CN108117561A - A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process - Google Patents
A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process Download PDFInfo
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- CN108117561A CN108117561A CN201611081861.2A CN201611081861A CN108117561A CN 108117561 A CN108117561 A CN 108117561A CN 201611081861 A CN201611081861 A CN 201611081861A CN 108117561 A CN108117561 A CN 108117561A
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- ginkolide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses 10 O ethylaminos ginkolide B of main metabolites in dimethylaminoethyl ginkgolide B mesylate body and its prepare and purify method, dimethylaminoethyl ginkgolide B mesylate has extensive pharmacological activity, has extensive and good application prospect.10 O ethylaminos ginkolide B of high-purity is prepared for the exploitation of dimethylaminoethyl ginkgolide B mesylate subsequent applications is promoted to be of great significance.Its preparation process mainly includes the halogenated ethamine containing blocking group with ginkolide B and amino and reacts, then sloughs blocking group.Purification process is to carry out column chromatographic isolation and purification using preparation liquid phase.So as to obtain 10 O ethylamino ginkolide Bs of high-purity.
Description
Technical field
The present invention relates to a kind of compound and its synthesis and purification technique more particularly to methanesulfonic amine silver lactone B generations
It thanks to synthesis and the refining technique of product, belongs to pharmaceutical technology field.
Background technology
Ischemic angiocardiopathy and cerebrovascular disease is the major disease that incidence is high, lethality is high, current most effective treatment means
It is platelet aggregation-against.But such drug easily causes bleeding, and exploitation can avoid the new platelet aggregation inhibitor of bleeding risk from being
The research hotspot in the whole world at present.One of veteran kind uniquely survived as Ginkgoaceae Ginkgo, the leaf of ginkgo and fruit have weight
The medical value wanted.Extract 6 terpenoids altogether from ginkgo leaf：Ginkgolide A, B, C, M, J and the new lactone of ginkgo,
They all have diterpene or hemiterpene structure.Ginkalide A and B have significant curative effect to treatment cardiovascular and cerebrovascular disease.
Ginkolide B (Ginkgolide B, GB) is a kind of diterpene for the six rings cage structure extracted from ginkgo leaf
Object is closed, is most strong platelet activating factor (PAF) antagonist found so far.But ginkolide B water solubility is not high, makes
Ginkgolides clinical practice is subject to great limitation.We select ginkolide B, and methanesulfonic amine ginkgo is prepared through semi-synthetic
Lactone B.It greatly improves water solubility, maintains the space structure and activity of ginkolide B, pharmacodynamics test knot
Fruit shows that this product and ginkolide B are substantially equivalent, is PAF competitive antagonists, there is platelet aggregation-against, antiplatelet to adhere to,
The pharmacological actions such as antiplatelet release, antithrombotic, anticoagulation.Dimethylaminoethyl ginkgolide B mesylate is a kind of mesylate, female
Core part is a kind of amino-containing molecule that ginkolide B obtains after derivative modify, and dimethylaminoethyl ginkgolide B mesylate divides
Minor is C24 H 33 O 10 N·CH 4 O 3S, molecular weight 591.63.
Dimethylaminoethyl ginkgolide B mesylate is semi-synthetic novel compounds, the Chinese patent of my company's application
(CN1749257B) its synthetic method is protected, does not have preparation listing both at home and abroad at present.Methanesulfonic amine ginkgolide
B structure formula is as follows：
The content of the invention
The technical problems to be solved by the invention are to find main metabolites in dimethylaminoethyl ginkgolide B mesylate body, and are made
It is standby to obtain high-purity metabolite.But above-mentioned product is present in the animal for taking dimethylaminoethyl ginkgolide B mesylate and human body blood
In liquid, stability is poor, it is extremely difficult to extract the compound of isolated high-purity.The metabolite sterling is prepared, for quantitative
The internal metabolic process for analyzing dimethylaminoethyl ginkgolide B mesylate has very great meaning.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
It is found in pharmacology and clinical trial, there are main metabolites 10-O- ethylamino ginkgoes for dimethylaminoethyl ginkgolide B mesylate
Lactone B, is the N of dimethylaminoethyl ginkgolide B mesylate, and N removes dimethyl metabolite.By separation and detection means, first sulphur is determined
The main metabolites structure of acid amide ginkolide B.Its structural formula is as follows：
Its preparation process is described as follows：Ginkolide B and amino are contained into blocking group（Benzyl）Halogenated ethamine mixing, with alkali
（Organic base or inorganic base）Acid binding agent is done, metal iodide makees catalyst, is mixed in organic solvent.Set reaction temperature 65
DEG C, reaction 20-30min is kept, adds in the organic solvent of the product easy to dissolve such as ethyl acetate or dichloromethane, filtering, filtrate
Concentration, obtained solid are（10-O-（N, N- dibenzyl）Ethylamino ginkolide B）.By metal catalytics such as above-mentioned product and Pb/C
Agent is reacted, and removes N, and N-protected group makees solvent with ethyl alcohol, and design temperature temperature is 60 DEG C, and the reaction was complete for monitoring, filters, filter
Liquid is concentrated to give 10-O- ethylamino ginkolide B crude products.
