CN102491982B

CN102491982B - Method for synthetizing 1,2,4-trioxane compound and purpose

Info

Publication number: CN102491982B
Application number: CN201110394240.0A
Authority: CN
Inventors: 伍贻康; 郝宏东; 李云
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2011-12-01
Filing date: 2011-12-01
Publication date: 2014-04-09
Anticipated expiration: 2031-12-01
Also published as: CN102491982A

Abstract

The invention relates to a method for synthetizing 1,2,4-trioxane compound and a purpose. Hydrogen peroxide is adopted to serve as a peroxy bond source reagent, and a hydroperoxy radical is connected in a target structure through hydroperoxy electrolysis ring-opening reaction of an epoxide. A product has remarkable external anti-malarial activity and can be used as a lead compound to prepare novel anti-malarial drug.

Description

1,2,4-trioxane compounds, preparation method and use

Technical field

The present invention relates to 1,2 of a series of similar Artemisinins, 4-trioxane compounds, preparation method and use.System with hydrogen peroxide, be that peroxide bridge source reagent is connected to hydroperoxy-base the precursor of synthetic artemisinin through the hydroperoxy-solution ring-opening reaction of epoxide, and then synthetic tool antimalarial active 1,2,4-trioxane compounds.

Background technology

Artemisinin (also containing 1,2,4-trioxane part-structure) is the antimalarial natural product that China scientific worker found in the seventies in last century.Because the mechanism of action of this compound is completely different from traditional antimalarial agent, the case of the antagonism property of medicine has extraordinary curative effect, from appearance, be just subject to the great attention of scientific circles.The compound medicine that Artemisinin and derivative thereof be core component of take is at present the treatment malaria one line chemicals that the WHO of the World Health Organization recommends at present.

Artemisinin structural formula is as follows:

Because the Artemisinin output due to natural origin is limited after all, synthetic is difficult to implement in technical scale because of the complicated structure of Artemisinin itself again, and development structure other organo-peroxide simple but still that have a better antimalarial active has just become the important directions of antimalarial agent research.

The real hard place of synthetic artemisinin or other any organo-peroxides is introducings of peroxide bridge.Up to the present the ways and means that can introduce peroxide bridge in organic compound structure is very limited.Simultaneously because peroxide bridge is a kind of energy-rich bond, very unstable, in a lot of organic syntheses, conventional reaction conditions all may cause the fracture of peroxide bridge.This just requires can not carry out react incompatible with peroxide bridge after peroxide bridge is introduced structure again.The reason of this two aspect is added in and just forces together early stage researchist finally all to select to use highly active peroxide reagent (as singlet oxygen, ozone) to complete the introducing of peroxide bridge.Due to singlet oxygen, ozone often causes many side reactions, and these methods all require special device simultaneously, and countries in the world chemist is seeking the method for easier introducing peroxide bridge for many years always.

Hydrogen peroxide is the very common mineral compound containing peroxide bridge.If concentration is not very high not only quite stable, be not convenient to preserve and use (33% hydrogen peroxide is for example to sell in common pharmacy as stable sterilizing agent), price is also cheap.So synthesize with hydrogen peroxide, in organo-peroxide document, someone studies for a long time.But use the peroxide bridge source that hydrogen peroxide is organic compound and be not easy, particularly, when carrying out the alkylated reaction of hydroperoxy-on the very large quaternary carbon of spatial obstacle, the example that can directly use for reference in document does not almost have.

Hydrogen peroxide and/or the strong acid catalysis of the peroxide hydrogenolysis reaction needed high density of early stage epoxide could realize, and substrate structure is also confined to very simple compound (e.g., Payne, G.B.; Smith, C.W.J.Org.Chem.1957,22,1682-1685; Adam, W., Rios, A., J.C.S. Chem.Comm.1971,822-823.).At report (Tang, Y. such as Vennerstrom in 2005; Dong, Y.; Wang, X.; Sriraghavan, K.; Wood, J.K.; Vennerstrom, J.L.J.Org.Chem.2005,70,5103-5110; More fully relevant reference paper is enumerated at Org.Lett.2009, in 11,2691) with 50% H ₂o ₂at MoO ₂(acac) ₂catalysis under realize the peroxide hydrogenolysis of two substrates as shown in reaction formula 1.Products therefrom is attended by the by product of hydrolysis.

