CN103787951B - A kind of method of synthesis of natural product Glycozolicine - Google Patents
A kind of method of synthesis of natural product Glycozolicine Download PDFInfo
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- CN103787951B CN103787951B CN201410027154.XA CN201410027154A CN103787951B CN 103787951 B CN103787951 B CN 103787951B CN 201410027154 A CN201410027154 A CN 201410027154A CN 103787951 B CN103787951 B CN 103787951B
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- totuidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of method of synthesis of natural product Glycozolicine; Belong to organic synthesis field.Be generate 2-(4-toluino) phenol with the reaction of copper catalysis 6-diazo-2-tetrahydrobenzene-1-ketone and para-totuidine, then prepare the method for natural product <b>GlycozolicineLEssT.LTssT.L T/b> through the C-C key coupling of Hypermethylation and palladium chtalyst; The method has the advantage that step is few, simple to operate, yield is high.
Description
Technical field
The invention belongs to organic synthesis field, specifically a kind of method of synthesis of natural product Glycozolicine.
Background technology
Natural product Glycozolicine is a kind of alkaloid containing carbazole structure, and it is separation and Extraction from Glycosmispentaphylla.
Current reported synthesis Glycozolicine method as follows:
1）Synthesis,(6),929-933;2011
2）Tetrahedron67(2011)5725e5731
Above-mentioned two kinds of equal Shortcomings of method: method (1) needs just can obtain target product by more step;
And method (2) problem is that the position of ring closure reaction exists selectivity and causes finally obtaining mixture.
Summary of the invention
The reaction that the invention provides a kind of copper catalysis 6-diazo-2-tetrahydrobenzene-1-ketone and para-totuidine generates 2-(4-toluino) phenol; C-C key coupling again through Hypermethylation and palladium chtalyst can obtain natural product Glycozolicine.Its reaction scheme is as follows:
A method of synthesis of natural product Glycozolicine, specifically carry out in accordance with the following steps:
(1) 6-diazo-2-tetrahydrobenzene-1-ketone, para-totuidine, copper catalyst and solvent are added in tube sealing, 80 degrees Celsius, under air-proof condition reaction within 3 hours, 2-(4-toluino) phenol can be obtained by high yield;
(2) in reaction flask, add 2-(4-toluino) phenol, methyl iodide, salt of wormwood and acetone under room temperature, be then warming up to 60 degrees Celsius of reactions and can obtain N-(2-p-methoxy-phenyl) para-totuidine;
(3), under nitrogen protection condition, in tube sealing, N-(2-p-methoxy-phenyl) para-totuidine, palladium and acetic acid is added; Then be warmed up to 140 degrees Celsius of lucifuges to react and can obtain Glycozolicine in 24 hours.
Copper catalyst wherein described in step (1) is: neutralized verdigris, cuprous chloride, cuprous bromide, cuprous iodide, cupric bromide, copper trifluoromethanesulfcomposite and acetylacetone copper, and wherein neutralized verdigris is optimum catalyst.
The atmosphere of the reaction wherein described in step (1) is respectively: nitrogen, air and oxygen, and optimum reaction condition is oxygen ambient conditions.
The solvent of the reaction wherein described in step (1) is: methylene dichloride, 1,2-ethylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, tetrahydrofuran (THF), toluene and acetonitrile, and reaction optimum solvent is Isosorbide-5-Nitrae-dioxane.
The solvent of the reaction wherein described in step (1) is: 40 degrees Celsius-110 degrees Celsius, and reaction optimum temps is 80 degrees Celsius.
6-diazo-2-tetrahydrobenzene-1-ketone wherein described in step (1): para-totuidine: the molar ratio of copper catalyst is: 1 ~ 3:1:0.005 ~ 0.2.
2-(4-toluino) phenol wherein described in step (2): methyl iodide: the molar ratio of salt of wormwood is: 1:6:3.
N-(2-p-methoxy-phenyl) para-totuidine wherein described in step (3): the molar ratio of palladium is: 1:1.3.
