms of disease.
Currently, reporting that the document of phenylpropanoids is few in the document of philippine flemingia root, a kind of new preparation side is found
Method isolates effective Phenylpropanoid Glycosides class noval chemical compound from natural plants, is isolated and purified to it, structural modification and synthesis,
Developing new drug is significant applied to the treatment of diseases associated with inflammation.
Summary of the invention
The purpose of the present invention is to provide a kind of Phenylpropanoid Glycosides classes isolated in a kind of dry root from Flemingia macrophylla
The preparation method of compound, containing for cellular inflammation factor NO can be inhibited by extracting isolated compound by the preparation method
The expressional function of amount and cellular inflammation factor TNF-α has the inhibiting effect to (- the OH) of hydroxyl radical free radical, and then has anti-
Scorching and antioxidant activity, is beneficial to the treatment of various diseases associated with inflammation, which can be developed into new drug.
Specifically, the preparation method of phenylpropanoids of the present invention includes the following steps：
S1. the root for taking Flemingia macrophylla is raw material, and dry, stripping and slicing extracts through ethanol solution, extracting solution is merged, dense
It is reduced to no alcohol taste, it is spare to obtain medicinal extract；
S2. gained medicinal extract in step S1 is dissolved in water, it is eluted using large pore resin absorption column, eluant, eluent is
Ethanol-water system collects the eluent of preceding 3 column volumes, is named as MM-1, spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reversed material ODS column and is eluted, eluant, eluent is first
Alcohol-water system elutes 18 column volumes, and the eluent of a flow point is collected by every 3 column volumes, collects 6 flow points in order,
It is respectively designated as MM-11, MM-12, MM-13, MM-14, MM-15, MM-16, it is spare；
S4. by the flow point MM-12 being collected into step S3 preparation liquid phase separation, mobile phase is methanol-water-acetic acid system
System collects eluent by peak sequence, collects 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124,
MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, mobile phase is methanol-water-acetic acid system
System collects eluent, obtains the phenylpropanoids after recrystallization.The phenylpropanoids purity is 99.84%.
Shown in the structural formula of the phenylpropanoids such as formula (1)：
Preferably, in step S1, the concentration of ethanol solution is 50~80 volume %, further preferably ethanol solution concentration
For 60 volume %.
Preferably, in step S1, the extraction time of ethanol solution is 2~4 times, is extracted 1~3 hour every time, further excellent
The extraction time for being selected as ethanol solution is 3 times, every time 2 hours.
Preferably, in step S2, macroporous absorbent resin uses D101 macroporous absorbent resin.
Preferably, in step S2, the volume ratio of ethyl alcohol and water is：0:100~15:85.
Preferably, in step S3, the volume ratio of methanol and water is 20:80~30:70, further preferably 25:75.
Preferably, in step S4, the volume ratio of methanol-water-acetic acid is 10:90:0.01~35:65:0.01, it is further excellent
It is selected as 15:85:0.01.
Preferably, in step S4, preparative liquid chromatography column is YMC, 20mm*250mm, and flow rate of mobile phase is：5~10ml/
Min, 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 column is YMC, 20mm*250mm, flow rate of mobile phase 5mL/min.
The present invention provides the phenylpropanoids that the preparation method is prepared.
And the phenylpropanoids being prepared as raw material through chemical synthesis process using the phenylpropanoids
Salt.Shown in the structure of the salt such as formula (II) or formula (III)：
Wherein, R is inorganic acid, R1Or R2Or R3For in sulfonate radical, alkali metal ion or ammonium root any one or any two
Kind is three kinds any.
Preferably, the inorganic acid is hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid or cream
Acid；The sulfonate radical is the sulfonate radical with aryl；The alkali metal ion be potassium ion, sodium ion, calcium ion, magnesium ion or
Lithium ion.
Preferably, the sulfonate radical with aryl is benzene sulfonic acid root or p-methyl benzenesulfonic acid root.
Preferably, the pharmaceutically acceptable salt is ammonium salt.