Wherein, the group R is amido protecting group, including easy leaving group benzyl or BOC；The group A is halogen
Element, including chlorine, bromine or iodine.
Wherein, the ginkgolide B contains blocking group with amino（Benzyl）Halogenated ethamine molar ratio be 1:0.8-
10, preferably 1:2-4.
Wherein, the inorganic base includes potassium carbonate, cesium carbonate, sodium carbonate, magnesium carbonate, sodium acid carbonate, saleratus, carbon
Sour calcium, calcium bicarbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate.The organic base bag
Include triethylamine, n,N-diisopropylethylamine, DBU, pyridine, ammonium hydroxide.
Wherein, the metal iodide includes potassium iodide, sodium iodide, magnesium iodide, silver iodide, zinc iodide and theirs is mixed
Close object, preferably potassium iodide, sodium iodide, zinc iodide.
It is as follows to isolate and purify process description：10-O- ethylamino ginkolide B crude products are passed through into preparative high-performance liquid chromatographic
It is isolated and purified, eluent freeze drying process, removes solvent.Obtain HPLC purity>90% 10-O- ethylamino ginkgoes
Lactone B highly finished product.
Wherein, the preparative high-performance liquid chromatographic model：2767/QDG of Waters, pillar model：Waters
sunfire 20*250mm 5um。
Wherein, the eluent is water：Methanol or water：Acetonitrile, and PH≤5.0, to add mobile phase PH≤5.0
Enter acid or buffer salt.Wherein acid or for trifluoracetic acid, methanesulfonic acid, acetic acid, hydrochloric acid, phosphoric acid, phosphate etc..
Description of the drawings
10-O- ethylamino ginkolide Bs are prepared for the present invention in Fig. 11H-NMR。
Fig. 2 is the HPLC purity figures that 10-O- ethylamino ginkolide Bs are prepared in the present invention.
Specific embodiment
According to following embodiments, the present invention may be better understood.It is however, as it will be easily appreciated by one skilled in the art that real
It applies the described content of example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Embodiment 1
In tri- mouthfuls of reaction bulbs of 25ml, 1.0g ginkolide Bs and 1.83gN, N- dibenzyl chlorethamin, 2.5gK are added in2CO3,
50mgKI, 10ml acetonitrile, magnetic agitation.65 DEG C of reaction temperature is set, keeps reaction 20min, TLC monitoring ginkolide B reaction
Completely.50ml ethyl acetate, filtering are added in, filtrate adds anhydrous sodium sulfate to dry, and filters, and filtrate concentration obtains（10-O-（N,N-
Dibenzyl）Ethylamino ginkolide B）Crude product 3.6g, yield>100%.
Embodiment 2
By 3.6g（10-O-（N, N- dibenzyl）Ethylamino ginkolide B）Crude product carries out column chromatography purifying（Pillar height 18cm, column footpath
5cm, eluant, eluent（Ethyl acetate：Dichloromethane=5:95）, TLC monitoring, the fraction of the product of single-point containing TLC merges, is concentrated under reduced pressure.
Obtain 762mg（10-O-（N, N- dibenzyl）Ethylamino ginkolide B）Highly finished product, HPLC purity 98.25%.
Embodiment 3
In tri- mouthfuls of reaction bulbs of 50ml, 750mg is added in（10-O-（N, N- dibenzyl）Ethylamino ginkolide B）Highly finished product,
0.8gPb/C, 25ml ethyl alcohol set reaction temperature as T=60 DEG C, maintain thermotonus 3h, stop reaction, reacting liquid filtering, filter
Liquid is concentrated under reduced pressure, and obtains 613mg 10-O- ethylamino ginkolide B crude products, yield 86.5%.
