CN103159777A - Synthetic method of halogenated artemisinin derivative - Google Patents
Synthetic method of halogenated artemisinin derivative Download PDFInfo
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- CN103159777A CN103159777A CN2013100697228A CN201310069722A CN103159777A CN 103159777 A CN103159777 A CN 103159777A CN 2013100697228 A CN2013100697228 A CN 2013100697228A CN 201310069722 A CN201310069722 A CN 201310069722A CN 103159777 A CN103159777 A CN 103159777A
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- artemisinin
- synthetic method
- derivative
- halo
- compound
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- 0 CC(*)C(C)(*)C(CC[C@@](C)C1CC[C@](C)OC2)[C@]12OO Chemical compound CC(*)C(C)(*)C(CC[C@@](C)C1CC[C@](C)OC2)[C@]12OO 0.000 description 1
- GLBDIEYQEKAIER-HCNDMPADSA-N C[C@H](CC[C@H]1C2(C)Cl)[C@H](CC3)[C@@]11OO[C@@]3(C)O[C@H]1OC2OCCO Chemical compound C[C@H](CC[C@H]1C2(C)Cl)[C@H](CC3)[C@@]11OO[C@@]3(C)O[C@H]1OC2OCCO GLBDIEYQEKAIER-HCNDMPADSA-N 0.000 description 1
Abstract
The invention discloses a synthetic method of halogenated artemisinin derivative with high efficiency, according to the invention, dehydrated dihydroartemisinin is taken as a raw material to synthesizing chloro-artemisinin, bromo-artemisinin and fluoro-artemisinin derivative. The method provided by the invention has the advantages of easy acquisition of raw material and simple operation. The method provided by the invention can prepare the chloro-artemisinin, bromo-artemisinin and fluoro-artemisinin derivative with high efficiency.
Description
Technical field
The present invention relates to a kind of method of new and effective synthesizing halogen Artemisinin series derivates, belong to chemosynthesis technical field.
Background technology
Artemisinin is the distinctive yellow Artemisinin of China, is a kind of sesquiterpene lactones compounds with peroxide bridge, and Artemisinin and derivative thereof are the novel anti-malarials of sesquiterpene lactones class that contains peroxide bridge, have efficient, fast, the characteristics such as low toxicity, safety; Be accompanied by technical progress, the medical usage of Artemisinin surmounts the use range as simple anti-malarial, multiple drug resistance pernicious malaria medicine already: research and application show, Artemisinin and derivative thereof also have anti-pneumocystis carinii pneumonia effect, anti-pregnant effect, anti-, the effect of curing oncoma, anti-schistosome function, treatment arch insect infection effect, few to cardiovascular effect, few to immune effect.
In recent years, the medicine scholar of global range has carried out studies show that of extensive and living level to Artemisinin and derivative thereof the especially antitumous effect of its derivative: Artemisinin and derivative thereof are in treatment leukemia and mammary cancer, it can kill cancer cell, but does not injure healthy cell on every side.With respect to the strong toxic side effect of finite sum that is equally the curative effect of the taxol of natural extract and camptothecine, it is stronger that Artemisinin and derivative thereof have an antitumour activity, wide spectrum, there is no the advantage of toxic side effect.China is in recent years also always in the research of encouraging energetically, advocate this representational natural product of China, and the application prospect of visible Artemisinin and derivative thereof is extensively.
The research of recent year on Artemisinin and derivative thereof has had very large progress, especially the research of halo Artemisinin, mainly concentrate on the bromo aspect, the patent that has no chloro and fluoro artemisinin derivative is delivered, synthetic and the research of a kind of Br-DHA of introducing in patent (CN200610144186), it has very high pharmaceutical activity, but it is only a kind of derivative of Artemisinin, can not satisfy research and the screening of future drugs.In fact halogenic substituent has active influence to the effectiveness of medicine, and especially fluorochemical, have a lot of medicines that go on the market now and all contain fluoro substituents, so the application prospect of halogen substituted chemical is more extensive.
