CN103288708B - The preparation method of 1- aryl -2- indolinone derivative - Google Patents
The preparation method of 1- aryl -2- indolinone derivative Download PDFInfo
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Abstract
The invention discloses a kind of methods for synthesizing 1- aryl -2- indolinone derivative, include the following steps: the aryl-substituted yl acetamide of N- (III) being dissolved in organic solvent, chlorination reagent is added, then reaction obtains the aryl-substituted yl acetamide of the chloro- N- of N- (II)；The aryl-substituted yl acetamide of the chloro- N- of N- and a certain amount of Lewis acid and appropriate organic solvent are reacted at a certain temperature, obtain 1- aryl -2- dihydroindolone (I).The method that invention provides is easy to operate, reagent is easy to get, cheap, mild condition, can synthesize a variety of 1- aryl -2- dihydroindolone (I) class compounds.
Description
Technical field
The present invention relates to the preparation methods of 1- aryl -2- indolinone derivative.
Background technique
1- aryl -2- indolinone derivative has important application value and research in medicine and chemical industry synthesis field
Meaning.It can be used as important intermediate and synthesizes a variety of chemical products and drug, such as nonsteroidal anti-inflammatory drug diclofenac sodium.
The document report synthetic method of a large amount of Benzazole compounds, still, synthesis for 1- aryl -2- indolinone derivative
Method report is less, and most important method is using friedel-craft reaction method building indolone cyclic structure (see Fig. 1).This method
There are reaction temperatures it is higher, cost of material is more expensive the disadvantages of.
Summary of the invention
The object of the present invention is to provide a kind of reagents to be easy to get, cheap, synthesis 1- virtue easy to operate, mild condition
The method of base -2- indolinone derivative (I).
Technical solution of the present invention is summarized as follows:
A method of synthesis 1- aryl -2- indolinone derivative includes the following steps: the aryl-substituted base of N-
Acetamide (III) is dissolved in organic solvent, and chlorination reagent is added, and then reaction obtains the aryl-substituted yl acetamide of the chloro- N- of N-
(II)；The aryl-substituted yl acetamide of the chloro- N- of N- and a certain amount of Lewis acid and appropriate organic solvent is anti-at a certain temperature
It answers, obtains 1- aryl -2- dihydroindolone (I).
Reaction equation are as follows:
Wherein, R1、R2It can separately or concurrently be H, NO2, NH2, F, Cl, Br, I, CN, OH, OCH3, OCH2O, CH3, CF3,
COOH, SO3H, CONH2, CONHR ', COOR '；Wherein R '=H or C1-10Alkyl (including alkyl and aryl)；Wherein R1、R2It can be with
For single, double or three replace simultaneously, position can be adjacent, alternate or opposite when single, double substitution.
Organic solvent are as follows: methylene chloride, chloroform, carbon tetrachloride, nitromethane, ether, ethyl acetate, hexamethylene,
N-hexane, trifluoroacetic acid, methanol, ethyl alcohol, petroleum ether, acetone, nitrobenzene, toluene, benzene, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy six
Ring, carbon disulfide, 1,2- dichloroethanes.
Chlorination reagent are as follows: NaOCl, t-BuOCl, NaOCl/HAc, NaOCl/HAc/t-BuOH, Ca (OCl)2/HAc、Ca
(OCl)2/Al2O3(wet)、TCCA、
Lewis acid are as follows: aluminum trichloride (anhydrous), silver nitrate, silver carbonate, silver sulfate, silver acetate, ferric trichloride, titanium tetrachloride,
Zinc chloride.
The molar ratio of Lewis acid catalyst and the chloro- N- of N- used (substituted aryl) substituted-phenyl acetamide (II): 0.3-1:
1。
Temperature are as follows: 0 DEG C-reflux temperature.
The present invention has raw material cheap and easy to get, and cost is relatively low, easy to operate, mild condition, high income, and post-processing is simple etc.
Feature.
Detailed description of the invention
Fig. 1 is the method for friedel-craft reaction building 1- aryl -2- dihydroindolone.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below.
The overall reaction equation of 1- aryl -2- indolinone derivative synthetic method of the present invention is as follows:
Embodiment 1
(a) preparation of N- (2,6- dichlorophenyl) phenyl acetamide (III-a)
Method one:
To the 250ml three-necked flask that thermometer, constant pressure funnel, reflux condensing tube and anhydrous calcium chloride drying tube are housed
In sequentially add 16.20g (0.1mol) 2,6-DCA, 9.49g (0.12mol) pyridine and 100ml acetone.Stirring, ice water
Bath cooling, is slowly added dropwise 15.45g (0.1mol) phenyllacetyl chloride.After completion of dropwise addition, ice-water bath is removed.Heating, flow back 4h.Stop
Reaction.