The invention provides a kind of method simple to operate in sum, the convenient and swift preparation realizing natural product Glycozolicine.
Advantage of the present invention: method of the present invention has simple to operate, that yield is high advantage.
Embodiment
Give specific examples to the present invention below to illustrate:
The synthesis of the Ith step: 2-(4-toluino) phenol
Embodiment 1: under oxygen ambient conditions, adds para-totuidine (2g), 6-diazo-2-tetrahydrobenzene-1-ketone (2.3g), neutralized verdigris (0.746g) and Isosorbide-5-Nitrae-dioxane (50mL) in tube sealing; Reaction system is warming up to 80 degrees Celsius of reactions 3 hours in confined conditions.Reaction solution is cooled to room temperature, and after decompression evaporates solvent, residual solution obtains 2-(4-toluino) phenol (2.9g, productive rate: 80%) by column chromatography purification;
1hNMR (400MHz, CDCl
3) δ 7.16 (d, J=7.6Hz, 1H), 7.09-7.04 (m; 3H), 6.98 (d, J=8.0Hz; 1H), 6.91-6.87 (m, 1H); 6.73 (d, J=8.0Hz, 1H); 5.80 (s, 1H), 5.21 (s; 1H), 2.29 (s, 3H);
13cNMR (125MHz, CDCl
3) δ 150.6,142.8,129.9,129.8,125.5,123.9,121.0,116.4,115.2,20.5
Embodiment 2: under oxygen ambient conditions, adds para-totuidine (2g), 6-diazo-2-tetrahydrobenzene-1-ketone (6.9g), neutralized verdigris (0.0186g) and Isosorbide-5-Nitrae-dioxane (50mL) in tube sealing; Reaction system is warming up to 80 degrees Celsius of reactions 3 hours in confined conditions.Reaction solution is cooled to room temperature, and after decompression evaporates solvent, residual solution obtains 2-(4-toluino) phenol (3.3g, productive rate: 88%) by column chromatography purification;
1hNMR (400MHz, CDCl
3) δ 7.16 (d, J=7.6Hz, 1H), 7.09-7.04 (m; 3H), 6.98 (d, J=8.0Hz; 1H), 6.91-6.87 (m, 1H); 6.73 (d, J=8.0Hz, 1H); 5.80 (s, 1H), 5.21 (s; 1H), 2.29 (s, 3H);
13cNMR (125MHz, CDCl
3) δ 150.6,142.8,129.9,129.8,125.5,123.9,121.0,116.4,115.2,20.5
The synthesis (literature method) of the IIth step: N-(2-p-methoxy-phenyl) para-totuidine
In single port bottle, add 2-(4-toluino) phenol (1.2g), methyl iodide (5.1g), salt of wormwood (2.4g) and acetone (10mL), reaction mixture is raised to 60 degrees Celsius of reactions 3 hours; Reaction solution cool to room temperature, to evaporate after solvent, raffinate acetic acid ethyl dissolution with brine It; After organic phase drying, evaporate to dryness; Resistates obtains N-(2-p-methoxy-phenyl) para-totuidine (1.15g, productive rate: 90%) by column chromatography purification
The synthesis (literature method) of the IIIth step: Glycozolicine
Under nitrogen protection condition, in tube sealing, add N-(2-p-methoxy-phenyl) para-totuidine (0.75g), palladium (1.02g) and acetic acid (40mL); Be warmed up to 140 degrees Celsius of lucifuges under a nitrogen atmosphere after reaction tubes sealing and react 24 hours.Reaction solution cool to room temperature, decompression evaporates acetic acid, and residual solution sodium carbonate solution alkali tune (pH=8) accesses afterwards, by ethyl acetate; Organic phase is dry, evaporate to dryness, and crude product obtains Glycozolicine(0.54g by column chromatography purification; Yield 73%)
1hNMR (400MHz, CDCl
3) δ 8.15 (s, 1H), 7.84 (s, 1H); 7.64 (d, J=7.6Hz, 1H), 7.34 (d; J=8.0Hz, 1H), 7.23 (d, J=8.4Hz; 1H), 7.13 (t, J=7.6Hz, 1H); 6.88 (d, J=8.0Hz, 1H), 4.00 (s; 3H), 2.52 (s, 3H);
13cNMR (100MHz, CDCl
3) δ 145.7,137.5,130.1,128.7,127.1,124.2,123.9,120.4,119.5,112.8,110.6,105.8,55.5,21.5
Shown by the above-mentioned example provided, the synthesis of natural product Glycozolicine can be realized by method provided by the invention easily, there is the advantage that step is few, simple to operate, yield is high.
