CN102002093B - Method for preparing triptolide derivative - Google Patents
Method for preparing triptolide derivative Download PDFInfo
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- CN102002093B CN102002093B CN201010543198XA CN201010543198A CN102002093B CN 102002093 B CN102002093 B CN 102002093B CN 201010543198X A CN201010543198X A CN 201010543198XA CN 201010543198 A CN201010543198 A CN 201010543198A CN 102002093 B CN102002093 B CN 102002093B
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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 article 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 that the configuration of β 2 unsaturated lactone ring five membered structures is unique is one of main active ingredient of generally acknowledging in the trypterygine plant, has biological activitys such as tangible anti-inflammatory, immunosuppression, antitumor and anti-male fertility.Since coming to light, 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 accomplished the complete synthesis of triptolide; And through 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 triptolide has obtained the diterpene lactone and toxicity is less through modifying, 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; Research show the diterpene analogue the enzyme catalysis product--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 triptolide alcohol derivative and the toxicity of treatment autoimmune disease, and has applied for patent.Yang etc. have accomplished (-)-triptolide (triPtophenolide) first; (-)-Triptonide (triptoni de); (-)-triptophenolide (triptophenolide), (-)-Lei quinone lactone ketone (triptoquinonide) mapping selective body complete synthesis.Vegeto-alkali 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, vegeto-alkali and a many glycosides preparation technology.Make a general survey of various preparing 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 are that the effective constituent of mass preparation trypterygine provides wide prospect, but corresponding technology of preparing also need be further perfect.So combining with conventional method of extraction, 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.
The object of the invention is realized through following technical scheme:
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 Rhocya stirred 3 hours under the room temperature, and reaction is finished; Add the ETHYLE 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; Filter, underpressure distillation removes and desolvates 100-200 order neutral alumina post on the spissated residuum; Use the chloroform wash-out, main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent; With acetone-ether recrystallization, obtain white crystals, be said triptolide alcohol derivative.
Main distillate fraction is collected in said TLC control, use volume ratio as the chloroform of 95:5 and methyl alcohol as developping agent.
In said acetone-ether recrystallization, the volume ratio of acetone and ether is 10:1.
Triptolide alcohol derivative according to the 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 following:
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 Rhocya; Stirred 3 hours under the room temperature, reaction is finished, and adds the layering of 80-1200ml ETHYLE ACETATE in the reaction solution, and 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, and underpressure distillation removes and desolvates 100-200 order neutral alumina post on the spissated residuum; Use the chloroform wash-out, main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent; With acetone-ether recrystallization, obtain white crystals, be said triptolide alcohol derivative.
Main distillate fraction is collected in said TLC control, use volume ratio as the chloroform of 95:5 and methyl alcohol as developping agent.In said 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) Rhocya; Stirring at room 3 hours, reaction is finished.Add the layering of 270ml ETHYLE 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 following:
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) Rhocya; Stirring at room 3 hours, reaction is finished.Add the layering of 1200ml ETHYLE 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) Rhocya; Stirring at room 3 hours, reaction is finished.Add the layering of 80ml ETHYLE 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: said preparing method's concrete steps are following: 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 Rhocya; Stirred 3 hours under the room temperature, reaction is finished; Add the ETHYLE 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; Filter, underpressure distillation removes and desolvates 100-200 order neutral alumina post on the spissated residuum; Use the chloroform wash-out, main distillate fraction is collected in TLC control, behind the pressure reducing and steaming solvent; With acetone-ether recrystallization, obtain white crystals, be said 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 said TLC control, use volume ratio as the chloroform of 95:5 and methyl alcohol as developping agent.
3. the preparation method of triptolide alcohol derivative according to claim 1, it is characterized in that: in said acetone-ether recrystallization, the volume ratio of acetone and ether is 10:1.
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