CN102432523B - Method for synthesizing 3-hydroxy-3-arylindole-2-one derivative - Google Patents
Method for synthesizing 3-hydroxy-3-arylindole-2-one derivative Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a 3-hydroxy-3-arylindole-2-one derivative shown as a structural formula (I), which comprises the following steps of: fully reacting raw materials such as an isatin compound shown as a structural formula (II) and arylboric acid shown as a structural formula (III) in an inert organic solvent in the presence of a copper catalyst, a nitrogen-containing bidentate ligand and an alkaline compound, and separating and purifying reaction liquid after the reaction is finished to obtain the 3-hydroxy-3-arylindole-2-one derivative, wherein the copper catalyst is one or any combination of copper trifluoromethanesulfonate, copper acetylacetonate, copper acetate, cuprous iodide, copper bromide, copper fluoride and copper chloride. The method is high in implementation value and good in social benefit and economic benefit.
Description
(1) technical field
The present invention relates to a kind of chemical synthesis process of 3-hydroxy-3-arylindole-2-one derivative.
(2) background technology
3-hydroxyl-3-(hetero) aryl indole-2-ketone compounds is the compound that a class has good biological activity and pharmacologically active, be widely used in the synthetic of agricultural chemicals, medicine, have very high practical value, its derivative is being brought into play active effect at aspects such as anticancer, anti-inflammatory, treatment hematologic diseases.
In prior art, (as: the Angew.Chem.Int.Ed.2011 that has, 50,7620) synthesize 3-hydroxyl-3-(hetero) aryl indole-2-one derivative compounds with intramolecular cyclization reaction, the method is to utilize metal palladium catalyst to be configured to ring structure, to the strict of the structure of reaction substrate and be difficult to obtain, and used catalyst is more expensive.Have (as J.Am.Chem.Soc.2004,126,12888 and Bioorg.Med.Chem.Lett.2010,20,3103) synthesize 3-hydroxyl-3-(hetero) aryl indole-2-ketone compounds with organometallic reagent (as Grignard reagent or organolithium reagent) as aromatic yl reagent-ing, the method is the nucleophilicity of utilizing organometallic reagent stronger, but due to the toxicity of organometallic reagent with to the restriction of functional group, and the shortcomings such as sensitivity of empty G﹠W are all being limited being widely used of this method.
For the above unfavorable factor of considering, therefore existing method is improved, develop a kind of efficient, cheapness, 3-hydroxy-3-arylindole-2-one derivative synthetic method has very large economic benefit and social benefit easily.
(3) summary of the invention
The purpose of this invention is to provide a kind of technique rationally, hypotoxicity, reaction conditions is gentle, reaction yield is high and the chemical synthesis process of the 3-hydroxy-3-arylindole-2-one derivative of good product quality.
For achieving the above object, the present invention adopts following technical scheme:
A kind of structure is suc as formula the synthetic method of the 3-hydroxy-3-arylindole-2-one derivative shown in (I), described method comprises the following steps: take structure suc as formula the isatin compounds shown in (II) and structure suc as formula the aryl boric acid shown in (III) as raw material, fully reaction in inert organic solvents under the existence of copper catalyst, nitrogenous bitooth ligand and basic cpd, reaction finishes afterreaction liquid and obtains described 3-hydroxy-3-arylindole-2-one derivative through separation and purification; Described copper catalyst is selected from following a kind of or several combination arbitrarily: copper trifluoromethanesulfcomposite, acetylacetone copper, neutralized verdigris, cuprous iodide, cupric bromide, cupric fluoride, cupric chloride;
Formula (I), (II) or (III) in, R
1And R
2Independently be selected from separately one of following: the alkyl of hydrogen, C1～C8, the alkoxyl group of C1～C8, allyl group, benzyl, hydrocinnamyl, halogen; R
3Be selected from one of following: phenyl, naphthyl, substituted-phenyl, the substituting group of described substituted-phenyl are the alkyl of C1～C8, alkoxyl group, trifluoromethyl, halogen, nitro or the phenyl of C1～C8.
