CN102002093A - Method for preparing triptolide derivative - Google Patents
Method for preparing triptolide derivative Download PDFInfo
- Publication number
- CN102002093A CN102002093A CN201010543198XA CN201010543198A CN102002093A CN 102002093 A CN102002093 A CN 102002093A CN 201010543198X A CN201010543198X A CN 201010543198XA CN 201010543198 A CN201010543198 A CN 201010543198A CN 102002093 A CN102002093 A CN 102002093A
- Authority
- CN
- China
- Prior art keywords
- triptolide
- preparation
- acetone
- alcohol derivative
- room temperature
- 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.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides a method for preparing a triptolide derivative, which comprises the following steps of: reacting triptolide used as a raw material respectively with tertiary butanol, oxalic acid, iodine and potassium rhodanide respectively at room temperature for 3 hours, separating, and then processing by using an aluminum peroxide column and recrystallizing to obtain the triptolide derivative. The invention has the advantages of no heating, short reaction time, easy easily obtained and low-cost material, simple and easy preparation method, low preparation cost, high yield and low isomer content and can be used to prepare effective component of Tripterygium wilfordii in a larger scale.
Description
Technical field
The present invention relates to a kind of preparation method of triptolide alcohol derivative.
Background technology
Trypterygine (Tripterygium wilfordii Hook.f.) is defended the Mao Ke tripterygium plant, and the whole world has 4 kinds, in homemade 4 kinds, 3 kinds are used as medicine.Because trypterygine has significantly physiologically active such as anti-inflammatory, immunosuppression, antitumor, anticancer, antifertility, during the nearly last ten years, has been widely used on the treatment of diseases such as rheumatosis, tetter, ephrosis; Its immunosuppressive action has shown great application prospect aspect organ transplantation.But the toxicity of trypterygine is very big, particularly liver, cardiovascular systems, urinary system, reproductive system, Digestive tract and neural system there are very big toxic side effect and mutagenesis, the rate of being poisoned to death is up to 29.6%, and these have all limited its application in clinical.Therefore the effective ways of the pure product of preparation prepared from active ingredients of tripterygium wilfordii are extracted in research, are the assurances of its clinical drug safety.
Complex chemical composition in the trypterygine plant, with diterpene representative triptolide is example, it is a kind of have 3 epoxide groups and α, the rosin alkane type diterpenoid of the configuration uniqueness of β 2 unsaturated lactone ring five membered structures, be one of main active ingredient of generally acknowledging in the trypterygine plant, have biological activitys such as tangible anti-inflammatory, immunosuppression, antitumor and anti-male fertility.Since being found, attracted numerous Pharmaceutical Chemists and pharmacologist's extensive concern.Domestic and international a plurality of research group and mechanism have carried out detailed research to triptolide and analogue, not only finished the complete synthesis of triptolide, and by a series of triptolide alcohol derivatives have been synthesized in transformation of triptolide structure diversity and modification, and carried out relevant pharmacologically active test, obtained the information of a large amount of relevant structure activity relationships.
The beginning of the nineties, for reducing the toxicity of trypterygine, people begin one's study prepared from active ingredients of tripterygium wilfordii are carried out oxidation or modification, successfully triptolide is oxidized to Triptonide, and by modifying triptolide has obtained the diterpene lactone and toxicity is less, the Triptolide 12,13-chlorohydrin of no mutagenesis, tripbromolide, yield is all higher.1997, Kutney has proposed the synthetic route by the synthetic diterpene analogue of westvaco rosin olefin(e) acid, studies show that the enzyme catalysis product of diterpene analogue--different triptophenolide can provide a series of new two terpene compounds, and quinones epoxy compounds wherein has anticancer and immune effect.According to the latest news, the someone has synthesized less, water-soluble higher immunosuppression and the liquor-saturated prodrug of antiphlogistic Triptolide of being used for of the triptolide alcohol derivative of treatment autoimmune disease and toxicity, and has applied for patent.Yang etc. have finished (-)-triptolide (triPtophenolide) first, (-)-Triptonide (triptoni de), (-)-triptophenolide (triptophenolide), (-)-Lei quinone lactone ketone (triptoquinonide) mapping selective body complete synthesis.Alkaloid in the trypterygine has immunosuppressive action, and can very effective treatment rheumatoid arthritis.People such as Li Ya have synthesized new alkaloids by frontalin analogs and isoprenoid.Forefathers' work provides favourable foundation for fairly large synthetic preparation trypterygine active substance in the future, and has opened up thinking for developing the new medicine preparation.