Seminar of the present invention also reported in 2009 that employing phospho-molybdic acid PMA (phosphomolybdic acid) can realize smoothly peroxide hydrogenolysis (Li, the Y. of many epoxide as catalyzer under mild conditions; Hao, H.-D.; Wu, Y.-K.Org.Lett.2009,11,2691-2694), comprise that some and the needed precursor species of synthetic artemisinin are like the substrate (reaction formula 2) of (the volution oxygen on six-membered carbon ring, but only have unsubstituted on substituting group, C-8a position on C-5a position).

Subsequently, what seminar of the present invention realized by means of outstanding catalyzer in 2011 has realized peroxide hydrogenolysis in the substrate more complicated, spatial obstacle is larger (there is substituting group epoxy spiro atom both sides) structure under mild conditions, and and then synthesized Artemisinin (reaction formula 3, Hao, H.-D.; Li, Y.; Han, W.-B.; Wu, Y.-K.Org Lett 2011,13,4212; Chinese Patent Application No. 201110162888.5).

Utilize same catalyzer seminar of the present invention from the more synthetic epoxy substrate that contains benzene ring structure, by the peroxide hydrogenolysis of epoxy, to introduce crucial peroxide bridge again, with obtaining having 1 of quite outstanding external antimalarial active by a few step simple reactions, 2,4-trioxane compounds.

Although existing in document, much synthesize 1,2, the method of 4-trioxane, but synthetic easy, do not relate to photosensitized oxidation or ozonize etc. and need specific installation/laboratory, there is so high antimalarial active and there is no precedent with ultraviolet chromophoric group (being to be convenient to follow the tracks of as needs further carry out experimental study in body).

Summary of the invention

The problem that will solve of the present invention is a kind of 1,2 of Artemisinin that is similar to, 4-trioxane (1,2,3).

The problem that will solve of the present invention also comprises a kind of synthetic method of above-claimed cpd.

The another one problem that will solve of the present invention is to provide a kind of above-claimed cpd.

Intermediate of the present invention has following structural formula:

X in formula, Y=H, H or O or H, OMe.

Preferably there is following structural formula:

Synthetic compound 1 and 2 method can be represented by following reaction formula 4:

Concrete reaction conditions is recommended as follows:

In organic solvent, under alkali effect, compound 4 obtains compound 6 with compound 5 at room temperature reaction.Organic solvent used can be tetrahydrofuran (THF), DMF (DMF), or methyl-sulphoxide (DMSO), or the mixed solvent of tetrahydrofuran (THF) and hexamethylphosphoramide; Alkali used can be NaOH, NaH, or NaNH ₂, recommendation response concentration (compound 4) is at 0.001M～3M.Temperature of reaction used is-40～+ 40 ℃, and the mol ratio between reactant used is compound 4: 5: alkali=1: 1～1.5: 1～5.Reaction times is 0.1～30 hour.

Under catalyzer, alkali and phosphine part exist, in organic solvent, there is ring-closure reaction again and obtain compound 7 in compound 6.Used catalyst can be Pd (OAc) ₂or PdCl ₂, alkali used can be the carbonate of basic metal or alkaline-earth metal, phosphine part used can be PPh ₃or PR ₃(alkyl that R is C1-C4), organic solvent used can be methylene dichloride, methyl alcohol, ethanol, Virahol, ether, tetrahydrofuran (THF) or acetonitrile, recommendation response concentration (compound 6) is at 0.001M～3M.Temperature of reaction used is 0～+ 120 ℃, and the mol ratio between reactant used is compound 6: alkali: Pd (OAc) 2: phosphine part=1: 1～10: 0.01～0.8: 1～5: 0.02～1.6.Reaction times is 0.5～30 hour.

