CN106748733A - A kind of preparation method of salviandic acid A salt - Google Patents
A kind of preparation method of salviandic acid A salt Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention provides a kind of preparation method of salviandic acid A salt, described preparation method is：Salviandic acid A is taken to be dissolved in the water, then it is 1.2~5.5 to adjust pH value with the aqueous solution of alkaline matter, collects precipitate, as described salviandic acid A salt；Of the invention to add aqueous slkali to improve pH using in the salviandic acid A aqueous solution, the method for separating out salviandic acid A salt has prepared stability by force, is difficult to be oxidized, and purity is high, the salviandic acid A product salt that impurity declines；This preparation method is efficient and simple and easy to apply, more suitable for industrialized production, is conducive to salviandic acid A salt development and application.
Description
(1) technical field
The present invention relates to a kind of preparation method of salviandic acid A salt.
(2) background technology
Salviandic acid A (Salvianicacid A) is contained a kind of water-soluble phenolic acids chemical combination in the labiate red sage root
Thing, is taught in isolated from the red sage root (LiLian-Niang, et in 1984 by Li Lianniang
al.PlantaMedica.1984,50:227).Salviandic acid A has stronger ischemic myocardial protection, antithrombus formation, anti-liver fine
Dimensionization waits pharmacological activity with anti-oxidant, has potential therapeutic value to cardiovascular and cerebrovascular disease.
Salviandic acid A is poor in the presence of easily oxidized, stability, is made various formulations it is difficult to ensure that its problem steady in a long-term.
CN105523926 A disclose the extraction separation and purification method of salviandic acid A and the preparation method of salviandic acid A salt, wherein employing
Salviandic acid A magnesium salts complexometry, but it is the magnesate complexes containing sodium chloride or potassium chloride that it obtains.CN102432467 B are public
A kind of preparation method of salviandic acid A magnesium salts is opened, this preparation method has technological process complexity, and production cost is high, is not suitable for work
The deficiency such as industry metaplasia product or preparation.
(3) content of the invention
It is strong it is an object of the invention to provide a kind of stability, it is difficult to be oxidized, the preparation side of purity salviandic acid A salt high
Method, preparation method of the present invention has good manufacturability, simple to operate, low production cost, the characteristics of being suitable to industrialized production or prepare.
The present invention is adopted the following technical scheme that：
A kind of preparation method of salviandic acid A salt, described preparation method is：
Salviandic acid A is taken to be dissolved in the water, then with the aqueous solution of alkaline matter adjust pH value be 1.2~5.5 (preferably 3.2~
4.2) precipitate, as described salviandic acid A salt, are collected.
In preparation method of the present invention, the salviandic acid A is 1 with the feed liquid mass ratio of water：0.25~4, preferably 1：
0.67~1.5.
The concentration of the aqueous solution of the alkaline matter is 1%~15%, preferably 4%~11%；Described alkaline matter bag
Highly basic, weak acid strong alkali salt are included, specifically for example：NaOH, sodium acid carbonate, sodium carbonate, potassium hydroxide, saleratus, potassium carbonate,
Magnesium hydroxide, magnesium bicarbonate, magnesium carbonate, calcium hydroxide, calcium bicarbonate, calcium carbonate, sodium citrate, sodium tartrate, potassium citrate,
Potassium tartrate, magnesium citrate or magnesium tartrate.
Obtained salviandic acid A salt of the invention is sodium salt, sylvite, magnesium salts or the calcium salt of salviandic acid A.
In the preparation method, the precipitate obtained by collection cleans with water, dry after, you can be directly used in preparation or and people
The acceptable pharmaceutic adjuvant of body is used for preparation together.
Salviandic acid A of the present invention is extracted by the raw material red sage root through water or ethanol water, macroporous resin column chromatography is separated,
Polyamide chromatography post separation is prepared.Its preparation method is for example referred to：Method disclosed in Chinese patent CN101361728B.
