CN103288708A - Preparation method for 1-aryl-2-indolinone derivatives - Google Patents
Preparation method for 1-aryl-2-indolinone derivatives Download PDFInfo
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- CN103288708A CN103288708A CN201310111698XA CN201310111698A CN103288708A CN 103288708 A CN103288708 A CN 103288708A CN 201310111698X A CN201310111698X A CN 201310111698XA CN 201310111698 A CN201310111698 A CN 201310111698A CN 103288708 A CN103288708 A CN 103288708A
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Abstract
The invention discloses a method for synthesis of 1-aryl-2-indolinone derivatives. The method comprises the following steps: dissolving N-aryl-substituted phenylacetamide (III) in an organic solvent, adding a chlorination reagent and carrying out a reaction so as to obtain N-chloro-N-aryl-substituted phenylacetamid (II); and subjecting N-chloro-N-aryl-substituted phenylacetamid to a reaction with a certain amount of Lewis acid and a proper amount of an organic solvent at a certain temperature so as to obtain 1-aryl-2-indolinone (I). The method provided by the invention has the advantages of simple operation, easily available reagents, a low price, mild conditions and capability of synthesizing a plurality of 1-aryl-2-indolinone (I) compounds.
Description
Technical field
The present invention relates to the preparation method of 1-aryl-2-indolinone derivative.
Background technology
1-aryl-2-indolinone derivative has important use value and Research Significance at medicine and the synthetic field of chemical industry.It can be used as the synthetic multiple Chemicals of important intermediate and medicine, as the nonsteroidal anti-inflammatory drug diclofenac etc.Bibliographical information the synthetic method of a large amount of Benzazole compounds, still less for the synthetic method of 1-aryl-2-indolinone derivative report, topmost method is to adopt Fu-Ke reaction method to make up indolone ring texture (see figure 1).There are shortcomings such as temperature of reaction is higher, cost of material is more expensive in this method.
Summary of the invention
The purpose of this invention is to provide that a kind of reagent is easy to get, the method for the synthetic 1-aryl-2-indolinone derivative (I) of low price, simple to operate, mild condition.
Technical scheme of the present invention is summarized as follows:
The method of a kind of synthetic 1-aryl-2-indolinone derivative comprises the steps: the aryl-substituted yl acetamide of N-(III) is dissolved in organic solvent, add chlorination reagent, and afterreaction obtains the aryl-substituted yl acetamide of N-chloro-N-(II); The aryl-substituted yl acetamide of N-chloro-N-and a certain amount of Lewis acid and an amount of organic solvent are reacted at a certain temperature, obtain 1-aryl-2-dihydroindolone (I).
Reaction formula is:
Wherein, R
1, R
2Can distinguish or simultaneously for H NO
2, NH
2, F, Cl, Br, I, CN, OH, OCH
3, OCH
2O, CH
3, CF
3, COOH, SO
3H, CONH
2, CONHR ', COOR '; Wherein R '=H or C
1-10Alkyl (comprising alkyl and aryl); R wherein
1, R
2Can be single, double or three replace simultaneously, the position can be adjacent, alternate or relative during single, double replacement.
Organic solvent is: methylene dichloride, trichloromethane, tetracol phenixin, Nitromethane 99Min., ether, ethyl acetate, hexanaphthene, normal hexane, trifluoroacetic acid, methyl alcohol, ethanol, sherwood oil, acetone, oil of mirbane, toluene, benzene, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, dithiocarbonic anhydride, 1, the 2-ethylene dichloride.
Chlorination reagent is: NaOCl, t-BuOCl, NaOCl/HAc, NaOCl/HAc/t-BuOH, Ca (OCl)
2/ HAc, Ca (OCl)
2/ Al
2O
3(wet), TCCA,
/ NaCl/H
2O.
Lewis acid is: aluminum trichloride (anhydrous), Silver Nitrate, silver carbonate, Sulfuric acid disilver salt, Silver monoacetate, iron trichloride, titanium tetrachloride, zinc chloride.
The mol ratio of Lewis acid catalyst and used N-chloro-N-(substituted aryl) substituted-phenyl ethanamide (II): 0.3-1: 1.
Temperature is: 0 ℃-reflux temperature.
The present invention has that raw material is cheap and easy to get, and cost is lower, and is simple to operate, mild condition, yield height, characteristics such as aftertreatment is simple.