Embodiment 4
By 500mg（10-O- ethylamino ginkolide Bs）Solid carries out preparation purifying by preparative high-performance liquid chromatographic instrument.It prepares
High performance liquid chromatography model：2767/QDG of Waters, pillar model：Waters sunfire 20*250mm 5um.It will
Sample is dissolved in 2ml methanol, is prepared（Column flow rate is 30ml/min.Mobile phase is water：Acetonitrile（0.5% TFA）, gradient
Elution）.Collect fraction containing product.Be concentrated under reduced pressure removal acetonitrile.Concentrate is freeze-dried.Obtain 107mg（10-O- ethylaminos silver
Apricot lactone B）Highly finished product.HPLC purity is 95.86%.
Claims (10)
- It is 1. a kind of such as chemical structural formula（Ⅰ）Shown compound 10-O- ethylamino ginkolide Bs。
- 2. the preparation method of I compound represented 10-O- ethylamino ginkolide Bs of chemical structural formula described in claim 1, It is characterized by comprising following steps：1）By ginkolide B and amino, the halogenated ethamine containing blocking group mixes, and does acid binding agent with alkali, metal iodide is catalyzed Agent is mixed in organic solvent, reacts and 10-O- is made（Bis- protecting group of N, N-）Ethylamino ginkolide B；2）By above-mentioned product removal N, N-protected group, purifying obtains 10-O- ethylamino ginkolide BsR is amido protecting group；A is halogen.
- 3. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 2, which is characterized in that described Group R is easy leaving group benzyl or BOC.
- 4. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 2, which is characterized in that described Group A is chlorine, bromine or iodine.
- 5. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 2, it is characterised in that step 1） Described in alkali be organic base or inorganic base.
- 6. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 2, which is characterized in that step 2）Described in deprotection agent metallic catalyst.
- 7. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 2, it is characterised in that described 10-O- ethylaminos ginkolide B carries out column chromatographic isolation and purification using liquid phase is prepared.
- 8. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 7, it is characterised in that preparation solution The mobile phase of phase is water：Methanol or water：Acetonitrile.
- 9. the preparation method of compound 10-O- ethylaminos ginkolide B according to claim 8, it is characterised in that add in acid Or buffer salt, adjust PH≤5 of mobile phase.
- It is 10. special according to the preparation method of any compound 10-O- ethylamino ginkolide Bs of claim 7-9 Sign is the mobile phase using freeze-drying method removal product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611081861.2A CN108117561A (en) | 2016-11-30 | 2016-11-30 | A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611081861.2A CN108117561A (en) | 2016-11-30 | 2016-11-30 | A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process |
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| CN108117561A true CN108117561A (en) | 2018-06-05 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1749257A (en) * | 2005-04-29 | 2006-03-22 | 秦引林 | Platelet activation factor resisting compound |
| CN101323621A (en) * | 2007-06-11 | 2008-12-17 | 秦引林 | Synthetic technological process of bilobalide B derivates |
| CN101685085A (en) * | 2008-09-22 | 2010-03-31 | 秦引林 | Method for analyzing high performance liquid chromatography of methanesulfonic amine ginkgolide B |
| CN105859744A (en) * | 2016-04-07 | 2016-08-17 | 南京工业大学 | Method for preparing dimethylamino ethyl bilobalide B by using micro reaction device |
| CN106032384A (en) * | 2015-03-11 | 2016-10-19 | 江苏柯菲平医药股份有限公司 | Method adopting micro-flow field reactor to prepare dimethylamino ethyl ginkgolide B |
-
2016
- 2016-11-30 CN CN201611081861.2A patent/CN108117561A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1749257A (en) * | 2005-04-29 | 2006-03-22 | 秦引林 | Platelet activation factor resisting compound |
| CN101323621A (en) * | 2007-06-11 | 2008-12-17 | 秦引林 | Synthetic technological process of bilobalide B derivates |
| CN101685085A (en) * | 2008-09-22 | 2010-03-31 | 秦引林 | Method for analyzing high performance liquid chromatography of methanesulfonic amine ginkgolide B |
| CN106032384A (en) * | 2015-03-11 | 2016-10-19 | 江苏柯菲平医药股份有限公司 | Method adopting micro-flow field reactor to prepare dimethylamino ethyl ginkgolide B |
| CN105859744A (en) * | 2016-04-07 | 2016-08-17 | 南京工业大学 | Method for preparing dimethylamino ethyl bilobalide B by using micro reaction device |
Non-Patent Citations (1)
| Title |
|---|
| YIN-LIN QIN ET AL.: ""An efficient etherification of Ginkgo biloba extracts with fewer side effects in a micro-flow system"", 《CHINESE CHEMICAL LETTERS》 * |
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