Further, described R
1Be preferably one of following: the alkyl of hydrogen, C1～C8, C1～C8 alkoxyl group, halogen, more preferably one of following: hydrogen, methyl, methoxyl group, halogen, more preferably one of following: hydrogen, methyl, methoxyl group, chlorine.
Further, described R
2Be preferably one of following: the alkyl of C1～C8, allyl group, benzyl, hydrocinnamyl, more preferably one of following: methyl, normal-butyl, n-hexyl, allyl group, benzyl, hydrocinnamyl.
Further, described R
3Be preferably one of following: phenyl, substituted-phenyl, the substituting group of described substituted-phenyl are selected from one of following: the alkyl of C1～C8, the alkoxyl group of C1～C8, trifluoromethyl, halogen, nitro or phenyl; The alkyl of described C1～C8 is preferably methyl, and the alkoxyl group of described C1～C8 is preferably methoxyl group.
It is one of following that nitrogenous bitooth ligand of the present invention can be selected from: a water phenanthroline, 4,7-dimethyl phenanthroline, dipyridyl, 4,4 '-dimethyl-2,2 '-dipyridyl; Be preferably a water phenanthroline.
Basic cpd of the present invention can be as mineral alkalis such as sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassiumphosphate, Potassium monofluoride, Repone K, lithium fluoride, lithiumbromide, sodium-acetate, potassium tert.-butoxides; Can be also the organic basess such as triethylamine, urotropine; It can be also the mixture of above-mentioned mineral alkali and organic bases.
The organic solvent of inert organic solvents of the present invention for not reacting with reactant, usually can select alkanes, halogenated hydrocarbon, the N of C1～C8, N, a kind of or several combination arbitrarily in-dimethylformamide class, ester class, alcohols, ethers, ketone, nitrile solvents, preferred methylene dichloride.The quality consumption of described inert organic solvents is 1～35 times of described isatin compounds quality, is preferably 15～25 times.
Copper catalyst of the present invention is preferably copper trifluoromethanesulfcomposite or acetylacetone copper.
The molar ratio of isatin compounds of the present invention and aryl boric acid, mantoquita, nitrogenous bitooth ligand and basic cpd is 1.0: 1.0～6.0: 0.01～1.0: 0.01～1.0: 1.0～5.0, be preferably 1.0: 2.0～4.0: 0.05～0.1: 0.05～0.1: 2.0～3.5, more preferably 1.0: 3.0～4.0: 0.05～0.1: 0.05～0.1: 2.5～3.5.
In the present invention, temperature of reaction is 30～150 ℃, is preferably 45～100 ℃; Reaction times is preferably 24～48h generally at 5～72h.
Separation and purification of the present invention can be adopted following method: the gained reaction solution first steams and desolventizes, add again saturated sodium bicarbonate, separate and get organic layer, the rotation evaporate to dryness, the crude product ethyl alcohol recrystallization is described 3-hydroxyl-3-Phenylindole-2-ketone derivatives after drying.
the concrete chemical synthesis process of described 3-hydroxy-3-arylindole-2-one derivative of recommending of the present invention carries out in accordance with the following steps: under room temperature, it is 1.0: 3.0～4.0: 0.05～0.1: 0.05～0.1: 2.5～3.5 isatin compounds with mol ratio, aryl boric acid, copper catalyst, nitrogenous bitooth ligand and basic cpd add in reactor, after the inert organic solvents dissolving, be warming up to 30-150 ℃, 5h-72h is to reacting completely in reaction, first steam and desolventize, add again saturated sodium bicarbonate, separate and get organic layer, the rotation evaporate to dryness, the crude product ethyl alcohol recrystallization, be described 3-hydroxyl-3-Phenylindole-2-ketone derivatives after drying.
