CN101823991A - Method for synthesizing dual-peroxide - Google Patents
Method for synthesizing dual-peroxide Download PDFInfo
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- CN101823991A CN101823991A CN200910047181A CN200910047181A CN101823991A CN 101823991 A CN101823991 A CN 101823991A CN 200910047181 A CN200910047181 A CN 200910047181A CN 200910047181 A CN200910047181 A CN 200910047181A CN 101823991 A CN101823991 A CN 101823991A
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Abstract
The invention discloses a method for synthesizing a dual-peroxide and relates to new application of phosphomolybdic acid as a catalyst for catalyzing reaction of hydrogen peroxide and a carbonyl compound to generate a bi-peroxy bond-containing product. The peroxide can be used for preparing an antimalarial compound.
Description
Technical field
The present invention relates to a kind of from free or some new dual-peroxides of preparing with the method for the ketone/aldehyde synthesizing dual-peroxide of ketal form protection and by this method and uses thereof.
Background technology
The organic peroxy compounds antimalarial agent that with the Artemisinin is representative is the best class chemicals of treatment malaria prospect at present.The structure more complicated of Artemisinin, its chemosynthesis are relatively more difficult comparatively speaking, up to the present can't carry out on industrially scalable, and all medicinal Artemisinins can only extract from the sweet wormwood herb that some south east asia produces.Because the Artemisinin output of natural origin is limited, develop that new structure is simple, to be easier to synthetic and still to have the active organo-peroxide of good antimalarial be the trend that can't change.External just someone sets about the research of this respect and has found the artificial organo-peroxide of the remarkable antimalarial active of a series of tools successively since the end of the eighties in last century, as: compound 2,3,4 ((a) Kim, H.-S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.; Masuyama, A.; Nojima, M.; McCullough, K.J.J.Chem.Soc., Perkin Trans.1 1999,1867-1870. (b) Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Ono, K.; Ogura, N.; Wataya, Y.J.Med.Chem.2002,45,1374-1378. (c) Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K.J.J.Med.Chem.2001,44,2357-2361. (d) Vennerstrom, J.L.; Dong, Y.; Andersen, S.L.; Ager, A.L.Jr.; Fu, H.-n.; Miller, R.E.; Wesche, D.L.; Kyle, D.E.; Gerena, L.; Walters, S.M.; Wood, J.K.; Edwards, G.; HOlme, A.D.; McLean, W.G.; Milhous, W.K.J.Med.Chem.2000,43,2753-2758. (e) Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.Tetrahedron Lett.1999,40,4077-4080. (f) Dong, Y.; Matile, H.; Chollet, J.; Kaminsky, R.; Wood, J.K.; Vennerstrom, J.L.J.Med.Chem.1999,42,1477-1480. (g) Kim, H.S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.; Masuyama, A.; Nojima, M.; McCullough, K.J.J.Chem.Soc., Perkin Trans.71999,1867-1870.)
One of main difficult point of synthetic organo-peroxide is the introducing of peroxide bridge.Because peroxide bridge is a kind of energy-rich bond, and is very unstable, may directly set up from laying respectively at two mutual couplings of the Sauerstoffatom the alkoxyl group hardly.Up to the present, nearly all artificial synthetic organo-peroxide all is to utilize the inorganic peroxy species (as oxygen, ozone or hydrogen peroxide) that contain peroxide bridge to obtain for peroxygen source links to each other to fetch by the limited several method carbon atom that the Sauerstoffatom at peroxide bridge two ends is different with the object construction kind respectively.Wherein hydrogen peroxide is owing to be more stable reagent, and preservation and use are all very convenient, and price is also very cheap, so be subjected in recent years paying close attention to more and more.
Forming together with diperoxy hydrogen compounds with hydrogen peroxide and carbonyl compound (aldehydes or ketones) interaction under the condition of protonic acid or Lewis acid existence is to be used for one of main method of introducing in organic compound peroxide bridge in recent years.The catalyzer of existing report comprises in the document: formic acid (uses Ledaal, T. as solvent; Solbjor, T.Acta Chem.Scand.1967,21,1658), the vitriol oil (Terent ' ev, A.O.; Platonov, M.M.; Ogibin, Y.N.Synth.Commun.2007,37,1281), boron trifluoride-ether complex (Terent ' ev, A.O.; Kutkin, A.V.Tetrahedron Lett.2003,44,7359), wolframic acid (Jefford, C.W.; Li, W.; Jaber, A.; Synth.Commun.1990,20,2589), sodium pyrosulfate-silica-gel mixture (NaHSO
4-SiO
2, Das, B.; Veeranjaneyulu, B.; Krishnaiah, M.; J.Mol.Catal.A 2008,284, and 116).But generally speaking effect is all satisfied inadequately, if though employed acid acidity is too strong or use the big yield of equivalent better can't be applied to the substrate that contains the acid labile group.And the acid of using acid more weak acid or catalytic amount low, the long reaction time of yield or must in advance ketone be converted into ketal and just can obtain better result as substrate often.
