CN103382208B - The preparation method of Arglabin - Google Patents
The preparation method of Arglabin Download PDFInfo
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- CN103382208B CN103382208B CN201210132964.2A CN201210132964A CN103382208B CN 103382208 B CN103382208 B CN 103382208B CN 201210132964 A CN201210132964 A CN 201210132964A CN 103382208 B CN103382208 B CN 103382208B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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Abstract
The present invention relates to the preparation method of a kind of Arglabin, the method include with a smile lactone and epoxidation reagent react 1,10 epoxidations have a smile on one's face lactone, 1,10 epoxidation has a smile on one's face lactone through 4 hydroxyls and the dehydration of the hydrogen of 3, i.e. prepares Arglabin.The feature of the method is that lactone prepares Arglabin through key intermediate 1,10 epoxidation lactones with a smile with a smile.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, the present invention relates to the preparation method of a kind of Arglabin.
Background technology
Arglabin belongs to guaiaci lignum sesquiterpene lactones compounds, it is to obtain from a kind of aerial parts separation and Extraction from Artemisia absinihium L (Artemisia) the class plant ArtemisiaglabellaKar.etKir. being grown on Kazakhstan, its antitumaous effect principle is suppression farnesyl transferase, this is a kind of enzyme determining oncogenic ras function, scientist thinks that this enzyme is sent out in the disease of human tumor and accounts for 20%-30% in reason, and Arglabin also shows that good anti-different tumor cell lines activity and toxicity (human tumor cell line IC50=0.9-5.0 μ gmL-1).In order to solve the water solubility problems of Arglabin, modifying with dimethyl amine in C (13) position, Arglabin-DMA has been registered listing in the republic of Kazakhstan, is used for treating breast carcinoma, colon cancer, ovarian cancer and pulmonary carcinoma.Arglabm and Arglabm-DMA structural formula is as shown below.
The productivity extracting Arglabin from plant only has 0.27%.And the complete synthesis step of the Arglabin reported at present is up to 20 steps (Kalidindi, S.；Jeong, W.B.；Schall, A.；Bandichhor, R.；Nosse, B.；Reiser, O.Angew.Chem.Int.Ed.2007,46,6361-6363), the factors such as reactions steps is long, and expense is high limit its commercial Application.
Prepare Arglabin with lactone with a smile for raw material and have no that document is reported at present, the raw material preparing Arglabin that the present invention provides is lactone with a smile, with a smile the preparation method of lactone we applied for patent of invention [application number: 201010153685, the applying date: 2010.04.23], the method raw material preparing Arglabin for raw material with lactone with a smile that the present invention provides is easy to get, it is easy to operation, and yield is high, being suitable to industrialized production, industrially prepared for Arglabin provides new synthetic method.
Summary of the invention
The structure following structure formula (I) of Arglabin, molecular formula is C15H18O3, molecular weight is 246, and No. CAS is 84692-91-1.
The invention provides the preparation method preparing Arglabin.
Specifically, a kind of method that the invention provides Arglabin preparing formula (I), the method include with a smile lactone and epoxidation reagent react 1,10 epoxidations have a smile on one's face lactone, 1,10 epoxidations have a smile on one's face lactone through 4 hydroxyls and the dehydration of the hydrogen of 3, i.e. prepare Arglabin.The feature of the method is that lactone prepares Arglabin through key intermediate 1,10 epoxidation lactones with a smile with a smile.
Method described above, including following two reactions steps:
Reactions steps one: with a smile lactone react with suitable epoxidation reagent in suitable reaction dissolvent 1,10 epoxidations have a smile on one's face lactone；
Reactions steps two: 1,10 epoxidation lactones with a smile react with suitable dehydrated reagent in suitable reaction dissolvent and i.e. obtain Arglabin.