Compound 7 obtains compound 8 with oxygenant effect under alkali exists in organic solvent.Alkali used can be carbonate or the supercarbonate of basic metal or alkaline-earth metal, and organic solvent used is CH ₂cl ₂or CHCl ₃, oxygenant used is m-chloroperoxybenzoic acid, recommendation response concentration (compound 7) is at 0.001M～3M.Temperature of reaction used is-10 ℃～+ 40 ℃, and the mol ratio between reactant used is compound 7: alkali: oxygenant=1: 1～10: 1～5.Reaction times is 0.5～30 hour.

Compound 8 under catalyzer exists with H ₂o ₂ether or methyl tertiary butyl ether solution effects obtain compound 9.H used ₂o ₂diethyl ether solution or methyl tertiary butyl ether (the saturated content conventionally obtaining is the H of about 0.5M ₂o ₂) by ether or methyl tertiary butyl ether, extract commercially available 33% hydrogen peroxide solution and obtain.Recommendation response concentration (compound 2) is at 0.001M～3M.Temperature of reaction used is-30 ℃～+ 30 ℃, and the reaction times is 2-30 hour.Described compound 8, catalyzer and H ₂o ₂mol ratio be 1: 0.01～0.10: 1～20.

Used catalyst is by NaMoO ₄react in acid (pH 0.05～6) aqueous solution with amino acid and obtain (throw out of separating out).NaMoO ₄and the mol ratio between amino acid is 1: 0.01～20.Amino acid used can be glycine or the derivative (configuration of chiral centre is unimportant) that replaces with alkyl or aryl on the methylene radical at its ester carbonyl group ortho position.Temperature of reaction used is 1 ℃～+ 60 ℃, and the reaction times is 0.1～30 hour.Described method for preparing catalyst is referring to CN201110162888.5.

There is acidic condition-ring closure reaction in compound 9, obtain compound 1 under acid catalyst exists in organic solvent.Acid catalyst used can be protonic acid (sulfuric acid, hydrochloric acid, p-toluenesulphonic acids, camphorsulfonic acid) or the Lewis acid (boron trifluoride, titanium tetrachloride) of organic or inorganic, and organic solvent used is CH ₂cl ₂or CHCl ₃, recommendation response concentration (compound 9) is at 0.001M～3M.Temperature of reaction used is-10 ℃～+ 40 ℃, and the mol ratio between reactant used is compound 9: acid catalyst=1: 0.01～0.8, and the reaction times is 0.5～30 hour.

Compound 1 obtains compound 2 with oxygenant effect under molysite exists in organic solvent.Described molysite can be the salt that the iron ion of divalence or trivalent and halogen ion form, organic solvent used be acetone, methylene dichloride,, ether or acetonitrile, described oxygenant is KMnO ₄, recommendation response concentration (compound 1) is at 0.001M～3M.Temperature of reaction used is-10 ℃～+ 40 ℃, and the mol ratio between reactant used is compound 1: molysite: oxygenant=1: 0.01～0.8: 1～10, and the reaction times is 0.5～30 hour.

Compound 2 obtains the corresponding hemiacetal of lactone carbonyl moiety reduction institute with reductive agent effect in organic solvent, and this hemiacetal is dissolved in and in alcohol, under acid catalyst effect, generates compound 3; Described alcohol is methyl alcohol, ethanol or Virahol.Organic solvent used is CH ₂cl ₂, CHCl ₃, acetonitrile, N, dinethylformamide, benzene or toluene, reductive agent used is diisobutylaluminium hydride (DIBAL-H), while generating compound 3 by the intermediate hemiacetal of partial reduction lactone 2 gained, acid catalyst used can be the protonic acid (sulfuric acid of organic or inorganic, hydrochloric acid, p-toluenesulphonic acids, camphorsulfonic acid) or Lewis acid (boron trifluoride ethyl ether complex, titanium tetrachloride), recommendation response concentration during reduction reaction (compound 2) is at 0.001M～3M, temperature of reaction used is-105 ℃～+ 25 ℃, mol ratio between reactant used is compound 2: reductive agent=1: 1～5, reaction times is 0.5～30 hour.Reaction density (compound 3) when intermediate hemiacetal forms compound 3 is at 0.001M～3M, intermediate hemiacetal: acid catalyst=1: 0.01～0.9, and temperature of reaction used is 0 ℃～+ 35 ℃.

