CN103483193A - Preparation method of ingenol mebutate - Google Patents
Preparation method of ingenol mebutate Download PDFInfo
- Publication number
- CN103483193A CN103483193A CN201310406558.5A CN201310406558A CN103483193A CN 103483193 A CN103483193 A CN 103483193A CN 201310406558 A CN201310406558 A CN 201310406558A CN 103483193 A CN103483193 A CN 103483193A
- Authority
- CN
- China
- Prior art keywords
- ingenol
- purity
- preparation
- product
- acid esters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/95—Spiro compounds containing "not free" spiro atoms
- C07C2603/98—Spiro compounds containing "not free" spiro atoms containing at least one ring with more than six ring members
Abstract
The invention relates to a preparation method of high-purity ingenol mebutate. The preparation method is characterized in that traditional Chinese medicine extracts containing low-purity ingenol are used for directly participating in synthesis, and a synthetic product is separated step by step. Compared with a method for synthesizing the high-purity ingenol mebutate by adopting high-purity ingenol, the preparation method of the high-purity ingenol mebutate has the advantage of low cost. Compared with a full-synthetic method, the preparation method of the high-purity ingenol mebutate has the advantages of low cost, less impurities and more safety.
Description
Technical field
The present invention relates to a kind of preparation method of high purity ingenol methyl butene acid esters, it is characterized in that using the Chinese medical extract of the ingenol that contains low-purity, the method for the highly purified ingenol methyl butene of semi-synthetic preparation acid esters.
Background technology
Ingenol methyl butene acid esters, be a kind of cell death inducer, is applicable to the topical therapeutic of solar keratosis.FDA approval listing in 2012, be used for the treatment of actinic keratosis.
Ingenol methyl butene acid esters parent nucleus is ingenol, and source is divided into synthetic or plant extract.Ingenol is the tetracyclic diterpene natural product.At present, after ingenol methyl butene acid esters is mainly total synthesis technology-synthetic parent nucleus abroad, resynthesis ingenol methyl butene acid esters; The domestic research that there is no at present ingenol methyl butene acid esters, parent nucleus is to be extracted as the master, but content is on the low side.
In the extract of the domestic root of Beijing euphorbia, ingenol content is all below 5%, and the low levels material generally is not suitable for semi-synthetic; And the extract of high-content is expensive.We carry out semi-synthetic research with the parent nucleus extracted at the ingenol methyl butene acid esters technology of research, and difficult point is to use the parent nucleus of low levels, carries out semi-syntheticly, passes through separation and purification treatment.The operable extract of the present invention is 1%-50% containing the purity of ingenol, all can synthesize the ingenol methyl butene acid esters of purity more than 99.9%.
Extract source containing ingenol is more, the ingredient complexity, as obtain highly purified ingenol, and can synthesize easily ingenol methyl butene acid esters, the ordinary method that obtains highly purified ingenol is the preparation of preparation liquid phase separation.It is simple that the method has preparation, the advantage that purity is high, but that shortcoming is cost is huge, at first needs Preparation equipment, Real-Time Monitoring, Fractional Collections cut; Next obtains cut and need to concentrate.Preparation liquid phase apparatus expensive, need a large amount of organic solvents, and extremely uneconomical, production efficiency is extremely low.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method that is prepared high purity ingenol methyl butene acid esters by low-purity ingenol mixture.
For solving the problems of the technologies described above, the present invention adopts following technical proposal:
Adopt the extract mixtures of low levels, directly synthesize, synthetic product is carried out to simple process, can obtain purity and be greater than 99% target product-ingenol methyl butene acid esters.
Ingenol extract (mass content 1-99%), adopt the technical literature route synthetic, to synthetic product, adopts following technical scheme to process:
The mixture of product 2, take silica gel as filler, with petroleum ether-ethyl acetate (5: 1 to 1: 5), carries out wash-out, according to the silicagel column color separated, collects first paragraph to the composition between the second segment coloring matter, and the purity of product 2 is greater than 90%.
The mixture of product 6, with petroleum ether-ethyl acetate (5: 1 to 1: 5) mixed solvent recrystallization, clean with the sherwood oil making beating the recrystallization obtained, and the purity of product 6 is greater than 99%.
