CN102491982A - Method for synthetizing 1,2,4-trioxane compound and purpose - Google Patents
Method for synthetizing 1,2,4-trioxane compound and purpose Download PDFInfo
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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
Technical field
The present invention relates to 1,2 of a series of similar Artemisinins, 4-trioxane compounds, preparation method and use.System uses ydrogen peroxide 50 to separate open loop as peroxide bridge source reagent through the hydroperoxy-of epoxide to react the precursor that the hydroperoxy-base is connected synthetic artemisinin, so 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 different fully with traditional antimalarial agent, the case of the antagonism property of medicine has extraordinary curative effect, just receives the great attention of scientific circles from coming out.Be that the compound medicine of core component is the treatment malaria one linearize medicine that the WHO of the World Health Organization recommends at present at present with Artemisinin and verivate thereof.
The Artemisinin structural formula is following:
Because because the Artemisinin output of natural origin is limited after all; Synthetic is difficult to implement in technical scale because of the structure more complicated of Artemisinin itself again, and development structure is simple but still other organo-peroxide that have a better antimalarial active has just become the important directions of antimalarial agent research.
The real difficult place of synthetic artemisinin or other any organo-peroxides is introducings of peroxide bridge.Up to the present the ways and means that can in organic compound structure, introduce peroxide bridge is very limited.Because peroxide bridge is a kind of energy-rich bond, very unstable simultaneously, reaction conditions commonly used all possibly cause the fracture of peroxide bridge in a lot of organic syntheses.This just requires after peroxide bridge is introduced structure, can not carry out the reaction incompatible with peroxide bridge again.The reason of this two aspect is added in and just forces early stage researchist all to select to use highly active peroxide reagent (like singlet oxygen, ozone) to accomplish the introducing of peroxide bridge at last together.Because singlet oxygen, ozone often causes many side reactions, and these methods all require special device simultaneously, and the countries in the world chemist is seeking the method for easier introducing peroxide bridge for many years always.
Ydrogen peroxide 50 is the very common mineral compound that contains peroxide bridge.Be not convenient to preserve and use (33% ydrogen peroxide 50 for example is to sell in common pharmacy as stable sterilizing agent) if concentration is not very high not only quite stable, price is also cheap.So synthesizing in the organo-peroxide document for a long time with ydrogen peroxide 50, the someone studies.But use ydrogen peroxide 50 as the peroxide bridge source of organic cpds and be not easy, particularly when the alkylated reaction that need on the very big quaternary carbon of spatial obstacle, carry out hydroperoxy-, the instance that can directly use for reference in the document does not almost have.
The hydrogen peroxide and/or the strong acid catalysis of the peroxide hydrogenolysis reaction needed high density of early stage epoxide could realize that substrate structure also is 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 comprehensively relevant reference paper is enumerated at Org.Lett.2009, in 11,2691) with 50% H
2O
2At MoO
2(acac)
2Catalysis realize down the peroxide hydrogenolysis of two substrates shown in reaction formula 1.Products therefrom is attended by the by product of hydrolysis.
Seminar of the present invention reported also in 2009 that employing phospho-molybdic acid PMA (phosphomolybdic acid) can realize peroxide hydrogenolysis (Li, the Y. of many epoxide smoothly as catalyzer under mild conditions; Hao, H.-D.; Wu, Y.-K.Org.Lett.2009,11,2691-2694), comprise some and the needed precursor species of synthetic artemisinin substrate (reaction formula 2) like (the volution oxygen on the six-membered carbon ring, but only on the C-5a position unsubstituted on substituting group, the C-8a position is arranged).
Subsequently; What seminar of the present invention realized by means of outstanding catalyzer in 2011 has realized the peroxide hydrogenolysis under mild conditions in substrate (all there the is substituting group epoxy spiro atom both sides) structure more complicated, that spatial obstacle is bigger; And and then synthesized Artemisinin (reaction formula 3, Hao, H.-D.; Li, Y.; Han, W.-B.; Wu, Y.-K.Org Lett 2011,13,4212; One Chinese patent application numbers 201110162888.5).