Compound of the present invention is not only synthetic convenient, and by the intermediate hemiacetal of reducing compound 2 gained except preparing the direct precursor of compound 3, can also be with being to synthesize the derivative that other are similar to compound 3; There is significant external antimalarial active, can be further used for preparing antimalarial agent.

Embodiment

Following embodiment will contribute to understand the present invention, but not limit content of the present invention.

Embodiment 1

By 4 (103mg, 0.60mmol) be dissolved in anhydrous THF Chinese named (2mL), add NaH (60% in mineral oil Chinese named, 77mg, 1.92mmol), after stirring at room 1h, add HMPA Chinese named (0.24mL, 1.2mmol), after 10min, drip 5 THF solution (300mg, 1.2mmol is dissolved in the anhydrous THF of 1mL).Stirred overnight at room temperature, adds saturated NH after the dilution that adds diethyl ether ₄cl solution cancellation reaction.By extracted with diethyl ether, merge organic phase, with anhydrous sodium sulfate drying after saturated nacl aqueous solution washing.Filter, concentrate and rapid column chromatography (EtOAc/PE Chinese named=1: 50) obtain colourless oil liquid 6 (160mg, 0.47mmol) yield 78%. ¹H NMR(300MHz，CDCl ₃)δ7.51(t，J＝7.0Hz，2H)，7.30(t，J＝7.3Hz，1H)，7.13(t，J＝7.7Hz，1H)，5.70-5.82(m，1H)，5.27(d，J＝6.4Hz，1H)，5.23(s，1H)，4.61(d，J＝13.1Hz，1H)，4.43(d，J＝13.3Hz，1H)，3.90-3.95(m，4H)，3.80(dd，J＝5.3，7.5Hz，1H)，1.74-1.88(m，2H)，1.62-1.74(m，2H)，1.32(s，3H)。 ¹³c NMR (75MHz, CDCl ₃) δ 138.6,138.1,132.4,129.1,128.7,127.3,122.6,117.5,109.9,81.2,77.4,77.0,76.6,69.5,64.6,34.7,29.8,23.9; FT-IR (film) 2981,2876,1568,1470,1441,1376,1207,1066,927,750cm ^-1.ESI-MS m/z 363.1 ([M+Na] ⁺). calculated value (Anal calcd for) C ₁₆h ₂₁o ₃br:C 56.32, H 6.20. measured value (Found): C 56.49, H 66.20.

Embodiment 2

6 (200mg, 0.58mmol) are dissolved in acetonitrile (12mL), add successively PPh ₃(60mg, 0.23mmol), K ₂cO ₃(480mg, 3.50mmol) and Pd (OAc) ₂(26mg, 0.12mmol).Reflux 36h in 80 ℃ of oil baths under argon atmospher.With ether dilution after washing, remove inorganics, organic phase is again with anhydrous sodium sulfate drying after saturated nacl aqueous solution washing.Filter, concentrate and rapid column chromatography (EtOAc/PE=1: 20), obtain weak yellow liquid 7 (114mg, 0.44mmol).Yield 76%. ¹h NMR (300MHz, CDCl ₃) δ 7.62-7.65 (m, 1H), 7.20-7.26 (m, 2H), 7.00-7.03 (m, 1H), 5.64 (s, 1H), 5.08 (s, 1H), 4.87 (d, J=15.2Hz, 1H), 4.75 (d, J=15.3Hz, 1H), 4.33 (t, J=6.2Hz, 1H), 3.89-3.98 (m, 4H), 1.72-2.06 (m, 4H), 1.37 (s, 3H). ¹³C NMR(75MHz，CDCl ₃)δ141.7，134.3，131.4，127.7，126.9，124.3，123.8，109.90，107.0，77.0，65.7，64.6，64.6，34.8，26.9，23.9；FT-IR(film)2980，2880，1635，1485，1449，1375，1255，1065，891，776cm ^-1；EI-MS m/z(％)260(M ⁺，3.68)，245(2.28)，198(53.51)；EI-HRMS calcd.for C ₁₆H ₂₀O ₃(M ⁺)260.1412，found 260.1425.