Summary of the invention
The present invention relates to a kind of synthetic method of halo artemisinin derivative, a kind of method of new and effective synthetic chloro, bromo, fluoro Artemisinin series derivates specifically, the present invention aim to provide a kind of can be efficiently the method for synthetic a large amount of Artemisinin halo derivatives fast, a kind of platform of storehouse is provided for the screening of high-activity compound.
A kind of method that it is chloro, bromo, fluoro artemisinin derivative that the present invention has proposed novel efficient synthesizing halogen Artemisinin series derivates with innovating, halo and nucleophilic substitution reaction occur as raw material one goes on foot in the Dihydroartemisinin (1) take dehydration, respectively synthetic chloro, bromo, fluoro Artemisinin series derivates (2).
Building-up reactions of the present invention is:
Wherein, X=F, Br, Cl.Any one
Wherein, M=RO, RNH, RNR ', RS, H, R; R is any group.For example, be CH
3OH, PhNH, CH
3NCH
3CH
2, CH
3S, PhCH
2
In the present invention, the feed ratio of described reaction is: the Dihydroartemisinin of dehydration (1): X
+: MH=1: 1~3: 0.1~100.Preferably, the feed ratio of described reaction can also be: the Dihydroartemisinin of dehydration (1): X
+: MH=1: 1~1.5: 0.1~2.
Wherein, described X
+For provide halogen just from compound.
Wherein, the compound that the halogen positive ion is provided is NBS (N-bromo-succinimide), NCS (N-chlorosuccinimide), NFSI (the two benzsulfamides of N-fluoro).
The compounds X of halogen positive ion preferably, is provided
+Be any one of the two benzsulfamides of N-bromo-succinimide, N-chlorosuccinimide or N-fluoro.
In the present invention, described reaction solvent used is acetone or tetrahydrofuran (THF).
In the present invention, MH is the compound with nucleophilicity.Wherein, if MH has n nucleophilic group, the n of a described MH nucleophilic group can connect n halo Artemisinin group; Wherein, n 〉=1.
Particularly, N
2Under protection, the Dihydroartemisinin of dehydration is dissolved in anhydrous acetone or anhydrous tetrahydrofuran (THF), adds the compound that the halogen positive ion is provided, and stirring at room half an hour adds the compound with nucleophilicity of acetone or tetrahydrofuran (THF) dissolving, and reaction is spent the night.Add deionized water and stirring 10 minutes, and added dichloromethane extraction 2 times, separatory, the organic phase anhydrous sodium sulfate drying is spin-dried for, and gets white solid.
The inventive method raw material is easily made, and is with low cost, easy and simple to handle, and middle through washing, extraction can obtain the finished product, and productive rate is high, is fit to the compound of synthetic a large amount of different halogens, different substituents.Utilize the inventive method can be efficient, high yield obtains chloro, bromo, fluoro Artemisinin series derivates.
It is a kind of by the synthetic halo artemisinin derivative of the described method of claim 1 of the present invention that the present invention also provides.The structure of this halo artemisinin derivative is suc as formula shown in (2).
Wherein, when the X in formula (2) is F, be the fluoro artemisinin derivative.
When the X in formula (2) is Br, be the bromo artemisinin derivative.
When the X in formula (2) is Cl, be the chloro artemisinin derivative.
Embodiment
Further set forth the present invention below in conjunction with specific embodiment.Below implement process of the present invention and method, except the following content of mentioning specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.Protection content of the present invention is not limited to following examples.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and take appending claims as protection domain.Following examples only are used for explanation the present invention, and are not used for limiting the scope of the invention.