Specifically, the preparation method of the salviandic acid A is usually：
(1) the raw material red sage root is pressed into feed liquid mass ratio 1：6~12 with the ethanol water of water or volume fraction 10%~90%
Mixing, extracts 1~3h at 70~100 DEG C, and filtrate is collected by filtration, and filter residue is carried 1~3 time again, merges each gained filtrate, obtains
Red sage root extract；
(2) step (1) gained red sage root extract is taken, is concentrated (being generally concentrated into 2~4 times of raw material red sage root quality), regulation
(routine operation, is adjusted pH to 3.5~6.0 with inorganic aqueous acid, described inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid
Deng), 110~130 DEG C of 1~6h of heating are warming up to, room temperature (20~30 DEG C) is cooled to afterwards, to filter, filtrate carries out macroreticular resin
Column chromatography for separation, first removed with water, the ethanol aqueous wash of volume fraction 10%~30% it is miscellaneous, then with volume fraction 30%~70%
Ethanol water is eluted, and collects the eluent containing salviandic acid A, and polyamide chromatography post point is proceeded after concentration (to without alcohol taste)
From first miscellaneous then water-soluble with the ethanol of volume fraction 50%~95% with water, the removing of the ethanol aqueous wash of volume fraction 20%~50%
Liquid is eluted, and collects the eluent containing salviandic acid A, and pH value is adjusted in concentration (to without alcohol taste) afterwards, and (routine operation uses basic species to 2~5
The aqueous solution of matter is adjusted, and described alkaline matter is as defined above), extracted through organic solvent, extract is concentrated, does
It is dry, obtain final product described salviandic acid A；
The described raw material red sage root is the dry root and rhizome of labiate red sage root Salvia miltiorrhiza Bge.,
Can be in conventional commercially available on the market；
Described macroreticular resin be HPD-100, HPD-100A, HPD-300, HPD-400, HPD-400A, HPD-450,
D101,1300-I, 1400 or AB-8；
The organic solvent for extracting is ethyl acetate, propyl acetate, butyl acetate, n-butanol or isopropanol；
Obtained salviandic acid A purity is 50%~100%, can be directly used for the preparation of follow-up salviandic acid A salt.
The beneficial effects of the present invention are：The present invention adds aqueous slkali to improve pH using in the salviandic acid A aqueous solution, separates out red
The method of phenolic acid A salt, has prepared stability by force, is difficult to be oxidized, and purity is high, the salviandic acid A product salt that impurity declines.This
Preparation method is simple, more suitable for industrialized production.Therefore, the present invention is a kind of efficient for the preparation of salviandic acid A salt is provided
And method simple and easy to apply, be conducive to salviandic acid A salt development and application.
(4) illustrate
Fig. 1：The high resolution mass spectrum of salviandic acid A sodium salt；
Fig. 2：Salviandic acid A sodium salt1H H NMR spectroscopies；
Fig. 3：Salviandic acid A sodium salt13C H NMR spectroscopies；
Fig. 4：The HMQC spectrums of salviandic acid A sodium salt.
(5) specific embodiment
Below by specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited in
This.
Embodiment 1~9 is the preparation embodiment of salviandic acid A, the method with reference to disclosed in the B of CN 101361728.The raw material red sage root
Purchased from Huayu Pharmaceutical Co., Ltd, Shanghai.
Embodiment 1
Raw material red sage root 200kg is mixed with the ethanol water 2000L of volume fraction 50%, 2h, mistake are extracted at 82 DEG C
Filtrate is collected in filter, and filter residue is carried 3 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
600L, pH is adjusted to 4.5 with hydrochloric acid solution, is warming up to 120 DEG C of heating 4h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out HPD-
100 macroporous resin column chromatographies are separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with volume fraction 50%
Ethanol water is eluted, and collects the eluent containing salviandic acid A, is concentrated into without proceeding polyamide chromatography post point after alcohol taste
From, it is first miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 35%, then eluted with the ethanol water of volume fraction 75%, collect
Eluent containing salviandic acid A, after being concentrated into without alcohol taste, pH value to 3.0 is adjusted with potassium bicarbonate solution, is extracted through ethyl acetate,
Extract is concentrated, dries, and obtains salviandic acid A 816g, content 93.20%.
Embodiment 2
Raw material red sage root 200kg is mixed with the ethanol water 2000L of volume fraction 50%, 2h, mistake are extracted at 82 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
400L, pH is adjusted to 4.4 with hydrochloric acid solution, is warming up to 120 DEG C of heating 2.5h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out HPD-
300 macroporous resin column chromatographies are separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with volume fraction 50%
Ethanol water is eluted, and collects the eluent containing salviandic acid A, is concentrated into without proceeding polyamide chromatography post point after alcohol taste
From, it is first miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 35%, then eluted with the ethanol water of volume fraction 75%, collect
Eluent containing salviandic acid A, after being concentrated into without alcohol taste, pH value to 3.0 is adjusted with solution of potassium carbonate, is extracted through propyl acetate, extraction
Take liquid concentrated, dry, obtain salviandic acid A 808g, content 93.80%.