Embodiment 3

7 (35mg, 0.13mmol) are dissolved in to CH ₂cl ₂(2mL), in, under ice-water bath, add Na ₂cO ₃(8.0mg, 0.07mmol) and metachloroperbenzoic acid (0.15mmol, contains 75% m-CPBA for m-CPBA, 34mg).After stirring at room 5h, add saturated NaHCO ₃solution and ether.The saturated Na of organic phase ₂sO ₃anhydrous sodium sulfate drying after solution and saturated nacl aqueous solution washing.Filter, concentrate and rapid column chromatography (EtOAc/PE=1: 10), obtain colourless viscous liquid 8 (32mg, 0.115mmol) yield 89%. ¹H NMR(300MHz，CDCl ₃)δ7.21-7.31(m，2H)，7.13(t，J＝3.8Hz，1H)，7.03(t，J＝3.7Hz，1H)，4.92(s，2H)，3.82-4.03(m，5H)，3.31(d，J＝4.4Hz，1H)，2.92(d，J＝4.7Hz，1H)，1.94-2.08(m，1H)，1.55-1.78(m，2H)，1.39-1.54(m，1H)，1.34(s，3H)。 ¹³C NMR(75MHz，CDCl ₃)δ137.5，133.6，127.7，127.1，123.5，123.2，109.8，68.1，64.7，64.6，55.9，54.0，35.1，23.9，23.7；FT-IR(film)2979，2878，1696，1494，1447，1375，1256，1207，1062，869，757cm ^-1；EI-MS m/z(％)276(M ⁺，0.21)，261(1.33)，243(0.58)；EI-HRMS calcd.for C ₁₆H ₂₀O ₄(M ⁺)276.1362，found 276.1358.

Embodiment 4

Substrate 8 (37mg, 0.13mmol) is dissolved in the hydrogen peroxide diethyl ether solution (1.5mL) of new preparation, adds wherein catalyzer " NaMoO ₄-Gly " (4mg, 0.013mmol), stirring at room 4h, adds ether and water, separatory.Organic phase is used anhydrous Na after water and saturated common salt water washing successively ₂sO ₄dry.Be spin-dried for rapid column chromatography after solvent (PE: diethyl ether=1: 1) colorless oil liquid 9 (20mg, 0.063mmol, productive rate 50%) and reclaim raw material 8 (10mg, 0.035mmol, 27%). ¹H NMR(300MHz，CDCl ₃)δ8.24(s，1H)，7.63(d，J＝7.3Hz，1H)，7.27-7.39(m，2H)，7.06(d，J＝7.8Hz，1H)，4.85(s，2H)，4.15(dd，J＝2.3，9.9Hz，1H)，3.90-4.04(m，5H)，3.83(dd，J＝8.3，11.2Hz，1H)，1.99-2.19(m，3H)，1.67-1.89(m，2H)，1.37(s，3H)。 ¹³C NMR(75MHz，CDCl ₃)δ136.1，134.2，127.7，127.1，126.4，123.6，109.9，82.3，67.6，64.5，64.0，40.6，35.7，23.8，22.9；FT-IR(film)3360，2927，1455，1377，1211，1099，1060，762，728cm ^-1；ESI-MS m/z 333.2([M+Na] ⁺)；ESI-HRMS calcd.For C ₁₆H ₂₂O ₆([M+Na] ⁺)333.13086，found 333.12989