Description of drawings
Accompanying drawing is that Fu-Ke reaction makes up the method for 1-aryl-2-dihydroindolone.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
The total reaction equation of 1-aryl of the present invention-2-indolinone derivative synthetic method is as follows:
Embodiment 1
(a) preparation of N-(2,6-dichlorophenyl) phenylacetamide (III-a)
Method one:
In the 250ml there-necked flask that thermometer, constant pressure funnel, reflux condensing tube and Calcium Chloride Powder Anhydrous drying tube are housed, add 16.20g (0.1mol) 2 successively, 6-dichlorphenamide bulk powder, 9.49g (0.12mol) pyridine and 100ml acetone.Stir, the ice-water bath cooling slowly drips 15.45g (0.1mol) phenyllacetyl chloride.After dripping end, remove ice-water bath.Heating, backflow 4h.Stopped reaction.
While hot reaction solution is poured in the hydrochloric acid soln of 250ml1.5mol/L, a large amount of yellow blocks of solid occur.Solid is leached, use 3mol/L hydrochloric acid soln, the 1mol/LNaOH solution of 100ml * 2, the 100ml * 2 deionized water wash of 100ml * 2 successively.Drying gets yellow solid.95% ethyl alcohol recrystallization gets white needle-like crystals 26.50g, yield 94.6%.Fusing point: 177.0-177.8 ℃.
Method two:
In the 250ml there-necked flask that thermometer, constant pressure funnel, reflux condensing tube and Calcium Chloride Powder Anhydrous drying tube are housed, add 16.20g (0.1mol) 2 successively, 6-dichlorphenamide bulk powder, 12.12g (0.12mol) triethylamine and 150ml methylene dichloride.Stir, the ice-water bath cooling slowly drips 15.45g (0.1mol) phenyllacetyl chloride, and the control reacting liquid temperature is no more than 25 ℃.After dripping end, remove ice-water bath.Heating, backflow 6h.Stopped reaction.
Reaction finishes the back and add the 50ml deionized water in reaction solution, and a large amount of white solids are separated out.Filter filter cake 100ml * 3 deionized water wash.The filtrate separatory is told organic phase.Organic phase is used hydrochloric acid soln, the 250ml * 2 deionized water wash of 3mol/L of 10%NaOH solution, 50ml * 2 of 50ml * 2 successively.Organic phase removes solvent under reduced pressure after with anhydrous magnesium sulfate drying, gets light yellow solid.Merge the gained solid, drying, 95% ethyl alcohol recrystallization gets white needle-like crystals 24.50g, yield 87.5%.
Method three:
In the 250ml there-necked flask that thermometer, constant pressure funnel, reflux condensing tube and Calcium Chloride Powder Anhydrous drying tube are housed, add 16.20g (0.1mol) 2,6-dichlorphenamide bulk powder and 80ml pyridine.Stir, the ice-water bath cooling slowly drips 15.45g (0.1mol) phenyllacetyl chloride.After dripping end, remove ice-water bath.Heating, backflow 4h.Stopped reaction.
Reaction solution removes solvent under reduced pressure, gets yellow solid.Use NaOH solution, the 100ml * 2 deionized water wash of 1mol/L of 3mol/L hydrochloric acid soln, 100ml * 2 of 100ml * 2 deionized waters, 100ml * 2 successively.Drying, 95% ethyl alcohol recrystallization gets white needle-like crystals 27.53g, yield 98.3%.
(b) preparation of N-chloro-N-(2,6-dichlorophenyl) phenylacetamide (II-a)
Method one:
To place ice-water bath with the 250ml there-necked flask that constant pressure funnel, Calcium Chloride Powder Anhydrous drying tube are housed of aluminium foil parcel, add 28.00g (0.1mol) N-(2,6-dichlorophenyl) phenylacetamide and 100ml methylene dichloride.Stir, the freshly prepd t-butyl hypochlorate of 11.39g (0.105mol) (preparation method's reference: Teeter H M, Bell E W.tert-Butyl hypochlorite.Organic Syntheses, Coll Vol4:125) dropwise is added drop-wise in the reaction solution.After finishing, temperature of reaction is increased to 25 ℃, continues reaction 10h, stopped reaction.