The mixture of product 7, after the sour water deprotection, take water as solvent recrystallization, obtains ingenol methyl butene acid esters, and purity is greater than 99%, and single mixing is less than 0.1%
Detection method 1:
The ingenol purity testing: the HPLC-ELSD method, chromatographic column is C18, mobile phase methanol (A)-water (B) system gradient elution, 0 minute A of time gradient epi-position is that 70%, 5 minute A is that 85%, 55 minute A is 95%, 35 ℃ of column temperatures.The detector condition is 110 ℃ of vaporization temperatures, 80 ℃ of atomization temperatures, gas flow rate 1.5L/min.
Detection method 2:
Ingenol methyl butene acid esters purity testing: the HPLC-UV method, chromatographic column is C18, detects wavelength 235nm, mobile phase methanol (A)-water (B) system gradient elution, 0 minute A of time gradient epi-position is that 70%, 5 minute A is 85%, within 55 minutes, A is 95%, 35 ℃ of column temperatures.
Below in conjunction with embodiment, the present invention is further elaborated, but the scope of protection of present invention is not limited to following embodiment.
Embodiment
Embodiment 1
Get Radix Kansui extract (ingenol content 4.1%, detection method is 1), to synthetic product, take following method to process:
The mixture of product 2, take silica gel as filler, with petroleum ether-ethyl acetate (1: 1) wash-out, according to the silicagel column color separated, collects first paragraph to the composition between the second segment coloring matter, detects the purity 92.3% of product 2 with detection method 1.
The mixture of product 6, with petroleum ether-ethyl acetate (2: 1) mixed solvent recrystallization, clean with the sherwood oil making beating the solid substance obtained, and the purity that detects product 6 with detection method 2 is greater than 99.2%.
The mixture of product 7, after 0.1N hydrochloric acid deprotection, take water as solvent recrystallization, obtains ingenol methyl butene acid esters, detects purity 99.5%, single assorted 0.05% with detection method 2.Product 7 is ingenol methyl butene acid esters through structural identification.
Embodiment 2
Get Radix Kansui extract (ingenol content 20.2%, detection method is 1), to synthetic product, take following method to process:
The mixture of product 2, take silica gel as filler, with petroleum ether-ethyl acetate (2: 1) wash-out, according to the silicagel column color separated, collects first paragraph to the composition between the second segment coloring matter, detects the purity 92.3% of product 2 with detection method 1.
The mixture of product 6, with petroleum ether-ethyl acetate (2: 1) mixed solvent recrystallization, clean with the sherwood oil making beating the solid substance obtained, and the purity that detects product 6 with detection method 2 is greater than 99.1%.
The mixture of product 7, after the hydrochloric acid deprotection, take water as solvent recrystallization, obtains ingenol methyl butene acid esters, detects purity 99.6%, single assorted 0.03% with detection method 2.Product 7 is ingenol methyl butene acid esters through structural identification.
Embodiment 3
Get root of Beijing euphorbia extract (ingenol content 3.2%, detection method is 1), to synthetic product, take following method to process:
The mixture of product 2, take silica gel as filler, with petroleum ether-ethyl acetate (1: 2) wash-out, according to the silicagel column color separated, collects first paragraph to the composition between the second segment coloring matter, detects the purity 91.5% of product 2 with detection method 1.
The mixture of product 6, with petroleum ether-ethyl acetate (2: 1) mixed solvent recrystallization, clean with the sherwood oil making beating the solid substance obtained, and the purity that detects product 6 with detection method 2 is greater than 99.6%.
The mixture of product 7, after the hydrochloric acid deprotection, take water as solvent recrystallization, obtains ingenol methyl butene acid esters, detects purity 99.8%, single assorted 0.05% with detection method 2.Product 7 is ingenol methyl butene acid esters through structural identification.
Claims (4)
1. the preparation method of a high purity ingenol methyl butene acid esters, is characterized in that using the Chinese medical extract containing ingenol of low-purity as starting raw material.
2. preparation method according to claim 1, is characterized in that in Chinese medical extract, the quality purity containing ingenol is 1%～50%.