Embodiment 5

9 (12mg, 0.038mmol) are dissolved in to CH ₂cl ₂(1mL), in, under stirring at room, add tosic acid (PTSA, 4mg, 0.02mmol).After stirred overnight at room temperature, add saturated NaHCO ₃and ether.Separate organic phase and wash with saturated nacl aqueous solution, anhydrous sodium sulfate drying.Filter, concentrate and column chromatography (EtOAc/PE=1: 20) obtain white solid 1 (7mg, 0.028mmol, yield 75%).M.p.74-76℃； ¹H NMR(300MHz，CDCl ₃)δ7.70(d，J＝6.8Hz，1H)，7.23-7.38(m，2H)，6.98(d，J＝6.4Hz，1H)，4.81(s，2H)，4.27(d，J＝11.7Hz，1H)，4.21(dd，J＝11.6，1.7Hz，1H)，3.69-3.90(m，1H)，2.31-2.52(m，1H)，1.84-2.19(m，3H)，1.43(s，3H)。 ¹³C NMR(125MHz，CDCl ₃)δ136.0，134.1，128.6，127.8，127.2，123.5，103.7，78.5，73.4，68.1，68.1，65.2，35.8，34.4，25.9，25.5；FT-IR(film)2927，2853，1490，1448，1372，1255，1215，1147，1104，1078，756cm ^-1；EI-MS m/z(％)248(M ⁺，0.46)，216(M ⁺-O ₂，18.19)，204(21.08)；EI-HRMS calcd.for C ₁₄H ₁₆O ₄(M ⁺)248.1049，found 248.1042.

Embodiment 6

1 (21mg, 0.077mmol) is dissolved in acetone (6mL), adds KMnO at-78 ℃ ₄(122mg, 0.77mmol) and FeCl ₃(77mg, 0.475mmol), maintains after this temperature stirs 2h and naturally heats up and stir 10h.Add ether and water.Organic phase is water and saturated nacl aqueous solution washing successively, anhydrous sodium sulfate drying.Filter, concentrate and rapid column chromatography (10: 1 PE/EtOAc), obtain 2 (20mg, 0.076mmol), yield 99%. ¹H NMR(300MHz，CDCl ₃)δ8.14-8.07(m，1H)，7.83-7.64(m，2H)，7.58-7.47(m，1H)，4.67-4.56(m，1H)，4.51(d，J＝7.9Hz，0.3H)，4.27-4.15(m，1.4H)，3.55(d，J＝7.9Hz，0.3H)，2.57-2.29(m，2H)，2.24-2.13(m，1.3H)，2.05-1.85(m，0.7H)，1.63(s，1H)，1.47(s，2H).FT-IR(film)2935，1736，1603，1458，1391，1275，1259，1200，1180，1150，1136，1122，1094，1076，1039，1024，845，757，694，592，561，550，543，535，524，512，504cm ^-1.EI-MS m/z(％)104(100)，76(57.46)，133(52.98)，230([M-O ₂] ⁺，28.11)，262(M ⁺，1.73)；EI-HRMS：calcd.for C ₁₄H ₁₄O ₅(M ⁺)262.0841，found 262.0838.