To use the catalytic shortcoming of classical acid in order overcoming, to use iodine (Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J.Org.Lett.2006,8,2491), rhenium heptoxide Re
2O
7(Ghorai, P.; P.H.Dussualt, Org.Lett.2008,10,4577), cerium oxide Ce (NH
4)
2(NO
3)
6(be abbreviated as CAN usually, Das, B.; Krishnaiah, M.; Veeranjaneyulu, B.; Tetrahedron Lett.2007,48,6286) etc. nonacid condition is implemented in the method for introducing peroxide bridge in the organic compound structure and has also been grown up recently.Yet when avoiding the catalytic shortcoming of classical acid, but these methods have been introduced other problems.For example rhenium heptoxide and iodine all can react with carbon-to-carbon double bond, so the olefines substrate all can't be suitable for.Cerium oxide then can oxidation kinds of protect group (as TBS (tertiary butyl dimethyl is silica-based), PMB (to methoxy-benzyl)).In fact the substrate of up to the present reporting in the document almost is simple ketone or the ketal that does not contain any other functional group all; Any precedent that then at all can not find as for the substrate that has in the organic synthesis protecting group commonly used.
Summary of the invention
The problem that will solve of the present invention provides acid-sensitive sense blocking group in the compatible substrate structure of a kind of energy and two keys synthetic together with the diperoxy ketal compounds new method and some new dual-peroxides are provided.This method can be represented by following reaction formula:
Above-mentioned solvent is recommended ether.
The substrate of reaction usefulness can be the ketone and the ketal thereof of replacement or unsubstituted cyclic or open chain, also replaces or unsubstituted phenyl aldehyde.
R wherein
1, R
2Be identical or different following group: H, C
1～C
6Alkyl, the C of replacement
1～C
6Alkyl, phenyl, substituted-phenyl, perhaps
Represent C
5～C
8Cycloalkyl or the C of cycloalkenyl group, replacement
5～C
8Cycloalkyl or cycloalkenyl group,
The C of described replacement
1～C
6The C of alkyl, substituted-phenyl or replacement
5～C
8Cycloalkyl or the substituting group on the cycloalkenyl group be selected from C
1～C
6Alkyl, C
1～C
6Alkoxyl group, C
1～C
6Ester group, OMOM ,-CH=CHCO
2Bn, OBz, OBn ,-C (CH
2) CO
2Et, OPMB, OCH
2CCH,
TBSO or CH
2CH
2CN, X represents CR
3R
4, NR
3Or O, R
3, R
4Be identical or different H or the C of being selected from
1～C
6The group of ester group.
Recommend: the C of described replacement
1～C
6Alkyl or the substituting group on the substituted-phenyl be selected from C
1～C
6Alkoxyl group, OMOM ,-CH=CHCO
2Bn, OBz, OBn ,-C (CH
2) CO
2Et, OPMB, OCH
2CCH,
X as previously mentioned; Five substituting groups on octatomic ring alkyl or the cycloalkenyl group of described replacement are C
1～C
6Alkyl, TBSO, CH
2CH
2CN, CH
2CH
2COOEt or
It is as follows that reaction conditions is recommended: (phosphomolybdic acid is abbreviated as PMA usually, and commodity contain some crystal water H usually at phospho-molybdic acid or its hydrate
3Mo
12O
40PxH
2O, [51429-74-4], Phosphomolybdic acid hydrate) act on down, compound 5 is converted into the carbonyl free or that protect with the ketal form in the compound 5 accordingly together with diperoxy ketal 6 with the hydrogen peroxide effect in solvent such as diethyl ether solution.Used temperature of reaction is recommended as-10 ℃～+ 30 ℃, and used hydrogen peroxide is recommended as its saturated solution (Saito, I. in ether; Nagata, R.; Yuba, K.; Matsuura, T.Tetrahedron Lett.1983,24,1737-1740, concentration is about 1M), the concentration of substrate ketone, aldehyde or ketal is recommended as 0.01～0.3M during reaction, further be recommended as 0.1M, the mol ratio between the used reactant is a compound 5: phospho-molybdic acid=1: 0.01～0.05.Reaction times is recommended as 2-10 hour.The hydrogen peroxide amount ratio is recommended as: substrate: hydrogen peroxide=1: 1-10 (mol ratio).