In reactions steps one as above, suitable epoxidation reagent/reaction dissolvent is: metachloroperbenzoic acid/(dichloromethane or chloroform), benzoyl hydroperoxide/(dichloromethane or chloroform), peroxy trifluoroacetic acid/(dichloromethane or chloroform), peracetic acid/(dichloromethane or chloroform), N-bromo-succinimide/(mixed solvent of oxolane/water), (sodium bromate and sodium sulfite)/(acetonitrile and the mixed solution of water), potassium hydrogen persulfate/(acetone, methylene chloride/water), (vanadyl acetylacetonate [VO (acac)2] and tertbutanol peroxide)/(dichloromethane or chloroform)；
In reactions steps two as above, suitable dehydrated reagent/reaction dissolvent is: trifluoroacetic anhydride/(pyridine and dichloromethane), trifluoromethanesulfanhydride anhydride/(pyridine and dichloromethane), (diethyl azodiformate and triphenylphosphine)/(pyridine and oxolane), thionyl chloride/pyridine, phosphorus oxychloride/pyridine, double [double (trifluoromethyl) phenethanol of a, a-]-diphenyl sulfur [Martin ' ssulfurane reagent]/(dichloromethane or chloroform).
Beneficial effect
The preparation method of Arglabin that the present invention provides solves Arglabin and prepares that productivity is low, the technological deficiency of cost, the method raw material preparing Arglabin for raw material with lactone with a smile that the present invention provides is easy to get, easily operated, yield is high, being suitable to industrialized production, industrially prepared for Arglabin provides new synthetic method.
Detailed description of the invention
In order to understand the present invention, further illustrate the present invention with embodiment below, but be not intended to the present invention.
Embodiment 1:1,10 epoxidations have a smile on one's face the preparation of lactone
Method one:
To be dissolved in 35mL dichloromethane by lactone (628mg, 12.5mmol) with a smile, be subsequently adding metachloroperbenzoic acid (680mg, 4.0mmol.Reaction system is positioned over and is stirred at room temperature, and reacts with TCL monitoring.After raw material disappears, reaction mixture is poured over 5%NaHCO3(60mL) in, organic facies is washed with water (20mL), collects organic facies, and uses Na2SO4Being dried, filter, vacuum rotary steam, obtain thick product silica column purification and obtain compound 1,10 epoxidations have a smile on one's face lactone 568mg, yield: 85%.1HNMR(CDCl3, 400MHz) and δ 6.17 (d, J=3.2Hz, 1H), 5.47 (d, J=2.8Hz, 1H), 4.04 (t, J=10.8Hz, 1H), 2.36-2.20 (m, 4H), 2.03-1.08 (m, 4H), 1.68-1.62 (m, 1H), 1.46 (s, 3H), 1.46 (d, J=12.8Hz, 1H), 1.29 (s, 3H)；13CNMR (CDCl3,100MHz) δ 169.5,137.9,119.5,81.7,79.5,69.7,62.1,55.3,49.2,37.2,33.2,29.3,23.1,23.0,21.8.
Method two:
To be dissolved in 35mL chloroform by lactone (628mg, 12.5mmol) with a smile, be subsequently adding metachloroperbenzoic acid (680mg, 4.0mmol).Reaction system is positioned over and is stirred at room temperature, and reacts with TCL monitoring.After raw material disappears, reaction mixture is poured over 5%NaHCO3(60mL) in, organic facies is washed with water (20mL), collects organic facies, and uses Na2SO4Being dried, filter, vacuum rotary steam, obtain thick product silica column purification and obtain compound 1,10 epoxidations have a smile on one's face lactone 523mg, yield: 78%.
Method three:
To be dissolved in 35mL dichloromethane by lactone (628mg, 12.5mmol) with a smile, be subsequently adding benzoyl hydroperoxide (552mg, 4.0mmol).Reaction system is positioned over and is stirred at room temperature, and reacts with TCL monitoring.After raw material disappears, reaction mixture is poured over 5%NaHCO3(60mL) in, organic facies is washed with water (20mL), collects organic facies, and uses Na2SO4Being dried, filter, vacuum rotary steam, obtain thick product silica column purification and obtain compound 1,10 epoxidations have a smile on one's face lactone 483mg, yield: 72%.