Beneficial effects of the present invention：
The present invention provides a kind of preparation method for new phenylpropanoids and its pharmaceutically acceptable salt, for the first time
A kind of isolated new phenylpropanoids, compound obtained can inhibit cell from the dry root of Flemingia macrophylla
There is the inhibition to (- the OH) of hydroxyl radical free radical to make for the content of inflammatory factor NO and the expressional function of cellular inflammation factor TNF-α
With, and then there is anti-inflammatory and antioxidant activity, it may be used as such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis
And/or the therapeutic agent of the diseases associated with inflammation such as arthritis.
The purpose of the present invention is pass through the prescription from FUKE QIANJIN PIAN and ' Qianjin ' capsule to treat ganopathy from traditional prescriptions of traditional Chinese medicine
In, a kind of new phenylpropanoids are made, and pass through reality by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying
Verifying is real, can be applied to diseases associated with inflammation, such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or pass
Save the treatment of the diseases such as inflammation.
Specifically, inventor is by the way that from the prescription of FUKE QIANJIN PIAN, ' Qianjin ' capsule to treat ganopathy, science chooses Flemingia macrophylla
Dry root, by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying, obtain Phenylpropanoid Glycosides class chemical combination of the present invention
Then object carries out test cell line to the compound, measure it to cellular inflammation factor NO, TNF-α and hydroxyl radical free radical (- OH)
Inhibition level, experiment show that the compound increases NO content caused by LPS in concentration (6.88-12.38 μ g/mL) range
There is apparent inhibiting effect, and shows apparent dose-dependence.In concentration (6.88-12.38 μ g/mL) range, energy
It significantly inhibits 264.7 cell of Raw and generates inflammatory factor TNF-α (p < 0.05), and be in significant dose-dependence, in concentration
There is apparent inhibiting effect to the raising of OH content caused by LPS in (4.13-12.38 μ g/mL) range, and shows certain agent
Measure dependence.
Detailed description of the invention
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 influence diagram of the phenylpropanoids of the present invention to cell activity.
Fig. 4 is inhibiting effect figure of the phenylpropanoids of the present invention to NO.
Fig. 5 is inhibiting effect figure of the phenylpropanoids of the present invention to TNF-α.
Fig. 6 is inhibiting effect figure of the phenylpropanoids of the present invention to IL-1 β.
Fig. 7 is inhibiting effect figure of the phenylpropanoids of the present invention to IL-6.
Fig. 8 is inhibiting effect figure of the phenylpropanoids of the present invention to OH.
Specific embodiment
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.Unless stated otherwise, raw material and equipment used in the present embodiment are the original of the art regular market purchase
Material and equipment.
The compound of the present invention is the change shown in phenylpropanoids shown in the formula (I) and formula (II) or formula (III)
Close object pharmaceutically acceptable salt.The compound can use the method provided by the invention extracted using Flemingia macrophylla as raw material
It is prepared, the structural formula that can also be provided according to the present invention is combined to be prepared using the methods of the chemical synthesis of this field.
As the salt of phenylpropanoids of the present invention, as long as pharmaceutically acceptable salt, can be enumerated as
The inorganic acid salt formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid；With
The sulfonate that sulfonic acid is formed；The alkali metal salt formed with the hydroxide of the alkali metal such as potassium, sodium, calcium, magnesium, lithium is formed with ammonium
Ammonium salt etc..
Phenylpropanoids of the present invention can be used as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/
Or the therapeutic agent of the diseases associated with inflammation such as arthritis.
The compounds of this invention can be used as pharmaceutical composition together with the auxiliary material and/or carrier that pharmaceutically allow, can also be with
Be added pharmaceutically allow auxiliary material and/or carrier in the case where with cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis,
The combination of one or more of Radix Angelicae Sinensis, Radix Codonopsis Chinese medicine or extract is used as pharmaceutical composition, and the compounds of this invention can be with
It is used as pharmaceutical composition together with other pharmaceutically acceptable effective components.
As pharmaceutical composition, tablet, capsule, powder, granule, pill, solution, suspension, syrup can be
Agent, injection, ointment, suppository, spray etc..
Further, tablet can be the manufactured sugar-coat in the case where auxiliary material and/or carrier that addition pharmaceutically allows
Piece, Film coated tablets, enteric coatings ply or two-ply, multilayer tablet.