Embodiment 7

Substrate 2 (15mg, 0.057mmol) is dissolved in to anhydrous CH ₂cl ₂(2mL), in, under-78C, add diisobutylaluminium hydride Chinese named (DIBAL-H, 1M cyclohexane solution, 0.13mL, 0.114mmol).Maintain after this temperature stirs 1h and add MeOH (0.5mL), soluble tartrate sodium water solution and ether), stirring at room is used extracted with diethyl ether to two-phase clarification, merges organic phase, anhydrous sodium sulfate drying after saturated common salt water washing.The crude product obtaining after filtering, concentrating is dissolved in anhydrous methanol (4mL), under stirring at room, adds p-TsOH (2mg).After 2h, add ether and saturated NaHCO ₃the aqueous solution.Separate organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrate and column chromatography (50: 1 PE/EtOAc), obtain 3 (15mg, 0.054mmol), colourless liquid, yield 95%. ¹H NMR(300MHz，CDCl ₃)δ7.68(d，J＝7.6Hz，0.7H)，7.57(d，J＝7.6Hz，0.3H)，7.43-7.29(m，2H)，7.25-7.17(m，1H)，5.45(s，0.3H)，5.43(s，0.7H)，4.42(d，J＝7.6Hz，0.3H)，4.34-4.14(m，2.4H)，3.56(s，3H)，3.53(d，J＝7.6Hz，0.3H)，2.53-2.39(m，1H)，2.20-2.04(m，2H)，2.01-1.82(m，1H)，1.59(s，1H)，1.44(s，2H).FT-IR(film)2934，2887，1453，1271，1257，1219，1200，1149，1094，1077，1053，1039，1013，759cm ^-1.EI-MS m/z(％)43(100)，149(48)，246([M-O ₂] ⁺，2.7)，262([M-O] ⁺，16)，278(M ⁺，2.1)；EI-HRMS：calcd.for C ₁₅H ₁₈O ₅(M ⁺)278.1154，found 278.1158.

Embodiment 8

Above-claimed cpd 1,2,3 external antimalarial active is responsible for measuring (referring to table one) by the Switzerland torrid zone and Sergio doctor Wittlin of publilc health institute (Swiss Tropical and Public Health Institute).

The external antimalarial active of table one, compound 1,2,3 ^a.

Compound	1	2	3	Chloroquine diphosphate	Artesunate
						IC ₅₀(ng/mL)	3.9	5.7	5.0	6.7	1.2

^adata take from the independent experiment that 2-3 carries out with plasmodium P.falciparum (NF45strain), and concrete grammar is referring to Snyder, C.; Chollet, J.; Santo-Tomas, J.; Scheurer, C.; Wittlin, S.Exp.Parasitol.2007,115,296-300).

Claims

1. one kind 1,2,4-trioxane compound, its feature has following structural formula:

X in formula, Y=H, H; Or O; Or H, OMe.

2. as claimed in claim 11,2,4-trioxane compound, its feature has following structural formula:

3. a synthetic method for compound as claimed in claim 1 or 2, is characterized in that obtaining by following step:

(1), Zhong organic solvent at 40～40 ℃ of He –, under alkali effect, compound 4 reacts with compound 5 and within 0.1～30 hour, obtains compound 6; Described organic solvent is the mixed solvent of tetrahydrofuran (THF), hexamethylphosphoramide, DMF, methyl-sulphoxide or tetrahydrofuran (THF) and hexamethylphosphoramide, and described alkali is NaOH, NaH or NaNH ₂; Described compound 4,5 and the mol ratio of alkali are 1:1～1.5:1～5;

(2), in organic solvent and at 0～120 ℃, there is ring-closure reaction and within 0.5～30 hour, obtain compound 7 in compound 6 under catalyzer, alkali and phosphine part exist; Described catalyzer is Pd (OAc) ₂or PdCl ₂, described alkali is the carbonate of basic metal or alkaline-earth metal; Described phosphine part is PPh ₃or PR ₃, wherein, the alkyl that R is C1-C4; Described compound 6, alkali, catalyzer and phosphine part mol ratio are 1:1～10:0.01～0.8:1～5:0.02～1.6;

(at 3 10～40 ℃ of) –, compound 7 obtains compound 8 for 0.5～30 hour with oxidant reaction under alkali exists in organic solvent; Described alkali is carbonate or the supercarbonate of basic metal or alkaline-earth metal; Described organic solvent is CH ₂cl ₂or CHCl ₃; Described oxygenant is m-chloroperoxybenzoic acid; The mol ratio of described compound 7, alkali and oxygenant is 1:1～10:1～5;

