CN106632202A - Purification method and preparation method for 4',7-diethyl tectorigenin - Google Patents
Purification method and preparation method for 4',7-diethyl tectorigenin Download PDFInfo
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- CN106632202A CN106632202A CN201611063899.7A CN201611063899A CN106632202A CN 106632202 A CN106632202 A CN 106632202A CN 201611063899 A CN201611063899 A CN 201611063899A CN 106632202 A CN106632202 A CN 106632202A
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- diethyl
- blackberry lily
- lily aglycon
- solvent
- preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for purifying 4',7-diethyl tectorigenin. The method comprises the following steps: (1) heating and dissolving the 4',7-diethyl tectorigenin in a solvent, performing filtering, and extracting filtrate; (2) adding an anti-solvent anhydrous ethanol into the filtrate; and performing cooling crystallization and filtering; (3) extracting filtered solids, and performing recrystallization by adopting the same solvent in step (1); (4) separating crystals, and performing drying. The invention further provides a method for preparing the 4',7-diethyl tectorigenin. The method comprises the following steps: (A) adding NaOH and an ethylation reagent into a raw material tectorigenin, and performing reaction to obtain a reaction solution; (2) performing acidification to regulate the pH value of the reaction solution to 1 to 2, adding water, and performing filtering and purification to obtain the 4',7-diethyl tectorigenin. According to the purification method and the preparation method, high-purity 4',7-diethyl tectorigenin can be conveniently and effectively prepared by process screening.
Description
Technical field
The present invention relates to drug world, and in particular to one kind 4 ', the purification process of 7-diethyl blackberry lily aglycon and preparation side
Method.
Background technology
Coxsackie virus (Coxsachie virus) is a kind of enterovirus, is divided into two kinds of A types and Type B, cell entry people
After body is bred in pharyngeal and intestinal mucosa cells, blood can be invaded and form viremia virusemia, then be disseminated to central nervous system, breathing
Road, heart, muscle, skin etc., can cause aseptic meningitis, sweating, acute myocarditis and pericarditis, prevalence
Property myalgia, upper sense, scar rash sphagitis and infantile diarrhea etc..
At present, clinic there is no the medicine of energy effectively treatment Coxsackie virus, commonly uses the antiviral drugs such as virazole and does
Disturb the expectant treatment to the ill such as element, nutritional formulations, Chinese herbal medicine astragalus Shenmai injection.
Patent CN101723926A discloses 4 ', and the preparation method of 7-diethyl blackberry lily aglycon and anti-Coxsackie virus are made
With its effect is better than Ribavirin.But, in its preparation method, sample does not have dissolving, filtration, crystallization this process, simply uses
95% ethanol elutes removing impurity repeatedly, and adopts assay method for area normalization method, and its content is not real content, its product
The true yield of product and purity is not high, and HPLC external standard methods assay is 97.23%, residue on ignition 1.2%.
Therefore, in order to improve product yield, and the product of higher purity is obtained as reference substance and then controls its quality,
Need a kind of 4 ' badly at present, the purification process and preparation method of 7-diethyl blackberry lily aglycon.
The content of the invention
To solve the above problems, the invention provides a kind of 4 ', the purification process of 7-diethyl blackberry lily aglycon, it include with
Lower step：
(1) by 4 ', 7-diethyl blackberry lily aglycon heating for dissolving in a solvent, is filtered, and takes filtrate；The solvent is selected from diformazan
Yl acetamide or chloroform；
(2) anti-solvent absolute ethyl alcohol, cooling crystallization is added to filter in filtrate；
(3) solid after filtering is taken, using identical solvent recrystallization in step (1)；
(4) crystal is isolated, is drying to obtain.
Further, the solvent and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is 5～10mL：1g.
Further, the solvent be selected from dimethyl acetamide, dimethyl acetamide and 4 ', 7-diethyl blackberry lily aglycon
Envelope-bulk to weight ratio is 10mL：1g, absolute ethyl alcohol and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is 5mL：1g.
Further, the solvent selected from chloroform, chloroform and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is 5mL：
1g, absolute ethyl alcohol and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is 10mL：1g.
The purification process of the present invention, by the screening of technique, particularly with the addition of this crystallization mode of anti-solvent absolute ethyl alcohol
Specific selection, highly purified 4 ' can be prepared with simple and effective, 7-diethyl blackberry lily aglycon, can as reference substance,
Quality for effective control medicine provides reliable guarantee.