Auxiliary material and/or carrier of the invention can be as follows：
Solid pharmaceutical preparation is made, additive, such as sucrose, lactose, cellulose sugar, maltitol, glucose, shallow lake can be used
Powder class, agar, alginates, chitin, chitosan class, pectin class, gum arabic class, gelatin class, collagen class, junket egg
White, albumin, calcium phosphate, D-sorbite, glycine, glycerol, polyethylene glycol, sodium bicarbonate, talcum etc..
Semisolid preparation is made, of animal or plant nature grease (olive oil, corn oil, castor oil etc.), mineral oil can be used
It is rouge (vaseline, albolene, solid paraffin etc.), wax class (jojoba oil, Brazil wax, beeswax etc.), partially synthetic or complete
Fatty acid glyceride (lauric acid, myristic acid, palmitinic acid etc.) of synthesis etc..
Liquid preparation is made, additive, such as sodium chloride, glucose, D-sorbite, glycerol, olive oil, the third two can be used
Alcohol, ethyl alcohol etc..In the case where injection especially is made, aseptic aqueous solution, such as physiological saline, isotonic solution, oiliness can be used
Liquid, such as sesame oil, soybean oil.Furthermore it is also possible to as needed, and with suspending agent appropriate, such as sodium carboxymethylcellulose, nonionic
Surfactant, cosolvent, such as Ergol, benzyl alcohol.
The amount of the effective component of these preparations is 0.01~80 weight % of preparation, is suitably 1~50 weight %, dosage
Symptom, weight, age according to patient etc. are different and change.
The preparation of 1 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.Alcohol reflux through 8 times of amounts 60%
It extracts 3 times, 2 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 10L water, it is washed using D101 large pore resin absorption column
De-, eluant, eluent is water, elutes 3 column volumes, collects eluent, is named as MM-1, spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reverse phase ODS column and is eluted, eluant, eluent is methanol-water
System, volume ratio 25:75,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. by the preparation liquid phase separation of the flow point MM-12 being collected into step S3, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 25:75:
0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, obtains the phenylpropanoids after recrystallization.
The preparation of 2 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 40kg is taken, it is dry using root as raw material, it is cut into small pieces.Alcohol reflux through 6 times of amounts 50%
It extracts 2 times, 1 hour every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 5L water, it is washed using D101 large pore resin absorption column
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 15:85,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reverse phase ODS column and is eluted, eluant, eluent is methanol-water
System, volume ratio 20:80,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. by the preparation liquid phase separation of the flow point MM-12 being collected into step S3, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 35:
65:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, obtains the phenylpropanoids after recrystallization.
The preparation of 3 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 60kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 7 times of amounts 70% mentions
It takes 4 times, 3 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 8L water, it is washed using D101 large pore resin absorption column
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 10:90,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reverse phase ODS column and is eluted, eluant, eluent is methanol-water
System, volume ratio 30:70,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. by the preparation liquid phase separation of the flow point MM-12 being collected into step S3, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 30:
70:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, obtains the phenylpropanoids after recrystallization.
The preparation of 4 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 8 times of amounts 60% mentions
It takes 2 times, 1.5 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 6L water, it is washed using D101 large pore resin absorption column
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 5:95,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reverse phase ODS column and is eluted, eluant, eluent is methanol-water
System, volume ratio 25:75,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. by the preparation liquid phase separation of the flow point MM-12 being collected into step S3, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 25:
75:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, obtains the phenylpropanoids after recrystallization.
The preparation of 5 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 8 times of amounts 80% mentions
It takes 2 times, 1.5 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 6L water, it is washed using D101 large pore resin absorption column
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 10:90,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reverse phase ODS column and is eluted, eluant, eluent is methanol-water
System, volume ratio 28:72,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. by the preparation liquid phase separation of the flow point MM-12 being collected into step S3, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 10:
90:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, obtains the phenylpropanoids after recrystallization.