Method four:
To be dissolved in 35mL dichloromethane by lactone (628mg, 12.5mmol) with a smile, be subsequently adding peroxy trifluoroacetic acid (520mg, 4.0mmol).Reaction system is positioned over and is stirred at room temperature, and reacts with TCL monitoring.After raw material disappears, reaction mixture is poured over 5%NaHCO3(60mL) in, organic facies is washed with water (20mL), collects organic facies, and uses Na2SO4Being dried, filter, vacuum rotary steam, obtain thick product silica column purification and obtain compound 1,10 epoxidations have a smile on one's face lactone 503mg, yield: 75%.
Method five:
To be dissolved in 35mL dichloromethane by lactone (628mg, 12.5mmol) with a smile, be subsequently adding peracetic acid (304mg, 4.0mmol).Reaction system is positioned over and is stirred at room temperature, and reacts with TCL monitoring.After raw material disappears, reaction mixture is poured over 5%NaHCO3(60mL) in, organic facies is washed with water (20mL), collects organic facies, and uses Na2SO4Being dried, filter, vacuum rotary steam, obtain thick product silica column purification and obtain compound 1,10 epoxidations have a smile on one's face lactone 550mg, yield: 82%.
Method six:
The NaHSO of 1M3(30mg, 0.29mmol) solution is added drop-wise to lactone (18.4mg, 0.074mmol), NaBrO with a smile3In the acetonitrile (1mL) of (22mg, 0.14mmol) and the mixed liquor of water (2mL), reactant liquor is stirred at room temperature reaction 48h, adds ethyl acetate extraction, organic layer Na2SO3, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and after filtration, pressurization is concentrated to give crude product, and silica gel column chromatography obtains 1, and 10 epoxidations have a smile on one's face lactone 14.7mg, yield: 75%.
Method seven:
By KHSO5(49mg, dichloromethane (2mL) dropwise it is added drop-wise at water (0.5mL) solution 0 DEG C 0.0813mmol), 0.5mL water buffer (pH=7.2), lactone (13.4mg with a smile, 0.0542mmol), acetone (40 microlitre), in the mixed liquor of 18 hats 6 ethers (2.86mg), after dropping, stirring reaction 6 hours, add dichloromethane extraction, organic layer water, saturated aqueous common salt washs, anhydrous sodium sulfate is dried, after filtration, pressurization is concentrated to give crude product, silica gel column chromatography obtains 1, 10 epoxidations have a smile on one's face lactone 10.8mg, yield: 76%.
Method eight:
Under nitrogen protection, tert-Butanol peroxide (3M toluene solution, 0.2mL) is added drop-wise in 0 DEG C of solution of dichloromethane of lactone (100.7mg) with a smile, is subsequently adding VO (acac)2(2.1mg), then it is stirred at room temperature 16 hours, saturated NaHSO3Solution (1mL) cancellation is reacted, and adds dichloromethane extraction, organic layer water, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and after filtration, pressurization is concentrated to give crude product, and silica gel column chromatography obtains 1, and 10 epoxidations have a smile on one's face lactone 72.9mg, yield: 68%.
The preparation of embodiment 3:Arglabin
Method one:
By compound 1,10 epoxidations have a smile on one's face lactone (50mg, 0.19mmol) and pyridine (0.24mL) joins in 5mL dichloromethane solution, then drip (CF at a temperature of 0 DEG C under Ar protective condition3CO)2O (0.24mL, 1.7mmol).Reaction mixture is stirred at room temperature overnight.Use NaHCO3Cancellation is reacted, and extracts with dichloromethane, uses MgSO4It is dried organic layer.Vacuum rotary steam removes solvent, the thick product silica column purification obtained, and obtains compound Arglabin2.5mg, yield 5%.1HNMR(CDCl3, 400MHz) and δ 6.14 (d, J=3.2Hz, 1H), 5.57 (s, 1H), 5.41 (d, J=3.2Hz, 1H), 4.00 (t, J=10.4Hz, 1H), 2.93 (br.d, J=10.8Hz, 1H), 2.77 (br.d, J=17.6Hz, 1H), 2.27-2.12 (m, 3H), 2.03 (m, 1H), 1.97 (brs, 3H), 1.84 (br.d, J=14.0HZ, 1H), 1.48 (m, 1H), 1.35 (s, 3H)；13CNMR(CDCl3, 400MHz) and δ 170.6,140.7,139.2,125.0,118.4,83.0,72.6,62.8,52.9,51.2,39.8,33.6,22.9,21.6,18.4.