Utilize same catalyzer seminar of the present invention to introduce crucial peroxide bridge from the epoxy substrate that easier synthetic contains benzene ring structure through the peroxide hydrogenolysis of epoxy again; With after a few step simple reaction obtains having 1 of quite outstanding external antimalarial active; 2,4-trioxane compounds.
Though have many synthetic 1 in the document; 2; The method of 4-trioxane; But synthetic easy, do not relate to photosensitized oxidation or ozonize etc. and need specific installation/laboratory, have so high antimalarial active and have ultraviolet chromophoric group (further carry out like needs experimental study is to be convenient to follow the tracks of in the body) beyond example still.
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 compound method of above-claimed cpd.
The another one problem that will solve of the present invention provides a kind of above-claimed cpd.
Midbody of the present invention has following structural formula:
X in the formula, Y=H, H or O or H, OMe.
Preferably have following structural formula:
Synthetic compound 1 and 2 method can be by following reaction formula 4 expressions:
Concrete reaction conditions is recommended as follows:
Compound 4 obtains compound 6 with compound 5 at room temperature reaction under the alkali effect in organic solvent.Used organic solvent can be a THF, N, dinethylformamide (DMF), or methyl-sulphoxide (DMSO), or the mixed solvent of THF and hexamethylphosphoramide; Used alkali can be NaOH, NaH, or NaNH
2, recommendation response concentration (compound 4) is at 0.001M～3M.Used temperature of reaction is-40～+ 40 ℃, and the mol ratio between the used reactant is compound 4: 5: alkali=1: 1～1.5: 1～5.Reaction times is 0.1～30 hour.
Ring-closure reaction takes place and gets compound 7 in compound 6 again in organic solvent in the presence of catalyzer, alkali and phosphine part.Catalyst system therefor can be Pd (OAc)
2Or PdCl
2, used alkali can be the carbonate of basic metal or earth alkali metal, used phosphine part can be PPh
3Or PR
3(R is the alkyl of C1-C4), used organic solvent can be methylene dichloride, methyl alcohol, ethanol, Virahol, ether, THF or acetonitrile, recommendation response concentration (compound 6) is at 0.001M～3M.Used temperature of reaction is 0～+ 120 ℃, and the mol ratio between the used reactant is a 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 the oxygenant effect in organic solvent in the presence of alkali.Used alkali can be the carbonate or the supercarbonate of basic metal or earth alkali metal, and used organic solvent is CH
2Cl
2Or CHCl
3, used oxygenant be between-chloroperoxybenzoic acid, recommendation response concentration (compound 7) is at 0.001M～3M.Used temperature of reaction is-10 ℃～+ 40 ℃, and the mol ratio between the used reactant is a compound 7: alkali: oxygenant=1: 1～10: 1～5.Reaction times is 0.5～30 hour.
Compound 8 is in the presence of catalyzer and H
2O
2Ether or MTBE solution effects obtain compound 9.Used H
2O
2Diethyl ether solution or MTBE (the saturated content that obtains usually is the H about 0.5M
2O
2) extract commercially available 33% hydrogen peroxide solution and get by ether or MTBE.Recommendation response concentration (compound 2) is at 0.001M～3M.Used temperature of reaction 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.
Catalyst system therefor is by NaMoO
4With amino acid reaction and get (throw out of being separated out) in acid (pH 0.05～6) aqueous solution.NaMoO
4And the mol ratio between the amino acid is 1: 0.01～20.Used amino acid can be glycocoll or on its ester carbonyl group adjacent methylene radical, have the substituted verivate of alkyl or aryl (configuration of chiral centre is unimportant).Used temperature of reaction is 1 ℃～+ 60 ℃, and the reaction times is 0.1～30 hour.Described method for preparing catalyst is referring to CN201110162888.5.
Ketal exchange-ring closure reaction takes place in compound 9 in organic solvent in the presence of acid catalyst, obtain compound 1.Used acid catalyst can be the protonic acid (sulfuric acid, hydrochloric acid, right-toluenesulphonic acids, camphorsulfonic acid) or the Lewis acid (boron trifluoride, titanium tetrachloride) of organic or inorganic, and used organic solvent is CH
2Cl
2Or CHCl
3, recommendation response concentration (compound 9) is at 0.001M～3M.Used temperature of reaction is-10 ℃～+ 40 ℃, and the mol ratio between the used reactant is a compound 9: acid catalyst=1: 0.01～0.8, the reaction times is 0.5～30 hour.