Reaction solution is poured into while hot in the hydrochloric acid solution of 250ml 1.5mol/L, a large amount of yellow blocks of solid occur.It will consolidate
Body filters out, successively with the 3mol/L hydrochloric acid solution of 100ml × 2, the 1mol/L NaOH solution of 100ml × 2,100ml × 2 go from
Sub- water washing.It is dry, obtain yellow solid.95% ethyl alcohol recrystallization obtains white needle-like crystals 26.50g, yield 94.6%.Fusing point:
177.0-177.8℃。
Method two:
To the 250ml three-necked flask that thermometer, constant pressure funnel, reflux condensing tube and anhydrous calcium chloride drying tube are housed
In sequentially add 16.20g (0.1mol) 2,6-DCA, 12.12g (0.12mol) triethylamine and 150ml methylene chloride.It stirs
It mixes, ice-water bath is cooling, and 15.45g (0.1mol) phenyllacetyl chloride is slowly added dropwise, and control reacting liquid temperature is no more than 25 DEG C.Knot is added dropwise
Shu Hou removes ice-water bath.Heating, flow back 6h.Stop reaction.
50ml deionized water is added into reaction solution after reaction, a large amount of white solids are precipitated.Filtering, filter cake are used
The washing of the deionized water of 100ml × 3.Filtrate liquid separation, separates organic phase.Organic phase successively use 50ml × 2 10%NaOH solution,
The hydrochloric acid solution of the 3mol/L of 50ml × 2, the washing of the deionized water of 250ml × 2.It depressurizes and steams after organic phase anhydrous magnesium sulfate drying
Except solvent, light yellow solid is obtained.Merge obtained solid, dry, 95% ethyl alcohol recrystallization obtains white needle-like crystals 24.50g, yield
87.5%.
Method three:
To the 250ml three-necked flask that thermometer, constant pressure funnel, reflux condensing tube and anhydrous calcium chloride drying tube are housed
Middle addition 16.20g (0.1mol) 2,6-DCA and 80ml pyridine.Stirring, ice-water bath is cooling, and 15.45g is slowly added dropwise
(0.1mol) phenyllacetyl chloride.After completion of dropwise addition, ice-water bath is removed.Heating, flow back 4h.Stop reaction.
Reaction solution evaporating solvent under reduced pressure, obtains yellow solid.Successively with the deionized water of l00ml × 2, the 3mol/L of 100ml × 2
Hydrochloric acid solution, the NaOH solution of the 1mol/L of 100ml × 2, the washing of the deionized water of 100ml × 2.It is dry, 95% ethyl alcohol recrystallization
Obtain white needle-like crystals 27.53g, yield 98.3%.
(b) preparation of the chloro- N- of N- (2,6- dichlorophenyl) phenyl acetamide (II-a)
Method one:
The 250ml three-necked flask equipped with constant pressure funnel, anhydrous calcium chloride drying tube wrapped up with aluminium foil is placed in ice
In water-bath, 28.00g (0.1mol) N- (2,6- dichlorophenyl) phenyl acetamide and 100ml methylene chloride is added.Stirring, will
(the preparation method reference: Teeter H M, Bell E W.tert- of 11.39g (0.105mol) freshly prepd t-butyl hypochlorate
Butyl hypochlorite.Organic Syntheses, Coll Vol 4:125) it is added drop-wise in reaction solution dropwise.It finishes
Afterwards, reaction temperature is increased to 25 DEG C, the reaction was continued 10h, stopping reaction.
Reaction solution evaporating solvent under reduced pressure is dried in vacuo 12h under the conditions of 20 DEG C.Yellowish solid 31.44g is obtained, yield is about
100%.
Method two:
Dress thermometer, constant pressure funnel and churned mechanically 500ml three-necked flask are placed in ice-water bath, are added
28.00g (0.1mol) N- (2,6- dichlorophenyl) phenyl acetamide and 100ml methylene chloride.Stirring, by 154.00ml sodium hypochlorite
Solution (available chlorine content >=10%) is added in flask.When temperature drops to 5 DEG C or less, it is added dropwise dropwise into reaction solution
39.40ml acetic acid, temperature maintain 5 DEG C hereinafter, being at the uniform velocity added dropwise in 2h.Continue to stir 1h, stops reaction.
By reaction solution liquid separation.Organic phase is washed with the deionized water of 50ml × 2.Anhydrous magnesium sulfate dries organic phase, and decompression is steamed
Except solvent, it is dried in vacuo 12h.Obtain faint yellow solid 31.20g, yield 99.2%.
Method three:
The 50ml three-necked flask of dress thermometer, constant pressure funnel and electromagnetic agitation is placed in ice-water bath, is sequentially added
1.40g (5mmol) N- (2,6- dichlorophenyl) phenyl acetamide, 25ml methylene chloride and 2.50g (2.5equiv, based on effective chlorine
Obtain) calcium hypochlorite.Stirring.When temperature drops to 5 DEG C or less, 3.00g acetic acid is added dropwise dropwise into reaction solution.Temperature maintains
At 5 DEG C hereinafter, being at the uniform velocity added dropwise in 30min.Continue to stir 1h, stops reaction.