Embodiment 3
Raw material red sage root 200kg is mixed with the ethanol water 2000L of volume fraction 50%, 2h, mistake are extracted at 82 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
400L, pH is adjusted to 4.6 with hydrochloric acid solution, is warming up to 120 DEG C of heating 3h, and room temperature is cooled to afterwards, is filtered, and it is big that filtrate carries out 1400
Hole resin column chromatography for separation, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with the ethanol water of volume fraction 50%
Eluant solution, collects the eluent containing salviandic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first uses
Water, the removing of the ethanol aqueous wash of volume fraction 35% are miscellaneous, then are eluted with the ethanol water of volume fraction 75%, collect and contain red phenol
The eluent of sour A, after being concentrated into without alcohol taste, pH value to 3.0 is adjusted with magnesium bicarbonate solution, through n-butyl acetate extraction, extract warp
Concentration, dries, and obtains salviandic acid A 797g, content 93.50%.
Embodiment 4
Raw material red sage root 200kg is mixed with the ethanol water 1600L of volume fraction 70%, 2h, mistake are extracted at 80 DEG C
Filtrate is collected in filter, and filter residue is carried 3 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
600L, pH is adjusted to 3.5 with hydrochloric acid solution, is warming up to 120 DEG C of heating 3.5h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out 1400
Macroporous resin column chromatography is separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with the ethanol of volume fraction 50%
The aqueous solution is eluted, and collects the eluent containing salviandic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first
It is miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 35%, then eluted with the ethanol water of volume fraction 70%, collect and contain pellet
The eluent of phenolic acid A, after being concentrated into without alcohol taste, pH value to 3.0 is adjusted with sodium bicarbonate solution, is extracted through ethyl acetate, extract
It is concentrated, dry, obtain salviandic acid A 903g, content 91%.
Embodiment 5
Raw material red sage root 200kg is mixed with the ethanol water 2400L of volume fraction 90%, 3h, mistake are extracted at 78 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
800L, pH is adjusted to 4.5 with salpeter solution, is warming up to 130 DEG C of heating 1h, and room temperature is cooled to afterwards, is filtered, and filtrate is carried out
1300-I macroporous resin column chromatographies are separated, first miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 30%, then use volume fraction
70% ethanol water is eluted, and collects the eluent containing salviandic acid A, is concentrated into without proceeding polyamide chromatography post after alcohol taste
Separate, it is first miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 50%, then eluted with the ethanol water of volume fraction 95%, receive
Eluent of the collection containing salviandic acid A, after being concentrated into without alcohol taste, pH value is adjusted to 2.0 with sodium carbonate liquor, through n-butyl acetate extraction,
Extract is concentrated, dries, and obtains salviandic acid A 711g, content 84%.
Embodiment 6
Raw material red sage root 200kg is mixed with water 1200L, 1h is extracted at 100 DEG C, filtrate is collected by filtration, filter residue carries 1 again
It is secondary, merge each gained filtrate, obtain red sage root extract；Gained red sage root extract is concentrated into 400L, is adjusted with salpeter solution
PH is warming up to 110 DEG C of heating 6h to 6, and room temperature is cooled to afterwards, filters, and filtrate carries out AB-8 macroporous resin column chromatography separation, first
It is miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 10%, then eluted with the ethanol water of volume fraction 30%, collect and contain pellet
The eluent of phenolic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first with water, the ethanol of volume fraction 20%
The aqueous solution elutes removal of impurities, then is eluted with the ethanol water of volume fraction 50%, collects the eluent containing salviandic acid A, is concentrated into
After without alcohol taste, pH value to 5.0 is adjusted with sodium hydroxide solution, extracted through propyl acetate, extract is concentrated, dried, obtain red phenol
Sour A 495g, content 63%.