For meeting clinical needs, fairly large preparation prepared from active ingredients of tripterygium wilfordii is imperative.Present stage, process scale prepares prepared from active ingredients of tripterygium wilfordii and all adopts the physics extraction method, and what be shaped has triptolide, alkaloid and a many glycosides preparation technology.Make a general survey of various preparation methods, the physics method is classic methods, but shortcoming is a length consuming time, and efficient is low, and extract is generally mixture.Biological process and chemical synthesis provide wide prospect for the effective constituent of mass preparation trypterygine, but corresponding technology of preparing also need be further perfect.So combining with traditional extracting method, modern separation means will play great prograding to the preparation of Chinese herbal medicine effective ingredients.
Summary of the invention
The invention provides the preparation method of short, simple triptolide alcohol derivative of a kind of reaction times.
Purpose of the present invention is achieved through the following technical solutions:
Earlier the 0.72-10.8g triptolide is dissolved in the 70-1000ml acetone, slowly drips trimethyl carbinol 10-150ml, at room temperature add the 0.18-2.7g oxalic acid then, iodine 0.32-4.8g and 3-45g potassium sulfocyanate stirred 3 hours under the room temperature, and reaction is finished; Add the ethyl acetate layering in the reaction solution, organic layer is washed 2～3 times with saturated sodium-chloride water solution, uses anhydrous magnesium sulfate drying then, filters, underpressure distillation removes and desolvates, 100-200 order neutral alumina post is used the chloroform wash-out on the spissated residuum, and main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent, with acetone-ether recrystallization, obtain white crystals, be described triptolide alcohol derivative.
Main distillate fraction is collected in described TLC control, is that the chloroform of 95:5 and methyl alcohol are as developping agent with volume ratio.
In described acetone-ether recrystallization, the volume ratio of acetone and ether is 10:1.
Triptolide alcohol derivative of the present invention is 12-isothiocyanic acid base-13-hydroxyl triptolide.
The present invention can synthesize 12-isothiocyanic acid base-13-hydroxyl triptolide specifically, and reaction process need not heating, and the reaction times is short, and raw material is easy to get and low value.The preparation method is simple, preparation cost is low and yield is high, and the content of isomer that obtains is few, can be used for preparing prepared from active ingredients of tripterygium wilfordii fairly largely.
Embodiment
The preparation method of triptolide alcohol derivative of the present invention, its technical scheme is as follows:
Earlier the 0.72-10.8g triptolide is dissolved in the 70-1000ml acetone, slowly drip trimethyl carbinol 10-150ml, at room temperature add the 0.18-2.7g oxalic acid then, iodine 0.32-4.8g and 3-45g potassium sulfocyanate stirred 3 hours under the room temperature, and reaction is finished, add the layering of 80-1200ml ethyl acetate in the reaction solution, organic layer is given a baby a bath on the third day after its birth inferior with saturated sodium-chloride water solution, anhydrous magnesium sulfate drying filters, underpressure distillation removes and desolvates, 100-200 order neutral alumina post is used the chloroform wash-out on the spissated residuum, and main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent, with acetone-ether recrystallization, obtain white crystals, be described triptolide alcohol derivative.
Main distillate fraction is collected in described TLC control, is that the chloroform of 95:5 and methyl alcohol are as developping agent with volume ratio.In described acetone-ether recrystallization, the volume ratio of acetone and ether is 10:1.