3. preparation method according to claim 1, its feature is petroleum ether-ethyl acetate at the eluting solvent to product 2, ratio is 5: 1 to 1: 5.
4. preparation method according to claim 1, its feature is petroleum ether-ethyl acetate at the eluting solvent to product 6, ratio is 5: 1 to 1: 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310406558.5A CN103483193A (en) | 2013-09-10 | 2013-09-10 | Preparation method of ingenol mebutate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310406558.5A CN103483193A (en) | 2013-09-10 | 2013-09-10 | Preparation method of ingenol mebutate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103483193A true CN103483193A (en) | 2014-01-01 |
Family
ID=49823850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310406558.5A Pending CN103483193A (en) | 2013-09-10 | 2013-09-10 | Preparation method of ingenol mebutate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103483193A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013050365A1 (en) * | 2011-10-04 | 2013-04-11 | Indena S.P.A. | Method of isolating ingenol |
| CN103119016A (en) * | 2010-07-20 | 2013-05-22 | 利奥实验室有限公司 | Method of producing ingenol-3-angelate |
-
2013
- 2013-09-10 CN CN201310406558.5A patent/CN103483193A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119016A (en) * | 2010-07-20 | 2013-05-22 | 利奥实验室有限公司 | Method of producing ingenol-3-angelate |
| WO2013050365A1 (en) * | 2011-10-04 | 2013-04-11 | Indena S.P.A. | Method of isolating ingenol |
Non-Patent Citations (2)
| Title |
|---|
| 李晓静: "巨大戟醇甲基丙烯酸酯", 《中国药物化学杂志》 * |
| 杜海燕: "从续随子种子中快速分离巨大戟二萜醇的方法研究", 《国外医学.中医中药分册》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103172598B (en) | Method for extracting paclitaxel from taxus chinensis branch and leaf | |
| CN105481711B (en) | Hydroxy-beta-sanshool monomer preparation method | |
| CN103570779A (en) | Method for preparing glycyrrhizin by simulated moving bed separation | |
| CN102311419A (en) | Refining and purification method of high content EGCG | |
| CN102557981A (en) | Purification method of capsaicine | |
| CN102199159B (en) | Method for separating and purifying ginkgolide C in ginkgo root bark | |
| CN104119245A (en) | Preparation method of high purity capsaicin monomer | |
| CN106632521A (en) | Method for extracting high-purity loganin from cornus officinalis fruits | |
| CN104803836B (en) | Extract from The Bud of Cleistocalyx Operculatus 4 ', 6 '-dihydroxy-3 ', the technique of 5 '-dimethyl-2 '-methoxy chalcones | |
| CN103483193A (en) | Preparation method of ingenol mebutate | |
| CN108997359A (en) | A method of chlorophyll is extracted from stevioside production waste residue | |
| CN102432420A (en) | Method for extracting and separating beta-elemene from Lantana camara | |
| CN104030935B (en) | A kind of method of reversed-phase resin purifying capsaicin monomer | |
| CN101353294A (en) | Separation and purification method of high-content resveratrol | |
| CN102432419A (en) | Method for extracting and separating beta-elemene from Eupatorium adenophorum | |
| CN104649901B (en) | A kind of preparation method of the material medicine ingenol methyl butene acid esters for treating actinic keratosiss | |
| CN111848357A (en) | Method for preparing high-purity cannabidiol by using ultra-high liquid chromatography | |
| CN105061455B (en) | It is a kind of can massively separating high purity gambogicacid and Neo-garcinolic acid simultaneously method | |
| CN103232513B (en) | Method for preparing tirucallol | |
| CN112390809B (en) | Method for extracting iridoid compound from patrinia scabiosaefolia fisch | |
| CN114426478B (en) | High-content gallic acid and preparation method thereof | |
| CN102531881A (en) | Separating and purifying method for roburic acid monomer | |
| CN102643324A (en) | Purification method of sanguisorbin I | |
| CN101596226A (en) | A kind of preparation method of Herba Epimedii total flavones | |
| CN103420968A (en) | Preparation method for jequirity quinone A |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140101 |