Embodiment 7
Raw material red sage root 250kg is mixed with the ethanol water 2000L of volume fraction 60%, 3h, mistake are extracted at 81 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
645L, pH is adjusted to 4.5 with salpeter solution, is warming up to 120 DEG C of heating 3h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out 1400
Macroporous resin column chromatography is separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with the ethanol of volume fraction 40%
The aqueous solution is eluted, and collects the eluent containing salviandic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first
It is miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 40%, then eluted with the ethanol water of volume fraction 80%, collect and contain pellet
The eluent of phenolic acid A, after being concentrated into without alcohol taste, pH value to 3.2 is adjusted with sodium bicarbonate solution, is extracted through ethyl acetate, extract
It is concentrated, dry, obtain salviandic acid A 1260g, content 95.8%.
Embodiment 8
Raw material red sage root 250kg is mixed with the ethanol water 2000L of volume fraction 60%, 3h, mistake are extracted at 81 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
638L, pH is adjusted to 4.6 with salpeter solution, is warming up to 120 DEG C of heating 3h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out 1400
Macroporous resin column chromatography is separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with the ethanol of volume fraction 40%
The aqueous solution is eluted, and collects the eluent containing salviandic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first
It is miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 40%, then eluted with the ethanol water of volume fraction 80%, collect and contain pellet
The eluent of phenolic acid A, after being concentrated into without alcohol taste, pH value to 3.2 is adjusted with sodium bicarbonate solution, is extracted through ethyl acetate, extract
It is concentrated, dry, obtain salviandic acid A 1600g, content 98.2%.
Embodiment 9
Raw material red sage root 250kg is mixed with the ethanol water 2000L of volume fraction 60%, 3h, mistake are extracted at 81 DEG C
Filtrate is collected in filter, and filter residue is carried 2 times again, merges each gained filtrate, obtains red sage root extract；Gained red sage root extract is concentrated into
635L, pH is adjusted to 4.6 with salpeter solution, is warming up to 120 DEG C of heating 3h, and room temperature is cooled to afterwards, is filtered, and filtrate carries out 1400
Macroporous resin column chromatography is separated, first removed with water, the ethanol aqueous wash of volume fraction 20% it is miscellaneous, then with the ethanol of volume fraction 40%
The aqueous solution is eluted, and collects the eluent containing salviandic acid A, is concentrated into without polyamide chromatography post separation is proceeded after alcohol taste, first
It is miscellaneous with water, the removing of the ethanol aqueous wash of volume fraction 40%, then eluted with the ethanol water of volume fraction 80%, collect and contain pellet
The eluent of phenolic acid A, after being concentrated into without alcohol taste, pH value to 3.2 is adjusted with sodium bicarbonate solution, is extracted through ethyl acetate, extract
It is concentrated, dry, obtain salviandic acid A 1554g, content 98.5%.
Embodiment 10~24 is the preparation embodiment of salviandic acid A salt.
Embodiment 10
Salviandic acid A 600g prepared by Example 1, with 2：8 w/v is dissolved in 2400mL water, filtering, plus
5% sodium carbonate liquor adjusts pH value to 1.2, filtering, collects precipitate, and conventional vacuum is drying to obtain salviandic acid A sodium salt 336g, pure
Degree 99.90%.
Embodiment 11
Salviandic acid A 600g prepared by Example 2, with 3：7 w/v is dissolved in 1400mL water, filtering, plus
15% sodium hydroxide solution adjusts pH value to 1.8, and precipitate is collected in activated carbon treatment, filtering, and drying under reduced pressure obtains final product salviandic acid A
Sodium salt 343g, purity 99.50%.
Embodiment 12
Salviandic acid A 600g prepared by Example 3, with 4：6 w/v is dissolved in 900mL water, plus 1% wine
Stone acid sodium solution adjusts pH value to 1.5, and precipitate is collected in activated carbon treatment, filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt
343g, purity 99.50%.
Embodiment 13
Salviandic acid A 100g prepared by Example 6, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Acid sodium solution adjusts pH value to 1.2, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 34g, purity 91.10%.
Embodiment 14
Salviandic acid A 100g prepared by Example 5, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Acid sodium solution adjusts pH value to 1.2, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 47g, purity 97.70%.
Embodiment 15
Salviandic acid A 100g prepared by Example 4, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Acid sodium solution adjusts pH value to 1.2, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 57g, purity 98.30%.