Method two:
By compound 1,10 epoxidations are had a smile on one's face lactone (100mg, 0.38mmol) and are dissolved in 9.6mL pyridine, at a temperature of 0 DEG C under Ar protective condition, drip (CF3SO2)2O (0.45mL, 2.37mmol).Reaction mixture is stirred at room temperature overnight.Use NaHCO3Cancellation is reacted, and extracts with dichloromethane, uses MgSO4It is dried organic layer.Vacuum rotary steam removes solvent, the thick product silica column purification obtained, and obtains compound Arglabin28.8mg, and yield is 29%.
Method three:
DEAD (0.1mL, 0.57mmol) reagent joins Ph at 0 DEG C3In the THF solution of P (151mg, 0.57mmol), being subsequently adding compound 1,10 epoxidations have a smile on one's face the THF solution of lactone (50mg, 0.19mmol).Reactant mixture at ambient temperature, stirs 3 days.After TLC detection, also surplus major part raw material does not react, and therefore adds 0.25mL pyridine, continues stirring 24h.Vacuum rotary steam removes major part solvent, and remaining product dichloromethane dissolves, and washes three times with NaOH (1M), and uses MgSO4Being dried, filter, vacuum rotary steam removes solvent, the thick product silica column purification obtained, and obtains compound Arglabin6.4mg, and yield is 13%.
Method four:
Compound 1,10 epoxidations are had a smile on one's face lactone (100mg) and are dissolved in pyridine, drip SOCl at 0 DEG C2.After being stirred at room temperature 2h, raw material is wholly absent.Reaction mixture is poured into saturated NaHCO3In, then it is extracted with ethyl acetate, and uses saturated NaHCO respectively3, saturated common salt washing organic layer, and use MgSO4Being dried, filter, vacuum rotary steam removes solvent, the crude product purified by silica gel column purification obtained, and obtains compound Arglabin26.8mg, and yield is 27%.
Method five:
By compound 1,10 epoxidations are had a smile on one's face lactone (100mg, 0.38mmol) and are dissolved in pyridine, are positioned over 0 DEG C or-40 DEG C, are slowly added to POCl3(0.09mL, 0.95mmol),.After 2.5h, raw material reaction is complete, adds ether, and organic layer uses saturated NaHCO respectively3, saturated common salt is washed three times, is used MgSO4Being dried, filter, vacuum rotary steam removes solvent, obtains thick product silica column purification, obtains compound Arglabin27.8mg, and yield is 28%.
Method six:
Being dissolved in 2mL dichloromethane by Martin ' ssulfurane reagent (382mg, 0.57mmol), in the condition of Ar protection, be slowly added dropwise compound 1,10 epoxidations have a smile on one's face the 4mL dichloromethane solution of lactone (100mg).Reaction mixture gradually becomes yellow, stirs 24h, and after reaction raw materials is wholly absent, vacuum rotary steam removes solvent, obtains yellow oily material, after thick product silica column purification, obtains compound Arglabin64.5mg, and yield is 65%.
Purposes and the method for the present invention are described by specific embodiment.Those skilled in the art can use for reference the links such as the suitable feed change of present disclosure, process conditions and realize other purpose corresponding, its relevant change is all without departing from present disclosure, all similar replacements and change will become apparent to those skilled in the art that and be considered as being included within the scope of the present invention.