Claims (1)
1. a synthesis of natural product
glycozolicinemethod, it is characterized in that carrying out in accordance with the following steps:
(1) 6-diazo-2-tetrahydrobenzene-1-ketone, para-totuidine, copper catalyst and solvent are added in tube sealing, 80 degrees Celsius, react under air-proof condition
3hour can obtain 2-(4-toluino) phenol;
(2) in reaction flask, add 2-(4-toluino) phenol, methyl iodide, salt of wormwood and acetone under room temperature, be then warming up to 60 degrees Celsius of reactions and can obtain N-(2-p-methoxy-phenyl) para-totuidine;
(3), under nitrogen protection condition, in tube sealing, N-(2-p-methoxy-phenyl) para-totuidine, palladium and acetic acid is added; Then be warmed up to 140 degrees Celsius of lucifuges to react and can obtain for 24 hours
glycozolicine;
described Glycozolicine is following structure
;
Copper catalyst wherein described in step (1) is neutralized verdigris;
The atmosphere of the reaction wherein described in step (1) is oxygen;
The solvent of the reaction wherein described in step (1) is Isosorbide-5-Nitrae-dioxane;
6-diazo-2-tetrahydrobenzene-1-ketone wherein described in step (1): para-totuidine: the molar ratio of copper catalyst is: 1 ~ 3:1:0.005 ~ 0.2;
2-(4-toluino) phenol wherein described in step (2): methyl iodide: the molar ratio of salt of wormwood is: 1:6:3;
N-(2-p-methoxy-phenyl) para-totuidine wherein described in step (3): the molar ratio of palladium is: 1:1.3.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1962635A (en) * | 2006-11-17 | 2007-05-16 | 浙江工业大学 | Indoles compound preparation method |
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| EP1207160A1 (en) * | 2000-11-20 | 2002-05-22 | Hanmi Pharm. Co., Ltd. | Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl)-methyl)-4H-carbazol-4-one |
| JP3500504B2 (en) * | 2001-02-14 | 2004-02-23 | 旭化成ファインケム株式会社 | Method for producing 2-hydroxycarbazole |
| CN102382038B (en) * | 2011-09-22 | 2013-05-08 | 浙江大学 | Preparation method for synthesizing carbazoles alkaloid Siamenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1962635A (en) * | 2006-11-17 | 2007-05-16 | 浙江工业大学 | Indoles compound preparation method |
Non-Patent Citations (4)
| Title |
|---|
| Catalytic Aerobic Synthesis of Aromatic Ethers from Non-Aromatic Precursors;Marc-Olivier Simon，等;《Angew. Chem.》;20121231;第124卷;第7655-7658页 * |
| Cu(I)-catalysed N–H insertion in water: a new tool for chemical biology;Kiril Tishinov，等;《Chem. Sci.》;20131231;第4卷;第4401-4406页 * |
| Reactions of 5-diazo-6,6-dimethyl-4-oxo-1-phenyl-4,5,6,7- tetrahydroindazole with amines and enamines in the presence of dirhodium tetraacetat;Strakova, I.，等;《Latvijas Kimijas Zurnals》;20081231;357-362 * |
| Total Synthesis of the Natural Carbazoles Glycozolicine, Mukoline, and Mukolidine, Starting from 4,5-Dimethyleneoxazolidin-2-ones;Rafael Bautista，等;《SYNTHESIS》;20111231;第6卷;第0929-0933页 * |
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