Embodiment 16
Salviandic acid A 100g prepared by Example 6, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Sour hydrogen magnesium solution adjusts pH value to 3.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A magnesium salts 36g, purity
92.10%.
Embodiment 17
Salviandic acid A 100g prepared by Example 5, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Sour hydrogen magnesium solution adjusts pH value to 3.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A magnesium salts 51g, purity
97.20%.
Embodiment 18
Salviandic acid A 100g prepared by Example 4, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Sour hydrogen magnesium solution adjusts pH value to 3.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A magnesium salts 58g, purity
98.60%.
Embodiment 19
Salviandic acid A 100g prepared by Example 6, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Potassium hydrogen phthalate solution adjusts pH value to 5.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sylvite 39g, purity
90.40%.
Embodiment 20
Salviandic acid A 100g prepared by Example 5, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Potassium hydrogen phthalate solution adjusts pH value to 5.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sylvite 52g, purity
96.80%.
Embodiment 21
Salviandic acid A 100g prepared by Example 4, with 5：5 w/v is dissolved in 100mL water, plus 5% carbon
Potassium hydrogen phthalate solution adjusts pH value to 5.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sylvite 58g, purity
97.50%.
Embodiment 22
Salviandic acid A 1260g prepared by Example 7, with 6：4 w/v is dissolved in 1030mL water, plus 5%
Sodium hydroxide solution adjusts pH value to 3.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 812g, purity
99.80%.
Embodiment 23
Salviandic acid A 1600g prepared by Example 8, with 6：4 w/v is dissolved in 1310mL water, plus 5%
Sodium hydroxide solution adjusts pH value to 3.5, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 948g, purity
99.80%.
Embodiment 24
Salviandic acid A 1554g prepared by Example 9, with 6：4 w/v is dissolved in 1269mL water, plus 5%
Sodium hydroxide solution adjusts pH value to 3.4, and precipitate is collected in filtering, and drying under reduced pressure obtains final product salviandic acid A sodium salt 915g, purity
99.80%.
It is below the interpretation of result to technical solution of the present invention：
Different purity raw material obtains salviandic acid A purity salt at various ph values, as shown in table 1.
Different purity raw material salviandic acid A is taken to be dissolved in the water, plus aqueous slkali adjusts different pH value, collecting precipitate drying is
Obtain salviandic acid A salt.
Table 1
Yield is dissolved with Different Weight ratio, as shown in table 2.
Raw material salviandic acid A is taken to be dissolved in different proportion water, plus aqueous slkali regulation pH value 3.6, collecting precipitate drying is
Obtain salviandic acid A salt.
Table 2
Salviandic acid A compares into salt fore-and-aft stability, as shown in table 3.
Table 3
Conclusion：The salviandic acid A salt of embodiment 10 is made by the salviandic acid A of embodiment 1, embodiment is made by the salviandic acid A of embodiment 2
11 salviandic acid A salt, the salviandic acid A salt of embodiment 12 is made up of the salviandic acid A of embodiment 3；As can be known from the table data, salviandic acid A is placed
Content is down to 75% or so from 93% or so after 1 year, and impurity increases to 9% from 4%, and after being made salviandic acid A salt, before placement
After be not changed in, so being made quite stable after salt.
High temperature, high humidity, highlight test
The high temperature of table 4 is investigated
The high humidity of table 5 is investigated
The illumination of table 6 is investigated
Conclusion：The salviandic acid A salt of embodiment 10 is made by the salviandic acid A of embodiment 1, from high temperature, high humidity, high light experimental data can
Know, into salt after more stablize.
Different purity salviandic acid A compares into solubility before and after salt, as shown in table 7.
Table 7
| Salviandic acid A embodiment | Salviandic acid A | It is water-soluble | Salviandic acid A salt embodiment | Salviandic acid A sodium salt | It is water-soluble |
| 6 | 63% | Easily dissolve | 16 | 92.1% | It is slightly molten |
| 5 | 84% | Easily dissolve | 17 | 97.2% | It is slightly molten |
| 4 | 91% | Easily dissolve | 18 | 98.6% | It is slightly molten |
The high resolution mass spectrum of Fig. 1~4 salviandic acid A sodium salt for preparing respectively of the invention,1H H NMR spectroscopies,13C H NMR spectroscopies,
HMQC is composed.