Embodiment one:
Earlier 2.4g (0.007mol) triptolide is dissolved in the 230ml acetone, slowly drip trimethyl carbinol 30ml, at room temperature add 0.6g (0.007mol) oxalic acid, iodine 1.07g (0.003mol) and 10g (0.1mol) potassium sulfocyanate, stirring at room 3 hours, reaction is finished.Add the layering of 270ml ethyl acetate in the reaction solution, organic layer is washed 2 times with saturated sodium-chloride water solution, anhydrous magnesium sulfate drying, filter, underpressure distillation removes and desolvates 100-200 order neutral alumina post on the residuum, use the chloroform wash-out, main distillate fraction (Rf:0.38 (CHCL3/MEOH 95:5), developer is a Kedd ' s reagent, is purple) is collected in TLC control.Behind the pressure reducing and steaming solvent,, obtain white crystals 1.65g with acetone-ether (volume ratio is 10:1) recrystallization.Yield: 80%.The characterization data of product is as follows:
MS?m/e?419(M+),IR(KBr)cm
-1:3439,3027,1728,1612,1414,1216,1078,1021
1H-NMR,ppm:0.92(3H,d,J=7Hz,16-H),1.01(3H,d,J=7Hz,17-H),1.14(3H,s,20-H),1.25(2H,d,J=7Hz,1-H),1.65(1H,m,6-H),2.04(1H,d,J=7Hz,2-H),2.17(1H,m,15-H),2.75(1H,m,5-H),3.17(1H,s,14-H),3.41(1H,d,J=4Hz,7-H),3.87(1H,d,J=6Hz,11-H),4.18(1H,m,12-H),4.70(2H,s,19-H),5.31(1H,s,3-OH),7.27（1H,s,14-OH）
Embodiment two:
Earlier 10.8g (0.03mol) triptolide is dissolved in the 1000ml acetone, slowly drip trimethyl carbinol 150ml, at room temperature add 2.7g (0.03mol) oxalic acid, iodine 4.8g (0.015mol) and 45g (0.45mol) potassium sulfocyanate, stirring at room 3 hours, reaction is finished.Add the layering of 1200ml ethyl acetate in the reaction solution, organic layer is given a baby a bath on the third day after its birth inferior with saturated sodium-chloride water solution, anhydrous magnesium sulfate drying, filter, underpressure distillation removes and desolvates 100-200 order neutral alumina post on the residuum, use the chloroform wash-out, main distillate fraction (CHCL3/MEOH 95:5 is as developping agent, and developer is a Kedd ' s reagent, is purple) is collected in TLC control.Behind the pressure reducing and steaming solvent,, obtain white crystals 7.6g with acetone-ether recrystallization.Yield 82%.
Embodiment three:
Earlier 0.72g (0.002mol) triptolide is dissolved in the 70ml acetone, slowly drip trimethyl carbinol 10ml, at room temperature add 0.18g (0.002mol) oxalic acid, iodine 0.32g (0.001mol) and 3g (0.03mol) potassium sulfocyanate, stirring at room 3 hours, reaction is finished.Add the layering of 80ml ethyl acetate in the reaction solution, organic layer is given a baby a bath on the third day after its birth inferior with saturated sodium-chloride water solution, anhydrous magnesium sulfate drying, filter, underpressure distillation removes and desolvates 100-200 order neutral alumina post on the residuum, use the chloroform wash-out, main distillate fraction (CHCL3/MEOH 95:5 is as developping agent, and developer is a Kedd ' s reagent, is purple) is collected in TLC control.Behind the pressure reducing and steaming solvent,, obtain white crystals 5.2g with acetone-ether recrystallization.Yield 84%.
Claims (3)
1. the preparation method of a triptolide alcohol derivative, it is characterized in that: described preparation method's concrete steps are as follows: earlier the 0.72-10.8g triptolide is dissolved in the 70-1000ml acetone, slowly drip trimethyl carbinol 10-150ml, at room temperature add the 0.18-2.7g oxalic acid then, iodine 0.32-4.8g and 3-45g potassium sulfocyanate, stirred 3 hours under the room temperature, reaction is finished; Add the ethyl acetate layering in the reaction solution, organic layer is washed 2～3 times with saturated sodium-chloride water solution, uses anhydrous magnesium sulfate drying then, filters, underpressure distillation removes and desolvates, 100-200 order neutral alumina post is used the chloroform wash-out on the spissated residuum, and main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent, with acetone-ether recrystallization, obtain white crystals, be described triptolide alcohol derivative.
2. the preparation method of triptolide alcohol derivative according to claim 1 is characterized in that: main distillate fraction is collected in described TLC control, is that the chloroform of 95:5 and methyl alcohol are as developping agent with volume ratio.