Reaction solution removes solvent under reduced pressure, vacuum-drying 12h under 20 ℃ of conditions.Get slightly yellow solid 31.44g, yield about 100%.
Method two:
To adorn thermometer, constant pressure funnel and churned mechanically 500ml there-necked flask and place ice-water bath, add 28.00g (0.1mol) N-(2,6-dichlorophenyl) phenylacetamide and 100ml methylene dichloride.Stir, 154.00ml chlorine bleach liquor (available chlorine content 〉=10%) is joined in the flask.When treating that temperature drops to below 5 ℃, dropwise drip 39.40ml acetic acid in reaction solution, temperature maintenance at the uniform velocity dropwises in 2h below 5 ℃.Continue to stir 1h, stopped reaction.
With the reaction solution separatory.Organic phase 50ml * 2 deionized water wash.The anhydrous magnesium sulfate drying organic phase removes solvent under reduced pressure, vacuum-drying 12h.Get faint yellow solid 31.20g, yield 99.2%.
Method three:
The 50ml there-necked flask of dress thermometer, constant pressure funnel and induction stirring places ice-water bath, add 1.40g (5mmol) N-(2 successively, the 6-dichlorophenyl) phenylacetamide, 25ml methylene dichloride and 2.50g (2.5equiv calculates by available chlorine) Losantin.Stir.When temperature drops to below 5 ℃, in reaction solution, dropwise drip 3.00g acetic acid.Temperature maintenance at the uniform velocity dropwises in 30min below 5 ℃.Continue to stir 1h, stopped reaction.
With reacting liquid filtering.Filter cake 15ml * 2 washed with dichloromethane.Merge organic phase.Organic phase 5ml * 2 deionized water wash.The anhydrous magnesium sulfate drying organic phase removes solvent under reduced pressure, vacuum-drying 12h.Get white solid 1.51g, yield 96.0%.
Method four:
In three mouthfuls of burnings of the 50ml that thermometer and induction stirring are housed, add 1.40g (5mmol) N-(2,6-dichlorophenyl) phenylacetamide, 25ml methylene dichloride.Open and stir, add 2.00g (2equiv calculates by available chlorine content) Losantin, the wet aluminium sesquioxide of 5.00g again.React 10h about 25 ℃.Stopped reaction.
With reacting liquid filtering, filter cake 15ml * 2 washed with dichloromethane.Merge organic phase.Organic phase 5ml * 2 deionized water wash.The anhydrous magnesium sulfate drying organic phase removes solvent under reduced pressure, vacuum-drying 12h.Get white solid 1.49g, yield 94.8%.
Method five:
In the there-necked flask that thermometer, constant pressure funnel and churned mechanically 25ml are housed, add 2.80g (10mmol) N-(2,6-dichlorophenyl) phenylacetamide, 10ml methylene dichloride and 1.85g (10mmol) trichloroisocyanuric acid (TCCA) successively.Open and stir,, at room temperature react 24h.Stopped reaction.
With reacting liquid filtering.Filtrate is carried out column chromatography for separation after concentrating.Get white solid 2.91g, yield 92.5%.
Method six:
The there-necked flask that thermometer, constant pressure funnel and churned mechanically 50ml are housed is placed ice-water bath, add 2.80g (10mmol) N-(2,6-dichlorophenyl) phenylacetamide, 10ml methylene dichloride and 0.37g (5mmol) trimethyl carbinol successively.Open and stir, in flask, add 12.30ml chlorine bleach liquor (available chlorine content 〉=10%).Then dropwise drip 3.15ml acetic acid in reaction solution, temperature maintenance at the uniform velocity dropwises in the 30min below 5 ℃.Remove ice-water bath, continue to stir 1h under the room temperature.Stopped reaction.
With the reaction solution separatory.Organic phase 50ml * 2 deionized water wash.The anhydrous magnesium sulfate drying organic phase removes solvent under reduced pressure, vacuum-drying 12h.Get faint yellow solid 3.13g, yield 99.5%.
Method seven:
Add 2.80g (10mmol) N-(2,6-dichlorophenyl) phenylacetamide, 18.40g (30mmol) in thermometer and the churned mechanically 100ml there-necked flask successively to being equipped with
1.76g (30mmol) sodium-chlor, 0.5ml water and 50ml methylene dichloride.Open and stir, at room temperature react 24h.Stopped reaction.