High resolution mass spectrum
(1) tester：Qstar Elite(Applietl Biosyhtems/MBS Sclex)
Determine element：C、H、O、Na
(2) measurement result such as table 8 below：
The high resolution mass spectrum of table 8 analyzes measurement result tables of data
High resolution mass spectrum determination data is parsed：
High resolution mass spectrum uses ESI+Ion mode, so the molecular formula that high resolution mass spectrum result is obtained is than sample molecule formula
Many hydrogen.There is a sodium ion in high resolution mass spectrum analysis result display molecule, illustrate that salviandic acid A is with the shape of sodium salt
Formula is present, and salviandic acid A and sodium ion are 1 in this product：1 one-tenth salt.
1H-NMR nuclear magnetic resoance spectrums
(1) instrument：MP-400
Solvent：DMSO-d6, internal standard：TMS
(2)1H nuclear magnetic resonances are composed, and see accompanying drawing 2
(3) determination data see the table below 9：
Table 91HNMR nuclear magnetic resonance measuring tables of data
| Atom sequence number | Chemical shift | Peak shape | Proton number | Corresponding proton | J(Hz) |
| A-5 | 6.80 | d | 1 | Φ-H | 8.4 |
| A-6 | 7.16 | d | 1 | Φ-H | 8.4 |
| A-7 | 7.88 | d | 1 | =C-H | 15.6 |
| A-8 | 6.29 | d | 1 | =C-H | 15.6 |
| B-2 | 6.75 | d | 1 | Φ-H | 8.4 |
| B-3 | 6.47 | d | 1 | Φ-H | 8.4 |
| B-6 | 6.67 | s | 1 | Φ-H | |
| B-7α | 2.81 | m | 1 | -CH2 | |
| B-7β | 3.01 | d | 1 | -CH2 | |
| B-8 | 4.98 | dd | 1 | -OCH | |
| C-2 | 7.01 | s | 1 | Φ-H | |
| C-5 | 6.60 | d | 1 | Φ-H | |
| C-6 | 6.79 | d | 1 | Φ-H | |
| C-7 | 6.53 | d | 1 | =C-H | 16.8 |
| C-8 | 7.04 | d | 1 | =C-H | 16.2 |
1HNMR nuclear magnetic resonance measurings data are parsed：
(1)1H-NMR spectrums occur in that the peaks of δ 2.5, and a broad peak occur in δ 3.2-4.8, illustrate there is a hydrone in molecule,
Matched with the TGA data of sample.
(2)1H-NMR spectrums occur in that the broad peaks of δ 9.03, about containing 6 protons, should be the 6 phenolic hydroxyl group hydrogen contained in molecule
Proton.
(3) high field region, δ 2.81, multiplet, containing 1 Hydrogen Proton；δ 3.01, it is bimodal, containing a Hydrogen Proton, respectively methylene
2 Hydrogen Protons on base B7, are influenceed by ortho position chiral carbon, and produce different chemical shifts.δ 4.98 is and carboxyl and ester group
Hydrogen Proton signal on connected methine carbon B8.
(4) low field area, δ 7.88 and δ 6.29, bimodal respectively containing 1 proton, coupling constant is 15.6, is trans alkene hydrogen
The upper Hydrogen Proton of A7, A8, δ 7.04 and δ 6.53, respectively containing 1 proton, bimodal, coupling constant is about 16.2, be trans alkene hydrogen C7,
The upper Hydrogen Protons of C8, illustrate there are 2 groups of trans double bond hydrogen atoms in molecule.
(5) low field area, δ 6.2~7.9, altogether containing 12 protons, wherein 4 is Hydrogen Proton, remaining 8 on trans alkene hydrogen
It is aromatic ring Hydrogen Proton, it is completely the same with molecular structure.
Nucleus magnetic hydrogen spectrum as shown by data, the nucleus magnetic hydrogen spectrum of salviandic acid A sodium is basically identical with the nucleus magnetic hydrogen spectrum of salviandic acid A, part
The displacement of Hydrogen Proton is slightly displaced from.
13C-NMR nuclear magnetic resoance spectrums
(1) instrument：ARX400
Solvent：DMSO-d6, internal standard：TMS
(2)13C nuclear magnetic resonances are composed, and see accompanying drawing 3
C, H correlation two dimensional NMR (HMQC) spectrogram are shown in accompanying drawing 4
(3) determination data see the table below 10：
Table 1013CNMR nuclear magnetic resonance data tables
13C-NMR nuclear magnetic resonance spectroscopies data are parsed：
(1)13CNMR spectrograms provide 25 groups of carbon atom signal peaks altogether, and wherein δ 119.24 contains 2 carbonaceous, illustrates molecule
In have 26 carbon.