The method of the new and effective synthetic chloro of the present invention, bromo, fluoro Artemisinin series derivates, its reaction process is as follows:
The Dihydroartemisinin (1) of the lower dehydration of N2 protection is dissolved in anhydrous acetone or anhydrous tetrahydrofuran (THF); add the compound that the halogen positive ion is provided; stirring at room half an hour adds the compound with nucleophilicity of acetone or tetrahydrofuran (THF) dissolving, and room temperature reaction spends the night.Aftertreatment: added deionized water and stirring 10 minutes, and added dichloromethane extraction 2 times, separatory merges organic phase, the organic phase anhydrous sodium sulfate drying, and 35 ℃ are spin-dried for, get white solid.Wherein, above-mentioned provide halogen just from compound be NBS, NCS, NFSI.Above-mentioned feed ratio is: the Dihydroartemisinin of dehydration (1): X
+: MH=1: 1~3: 0.1~100.
Embodiment 1
Synthetic following bromo compound:
In the bottle with two necks of 50mL, add the Dihydroartemisinin (1) (50mg, 0.13mmol) of dehydration, be replaced as N
2Atmosphere adds the anhydrous THF of 2mL, adds the N-bromo-succinimide NBS (35mg, 0.13mmol) of 1mLTHF dissolving, stirring at room 30min adds dehydrated alcohol (1mL, 17mmol), stirred overnight at room temperature adds 5mL to go to add CH from water stirring 10min
2Cl
2(10mLx2) extraction, separatory merges organic phase, the organic phase anhydrous sodium sulfate drying, 35 ℃ are spin-dried for, and get the product white solid, total recovery 90%.
1HNMR(400MHz,CDCl3),5.48(s,1H),4.83(d,1H),3.93~3.85(m,1H),3.67~3.60(m,1H),2.35~2.33(m,2H),2.29(s,3H),1.91~1.87(m,3H),1.91~1.87(m,2H),1.61~1.60(d,1H),1.53(s,3H),1.43~1.41(d,2H),1.28~1.24(m,3H),1.10(d,3H),0.95~0.93(m,3H),0.89~0.87(m,3H)
ESI-MS:413.1([M+Na]
+)
Embodiment 2
Synthetic following chlorinated compound:
In the bottle with two necks of 50mL, add the Dihydroartemisinin (1) (50mg, 0.13mmol) of dehydration, be replaced as N
2Atmosphere adds the anhydrous propanone of 2mL, adds the N-chlorosuccinimide NCS (26mg, 0.13mmol) of 1mL acetone solution, stirring at room 30min adds without water glycol (1mL, 18mmol), stirred overnight at room temperature adds 5mL deionized water and stirring 10min, adds CH
2Cl
2(10mLx2) extraction, separatory merges organic phase, the organic phase anhydrous sodium sulfate drying, 35 ℃ are spin-dried for, and get the product white solid, total recovery 86%.
1HNMR(400MHz,CDCl3),5.53(s,1H),4.84(s,1H),3.98~3.94(m,1H),3.78~3.70(m,3H),2.38~2.30(m,3H),2.031.88(m,8H),1.64~1.26(m,3H),1.11(s,5H),0.96~0.95(d,3H),0.88~0.75(m,3H)
ESI-MS:385.0([M+Na]
+)
Embodiment 3
Synthetic following fluoric compound:
In the bottle with two necks of 50mL, add the Dihydroartemisinin (1) (50mg, 0.13mmol) of dehydration, be replaced as N
2Atmosphere adds the anhydrous THF of 2mL, adds the two benzsulfamide NFSI (60mg, 0.13mmol) of N-fluoro of 1mLTHF dissolving, stirring at room 30min adds anhydrous methanol (1mL, 25mmol), stirred overnight at room temperature adds 5mL deionized water and stirring 10min, adds CH
2Cl
2(10mLx2) extraction, separatory merges organic phase, the organic phase anhydrous sodium sulfate drying, 35 ℃ are spin-dried for, and get the product white solid, total recovery 89%.