3. the preparation method of triptolide alcohol derivative according to claim 1, it is characterized in that: in described acetone-ether recrystallization, the volume ratio of acetone and ether is 10:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010543198XA CN102002093B (en) | 2010-11-15 | 2010-11-15 | Method for preparing triptolide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010543198XA CN102002093B (en) | 2010-11-15 | 2010-11-15 | Method for preparing triptolide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102002093A true CN102002093A (en) | 2011-04-06 |
| CN102002093B CN102002093B (en) | 2012-08-08 |
Family
ID=43809820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010543198XA Expired - Fee Related CN102002093B (en) | 2010-11-15 | 2010-11-15 | Method for preparing triptolide derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102002093B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107243011A (en) * | 2017-01-12 | 2017-10-13 | 江西中医药大学 | Application of the Diterpene glucosides in anti-inflammatory drug is prepared |
-
2010
- 2010-11-15 CN CN201010543198XA patent/CN102002093B/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107243011A (en) * | 2017-01-12 | 2017-10-13 | 江西中医药大学 | Application of the Diterpene glucosides in anti-inflammatory drug is prepared |
| CN107243011B (en) * | 2017-01-12 | 2020-09-01 | 江西中医药大学 | Application of abietane diterpene glycoside in preparation of anti-inflammatory drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102002093B (en) | 2012-08-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xiao et al. | Triterpenoids from the Schisandraceae family | |
| Joshi et al. | Epoxide group relationship with cytotoxicity in withanolide derivatives from Withania somnifera | |
| Takatsuto et al. | Stereoselective synthesis of plant growth-prompting steroids, brassinolide, castasterone, typhasterol, and their 28-nor analogues | |
| US9416083B2 (en) | Method of isolating ingenol | |
| Chang et al. | Cytotoxic sesquiterpenes from Magnolia kachirachirai | |
| CN110903340A (en) | Tetracyclic triterpene derivative, and pharmaceutical composition and application thereof | |
| Jiang et al. | New cytotoxic ergostane-type sterols from the Chinese soft coral Sinularia sp. | |
| Wong et al. | Plant anticancer agents XXXIX: Triterpenes from Iris missouriensis (Iridaceae) | |
| CN101058598B (en) | Method of synthesizing 2alpha,3alpha-epoxy-16alpha-bromo-5alpha-androsterone-17-one | |
| Xiao-An et al. | Synthesis and biological evaluation of arjunolic acid, bayogenin, hederagonic acid and 4-epi-hederagonic acid as glycogen phosphorylase inhibitors | |
| Usui et al. | A highly stereoselective intramolecular Diels–Alder reaction for construction of the AB ring moiety of bruceantin | |
| CN102002093B (en) | Method for preparing triptolide derivative | |
| Okamoto et al. | Iron (III) picolinate-induced oxygenation and subsequent rearrangement of triterpenoid derivatives with hydrogen peroxide | |
| Lochyński et al. | Lactones. Part 15: synthesis of chiral spirolactones with a carane system—insect feeding deterrents | |
| Musumeci et al. | CH3ReO3-catalyzed oxidation of cholesta-5, 7-dien-3β-yl acetate with the urea-hydrogen peroxide adduct under various conditions. Synthesis of the natural epoxy sterol 9α, 11α-epoxy-5α-cholest-7-en-3β, 5, 6β-triol | |
| Aiyar et al. | Podophyllotoxin derivatives. 3. The remaining diastereo C-4 alcohols and ketone of the L series | |
| Kumaran et al. | An enantiodivergent protocol from R-(−)-carvone: synthesis of dihydroagarofuran sesquiterpenoid 1-deacetoxy-ent-orbiculin A | |
| Ceccherelli et al. | Biogenetic-type transformation of 3-keto-4, 5-epoxy-eudesmanes: synthesis of cyperanes, eremophilanes and spirovetivanes | |
| CN102276466B (en) | Novel triterpene compound of C3,4 split ring and preparation method thereof | |
| Wang et al. | Saccopetrins A and B, two novel γ-lactones from Saccopetalum prolificum | |
| Liu et al. | Synthetic studies towards 1α-hydroxysolasodine from diosgenin and the unexpected tetrahydrofuran ring opening in the Birch reduction process | |
| CN101089012B (en) | Complete E/F ring-opening synthesis process of 26-chloro-3beta, 16beta-diacetyloxy-22-one-(5-) cholestane (cholestene) with sterioside | |
| CN115626947B (en) | Synthesis and application of pentacyclic triterpene natural product | |
| CN108938608A (en) | A kind of preparation method of gorgonian source diterpenoid antitumor compound | |
| Wei et al. | Discovery of two ent-atisane diterpenoid lactones with AChE inhibitory activity from the roots of Euphorbia fischeriana |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120808 Termination date: 20141115 |
|
| EXPY | Termination of patent right or utility model |