CN107488207A - A kind of process for purification of Isoglycyrrhiza acid methyl esters - Google Patents
A kind of process for purification of Isoglycyrrhiza acid methyl esters Download PDFInfo
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- CN107488207A CN107488207A CN201610418155.6A CN201610418155A CN107488207A CN 107488207 A CN107488207 A CN 107488207A CN 201610418155 A CN201610418155 A CN 201610418155A CN 107488207 A CN107488207 A CN 107488207A
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- China
- Prior art keywords
- acid methyl
- methyl esters
- filter cake
- methanol
- isoglycyrrhiza acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
Abstract
The present invention, by purification step, obtains Isoglycyrrhiza acid methyl esters fine work using Isoglycyrrhiza acid methyl esters crude product as raw material, can control the content of impurity A below 0.3%, it is ensured that single impurity content control is below 0.1% in magnesium isoglycyrrhetate.Preparation method of the present invention is simple, technique favorable reproducibility, simple to operate, high income, and the purity of products obtained therefrom is high, is adapted to industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, is related to magnesium isoglycyrrhetate, and in particular to a kind of Isoglycyrrhiza acid methyl esters refines
Method.
Background technology
Magnesium isoglycyrrhetate is entitled by the honest liver cell protective agent for becoming a fine day research and development, chemistry：18 α, 20 β-carboxyl -11- oxygen
For the positive beta-yl -2-O- β-D- glucopyranoside aldehydic acid base-α-D- glucopyranoside aldehydic acid magnesium four of oleanane -12- alkene -3
Hydrate；The test of pesticide effectiveness shows that it causes acute liver injury of rats to have preventive and therapeutic effect D-Gal, can prevent animal
Serum transaminase raises, and mitigates degeneration of liver cells, necrosis and inflammatory cell infiltration；Cause rat chronic hepatic injury to carbon tetrachloride
With therapeutic effect, improve CCl4Cause the liver function of chronic liver injury rat, reduce NO levels, mitigate liver tissues inflammatory activity
Degree and fibrosis；Inducing mouse immune hepatic lesion to Gal/FCA also has protective effect, reduces serum transaminase and blood plasma
NO is horizontal, mitigates hepatic tissue infringement, improves mouse survival rate.
Patent CN1615886A discloses a kind of synthetic method of magnesium isoglycyrrhetate, and its synthetic route is as follows:
In above-mentioned synthetic method, confirmed repeatedly through overtesting, it is found that a small amount of cis glycyrrhizic acid methyl esters is difficult to be removed, and
There is an impurity A to be introduced by raw material, it is difficult to remove, directly affect the quality of finished product.Impurity A structure is seen below:
。
Confirm in further experiment, refined from compound 3, prepared with the refined participation reaction of compound 3 different
Glycyrrhizic acid magnesium, effect are preferable.Compound 3 be Isoglycyrrhiza acid methyl esters (trans-GA-Me), molecular formula is：C45H68O16；Molecular weight
For：865.01.Refined on compound 3, CN1381463A and CN102584928A employ the mode that methanol washs,
L.A.Baltina, N.G.Serdyuk. et al. also using methanol washing by the way of [Pharmaceutical chemistry Journal VOl 30.NO.10.1996] purified compound 3；By testing repeated multiple times refined confirmation, methanol detergent is used
The effect of key intermediate compound 3 processed is unsatisfactory, and the end-product magnesium isoglycyrrhetate purity of preparation is not high.
The content of the invention
In order to solve the above-mentioned technical problem, it is an object of the invention to provide a kind of process for purification of Isoglycyrrhiza acid methyl esters,
Isoglycyrrhiza acid methyl esters purity prepared by this method is high.
The object of the present invention is achieved like this：
A kind of process for purification of Isoglycyrrhiza acid methyl esters, it is characterised in that comprise the following steps：
(1) Isoglycyrrhiza acid methyl esters crude product is dissolved with DMF and methanol-purifying water mixed solution, stirs 1-24h at 20-90 DEG C, then
In 0-25 DEG C of stirring and crystallizing 1-12h, filtering, filter cake is collected；
(2) filter cake of step (1) is added in organic solvent, 1-2h is stirred under the conditions of 10-45 DEG C, filtered, collect filter cake；
One or more mixing of the described organic solvent in methanol, ethanol, isopropanol, acetone, acetonitrile；
(3) filter cake of step (2) is added in refined soln, stirs dissolved clarification, add activated carbon, 1-2h is stirred at 40-80 DEG C,
Filtering, filtrate are cooled to 0-20 DEG C, stirring and crystallizing 1-12h, filtering, are dried to obtain Isoglycyrrhiza acid methyl esters fine work；It is described refined molten
Agent one or more mixing in tetrahydrofuran, ethyl acetate, methanol or acetonitrile.