Present invention also offers one kind prepares 4 ', and the method for 7-diethyl blackberry lily aglycon, it is comprised the following steps：
(A) with blackberry lily aglycon as raw material, to add and obtain reactant liquor after NaOH and ethylating agent reaction；
(B) acid adding, adjust reactant liquor pH value to pH=1～2, add water, filter, purify 4 ', 7-diethyl belamcandin
Unit.
Further, the purifying is carried out according to aforesaid purification process.
Further, the blackberry lily aglycon and the weight ratio of NaOH are 1:1.
Further, the ethylating agent is selected from diethyl carbonate, iodoethane, bromoethane or dithyl sulfate；It is preferred that
Dithyl sulfate.
Further, in step (A), the temperature of the reaction is 100 DEG C.
Further, the acid is hydrochloric acid.
Blackberry lily aglycon is 5,7,4 ' trihydroxy-isoflavone compounds, with the presence of three free phenolic hydroxyl groups, is alkylated (ethyl
Change) reaction theory product has 7, and in addition the oxygen key of blackberry lily aglycon C rings easily occurs cracking in the presence of highly basic becomes Cha Er
Ketone, so that product up to more than 10 is planted.Inventor in the groping of preparation method, to course of reaction thin-layer chromatography with
Track, by many experiments, it was demonstrated that blackberry lily aglycon is 1 with NaOH charge ratio:Gained product accessory substance is few when 1, target
Product 4 ', 7-diethyl blackberry lily aglycon yield height (thin layer condition：Fixing phase is silica G F254, solvent is chloroform：Methyl alcohol (10：
0.5)).Thin layer chromatogram is shown in Fig. 1, and HPLC collection of illustrative plates is shown in Fig. 2～5.
From figure 1 it appears that blackberry lily aglycon：NaOH (1:1) impurity of product when is minimum.
From figure 2 it can be seen that blackberry lily aglycon：NaOH (1:0.2) product has 4 accessory substances when, and target product is accounted for
Gross product 83.7% (area normalization method).
From figure 3, it can be seen that blackberry lily aglycon：NaOH (1:0.5) product has 3 accessory substances when, and target product is accounted for
Gross product 87.9% (area normalization method).
Figure 4, it is seen that blackberry lily aglycon：NaOH (1:1) product has 1 accessory substance when, and target product is accounted for always
Product 90.2% (area normalization method).
Obviously, the above of the invention, according to the ordinary technical knowledge and customary means of this area, without departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other various ways can also be made, is replaced or is changed.
By the following examples the specific embodiment of form, remakes further specifically to the above of the present invention
It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to Examples below.It is all based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Description of the drawings
Fig. 1 is thin layer collection of illustrative plates of the assistant ingredients than lower product.A little 1 is followed successively by from left to right：Blackberry lily aglycon：Hydroxide
Sodium (1:0.2) product (4 impurity spots) when；Point 2：Blackberry lily aglycon：NaOH (1:0.5) product (3 when
Individual impurity spot) point 3：Blackberry lily aglycon：NaOH (1:1) product (1 impurity spot) when；Point 4：4 ', 7-diethyl
Base blackberry lily aglycon reference substance.
Fig. 2 is blackberry lily aglycon：NaOH (1:0.2) the HPLC collection of illustrative plates of product when.
Fig. 3 is blackberry lily aglycon：NaOH (1:0.5) the HPLC collection of illustrative plates of product when.
Fig. 4 is blackberry lily aglycon：NaOH (1:1) the HPLC collection of illustrative plates of product when.
Fig. 5 is 4 ', the HPLC collection of illustrative plates of 7-diethyl blackberry lily aglycon reference substance.
Specific embodiment
Reagent source is Chengdu Ke Long chemical reagents factory, is analysis pure.
Blackberry lily aglycon is self-control, content>98% (area normalization method), is specifically shown in patent ZL 200910308146.1.
Embodiment 14 ', the preparation of 7-diethyl blackberry lily aglycon
Weigh blackberry lily aglycon 100g, plus NaOH 100g, 95% ethanol 1000mL, diethyl carbonate 200mL, water-bath backflow
Reaction 2 hours, takes out, and with appropriate 36% hydrochloric acid pH=1～2 are neutralized to, and the stirring that adds water lets cool, and filters, and 60 DEG C of drying under reduced pressure are obtained
Pale yellow powder, i.e., 4 ', 7-diethyl blackberry lily aglycon, yield 50%, purity 60% (HPLC area normalization methods).