Compound 1 obtains compound 2 with the oxygenant effect in organic solvent in the presence of molysite.Said molysite can be the salt that divalence or tervalent iron ion and halogen ion form, used organic solvent be acetone, methylene dichloride,, ether or acetonitrile, said oxygenant are KMnO
4, recommendation response concentration (compound 1) is at 0.001M～3M.Used temperature of reaction is-10 ℃～+ 40 ℃, and the mol ratio between the used reactant is a compound 1: molysite: oxygenant=1: 0.01～0.8: 1～10, the reaction times is 0.5～30 hour.
Compound 2 obtains the corresponding semi-acetal of lactone carbonyl moiety reduction institute with the reductive agent effect in organic solvent, this semi-acetal is dissolved in and under the acid catalyst effect, generates compound 3 in the alcohol; Described alcohol is methyl alcohol, ethanol or Virahol.Used organic solvent is CH
2Cl
2, CHCl
3, acetonitrile, N, dinethylformamide, benzene or toluene, used reductive agent are diisobutylaluminium hydride (DIBAL-H); When generating compound 3 by the midbody semi-acetal of partial reduction lactone 2 gained used acid catalyst can be organic or inorganic protonic acid (sulfuric acid, hydrochloric acid, right-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, and used temperature of reaction is-105 ℃～+ 25 ℃; Mol ratio between the used reactant is a compound 2: reductive agent=1: 1～5, the reaction times is 0.5～30 hour.Reaction density (compound 3) when the midbody semi-acetal forms compound 3 is at 0.001M～3M, and the midbody semi-acetal: acid catalyst=1: 0.01～0.9, used temperature of reaction are 0 ℃～+ 35 ℃.
Compound of the present invention is not only synthetic convenient, and by the midbody semi-acetal of reducing compound 2 gained except that the direct precursor that can prepare compound 3, can also use is to synthesize the verivate that other are similar to compound 3; Have the remarkable vitro antimalarial active, can be further used for preparing antimalarial agent.
Embodiment
Following embodiment will help to understand the present invention, but not limit content of the present invention.
Embodiment 1
(103mg 0.60mmol) is dissolved in the anhydrous THF Chinese named (2mL), adds NaH (60% in mineral oil Chinese named with 4; 77mg; 1.92mmol), adding HMPA Chinese named behind the stirring at room 1h (0.24mL, 1.2mmol); The THF solution of Dropwise 5 behind the 10min (300mg, 1.2mmol are dissolved among the anhydrous THF of 1mL).Stirred overnight at room temperature, the dilution back that adds diethyl ether adds saturated NH
4Cl solution cancellation reaction.Use extracted with diethyl ether, merge organic phase, with saturated nacl aqueous solution washing back anhydrous sodium sulfate drying.Filter, concentrate and rapid column chromatography (EtOAc/PE Chinese named=1: 50) 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, and H 6.20. measured value (Found): C 56.49, H 66.20.