The present invention compared with prior art, its beneficial effect is mainly reflected in: 1. reaction yield is relatively high, good product quality; 2. operational path is advanced rationally, reaction conditions is gentle; 3. the few and low price of catalyst levels; Therefore the present invention has larger implementary value and economic results in society.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is dimethylbenzene 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are dropped in reactor, add xylene soluble, temperature of reaction is 100 ℃, and afterreaction finished in 48 hours.
After reaction finishes, organic solvent is reclaimed in underpressure distillation, and the ethyl alcohol recrystallization of solid through crossing with the calcium chloride drying that remains in reaction flask gets white solid, namely gets N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 14.8g, yield 62%, purity 98.1%.
Nuclear magnetic resonance spectrum (Bruke):
1H NMR (CDCl
3, 500MHz): δ (ppm)=3.17 (3H, s), 3.40 (1H, s), 6.83 (1H, d, J=10Hz), 7.02 (1H, t, J=10Hz), 7.18-7.32 (7H, m);
13C NMR (CDCl
3, 125MHz): δ (ppm)=26.5,77.9,108.7,123.5,124.9,125.3,128.3,128.6,129.9,131.6,140.1,143.5,177.5.
Embodiment 2:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, 4,4 '-dimethyl-2,2 '-dipyridyl, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 0.92g (0.005mol); 4,4 '-dimethyl-2,2 '-dipyridyl 2.08g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is dimethylbenzene 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
All the other are with embodiment 1, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 11.9g, yield 50%, purity 98.5%.
Embodiment 3:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, cesium carbonate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Cesium carbonate 97.8g (0.3mol); Organic solvent is dimethylbenzene 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
All the other are with embodiment 1, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 13.9g, yield 58%, purity 98.4%.
Embodiment 4:
N-methyl-isatin, phenylo boric acid, cuprous iodide, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Cuprous iodide 0.95g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is dimethylbenzene 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
All the other are with embodiment 1, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 13.6g, yield 57%, purity 97.9%.
Embodiment 5:
N-methyl-isatin, phenylo boric acid, cupric bromide, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is toluene 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
All the other are with embodiment 1, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 13.9g, yield 58%, purity 99.2%.
Embodiment 6:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is methylene dichloride 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are dropped in reactor, add the rear sealing of methylene dichloride dissolving.Temperature of reaction is 80 ℃, and 48 hours finish.
After reaction finishes, organic solvent is reclaimed in underpressure distillation, and the ethyl alcohol recrystallization of solid through crossing with the calcium chloride drying that remains in reaction flask gets white solid, namely gets N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 17.1g, yield 71%, purity 99%.
Embodiment 7:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 2.0: 0.1: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 24.4g (0.2mol); Copper trifluoromethanesulfcomposite 3.6g (0.01mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is methylene dichloride 322g, and its total consumption is 20 times of N-methyl-isatin quality.
All the other are with embodiment 6, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 19.6g, yield 82%, purity 98.8%.
Embodiment 8:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 3.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 36.6g (0.3mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is methylene dichloride 322g, and its total consumption is 20 times of N-methyl-isatin quality.
All the other are with embodiment 6, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 20.6g, yield 86%, purity 99.2%.
Embodiment 9:
N-methyl-isatin, phenylo boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 4.0: 0.05: feed intake at 0.1: 3.0, and N-methyl-isatin 16.1g (0.1mol); Phenylo boric acid 48.8g (0.4mol); Copper trifluoromethanesulfcomposite 1.8g (0.005mol); One water phenanthroline 2.0g (0.01mol); Lithium Hydroxide Monohydrate 12.6g (0.3mol); Organic solvent is methylene dichloride 241.5g, and its total consumption is 15 times of N-methyl-isatin quality.
All the other are with embodiment 6, products obtained therefrom N-methyl-3-hydroxyl-3-Phenylindole-2-ketone 21.9g, yield 91%, purity 99.3%.