Embodiment 24 ', the preparation of 7-diethyl blackberry lily aglycon
Weigh blackberry lily aglycon 100g, plus NaOH 100g, 95% ethanol 1000mL, iodoethane 200mL, water-bath back flow reaction
30 minutes, take out, with appropriate 36% hydrochloric acid pH=1～2 are neutralized to, the stirring that adds water lets cool, filter, 60 DEG C of drying under reduced pressure obtain light
Yellow powder, i.e., 4 ', 7-diethyl blackberry lily aglycon, yield 75%, purity 78% (HPLC area normalization methods).
Embodiment 34 ', the preparation of 7-diethyl blackberry lily aglycon
Weigh blackberry lily aglycon 100g, plus NaOH 100g, 95% ethanol 1000mL, bromoethane 200mL, water-bath back flow reaction 1
Hour, take out, pH=1～2 are neutralized to appropriate 36% hydrochloric acid, the stirring that adds water lets cool, and filters, and 60 DEG C of drying under reduced pressure obtain yellowish
Color powder, i.e., 4 ', 7-diethyl blackberry lily aglycon, yield 70%, purity 72% (HPLC area normalization methods).
Embodiment 44 ', the preparation of 7-diethyl blackberry lily aglycon
Weigh blackberry lily aglycon 100g, plus NaOH 100g, 95% ethanol 1000mL, dithyl sulfate 200mL, water-bath backflow
Reaction 30 minutes, takes out, and with appropriate 36% hydrochloric acid pH=1～2 are neutralized to, and the stirring that adds water lets cool, and filters, 60 DEG C of drying under reduced pressure,
Obtain pale yellow powder, i.e., 4 ', 7-diethyl blackberry lily aglycon, yield 85%, purity 90% (HPLC area normalization methods).
Embodiment 54 ', the purifying of 7-diethyl blackberry lily aglycon
4 ', 7-diethyl blackberry lily aglycon 10g of the preparation of above-described embodiment 4 are taken, plus 100 DEG C of dimethyl acetamide 100mL adds
Heat of solution, filters while hot, and filtrate adds absolute ethyl alcohol 50mL, shakes up, and places crystallization, and crystallization is filtered, and coarse-grain adds dimethyl second
100 DEG C of heating for dissolving of acid amides 80mL, filter while hot, and filtrate adds absolute ethyl alcohol 40mL, shakes up, and place crystallization, obtain faint yellow
Flaky crystal, filters, and 60 DEG C of drying under reduced pressure 24 hours obtain 4 ', 7-diethyl blackberry lily aglycon 5.5g, and content 99.12% is (outside HPLC
Mark method).
Embodiment 64 ', the purifying of 7-diethyl blackberry lily aglycon
4 ', 7-diethyl blackberry lily aglycon 10g of the preparation of above-described embodiment 4, plus 70 DEG C of heating for dissolving of chloroform 50mL are taken, is taken advantage of
Heat filtering, filtrate adds absolute ethyl alcohol 100mL, shakes up, and places crystallization, and crystallization is filtered, and coarse-grain adds 40mL70 DEG C of heating of chloroform
Dissolving, filters while hot, and filtrate adds absolute ethyl alcohol 80mL, shakes up, and places crystallization, obtains faint yellow acicular crystal, filters, 60 DEG C
Drying under reduced pressure 24 hours, obtains 4 ', 7-diethyl blackberry lily aglycon 7.0g, content 99.56% (HPLC external standard methods)..
Comparative example 14 ', the purifying of 7-diethyl blackberry lily aglycon
4 ', 7-diethyl blackberry lily aglycon 10g of the preparation of above-described embodiment 4, plus 80 DEG C of heating for dissolving of methyl alcohol 500mL are taken, is taken advantage of
Heat filtering, places crystallization, and crystallization is filtered, and coarse-grain adds methyl alcohol 80 DEG C of heating for dissolving of 400mL, filters while hot, places crystallization, knot
Crystalline substance is filtered, and obtains faint yellow granular crystal, is filtered, and 60 DEG C of drying under reduced pressure 24 hours obtain 4 ', 7-diethyl blackberry lily aglycon 5.0g,
Content 98.52% (HPLC external standard methods).
Comparative example 24 ', the purifying of 7-diethyl blackberry lily aglycon
4 ', 7-diethyl blackberry lily aglycon 10g of the preparation of above-described embodiment 4, plus 80 DEG C of heating for dissolving of ethanol 400mL are taken, is taken advantage of
Heat filtering, places crystallization, and crystallization is filtered, and coarse-grain adds ethanol 80 DEG C of heating for dissolving of 300mL, filters while hot, places crystallization, knot
Crystalline substance is filtered, and obtains faint yellow acicular crystal, is filtered, and 60 DEG C of drying under reduced pressure 24 hours obtain 4 ', 7-diethyl blackberry lily aglycon 6.0g,
Content 98.75% (HPLC external standard methods).