With reacting liquid filtering.Filtrate is used 10ml * 2 deionized water wash.The anhydrous magnesium sulfate drying organic phase removes solvent under reduced pressure, vacuum-drying 12h.Get white solid 3.14g, yield 99.8%.
(c) preparation of 1-(2,6-dichlorophenyl)-2-dihydroindolone (I-a)
Method one:
N-chloro-N-(2, the 6-dichlorophenyl) phenylacetamide (II-a) of 31.46g (0.1mol) is joined in the 500mL round-bottomed bottle, add the 250mL methylene dichloride, stir.Cool off at ice-water bath.Add 33.25g (0.25mol) aluminum trichloride (anhydrous).React 4h under the ice-water bath condition.Then move to and continue reaction 8h under the room temperature.Stopped reaction.
Under 30 ℃ of conditions, remove reaction solution under reduced pressure solvent.The solid that obtains 50ml * 3 methylbenzene extraction.Merge organic phase.In organic phase, add the 5ml deionized water, yellow solid occurs.Filter, with 30ml * 3 toluene wash filter cakes.Merge organic phase, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets faint yellow solid.Recrystallizing methanol gets faint yellow granular solids 18.41g, yield 66.2%.Fusing point: 123.0-123.7 ℃.ESI-MS?m/z278[M+H]
+；
1H-NMR(400MHz，CDCl
3)δppm7.51(2H，s)7.41(1H，t，J＝8.0Hz)，7.38(1H，d，J＝8.0Hz)，7.10(1H，t，J＝8.0Hz)，6.41(1H，d，J＝8.0Hz)，3.79(2H，s)。
Method two:
N-chloro-N-(2, the 6-dichlorophenyl) phenylacetamide (II-a) of 31.46g (0.1mol) is joined in the 500mL round-bottomed bottle, add the 250mL methylene dichloride, stir, add 33.25g (0.25mol) aluminum trichloride (anhydrous).Reaction 4h.Stopped reaction.
Reaction solution is poured in the frozen water, produced a large amount of yellow solids.Filter, with the filtrate separatory.Water with the 50ml dichloromethane extraction once.Merge organic phase, with 3ml * 2 deionized water wash, anhydrous magnesium sulfate drying removes solvent under reduced pressure, gets black solid.This solid gets slightly yellow solid 10.80g, yield 38.9% through column chromatography for separation.
Method three:
N-chloro-N-(2, the 6-dichlorophenyl) phenylacetamide (II-a) of 3.15g (10mmol) is joined in the 100mL round-bottomed bottle, add the 50mL trifluoroacetic acid, stir.Cool off at ice-water bath.Add 3.32g (20mmol) aluminum trichloride (anhydrous).React 8h under the ice-water bath condition.Stopped reaction removes solvent under reduced pressure.Column chromatography for separation obtains faint yellow granular solids 0.87g, yield 31.3%.
Embodiment 2
(a) preparation of N-(4-chloro-phenyl-) phenylacetamide (III-b)
Be raw material with p-Chlorobenzoic acid amide and phenyllacetyl chloride, according to embodiment 1 (a) method one preparation N-(4-chloro-phenyl-) phenylacetamide (III-b), final white needle-like crystals 23.95g, yield 96.3%.Fusing point: 161.5-163.9 ℃
(b) preparation of N-chloro-N-(4-chloro-phenyl-) phenylacetamide (II-b)
Be raw material with N-(4-chloro-phenyl-) phenylacetamide (III-b), according to embodiment 1 (b) method one preparation N-chloro-N-(4-chloro-phenyl-) phenylacetamide (II-b), final faint yellow solid 27.98g, yield about 100%.