Institute of the present invention synthetic can be used as the synthetic active ring-type organo-peroxide of tool anti-malarial together with diperoxy ketal/aldehyde.
The invention provides the synthetic corresponding method of a kind of new ketone/aldehyde cpd together with diperoxy ketal/aldehyde from free or protection.With report in the document all use protonic acids or the acid catalyzed similar approach of Lewis to compare the present invention to have that catalyst levels is few, the low catalytic efficiency advantages of higher of acidity, and all effectively same to free ketone or ketal.Used condition is obviously much gentle, not only effective to simple substrate, to have acid-sensitive sense protecting group such as tertiary butyl dimethyl silica-based (tert-butyldimethylsilyl, TBS), (methoxymethyl MOM) is suitable for methoxymethyl too.With use iodine, the rhenium heptoxide reported in the document; compare with the method for cerium oxide; then the most tangible advantage is can be suitable for the carbon-carbon double key and/or such as to methoxy-benzyl those easily oxidized (p-methoxybenzyl, PMB) substrates of protecting group.In addition, the catalyst system therefor phospho-molybdic acid price rhenium heptoxide more best than effect in the document up to the present is much lower.
Embodiment
Following embodiment will help to understand the present invention, but not limit content of the present invention.
Table one. the catalytic peroxy ketal reaction of phospho-molybdic acid example, reaction conditions is referring to embodiment one.
Embodiment 1
To the diethyl ether solution of hydrogen peroxide (ca.1M, add in 5mL) pimelinketone (98.1mg, 1.0mmol) and phospho-molybdic acid (3mg, ca.0.02mmol).Reaction solution washes (5mL) stirring at room 3 hours with water after (20mL) dilution that adds diethyl ether.Water ethyl acetate (3 * 20mL) back extractions.Merge organic phase, successively water (2 * 10mL) and saturated aqueous common salt (2 * 10mL) wash anhydrous sodium sulfate drying.Remove behind siccative and the solvent with silica gel column chromatography (2: 1n-hexane/EtOAc) separate obtain white solid (141mg, 0.95mmol, 95%yield): M.p.47-49 ℃ of (Terent ' ev, A.O.; Platonov, M.M.; Ogibin, Y.N.; Nikishin, G.I.Synth.Commun.2007,37,1281-1287; M.p.48-50 ℃).
1HNMR (300MHz, CDCl
3) δ 8.79 (s, 2H), 1.84 (t, J=5.7 Hz, 4H), 1.52-1.65 (m, 4H), 1.40-1.51 (m, 2H).
Claims (8)
1. one kind from ketone, aldehyde or ketal, with the method that hydrogen peroxide comes synthesizing dual-peroxide, it is characterized in that hydrate with phospho-molybdic acid or phospho-molybdic acid is as catalyzer.
2. the method for claim 1 is characterized in that described ketone or aldehyde are
Described ketal is
Described dual-peroxide is
R wherein
1, R
2Be identical or different following group: H, C
1～C
6Alkyl, the C of replacement
1～C
6Alkyl, phenyl, substituted-phenyl, perhaps
Represent C
5～C
8Cycloalkyl or the C of cycloalkenyl group, replacement
5～C
8Cycloalkyl or cycloalkenyl group,
The C of described replacement
1～C
6The C of alkyl, substituted-phenyl or replacement
5～C
8Cycloalkyl or the substituting group on the cycloalkenyl group be selected from C
1～C
6Alkyl, C
1～C
6Alkoxyl group, C
1～C
6Ester group, OMOM ,-CH=CHCO
2Bn, OBz, OBn ,-C (CH
2) CO
2Et, OPMB, OCH
2CCH,
TBSO or CH
2CH
2CN, X represents CR
3R
4, NR
3Or O, R
3, R
4Be identical or different H or the C of being selected from
1～C
6The group of ester group.