(at 4 30～+ 30 ℃ of) –, compound 8 under catalyzer exists with saturated H ₂o ₂ether or methyl tertiary butyl ether solution reaction within 2-30 hour, obtain compound 9; Described compound 8, catalyzer and H ₂o ₂mol ratio be 1:0.01～0.10:1～20;

Described catalyzer is by NaMoO ₄react 0.1～30 hour and obtain in 1～+ 60 ℃ and pH0.05～6 acidic aqueous solution with amino acid; NaMoO ₄and the mol ratio between amino acid is 1:0.01～20; Described amino acid is glycine;

(5) there is acidic condition-ring closure reaction in compound 9 under acid catalyst exists in organic solvent, within 0.5～30 hour, obtains compound 1; Described acid catalyst is sulfuric acid, hydrochloric acid, p-toluenesulphonic acids, camphorsulfonic acid, boron trifluoride ethyl ether complex or titanium tetrachloride; Described organic solvent is CH ₂cl ₂or CHCl ₃; Described temperature of reaction Wei – 10～+ 40 ℃, described compound 9 and the mol ratio of acid catalyst are 1:0.01～0.8;

(6) compound 1 obtains compound 2 for 0.5～30 hour with oxidant reaction under molysite exists in organic solvent; Described molysite is the salt that the iron ion of divalence or trivalent and halogen ion form, described organic solvent be acetone, methylene dichloride,, ether or acetonitrile; Described oxygenant is KMnO ₄; 10 ℃～+ 40 ℃ of described temperature of reaction Wei –, described compound 1, molysite and oxygenant mol ratio are 1:0.01～0.8:1～10.

(7) Zhong organic solvent at 105～25 ℃ of He –, compound 2 obtains the corresponding intermediate hemiacetal of lactone carbonyl moiety reduction institute with reductive agent effect, and this hemiacetal is dissolved in 0～+ 35 ℃, under methyl alcohol neutralizing acid catalyst action, generates compound 3; Described reductive agent is diisobutylaluminium hydride; Described acid catalyst is p-toluenesulphonic acids; Described compound 2 and the mol ratio of reductive agent are 1:1～5, and the reaction times is 0.5～30 hour; The mol ratio of intermediate hemiacetal and acid catalyst is 1:0.01～0.9;

Described compound 1,2,3,4,5,6,7,8 and 9 has following structural formula:

4. synthetic method as claimed in claim 3, is characterized in that in described step (1), the concentration of compound 4 in reaction soln is 0.001M～3M; Compound 6 described in step (2) concentration in reaction soln is 0.001M～3M; Compound 7 described in step (3) concentration in reaction soln is 0.001M～3M; Compound 9 described in step (5) concentration in reaction soln is 0.001M～3M; Compound 1 described in step (6) concentration in reaction soln is 0.001M～3M; During compound 2 reduction reaction described in step (7), in reaction soln, concentration is 0.001M～3M; When intermediate hemiacetal forms compound 3, compound 3 concentration in reaction soln is 0.001M～3M.

5. synthetic method as claimed in claim 3, is characterized in that the temperature of reaction described in step (1) is room temperature.

6. synthetic method as claimed in claim 3, is characterized in that the H described in step (4) ₂o ₂diethyl ether solution or methyl tertiary butyl ether system by ether or methyl tertiary butyl ether, extract commercially available 33% hydrogen peroxide solution and obtain.

7. synthetic method as claimed in claim 3, is characterized in that the organic solvent described in step (2) is methylene dichloride, methyl alcohol, ethanol, Virahol, ether, tetrahydrofuran (THF) or acetonitrile;

8. synthetic method as claimed in claim 3, is characterized in that the organic solvent described in step (7) is CH ₂cl ₂, CHCl ₃, benzyl cyanide, DMF, benzene or toluene.

9. a compound as claimed in claim 1 or 2 application in preparing the medicine of antimalarial.