Embodiment 2
(200mg 0.58mmol) is dissolved in the acetonitrile (12mL), adds PPh successively with 6
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.Remove inorganics with ether dilution after washing, organic phase is again with saturated nacl aqueous solution washing back anhydrous sodium sulfate drying.Filter, concentrate and rapid column chromatography (EtOAc/PE=1: 20), 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
(35mg 0.13mmol) is dissolved in CH with 7
2Cl
2(2mL), ice-water bath adds Na down
2CO
3(8.0mg, 0.07mmol) and metachloroperbenzoic acid (0.15mmol contains 75% m-CPBA for m-CPBA, 34mg).Add saturated NaHCO behind the stirring at room 5h
3Solution and ether.Organic phase is used saturated Na
2SO
3Solution and saturated nacl aqueous solution washing back anhydrous sodium sulfate drying.Filter, concentrate and rapid column chromatography (EtOAc/PE=1: 10), 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
(37mg 0.13mmol) is dissolved in the ydrogen peroxide 50 diethyl ether solution (1.5mL) of new preparation, to wherein adding catalyzer " NaMoO to substrate 8
4-Gly " (4mg, 0.013mmol), stirring at room 4h adds ether and water, separatory.Organic phase is used anhydrous Na after water and the saturated common salt water washing successively
2SO
4Dry.Revolve rapid column chromatography behind the dried 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
(12mg 0.038mmol) is dissolved in CH with 9
2Cl
2(1mL), add under the stirring at room tosic acid (PTSA, 4mg, 0.02mmol).Add saturated NaHCO after the stirred overnight at room temperature
3And ether.Tell organic phase and wash, anhydrous sodium sulfate drying with saturated nacl aqueous solution.Filter, concentrate and column chromatography (EtOAc/PE=1: 20) get 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
(21mg 0.077mmol) is dissolved in the acetone (6mL), and-78 ℃ add KMnO down with 1
4(122mg, 0.77mmol) and FeCl
3(77mg 0.475mmol), keeps and heats up naturally and stirring 10h after this temperature stirs 2h.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), 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
(15mg 0.057mmol) is dissolved in anhydrous CH with substrate 2
2Cl
2(2mL), and adding diisobutylaluminium hydride Chinese named under the-78C (DIBAL-H, the 1M cyclohexane solution, 0.13mL, 0.114mmol).Keep and add MeOH (0.5mL), soluble tartrate sodium water solution and ether after this temperature stirs 1h), stirring at room to two is clarified the back mutually and is used extracted with diethyl ether, merges organic phase, anhydrous sodium sulfate drying after the saturated common salt water washing.The bullion that obtains after filtering, concentrating is dissolved in the anhydrous methanol (4mL), adds p-TsOH (2mg) under the stirring at room.Add ether and saturated NaHCO behind the 2h
3The aqueous solution.Tell organic phase and use saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrate and column chromatography (50: 1 PE/EtOAc), 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 | The 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 (9)
1. one kind 2,4-trioxane compound, its characteristic has following structural formula:
X in the formula, Y=H,, O or, OMe.
2. as claimed in claim 11,2,4-trioxane compound, its characteristic has following structural formula:
3. compound method of compound according to claim 1 or claim 2 is characterized in that obtaining through following step:
(1) under-40～40 ℃ of organic solvent neutralizations, compound 4 obtained compound 6 in 0.1～30 hour with compound 5 reactions under the alkali effect; Described organic solvent is THF, hexamethylphosphoramide, N, and the mixed solvent of dinethylformamide, methyl-sulphoxide or THF and hexamethylphosphoramide, described alkali are NaOH, NaH or NaNH
2The mol ratio of described compound 4,5 and alkali is 1: 1～1.5: 1～5;
(2) in organic solvent and under 0～120 ℃, ring-closure reaction takes place and got compound 7 in 0.5～30 hour in compound 6 in the presence of catalyzer, alkali and phosphine part; Described catalyzer is Pd (OAc)
2Or PdCl
2, described alkali is the carbonate of basic metal or earth alkali metal; Described phosphine part is PPh
3Or PR
3, wherein, R is the alkyl of 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;
(3) under-10～40 ℃, compound 7 obtained compound 8 in 0.5～30 hour with oxidant reaction in organic solvent in the presence of alkali; Described alkali is the carbonate or the supercarbonate of basic metal or earth alkali metal; Described organic solvent is CH
2C1
2Or CHCl