(2) high field region, δ 36.85 is mesomethylene carbon, related to 2 hydrogen in HMQC figures, is B7 carbon；δ 74.58 is secondary
Methyl carbon, it is related to 1 hydrogen in HMQC figures, it is B8 carbon.Compared with the carbon of salviandic acid A spectrum, the B7 displacement of carbon is found
Slightly to field offset high, then slightly to low field offset, this is due to the influence into sodium salt for the displacement of B8 carbon.
(3) low field area, δ 172.31 is B9 carbonyl carbon in carboxylate；δ 166.43, is A9 carbonyl carbon in ester group.
(4) chemical shift is aromatic ring carbon atom or olefinic carbon in the carbon atom of δ 113~148.Wherein on phenyl ring not by
The chemical shift of substituted carbon atom in δ 113~121, chemical shift δ 143~147 carbon atom on phenyl ring with hydroxyl phase
Carbon atom even.δ 119.24 is related to 2 fragrant hydrogen in HMQC correlation figures containing 2 carbon atoms.
Nuclear-magnetism carbon modal data shows that the carbon of salviandic acid A sodium salt is composed compared with the carbon of salviandic acid A is composed, carbonyl carbon B9 and therewith phase
B8 carbon chemical shifts even are slightly migrated to low field, and other carbon atom displacements are basically identical.
Claims (9)
1. a kind of preparation method of salviandic acid A salt, it is characterised in that described preparation method is：
Salviandic acid A is taken to be dissolved in the water, then it is 1.2~5.5 to adjust pH value with the aqueous solution of alkaline matter, collects precipitate, i.e.,
It is described salviandic acid A salt.
2. the preparation method of salviandic acid A salt as claimed in claim 1, it is characterised in that regulation pH value is 3.2~4.2.
3. the preparation method of salviandic acid A salt as claimed in claim 1, it is characterised in that the feed liquid matter of the salviandic acid A and water
Amount is than being 1：0.25~4.
4. the preparation method of salviandic acid A salt as claimed in claim 3, it is characterised in that the feed liquid matter of the salviandic acid A and water
Amount is than being 1：0.67~1.5.
5. the preparation method of salviandic acid A salt as claimed in claim 1, it is characterised in that the aqueous solution of the alkaline matter
Concentration is 1%~15%.
6. the preparation method of salviandic acid A salt as claimed in claim 5, it is characterised in that the aqueous solution of the alkaline matter
Concentration is 4%~11%.
7. the preparation method of salviandic acid A salt as claimed in claim 1, it is characterised in that the aqueous solution of the alkaline matter by
Alkaline matter is soluble in water as follows is formulated：NaOH, sodium acid carbonate, sodium carbonate, potassium hydroxide, saleratus, carbonic acid
Potassium, magnesium hydroxide, magnesium bicarbonate, magnesium carbonate, calcium hydroxide, calcium bicarbonate, calcium carbonate, sodium citrate, sodium tartrate, citric acid
Potassium, potassium tartrate, magnesium citrate or magnesium tartrate.
8. the preparation method of salviandic acid A salt as claimed in claim 1, it is characterised in that described salviandic acid A is by the raw material red sage root
Extracted through water or ethanol water, macroporous resin column chromatography is separated, polyamide chromatography post separation is prepared.