The compound that embodiment 1 to embodiment 5 is prepared carries out mass spectrum, nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra
Detection, as a result prove gained compound be：3 ', 5 '-dihydroxy -4 '-glucosyl group-phenyl -3- hydroxy methyl propionate.It is tied
Shown in structure formula such as formula (I)：
Its mass spectrum, nuclear magnetic resonance spectroscopy, the spectral data of carbon-13 nmr spectra are as follows：
HR-ESIMS shows [M+Na]+for m/z 399.1889, and in conjunction with nuclear-magnetism feature, can obtain molecular formula is C15H20O11, no
Saturation degree is 6.
1H-NMR(600MHz,CD3OD):6.60(d,1H),6.47(d,1H),4.95(s,1H),4.94(m,2H),3.00-
4.00(glc-H),2.71(m,2H)。
13C-NMR(150MHz,CD3OD):170.5(C-1),150.7(C-1'),150.2(C-4'),135.5(C-3',
5'),114.7(C-2',6'),101.2(C-1”),61.5-77.8(C2”-C6”),61.1(C-2),38.69(C-3)。
The preparation of 6 phenylpropanoids salt of embodiment
The preparation of phenylpropanoids hydrochloride：
Saturation hydrochloric acid will be added dropwise under stirring in the compound methanol solution to pH value 2-3, the lower dropwise addition acetonitrile of stirring filters,
It is dried to obtain white powder solid, the as hydrochloride of phenylpropanoids.
The preparation of phenylpropanoids sulfonate：
The hydroxide of alkali metal is added in the reaction system containing the compound, solvent, sulfonic acid, neutral oil and promotor
Object is added solvent, lower alcohol and kicker, is passed through carbon dioxide, isolated white powder solid, as Phenylpropanoid Glycosides class
Close the sulfonate of object.
The preparation of phenylpropanoids sylvite or sodium salt：
The KOH or N that will be dissolved in ethyl alcoholaOH is added in the phenylpropanoids, stirs lower heating reflux reaction, cold system
Room temperature, stir it is lower acetonitrile is added dropwise, filter, dry white solid, the as sylvite or sodium salt of the phenylpropanoids.
The preparation of phenylpropanoids ammonium salt：
Saturation ammonium hydroxide will be added dropwise under stirring in the compound methanol solution to pH value 9-11, the lower dropwise addition acetonitrile of stirring filters,
It is dried to obtain white solid, the as ammonium salt of phenylpropanoids.
The spectral data of above-mentioned phenylpropanoids salt：
Phenylpropanoids hydrochloride：ESIMS shows m/z 412.67, nuclear-magnetism feature1H-NMR(600MHz,CD3OD)
:1H-NMR(600MHz,CD3OD):6.63(d,1H),6.49(d,1H),5.05(s,1H),4.98(m,2H),3.00-4.00
(glc-H),2.74(m,2H)。
Phenylpropanoids sulfonate：ESIMS is shown as m/z 504.28, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):1H-NMR(600MHz,CD3OD):6.55(d,1H),6.36(d,1H),4.90(s,1H),4.91(m,2H),3.00-
4.00(glc-H),2.51(m,2H)。
Phenylpropanoids sylvite or sodium salt：
Sylvite ESIMS shows m/z 452.19, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.70(d,1H),6.57
(d,1H),4.94(s,1H),4.91(m,2H),3.00-4.00(glc-H),2.70(m,2H)。
Sodium salt ESIMS shows m/z 420.19, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.56(d,1H),6.46
(d,1H),4.74(s,1H),4.51(m,2H),3.00-4.00(glc-H),2.60(m,2H)。
Phenylpropanoids ammonium salt：ESIMS shows m/z 406.57, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1H-NMR(600MHz,CD3OD):6.63(d,1H),6.33(d,1H),4.94(s,1H),4.91(m,2H),3.00-4.00
(glc-H),2.77(m,2H)。
Shown in the structural formula such as formula (IV) of above-mentioned phenylpropanoids salt~formula (VIII).
Wherein, formula (IV) is the phenylpropanoids hydrochloride being prepared, and formula (V) is the Phenylpropanoid Glycosides being prepared
One of sulfonate of class compound, formula (VI) are one of sylvite for the phenylpropanoids being prepared, formula
It (VII) is one of sodium salt for the phenylpropanoids being prepared, formula (VIII) is the phenylpropanoids being prepared
One of ammonium salt.