Further, process for purification of the present invention comprises the following steps：
(1) Isoglycyrrhiza acid methyl esters crude product and DMF are added in reaction bulb, methanol-purifying water mixed solution is added dropwise, at 70-80 DEG C
1-2h is stirred, is cooled to 20-25 DEG C of stirring and crystallizing 8-12h, is filtered, collects filter cake；
(2) filter cake is added in organic solvent, stirred under the conditions of 25-35 DEG C, filtered, collect filter cake；
(3) filter cake is added in refined soln, stirs dissolved clarification, add activated carbon, in 65-75 DEG C of stirring, filtering, filtrate cooling
To 0-5 DEG C, stirring and crystallizing 8-12h, filtering, Isoglycyrrhiza acid methyl esters fine work is dried to obtain.
Preferably, the volume ratio of the methanol described in step (1) and water is 1:9 - 9:1, preferably 5:1.
Preferably, Isoglycyrrhiza acid methyl esters and DMF mass volume ratio described in step (1) are 1:9 - 9:Between 1, preferably
1:2。
The present invention has following beneficial effect：
The present invention, by purification step, obtains Isoglycyrrhiza acid methyl esters fine work using Isoglycyrrhiza acid methyl esters crude product as raw material, can will be miscellaneous
Matter A content is controlled below 0.3%, it is ensured that below 0.1%, that produces is different for single impurity content control in magnesium isoglycyrrhetate
Glycyrrhizic acid magnesium finished product is fully achieved or higher than pharmacopoeial requirements.Preparation method of the present invention is simple, technique favorable reproducibility, simple to operate,
High income, the purity of products obtained therefrom is high, is adapted to industrialized production.
Embodiment
Content for a better understanding of the present invention, further illustrated below in conjunction with specific embodiment to make.But
These embodiments can not form limiting the scope of the invention.
Embodiment 1：Isoglycyrrhiza acid methyl esters（Compound 3）Synthesis
Compound 2 is added in reaction bulb（40g, 0.048mol）, absolute methanol（300ml）, stirring and dissolving, cool to 0
DEG C, chloroacetic chloride is added dropwise（15.5ml 0.218mol）, 30min is added dropwise, and is warming up to room temperature reaction 2h, filtering, filter cake methanol
Wash secondary, obtain the crude product of Isoglycyrrhiza acid methyl esters, HPLC purity is 94.5%, and the content of impurity A is 2.5%.
Embodiment 2：Isoglycyrrhiza acid methyl esters（Compound 3）It is refined
By Isoglycyrrhiza acid methyl esters crude product（10.0g 0.0115mol）Add in reaction bulb, add DMF20ml, stir dissolved clarification, heating
To 70 DEG C, the mixed solution of methanol-purified water is slowly added dropwise（5:1）Untill system just becomes cloudy, 25 DEG C are cooled to, is stirred
8h is mixed, is filtered.Filter cake is beaten 2h with methanol 100ml at 35 DEG C, and filtering, filter cake is added in 80ml tetrahydrofurans, and backflow is stirred
Dissolved clarification is mixed, 1h is stirred, slow cooling to 0 DEG C of crystallization 8h, filtering, is dried under reduced pressure 12h at 50 DEG C, obtains 8.0g to Isoglycyrrhiza acid methyl esters
Fine work, mass yield 80%, the content of impurity A is 0.3%.
Embodiment 3：Isoglycyrrhiza acid methyl esters（Compound 3）It is refined
By Isoglycyrrhiza acid methyl esters crude product（15.0g 0.0175mol）Add in reaction bulb, add DMF28ml, dissolved clarification is stirred at room temperature,
68 DEG C are heated to, the mixed solution of methanol-purified water is slowly added dropwise（5:1）Untill system just becomes cloudy, 25 are cooled to
DEG C, stir 10h, filtering.Filter cake is beaten 2h with methanol 200ml at 35 DEG C, and filtering, filter cake is added in 80ml tetrahydrofurans,
Return stirring dissolved clarification, 1h is stirred, slow cooling to 0 DEG C of crystallization 6h, filtering, 12h is dried under reduced pressure at 50 DEG C, obtains 12.3g to different sweet
Methyl oxalate fine work, mass yield 82%, the content of impurity A is 0.22%.
With reference to embodiment 1, run according to following parameter
By the refined Isoglycyrrhiza acid methyl esters of above example, magnesium isoglycyrrhetate is prepared in method disclosed in CN1615886A, eventually
The single impurity content of product is below 0.1%.
Embodiment 4：The preparation of magnesium isoglycyrrhetate
By refined Isoglycyrrhiza acid methyl esters（Compound 3）10g, add sodium hydroxide（3mol/L）25ml, it is heated to reflux to molten
Liquid is clarified, about 2h dissolved clarifications, is cooled to room temperature, is added dilute sulfuric acid and is adjusted pH3.0, uses extracting n-butyl alcohol.After decompression is spin-dried for n-butanol, remain
Excess adds 90% glacial acetic acid, is heated to 80 DEG C of dissolved clarifications, is cooled to room temperature, filters, and Isoglycyrrhiza acid 8.5g must be refined after drying.