Claims (2)
1. the method preparing Arglabin, the method include with a smile lactone and epoxidation reagent react 1,10 epoxidations have a smile on one's face lactone, 1,10 epoxidation has a smile on one's face lactone through 4 hydroxyls and the dehydration of the hydrogen of 3, i.e. prepares Arglabin,
Method the most according to claim 1, the method includes following two reactions steps:
Reactions steps one: with a smile lactone react with suitable epoxidation reagent in suitable reaction dissolvent 1,10 epoxidations have a smile on one's face lactone, described epoxidation reagent is metachloroperbenzoic acid, and reaction dissolvent is dichloromethane or chloroform；Or, described epoxidation reagent is benzoyl hydroperoxide, and reaction dissolvent is dichloromethane or chloroform；Or, described epoxidation reagent is peroxy trifluoroacetic acid, and reaction dissolvent is dichloromethane or chloroform；Or, described epoxidation reagent is peracetic acid, and reaction dissolvent is dichloromethane or chloroform；Or, described epoxidation reagent is N-bromo-succinimide, and reaction dissolvent is the mixed solvent of oxolane and water；Or, described epoxidation reagent is sodium bromate and sodium sulfite, and reaction dissolvent is the mixed solution of acetonitrile and water；Or, described epoxidation reagent is potassium hydrogen persulfate, and reaction dissolvent is acetone, dichloromethane and water；Or, described epoxidation reagent is vanadyl acetylacetonate and tertbutanol peroxide, and reaction dissolvent is dichloromethane or chloroform；
Reactions steps two: 1,10 epoxidation lactones with a smile react with suitable dehydrated reagent in suitable reaction dissolvent and i.e. obtain Arglabin, and described dehydrated reagent is trifluoroacetic anhydride, and reaction dissolvent is pyridine and dichloromethane；Or, described dehydrated reagent is trifluoromethanesulfanhydride anhydride, and reaction dissolvent is pyridine and dichloromethane；Or, described dehydrated reagent is diethyl azodiformate and triphenylphosphine, and reaction dissolvent is pyridine and oxolane；Or, described dehydrated reagent is thionyl chloride, and reaction dissolvent is pyridine；Or, described dehydrated reagent is phosphorus oxychloride, and reaction dissolvent is pyridine；Or, described dehydrated reagent is double [double (trifluoromethyl) phenethanol of a, a-]-diphenyl sulfur, and reaction dissolvent is dichloromethane or chloroform.
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| PCT/CN2013/074724 WO2013163936A1 (en) | 2012-05-03 | 2013-04-25 | Preparation method of arglabin |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012824A1 (en) * | 2004-07-30 | 2006-02-09 | Chemieanlagenbau Chemnitz Gmbh | Method for producing dimethylaminoarglabine hydrochloride |
| WO2008035958A1 (en) * | 2006-09-19 | 2008-03-27 | Adekenov Sergazy Mynzhasarovic | Method for production of hydrochloride 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide, the lyophilized antitumor preparation 'arglabin' |
| CN101966176A (en) * | 2010-10-18 | 2011-02-09 | 天津尚德药缘科技有限公司 | Application of michelia lactone and derivatives thereof in treatment of hepatitis C |
| CN102234259A (en) * | 2010-04-23 | 2011-11-09 | 天津尚德药缘科技有限公司 | Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof |
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| CN102372723B (en) * | 2010-08-19 | 2014-03-26 | 石药集团中奇制药技术（石家庄）有限公司 | Method for extracting arglabin from artemisia myriantha |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006012824A1 (en) * | 2004-07-30 | 2006-02-09 | Chemieanlagenbau Chemnitz Gmbh | Method for producing dimethylaminoarglabine hydrochloride |
| WO2008035958A1 (en) * | 2006-09-19 | 2008-03-27 | Adekenov Sergazy Mynzhasarovic | Method for production of hydrochloride 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide, the lyophilized antitumor preparation 'arglabin' |
| CN102234259A (en) * | 2010-04-23 | 2011-11-09 | 天津尚德药缘科技有限公司 | Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof |
| CN101966176A (en) * | 2010-10-18 | 2011-02-09 | 天津尚德药缘科技有限公司 | Application of michelia lactone and derivatives thereof in treatment of hepatitis C |
Non-Patent Citations (1)
| Title |
|---|
| Enantioselective Synthesis of Arglabin;Srinivas Kalidindi et al.;《Angew. Chem. Int. Ed.》;20071231;第46卷;第6362-6363页 * |
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