7 application test of experimental example
Compound and salt of the present invention stress be with the shadows of inflammation to LPS 264.7 oxidative macrophage of RAW induced
It rings.(it is convenient in order to be recorded in experimentation, below by phenylpropanoids of the present invention marked as：Drug MM-125,
I.e. heretofore described drug MM-125 refers to phenylpropanoids shown in formula (I) or its is pharmaceutically acceptable
Salt.)
1 materials and methods
1.1 drugs and instrument
Lipopolysaccharides (lipopolysaccharide, LPS), MTT are purchased from Sigma company；Mouse macrophage Raw264.7
Purchased from the refined cell bank in Hunan；PBS；DMEM high glucose medium, fetal calf serum, penicillin and streptomysin；Full-automatic microplate reader；Constant temperature
CO2Incubator.
Mouse IL 1-β (IL-1- β) ELISA detection kit, lot number：2014/06(96T)；Small mIL6
(IL-6) ELISA detection kit, lot number：2014/06(96T)；Murine tumor necrosis factor-α (TNF-α) ELISA detection examination
Agent box, lot number：2014/06(96T)；Mouse nitrous oxide (NO) ELISA detection kit, lot number：2014/10(96T)；Mouse
Hydroxyl radical free radical (OH) ELISA detection kit, lot number：2014/10(96T).
1.2 medicine preparation
It is dissolved first with a small amount of DMSO, certain concentration is then diluted to DMEM, is less than DMSO content in final concentration
1‰。
1.3 cell culture
Mouse macrophage Raw 264.7 be incubated at containing 10% heat inactivation (56 DEG C, 30min) fetal calf serum (FBS),
10U/mL Benzylpenicillin sodium salt, 100 μ g/mL streptomysins DMEM culture medium in, 37 DEG C, 5%CO2Growth is incubated in constant incubator.
The measurement of 1.4 cell viabilities
Cell viability is measured by mtt assay.Cell suspension inoculation is made in cell to incubate in 96 orifice plates (1 × 104/hole)
It educates for 24 hours, resynchronization for 24 hours, then by the drug effect of various concentration in cell 2h, then adds LPS (30 μ g/mL) stimulation
For 24 hours, it inhales and abandons former culture medium, the MTT (0.5mg/mL) that 100 μ L are added in every hole continues to be incubated for 4h, inhales and abandons culture medium, and every hole is added
The DMSO of 150 μ L, shaking table shake 10min, and absorbance is measured at 490nm.
1.5NO assay
264.7 cell inoculation of Raw in 96 orifice plates for 24 hours, resynchronization for 24 hours, then by the drug effect of various concentration in thin
Then born of the same parents 2h adds LPS (30 μ g/mL) stimulation for 24 hours, finally collect supernatant, and on 10000rpm centrifugation 5min, packing
- 80 DEG C are placed in clearly to save backup.Pass through mouse NO kit measurement NO content.
1.6 inflammatory factor TNF-α, IL-1 β, IL-6 measurement
Sample takes 1.5 samples prepared for subsequent inflammation factor determination.Cell generation TNF-α, IL-1 β, IL-6's
By mouse TNF-α, IL-1 β, IL-6 kit is measured for amount.
1.7OH assay
Sample takes 1.5 samples prepared for OH factor determination.Pass through OH kit measurement content.
1.8 statistical analysis
Using SPSS17.0 software, experimental data is with (x ± s is indicated；The data obtained is by with one-way analysis of variance, side
Poor homogeneous is examined with LSD, and heterogeneity of variance is examined with Dunnett T3.
2 experimental results
2.1 cell viability
Influence of the drug to cell viability is evaluated by mtt assay.As shown in figure 3, drug MM-125 is in 1.37-12.37 μ
264.7 cell viability of Raw is had no significant effect in g/mL concentration range；Therefore the drug concentration pair under this range of concentrations
It is suitable in subsequent experimental.