1HNMR(400MHz,CDCl3),5.46(s,1H),4.75(s,1H),3.54(s,1H),2.37~2.31(m,1H),2.02~1.56(m,6H),1.50(s,1H),1.48~1.42(m,3H),1.33(s,1H),1.28~1.26(m,6H),1.10(d,3H),0.95~0.93(m,3H),0.89~0.87(m,3H)
ESI-MS:339.1([M+Na]
+)?。
Claims (7)
1. the synthetic method of a halo artemisinin derivative as the formula (2), is characterized in that, described method is take the Dihydroartemisinin of dehydration as raw material, and a step, halo and nucleophilic substitution reaction, synthesizing halogen artemisinin derivative occured; Described building-up reactions is:
Wherein,
X=F, Br, or Cl;
M=RO,RNH,RNR’,RS,H,R;
R is any group.
2. synthetic method as claimed in claim 1, is characterized in that, described X
+For the compound of halogen positive ion is provided, MH is the compound with nucleophilicity.
3. synthetic method as claimed in claim 1, is characterized in that, described X
+Be N-bromo-succinimide, N-chlorosuccinimide, the two benzsulfamides of N-fluoro.
4. synthetic method as claimed in claim 1, is characterized in that, described reaction solvent used is acetone or tetrahydrofuran (THF).
5. synthetic method as claimed in claim 1, is characterized in that, the n of a described MH nucleophilic group can connect n halo Artemisinin group; Wherein, n 〉=1.
6. synthetic method as claimed in claim 2, is characterized in that, the feed ratio of described reaction is: the Dihydroartemisinin of dehydration: X
+: MH=1:1~3:0.1~100.
7. press the halo artemisinin derivative as the formula (2) that the described synthetic method of claim 1 prepares for one kind.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104086560A (en) * | 2014-07-03 | 2014-10-08 | 唐心建 | Halogenated artemisinin mother nucleus, halogenated artemisinin derivatives, halogenated dihydroartemisinin and halogenated decarbonylation artemisinin and medical use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0456149A1 (en) * | 1990-05-07 | 1991-11-13 | Hoechst Aktiengesellschaft | 9-Substituted compounds of 3 alpha, 11 alpha-Epoxy-3,4,5, 5a alpha,6,7,8,8a,9,11,11a-undecahydro-3 beta, 6 alpha, 9-trimethylfurano[3,4-j][1,2]-benzodioxepin, processes for their preparation and their use as antiprotozoal and antiviral agents |
CN101367822A (en) * | 2007-08-17 | 2009-02-18 | 四川科伦药业股份有限公司 | Novel dihydro arteannuin derivant, preparation method and uses as medicament |
-
2013
- 2013-03-05 CN CN2013100697228A patent/CN103159777A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0456149A1 (en) * | 1990-05-07 | 1991-11-13 | Hoechst Aktiengesellschaft | 9-Substituted compounds of 3 alpha, 11 alpha-Epoxy-3,4,5, 5a alpha,6,7,8,8a,9,11,11a-undecahydro-3 beta, 6 alpha, 9-trimethylfurano[3,4-j][1,2]-benzodioxepin, processes for their preparation and their use as antiprotozoal and antiviral agents |
CN101367822A (en) * | 2007-08-17 | 2009-02-18 | 四川科伦药业股份有限公司 | Novel dihydro arteannuin derivant, preparation method and uses as medicament |
Non-Patent Citations (2)
Title |
---|
BINDURNADHAVAN VENUGOPALAN,等: "Radical initiated reactions of artemisinin derivatives", 《J. CHEM. SOC., PERKIN TRANS. 1》, no. 10, 1 January 1996 (1996-01-01), pages 1015 - 1020 * |
DHARMARAJAN SRIRAM,等: "Aromatic amino analogues of artemisinin: synthesis and in vivo antimalarial activity", 《MED CHEM RES》, vol. 19, no. 6, 13 May 2009 (2009-05-13), pages 524 - 532, XP019849437 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104086560A (en) * | 2014-07-03 | 2014-10-08 | 唐心建 | Halogenated artemisinin mother nucleus, halogenated artemisinin derivatives, halogenated dihydroartemisinin and halogenated decarbonylation artemisinin and medical use thereof |
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Application publication date: 20130619 |