9. the preparation method of salviandic acid A salt as claimed in claim 8, it is characterised in that described salviandic acid A is as follows
Prepare：
(1) the raw material red sage root is pressed into feed liquid mass ratio 1：6~12 mix with the ethanol water of water or volume fraction 10%~90%,
1~3h is extracted at 70~100 DEG C, filtrate is collected by filtration, filter residue is carried 1~3 time again, merge each gained filtrate, obtain the red sage root
Extract solution；
(2) take step (1) gained red sage root extract, concentration, regulation pH to 3.5~6.0, be warming up to 110~130 DEG C heating 1~
6h, is cooled to room temperature afterwards, filtering, and filtrate carries out macroporous resin column chromatography separation, first with water, the second of volume fraction 10%~30%
Alcohol solution elutes removal of impurities, then is eluted with the ethanol water of volume fraction 30%~70%, collects the wash-out containing salviandic acid A
Liquid, proceeds polyamide chromatography post separation after concentration, first removed with water, the ethanol aqueous wash of volume fraction 20%~50%
It is miscellaneous, then eluted with the ethanol water of volume fraction 50%~95%, the eluent containing salviandic acid A is collected, pH value is adjusted after concentration
To 2~5, extracted through organic solvent, extract is concentrated, dried, obtain final product described salviandic acid A；
Described macroreticular resin be HPD-100, HPD-100A, HPD-300, HPD-400, HPD-400A, HPD-450, D101,
1300-I, 1400 or AB-8；
The organic solvent for extracting is ethyl acetate, propyl acetate, butyl acetate, n-butanol or isopropanol.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018145622A1 (en) * | 2017-02-07 | 2018-08-16 | 正大青春宝药业有限公司 | Method for preparing salvianolic acid a salt |
| CN109748793A (en) * | 2018-12-29 | 2019-05-14 | 正大青春宝药业有限公司 | A method of different salviandic acid A 1 and different salviandic acid A 2 in removal salviandic acid A sodium |
| CN110403928A (en) * | 2019-07-17 | 2019-11-05 | 正大青春宝药业有限公司 | A kind of salviandic acid A salt composite and its preparation method and application |
| WO2022233310A1 (en) * | 2021-05-06 | 2022-11-10 | 台州永健医药科技有限公司 | Salvianolic acid a salt hydrate, preparation method therefor, and use thereof |
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| CN100999470A (en) * | 2006-11-17 | 2007-07-18 | 北京本草天源药物研究院 | Salvia minium phenolic acid A and process of preparing preparation and use |
| CN102432467A (en) * | 2011-09-30 | 2012-05-02 | 吴谢军 | Salvianolic acid A magnesium salt, preparation method and use of the salvianolic acid A magnesium salt, and salvianolic acid A magnesium salt-containing freeze-dried powder injection composition |
| CN102863338A (en) * | 2008-12-30 | 2013-01-09 | 北京本草天源药物研究院 | Compound and medical use thereof |
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| CN101361728B (en) * | 2007-08-08 | 2012-10-03 | 正大青春宝药业有限公司 | Salvianolic acid A injection and preparation method thereof |
| CN105523926B (en) * | 2015-12-29 | 2018-05-22 | 山东大学 | A kind of extraction separation and purification method of salviandic acid A and the preparation method of salviandic acid A salt |
| CN106748733A (en) * | 2017-02-07 | 2017-05-31 | 正大青春宝药业有限公司 | A kind of preparation method of salviandic acid A salt |
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| CN100999470A (en) * | 2006-11-17 | 2007-07-18 | 北京本草天源药物研究院 | Salvia minium phenolic acid A and process of preparing preparation and use |
| CN102863338A (en) * | 2008-12-30 | 2013-01-09 | 北京本草天源药物研究院 | Compound and medical use thereof |
| CN102432467A (en) * | 2011-09-30 | 2012-05-02 | 吴谢军 | Salvianolic acid A magnesium salt, preparation method and use of the salvianolic acid A magnesium salt, and salvianolic acid A magnesium salt-containing freeze-dried powder injection composition |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018145622A1 (en) * | 2017-02-07 | 2018-08-16 | 正大青春宝药业有限公司 | Method for preparing salvianolic acid a salt |
| CN109748793A (en) * | 2018-12-29 | 2019-05-14 | 正大青春宝药业有限公司 | A method of different salviandic acid A 1 and different salviandic acid A 2 in removal salviandic acid A sodium |
| CN109748793B (en) * | 2018-12-29 | 2021-07-09 | 正大青春宝药业有限公司 | Method for removing isosalvianolic acid A1 and isosalvianolic acid A2 from sodium salvianolic acid A |
| CN110403928A (en) * | 2019-07-17 | 2019-11-05 | 正大青春宝药业有限公司 | A kind of salviandic acid A salt composite and its preparation method and application |
| WO2022233310A1 (en) * | 2021-05-06 | 2022-11-10 | 台州永健医药科技有限公司 | Salvianolic acid a salt hydrate, preparation method therefor, and use thereof |
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