The generation of 2.2 Drug inhibition NO
As shown in figure 4, by LPS stimulate 264.7 cell of Raw, generate NO (48.66 ± 1.66IU/mL) content with just
Often group NO (29.05 ± 0.85IU/mL) compares significantly raised (p < 0.01).Drug MM-125 is in concentration (6.88 ± 12.38 μ g/
ML) there is apparent inhibiting effect to the raising of NO content caused by LPS in range, and show apparent dose-dependence.
2.3 Drug inhibition TNF-α, the generation of IL-1 β, IL-6
As shown in Figures 5 to 7,264.7 cell of Raw, 264.7 cellular inflammation factor TNF-α of Raw are stimulated by LPS
(127.98 ± 4.65pg/mL), IL-1 β (347.55 ± 9.56pg/mL), IL-6 (201.67 ± 10.32pg/mL) content with just
Often group TNF-α (67.12 ± 4.00pg/mL), IL-1 β (160.88 ± 13.10pg/mL), IL-6 (111.13 ± 8.06pg/mL)
It is significantly raised (p < 0.01) compared to content；Illustrate that LPS can stimulate 264.7 cell of Raw to generate a large amount of inflammatory factors.
Drug MM-125 can significantly inhibit the generation of 264.7 cell of Raw in concentration (6.88-12.38 μ g/mL) range
Inflammatory factor TNF-α (p < 0.05), and be in significant dose-dependence；At various concentrations, Raw cannot be significantly inhibited
264.7 cells generate IL-1 β, IL-6 (p > 0.05).
The generation of 2.4 Drug inhibition OH
As shown in figure 8, by LPS stimulate 264.7 cell of Raw, generate OH (106.00 ± 3.90ng/mL) content with
Normal group OH (64.62 ± 2.18ng/mL) compares significantly raised (p < 0.01).
Drug MM-125 has the raising of OH content caused by LPS in concentration (4.13-12.38 μ g/mL) range apparent
Inhibiting effect, and show certain dose-dependence.
This experiment has studied drug MM-125 to mouse macrophage NO, TNF-α, IL-1 β, IL-6, OH through in vitro culture
The influence of generation.
Drug MM-125 also has certain inhibiting effect to TNF-α to the obvious inhibiting effect that has of factor NO,
But it is to IL-1 β, and IL-6 illustrates that it has certain anti-inflammatory activity without obvious inhibiting effect；It has apparent suppression to OH's
Effect processed illustrates that it has preferable antioxidant activity.
Embodiment 8
The preparation of tablet：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilize the change
Close object and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of metal, is pressed
The compound or its any one salt and excipient weight ratio are 1:Excipient, pelletizing press sheet is added in 10 ratio.
Embodiment 9
The preparation of powder：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilize the change
Close object and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of metal, is pressed
Powder is made in conventional powder preparation method.
Embodiment 10
The preparation of capsule or granule：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, with
And utilize the compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid)
Or the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of sulfonic acid or alkali metal
Manufactured salt is 1 by the compound or its any one salt and excipient weight ratio:Excipient is added in 10 ratio, and glue is made
Wafer or granule.
Embodiment 11
The preparation of injection：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilizing should
Compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal,
Injection is made in routinely water for injection, refined filtration, encapsulating sterilizing.
Embodiment 12
A kind of pharmaceutical composition is made phenylpropanoids shown in formula (I) containing 1 method of embodiment, and utilizes
The compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid
Or made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal
Salt and cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, powder and auxiliary material made of Radix Codonopsis.
Embodiment 13
Phenylpropanoids shown in formula (I), and golden cherry is made containing 1 method of embodiment in a kind of pharmaceutical composition
Root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, powder and auxiliary material made of Radix Codonopsis.
Embodiment 14
Phenylpropanoids shown in formula (I), and golden cherry is made containing 1 method of embodiment in a kind of pharmaceutical composition
Root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis extract and auxiliary material.Extract is by patent announcement number
CN1078079C、CN1170549C、CN1158087C、CN1330335C、CN1296071C、CN1321631C、CN1296072C、
Extracting method is prepared in any one of CN1296073C or several patent documents.