3Described oxygenant be between-chloroperoxybenzoic acid; The mol ratio of described compound 7, alkali and oxygenant is 1: 1～10: 1～5;
(4) under-30～+ 30 ℃, compound 8 in the presence of catalyzer with saturated H
2O
2Ether or MTBE solution reaction obtained compound 9 in 2-30 hour; Described compound 8, catalyzer and H
2O
2Mol ratio be 1: 0.01～0.10: 1～20;
Described catalyzer is by NaMoO
4With amino acid 1～+ 60 ℃ with pH 0.05～6 acidic aqueous solution in reacted 0.1～30 hour and get; NaMoO
4And the mol ratio between the amino acid is 1: 0.01～20; Described amino acid is glycocoll or on its ester carbonyl group adjacent methylene radical, has the substituted verivate of alkyl or aryl;
(5) ketal exchange-ring closure reaction takes place in compound 9 in organic solvent in the presence of acid catalyst, obtains compound 1 in 0.5～30 hour; Described acid catalyst is the protonic acid (sulfuric acid, hydrochloric acid, right-toluenesulphonic acids, camphorsulfonic acid) or the Lewis acid (boron trifluoride, titanium tetrachloride) of organic or inorganic, and described organic solvent is CH
2C1
2Or CHCl
3Described temperature of reaction is-10～+ 40 ℃, and the mol ratio of described compound 9 and acid catalyst is 1: 0.01～0.8;
(6) compound 1 obtained compound 2 in 0.5～30 hour with oxidant reaction in organic solvent in the presence of molysite; Described molysite is the salt that divalence or tervalent iron ion and halogen ion form, described organic solvent be acetone, methylene dichloride,, ether or acetonitrile; Described oxygenant is KMnO
4Described temperature of reaction is-10 ℃～+ 40 ℃, and described compound 1, molysite and oxygenant mol ratio are 1: 0.01～0.8: 1～10.
(7) under-105～25 ℃ of organic solvent neutralizations, compound 2 obtains lactone carbonyl moiety reduction institute corresponding intermediates semi-acetal with the reductive agent effect, this semi-acetal be dissolved in 0～+ 35 ℃ with alcohol under the acid catalyst effect generation compound 3; Described reductive agent is a diisobutylaluminium hydride; Described acid catalyst is the protonic acid or the Lewis acid of organic or inorganic; The mol ratio of described compound 2 and reductive agent is 1: 1～5, and the reaction times is 0.5～30 hour; The mol ratio of midbody semi-acetal 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. compound method as claimed in claim 3 is characterized in that the concentration of compound 4 in reaction soln is 0.001M～3M in the described step (1); Compound 6 described in the step (2) concentration in reaction soln is 0.001M～3M; Compound 7 described in the step (3) concentration in reaction soln is 0.001M～3M; Compound 2 described in the step (4) concentration in reaction soln is 0.001M～3M; Compound 9 described in the step (5) concentration in reaction soln is 0.001M～3M; Compound 1 described in the step (6) concentration in reaction soln is 0.001M～3M; During compound 2 reduction reactions described in the step (7) in reaction soln concentration be 0.001M～3M; Compound 3 concentration in reaction soln was 0.001M～3M when the midbody semi-acetal formed compound 3.
5. compound method as claimed in claim 3 is characterized in that the temperature of reaction described in the step (1) is a room temperature.
6. compound method as claimed in claim 3 is characterized in that the H described in the step (4)
2O
2Diethyl ether solution or MTBE (the saturated content that obtains usually is the H about 0.5M
2O
2) extract commercially available 33% hydrogen peroxide solution and get by ether or MTBE.
7. compound method as claimed in claim 3 is characterized in that the organic solvent described in the step (2) is methylene dichloride, methyl alcohol, ethanol, Virahol, ether, THF or acetonitrile.
8. compound method as claimed in claim 3 is characterized in that the acid catalyst described in the step (7) is sulfuric acid, hydrochloric acid, right-toluenesulphonic acids, camphorsulfonic acid, boron trifluoride ethyl ether complex or titanium tetrachloride; Described organic solvent is CH
2Cl
2, CHCl
3, benzyl cyanide, N, the described alcohol of dinethylformamide, benzene or toluene is methyl alcohol, ethanol or Virahol.
9. a compound according to claim 1 or claim 2 is characterized in that being used to prepare antimalarial agent.
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| Title |
|---|
| LI, Y. ET AL: "Facile Ring-Opening of Oxiranes by H2O2 Catalyzed by Phosphomolybdic Acid", 《ORGANIC LETTERS》 * |
| LI,Y. ET AL: "Simple Analogues of Qinghaosu (Artemisinin)", 《CHEM. ASIAN J.》 * |
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