(c) preparation of 1-(4-chloro-phenyl-)-2-dihydroindolone (I-b)
Be raw material with N-chloro-N-(4-chloro-phenyl-) phenylacetamide (II-b), according to embodiment 1 (c) method one preparation 1-(4-chloro-phenyl-)-2-dihydroindolone (I-b), final faint yellow solid 17.61g, yield 72.3%.Fusing point: 126.6-127.6 ℃.ESI-MS?m/z244[M+H]
+；
1H-NMR(400MHz，CDCl
3)δppm7.50(2H，d，J＝5.6Hz)7.38(2H，d，J＝5.6Hz)，7.30(1H，d，J＝8.0Hz)，7.10(1H，t，J＝8.0Hz)，6.79(1H，d，J＝8.0Hz)，3.72(2H，s)。
Claims (6)
1. the method for synthetic 1-aryl-2-indolinone derivative, its feature comprises the steps: the aryl-substituted yl acetamide of N-(III) is dissolved in organic solvent, add chlorination reagent, and afterreaction obtains the aryl-substituted yl acetamide of N-chloro-N-(II); The aryl-substituted yl acetamide of N-chloro-N-and a certain amount of Lewis acid and an amount of organic solvent are reacted at a certain temperature, obtain 1-aryl-2-dihydroindolone (I); Reaction formula is:
Wherein, R
1, R
2Can distinguish or simultaneously for H NO
2, NH
2, F, Cl, Br, I, CN, OH, OCH
3, OCH
2O, CH
3, CF
3, COOH, SO
3H, CONH
2, CONHR ', COOR '; Wherein R '=H or C
1-10Alkyl (comprising alkyl and aryl); R wherein
1, R
2Can be single, double or three replace simultaneously, the position can be adjacent, alternate or relative during single, double replacement.
2. method according to claim 1, it is characterized in that described organic solvent is: methylene dichloride, trichloromethane, tetracol phenixin, Nitromethane 99Min., ether, ethyl acetate, hexanaphthene, normal hexane, trifluoroacetic acid, methyl alcohol, ethanol, sherwood oil, acetone, oil of mirbane, toluene, benzene, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, dithiocarbonic anhydride, 1, the 2-ethylene dichloride.
3. method according to claim 1 is characterized in that described chlorination reagent is: NaOCl, t-BuOCl, NaOCl/HAc, NaOCl/HAc/t-BuOH, Ca (OCl)
2/ HAc, Ca (OCl)
2/ Al
2O
3(wet), TCCA,
/ NaCl/H
2O.
4. method according to claim 1 is characterized in that described Lewis acid is: aluminum trichloride (anhydrous), Silver Nitrate, silver carbonate, Sulfuric acid disilver salt, Silver monoacetate, iron trichloride, titanium tetrachloride, zinc chloride.
5. method according to claim 1 is characterized in that described temperature is: 0 ℃-reflux temperature.
6. method according to claim 1 is characterized in that the mol ratio of described Lewis acid catalyst and the used aryl-substituted yl acetamide of N-chloro-N-(II) is 0.3-1: 1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061291A (en) * | 2015-09-08 | 2015-11-18 | 张涛 | Synthesis method of condensed-heterocycle-substituted indolone compounds |
| CN111100057A (en) * | 2019-12-04 | 2020-05-05 | 天方药业有限公司 | Method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone |
| CN111138338A (en) * | 2020-01-20 | 2020-05-12 | 中国人民解放军61699部队 | Synthesis method of photocatalytic fluoroalkyl indoline |
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2013
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ280388B6 (en) * | 1990-01-08 | 1996-01-17 | Chemopharma A.S. | Sodium ortho-(2,6-dichloroaniline)-phenylacetate purification method |
Non-Patent Citations (3)
| Title |
|---|
| ADRI VAN DEN HOOGENBAND ET AL.,: "An efficient synthesis of 4-bromo-N-substituted oxindoles by an intramolecular copper-catalyzed amidation reaction", 《TETRAHEDRON LETTERS》 * |
| ALEX ALDER ET AL.,: "Intramolecular Thermal Cyclization Reactions of Diacryloylamines", 《J. AM. CHEM. SOC.》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061291A (en) * | 2015-09-08 | 2015-11-18 | 张涛 | Synthesis method of condensed-heterocycle-substituted indolone compounds |
| CN105061291B (en) * | 2015-09-08 | 2017-08-04 | 江俞 | A kind of synthetic method of miscellaneous thick cyclosubstituted indole ketone compound |
| CN111100057A (en) * | 2019-12-04 | 2020-05-05 | 天方药业有限公司 | Method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone |
| CN111100057B (en) * | 2019-12-04 | 2021-06-11 | 天方药业有限公司 | Method for synthesizing diclofenac sodium intermediate 1- (2, 6-dichlorophenyl) indoline-2-ketone |
| CN111138338A (en) * | 2020-01-20 | 2020-05-12 | 中国人民解放军61699部队 | Synthesis method of photocatalytic fluoroalkyl indoline |
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