Embodiment 15
A kind of pharmaceutical composition is made phenylpropanoids shown in formula (I) containing 1 method of embodiment, and utilizes
The compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid
Or made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal
Salt and cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis extract and auxiliary material.Extract be by
Patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C,
Extracting method is prepared in any one of CN1296072C, CN1296073C or several patent documents.
Basic principles and main features of the invention and advantage of the invention has been shown and described above.The technology of this field
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, this is to this
It is for the technical staff of field it will be apparent that these changes and improvements all fall within the protetion scope of the claimed invention.This hair
Bright claimed range is defined by the appending claims and its equivalent thereof.
Claims (15)
1. a kind of preparation method of phenylpropanoids, which is characterized in that the structural formula of phenylpropanoids such as formula (I) institute
Show,
The preparation method includes the following steps：
S1. the root for taking Flemingia macrophylla is raw material, and dry, stripping and slicing extracts through ethanol solution, extracting solution is merged, is concentrated into
Without alcohol taste, it is spare to obtain medicinal extract；
S2. gained medicinal extract in step S1 is dissolved in water, it is eluted using large pore resin absorption column, eluant, eluent is second
Alcohol-water system collects the eluent of preceding 3 column volumes, is named as MM-1, spare；
S3. the flow point MM-1 being collected into step S2 is chromatographed with reversed material ODS column and is eluted, eluant, eluent is methanol-water
System elutes 18 column volumes, and the eluent of a flow point is collected by every 3 column volumes, collects 6 flow points in order, respectively
It is named as MM-11, MM-12, MM-13, MM-14, MM-15, MM-16, it is spare；
S4. by the flow point MM-12 being collected into step S3 preparation liquid phase separation, mobile phase is methanol-water-acetic acid system, is pressed
Peak sequence collects eluent, collects 7 flow points altogether, is respectively designated as MM-121, MM-122, MM-123, MM-124, MM-
125, MM-126, MM-127, it is spare；
S5. the flow point MM-125 being collected into step S4 preparation liquid phase is purified, mobile phase is methanol-water-acetic acid system, is received
Collect eluent, obtains the phenylpropanoids after recrystallization.
2. preparation method according to claim 1, it is characterised in that：In step S1, the concentration of ethanol solution is 50~80
Volume %.
3. preparation method according to claim 2, it is characterised in that：In step S1, the concentration of ethanol solution is 60 bodies
Product %.
4. preparation method according to claim 1, it is characterised in that：In step S1, the extraction time of ethyl alcohol is 2~4 times,
It extracts 1~3 hour every time.
5. the preparation method according to claim 4, it is characterised in that：In step S1, the extraction time of ethyl alcohol is 3 times, often
It is secondary to extract 2 hours.
6. preparation method according to claim 1, it is characterised in that：In step S2, macroporous absorbent resin is big using D101
Macroporous adsorbent resin.
7. preparation method according to claim 1, it is characterised in that：In step S2, the volume ratio of ethyl alcohol and water is 0:100
~15:85.
8. preparation method according to claim 1, it is characterised in that：In step S3, the volume ratio of eluant, eluent methanol and water
It is 20:80~30:70.
9. preparation method according to claim 8, it is characterised in that：In step S3, the volume ratio of eluant, eluent methanol and water
It is 25:75.
10. preparation method according to claim 1, it is characterised in that：In step S4, the volume ratio of methanol-water-acetic acid is
10:90:0.01~35:65:0.01.
11. preparation method according to claim 10, it is characterised in that：In step S4, the volume ratio of methanol-water-acetic acid
It is 15:85:0.01.
12. preparation method according to claim 1, it is characterised in that：In step S4, the chromatographic column for preparing liquid phase is YMC,
20mm*250mm, flow rate of mobile phase are 5~10mL/min.
13. preparation method according to claim 12, it is characterised in that：In step S4, flow rate of mobile phase 5mL/min.
14. preparation method according to claim 1, which is characterized in that in step S5, the volume ratio of methanol-water-acetic acid is
15:85:0.01。
15. preparation method according to claim 1, it is characterised in that：In step S5, the chromatographic column for preparing liquid phase is YMC,
20mm*250mm, flow rate of mobile phase 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 |
| 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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| 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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