Claims (10)
1. one kind 4 ', the purification process of 7-diethyl blackberry lily aglycon, it is characterised in that：It is comprised the following steps：
(1) by 4 ', 7-diethyl blackberry lily aglycon heating for dissolving in a solvent, is filtered, and takes filtrate；The solvent is selected from dimethyl second
Acid amides or chloroform；
(2) anti-solvent absolute ethyl alcohol, cooling crystallization is added to filter in filtrate；
(3) solid after filtering is taken, using identical solvent recrystallization in step (1)；
(4) crystal is isolated, is drying to obtain.
2. purification process according to claim 1, it is characterised in that：The solvent and 4 ', 7-diethyl blackberry lily aglycon
Envelope-bulk to weight ratio is 5～10mL：1g.
3. purification process according to claim 2, it is characterised in that：The solvent is selected from dimethyl acetamide, dimethyl
Acetamide and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is 10mL：1g, absolute ethyl alcohol and 4 ', 7-diethyl belamcandin
The envelope-bulk to weight ratio of unit is 5mL：1g.
4. purification process according to claim 2, it is characterised in that：The solvent selected from chloroform, chloroform and 4 ', 7-diethyl
The envelope-bulk to weight ratio of base blackberry lily aglycon is 5mL：1g, absolute ethyl alcohol and 4 ', the envelope-bulk to weight ratio of 7-diethyl blackberry lily aglycon is
10mL：1g.
5. one kind prepares 4 ', the method for 7-diethyl blackberry lily aglycon, it is characterised in that：It is comprised the following steps：
(A) with blackberry lily aglycon as raw material, to add and obtain reactant liquor after NaOH and ethylating agent reaction；
(B) acid adding, adjust reactant liquor pH value to pH=1～2, add water, filter, purify 4 ', 7-diethyl blackberry lily aglycon.
6. preparation method according to claim 5, it is characterised in that：The purifying includes any one of claim 1-4 institute
The purification process stated.
7. the preparation method according to claim 6 or 7, it is characterised in that：The weight of the blackberry lily aglycon and NaOH
Than for 1:1.
8. the preparation method according to claim 6 or 7, it is characterised in that：The ethylating agent selected from diethyl carbonate,
Iodoethane, bromoethane or dithyl sulfate；Preferably sulfuric acid diethylester.
9. the preparation method according to any one of claim 6-8, it is characterised in that：In step (A), the temperature of the reaction
For 100 DEG C.
10. the preparation method according to any one of claim 6-9, it is characterised in that：The acid is hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611063899.7A CN106632202A (en) | 2016-11-28 | 2016-11-28 | Purification method and preparation method for 4',7-diethyl tectorigenin |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611063899.7A CN106632202A (en) | 2016-11-28 | 2016-11-28 | Purification method and preparation method for 4',7-diethyl tectorigenin |
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| CN106632202A true CN106632202A (en) | 2017-05-10 |
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| CN201611063899.7A Pending CN106632202A (en) | 2016-11-28 | 2016-11-28 | Purification method and preparation method for 4',7-diethyl tectorigenin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117327042A (en) * | 2023-12-01 | 2024-01-02 | 四川省中医药科学院 | Method for preparing 8,8 '-methylene-bisblackberry lily aglycone-5' -sodium sulfonate on large scale |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723926A (en) * | 2008-10-10 | 2010-06-09 | 四川省中医药科学院 | Isoflavone derivative and preparation method and application thereof |
-
2016
- 2016-11-28 CN CN201611063899.7A patent/CN106632202A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723926A (en) * | 2008-10-10 | 2010-06-09 | 四川省中医药科学院 | Isoflavone derivative and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 史高杨: "《有机化学实验》", 31 August 2015, 合肥工业大学出版社 * |
| 袁崇均等: "川产道地药材川射干系统开发研究(综述)", 《四川中医》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117327042A (en) * | 2023-12-01 | 2024-01-02 | 四川省中医药科学院 | Method for preparing 8,8 '-methylene-bisblackberry lily aglycone-5' -sodium sulfonate on large scale |
| CN117327042B (en) * | 2023-12-01 | 2024-02-02 | 四川省中医药科学院 | Method for preparing 8,8 '-methylene-bisblackberry lily aglycone-5' -sodium sulfonate on large scale |
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Application publication date: 20170510 |