Embodiment 10～33:
Isatin, aryl boric acid, copper trifluoromethanesulfcomposite, a water phenanthroline, Lithium Hydroxide Monohydrate are take molar ratio as 1.0: 4.0: 0.05: add 80 ℃ of methylene dichloride heated sealed after feeding intake at 0.1: 3.0, reacted 48 hours, all the other steps are with embodiment 6, and result is as shown in the table:
Claims (5)
1. a structure is suc as formula the synthetic method of the 3-hydroxy-3-arylindole-2-one derivative shown in (I), described method comprises the following steps: take structure suc as formula the isatin compounds shown in (II) and structure suc as formula the aryl boric acid shown in (III) as raw material, fully reaction in inert organic solvents under the existence of copper catalyst, nitrogenous bitooth ligand and basic cpd, reaction finishes afterreaction liquid through separation and purification, obtains described 3-hydroxyl-3-Phenylindole-2-ketone derivatives; Described copper catalyst is copper trifluoromethanesulfcomposite;
Formula (I), (II) or (III) in, described R
1For one of following: the alkyl of hydrogen, C1～C8, the alkoxyl group of C1～C8, halogen; Described R
2For one of following: the alkyl of C1～C8, allyl group, benzyl, hydrocinnamyl; R
3Be selected from one of following: phenyl, naphthyl, substituted-phenyl, the substituting group of described substituted-phenyl are the alkyl of C1～C8, alkoxyl group, trifluoromethyl, halogen, nitro or the phenyl of C1～C8;
Described nitrogenous bitooth ligand is a water phenanthroline; Described basic cpd is Lithium Hydroxide Monohydrate; Described inert organic solvents is methylene dichloride.
2. the synthetic method of 3-hydroxy-3-arylindole-2-one derivative as claimed in claim 1, it is characterized in that: the molar ratio of described isatin compounds and aryl boric acid, copper catalyst, nitrogenous bitooth ligand and basic cpd is 1.0:1.0～6.0:0.01～1.0:0.01～1.0:1.0～5.0; The quality consumption of described inert organic solvents is 1～35 times of described isatin compounds quality.
3. the synthetic method of 3-hydroxy-3-arylindole-2-one derivative as claimed in claim 1, it is characterized in that: the molar ratio of described isatin compounds, aryl boric acid, copper catalyst, nitrogenous bitooth ligand and basic cpd is 1.0:2.0～4.0:0.05～0.1:0.05～0.1:2.0～3.5; The quality consumption of described inert organic solvents is 15～25 times of described isatin compounds quality.
4. the synthetic method of 3-hydroxy-3-arylindole-2-one derivative as claimed in claim 1, it is characterized in that: described reaction is carried out under the temperature condition of 30～150 ℃.
5. the synthetic method of 3-hydroxy-3-arylindole-2-one derivative as claimed in claim 4, it is characterized in that: temperature of reaction is 45～100 ℃, the reaction times is 24～48h.
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| CN102952061B (en) * | 2012-10-18 | 2014-10-01 | 上海大学 | N-substituted indole-diketone compound and preparation method thereof |
| CN103342651B (en) * | 2013-07-22 | 2014-07-02 | 温州大学 | Synthesis method of diaryl aniline compound |
| CN104059012B (en) * | 2014-07-02 | 2016-09-21 | 郑攀锋 | A kind of preparation method of pharmaceutical intermediate indole-2,3-cyclohexadione compounds |
| CN108424380B (en) * | 2018-03-05 | 2021-12-24 | 河南师范大学 | Method for synthesizing 3H-indole-3-ketone derivative |
| CN110194733B (en) * | 2019-06-25 | 2022-11-15 | 上海应用技术大学 | Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound |
| CN112920191B (en) * | 2021-01-12 | 2022-03-25 | 南宁师范大学 | Arylethynyl oxindole oxirane as well as preparation method and application thereof |
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| US20030171593A1 (en) * | 2001-12-20 | 2003-09-11 | Cellier Pascal Philippe | Process for arylating or vinylating or alkynating a nucleophilic compound |
| CN1668595A (en) * | 2002-05-31 | 2005-09-14 | 罗狄亚化学公司 | Method of forming a carbon-carbon or carbon-heteroatom linkage |
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