3. method as claimed in claim 2 is characterized in that the C of described replacement
1～C
6Alkyl or the substituting group on the substituted-phenyl be selected from C
1～C
6Alkoxyl group, OMOM ,-CH=CHCO
2Bn, OBz, OBn ,-C (CH
2) CO
2Et, OPMB, OCH
2CCH,
X is as described in the claim 2;
Five the substituting groups on octatomic ring alkyl or the cycloalkenyl group that replace are C
1～C
6Alkyl, TBSO, CH
2CH
2CN, CH
2CH
2COOEt or
4. method as claimed in claim 1 or 2, it is characterized in that described temperature of reaction is-10 ℃～+ 30 ℃, reaction times is 2-10 hour, the concentration of ketone, aldehyde or ketal is 0.01～0.3M during reaction, and the mol ratio between the used reactant is ketone, aldehyde or ketal: phospho-molybdic acid is 1: (0.01～0.05).
5. method as claimed in claim 1 or 2 is characterized in that used hydrogen peroxide is its saturated solution in ether.
6. a class dual-peroxide is characterized in that structural formula is
R wherein
1, R
2As described in claim 3, and
And R
2Only be the alkyl that following group replaces: OMOM ,-CH=CHCO
2Bn, OBz, OBn ,-C (CH
2) CO
2Et, OPMB, OCH
2CCH,
Or
X is as described in the claim 3;
Perhaps
Represent C
1～C
6Ester group, TBSO or CH
2CH
2The C that CN replaces
5～C
8Cycloalkyl or cycloalkenyl group.
7. the described dual-peroxide of claim 6 is characterized in that structural formula is
8. the purposes of claim 6 or 7 described dual-peroxides is characterized in that being used for synthetic antimalarial compound.
Priority Applications (1)
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|---|---|---|---|
| CN200910047181A CN101823991A (en) | 2009-03-06 | 2009-03-06 | Method for synthesizing dual-peroxide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910047181A CN101823991A (en) | 2009-03-06 | 2009-03-06 | Method for synthesizing dual-peroxide |
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|---|---|
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Family
ID=42688182
Family Applications (1)
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|---|---|---|---|
| CN200910047181A Pending CN101823991A (en) | 2009-03-06 | 2009-03-06 | Method for synthesizing dual-peroxide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491982A (en) * | 2011-12-01 | 2012-06-13 | 中国科学院上海有机化学研究所 | Method for synthetizing 1,2,4-trioxane compound and purpose |
| JP2016138050A (en) * | 2015-01-26 | 2016-08-04 | シーシーアイ株式会社 | NEW gem-DIHYDROPEROXIDE COMPOUND |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3935278A (en) * | 1970-03-04 | 1976-01-27 | Atlantic Richfield Company | Process for preparing diperoxide from an organic hydro-peroxide and a ketone |
| CN101208346A (en) * | 2005-05-27 | 2008-06-25 | 阿迈瑞斯生物技术公司 | Conversion of amorpha-4,11- diene to artemisinin and artemisinin precursors |
-
2009
- 2009-03-06 CN CN200910047181A patent/CN101823991A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3935278A (en) * | 1970-03-04 | 1976-01-27 | Atlantic Richfield Company | Process for preparing diperoxide from an organic hydro-peroxide and a ketone |
| CN101208346A (en) * | 2005-05-27 | 2008-06-25 | 阿迈瑞斯生物技术公司 | Conversion of amorpha-4,11- diene to artemisinin and artemisinin precursors |
Non-Patent Citations (2)
| Title |
|---|
| BISWANATH DAS等: "A simple and efficient synthesis of gem-dihydroperoxides from ketones using aqueous hydrogen peroxide and catalytic ceric ammonium nitrate", 《TETRAHEDRON LETTERS》 * |
| KATJA ZŸMITEK,†等: "Iodine as a Catalyst for Efficient Conversion of Ketones to gem-Dihydroperoxides by Aqueous Hydrogen Peroxide", 《ORGANIC LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491982A (en) * | 2011-12-01 | 2012-06-13 | 中国科学院上海有机化学研究所 | Method for synthetizing 1,2,4-trioxane compound and purpose |
| JP2016138050A (en) * | 2015-01-26 | 2016-08-04 | シーシーアイ株式会社 | NEW gem-DIHYDROPEROXIDE COMPOUND |
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Application publication date: 20100908 |