Refined Isoglycyrrhiza acid 8.5g is dissolved in 50ml70% isopropanol, adds basic magnesium carbonate 1.1g, back flow reaction is extremely
Untill being released without carbon dioxide.The a small amount of insoluble matter of slightly cold rear elimination, filtrate are cooled to 0-5 DEG C.Filtering, washed with isopropanol solid
Body, drain, be dried under reduced pressure to obtain magnesium isoglycyrrhetate 7.5g（Yield：86%, purity 99.8%, single miscellaneous ﹤ 0.1%）.
Embodiment 5：Conventional method refines Isoglycyrrhiza acid methyl esters（Compound 3）
By compound 2（10g）, methanol 100ml is added, is stirred at room temperature, is slowly added to chloroacetic chloride 4ml, 20min is dripped
Finish, continue to stir 8h, be cooled to 0-5 DEG C, filtering, filter cake is washed 3 times with methanol, obtains glycyrrhizic acid methyl esters 5.0g, yield 48% is pure
Degree 96%, the content 2.5% of impurity A.
With reference to embodiment 5, by this area conventional method, to the Isoglycyrrhiza acid methyl esters crude product obtained in embodiment 1（Chemical combination
Thing 3）Refined, the process for refining Contrast on effect result of Isoglycyrrhiza acid methyl esters is as follows：
。
As seen from the above table, although various process for purification can be effectively reduced the content of impurity A, effect, which is appointed, is not so
Highly desirable, the compound 3 obtained by the above method continues to do backward, does not obtain qualified finished product（List is miscellaneous to be less than
0.1%）, and the process for purification of the present invention can then make it that the list of magnesium isoglycyrrhetate is miscellaneous and control below 0.1%, this effect is relative
In the conventional method of above-mentioned prior art, it is clear that have significant progressive.
Claims (6)
1. a kind of process for purification of Isoglycyrrhiza acid methyl esters, it is characterised in that comprise the following steps：
(1) Isoglycyrrhiza acid methyl esters crude product is dissolved with DMF and methanol-purifying water mixed solution, stirs 1-24h at 20-90 DEG C, then
In 0-25 DEG C of stirring and crystallizing 1-12h, filtering, filter cake is collected；
(2) filter cake of step (1) is added in organic solvent, 1-2h is stirred under the conditions of 10-45 DEG C, filtered, collect filter cake；
One or more mixing of the described organic solvent in methanol, ethanol, isopropanol, acetone, acetonitrile；
(3) filter cake of step (2) is added in refined soln, stirs dissolved clarification, add activated carbon, 1-2h is stirred at 40-80 DEG C,
Filtering, filtrate are cooled to 0-20 DEG C, stirring and crystallizing 1-12h, filtering, are dried to obtain Isoglycyrrhiza acid methyl esters fine work；It is described refined molten
Agent one or more mixing in tetrahydrofuran, ethyl acetate, methanol or acetonitrile.
2. method as claimed in claim 1, it is characterised in that comprise the following steps：
(1) Isoglycyrrhiza acid methyl esters crude product and DMF are added in reaction bulb, methanol-purifying water mixed solution is added dropwise, at 70-80 DEG C
1-2h is stirred, is cooled to 20-25 DEG C of stirring and crystallizing 8-12h, is filtered, collects filter cake；
(2) filter cake is added in organic solvent, stirred under the conditions of 25-35 DEG C, filtered, collect filter cake；
(3) filter cake is added in refined soln, stirs dissolved clarification, add activated carbon, in 65-75 DEG C of stirring, filtering, filtrate cooling
To 0-5 DEG C, stirring and crystallizing 8-12h, filtering, Isoglycyrrhiza acid methyl esters fine work is dried to obtain.
3. method as claimed in claim 1 or 2, it is characterised in that：The volume ratio of methanol and water in the step (1) is 1:9
- 9:1。
4. method as claimed in claim 3, it is characterised in that：The volume ratio of methanol and water in the step (1) is 5:1.
5. method as claimed in claim 1 or 2, it is characterised in that：Isoglycyrrhiza acid methyl esters and DMF quality in the step (1)
Volume ratio is 1:9 - 9:Between 1.
6. method as claimed in claim 5, it is characterised in that：Isoglycyrrhiza acid methyl esters and DMF quality volume in the step (1)
Than for 1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610418155.6A CN107488207A (en) | 2016-06-13 | 2016-06-13 | A kind of process for purification of Isoglycyrrhiza acid methyl esters |
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| CN201610418155.6A CN107488207A (en) | 2016-06-13 | 2016-06-13 | A kind of process for purification of Isoglycyrrhiza acid methyl esters |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
-
2016
- 2016-06-13 CN CN201610418155.6A patent/CN107488207A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
Non-Patent Citations (1)
| Title |
|---|
| 朱洪法等: "《精细化工产品制造技术》", 31 January 2002 * |
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Application publication date: 20171219 |