Reaction solution is filtered.Filter cake is washed with the methylene chloride of 15ml × 2.Merge organic phase.Organic phase with 5ml × 2 go from
Sub- water washing.Anhydrous magnesium sulfate dries organic phase, and evaporating solvent under reduced pressure is dried in vacuo 12h.Obtain white solid 1.51g, yield
96.0%.
Method four:
1.40g (5mmol) N- (2,6- dichlorophenyl) is added into tri- mouthfuls of the 50ml burnings equipped with thermometer and electromagnetic agitation
Phenyl acetamide, 25ml methylene chloride.Stirring is opened, 2.00g (2equiv is calculated by available chlorine content) hypochlorous acid is added
The wet aluminum oxide of calcium, 5.00g.25 DEG C or so reaction 10h.Stop reaction.
Reaction solution is filtered, filter cake is washed with the methylene chloride of 15ml × 2.Merge organic phase.Organic phase with 5ml × 2 go from
Sub- water washing.Anhydrous magnesium sulfate dries organic phase, and evaporating solvent under reduced pressure is dried in vacuo 12h.Obtain white solid 1.49g, yield
94.8%.
Method five:
2.80g is sequentially added into the three-necked flask equipped with thermometer, constant pressure funnel and churned mechanically 25ml
(10mmol) N- (2,6- dichlorophenyl) phenyl acetamide, 10ml methylene chloride and 1.85g (10mmol) sym-closene
(TCCA).Stirring is opened, it reacts at room temperature for 24 hours.Stop reaction.
Reaction solution is filtered.Column chromatography for separation is carried out after filtrate concentration.Obtain white solid 2.91g, yield 92.5%.
Method six:
Three-necked flask equipped with thermometer, constant pressure funnel and churned mechanically 50ml is placed in ice-water bath, successively
2.80g (10mmol) N- (2,6- dichlorophenyl) phenyl acetamide, 10ml methylene chloride and 0.37g (5mmol) tert-butyl alcohol is added.It opens
Stirring is opened, 12.30ml liquor natrii hypochloritis (available chlorine content >=10%) is added into flask.And it is dripped dropwise in backward reaction solution
Add 3.15ml acetic acid, temperature maintains 5 DEG C hereinafter, being at the uniform velocity added dropwise in 30min.Ice-water bath is removed, continues to stir at room temperature
1h.Stop reaction.
By reaction solution liquid separation.Organic phase is washed with the deionized water of 50ml × 2.Anhydrous magnesium sulfate dries organic phase, and decompression is steamed
Except solvent, it is dried in vacuo 12h.Obtain faint yellow solid 3.13g, yield 99.5%.
Method seven:
2.80g (10mmol) N- (2,6- bis- is sequentially added in equipped with thermometer and churned mechanically 100ml three-necked flask
Chlorphenyl) phenyl acetamide, 18.40g (30mmol)1.76g (30mmol) sodium chloride, 0.5ml water and 50ml dichloromethane
Alkane.Stirring is opened, is reacted at room temperature for 24 hours.Stop reaction.
Reaction solution is filtered.Filtrate is washed with the deionized water of 10ml × 2.Anhydrous magnesium sulfate dries organic phase, removes under reduced pressure
Solvent is dried in vacuo 12h.Obtain white solid 3.14g, yield 99.8%.
(c) preparation of 1- (2,6- dichlorophenyl) -2- dihydroindolone (I-a)
Method one:
The chloro- N- of N- (2, the 6- dichlorophenyl) phenyl acetamide (II-a) of 31.46g (0.1mol) is added to 500mL round bottom
In bottle, 250mL methylene chloride, stirring is added.It is cooling in ice-water bath.33.25g (0.25mol) aluminum trichloride (anhydrous) is added.Ice water
4h is reacted under the conditions of bath.The 8h that then moves to that the reaction was continued at room temperature.Stop reaction.
By reaction solution under the conditions of 30 DEG C evaporating solvent under reduced pressure.Obtained solid is extracted with the toluene of 50ml × 3.Merge organic
Phase.5ml deionized water is added into organic phase, yellow solid occurs.Filtering, washs filter cake with the toluene of 30ml × 3.Merge organic
Phase, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains faint yellow solid.Recrystallizing methanol obtains faint yellow granular solids 18.41g,
Yield 66.2%.Fusing point: 123.0-123.7 DEG C.ESI-MS m/z 278[M+H]+；1H-NMR (400MHz, CDCl3)δppm
7.51 (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:
The chloro- N- of N- (2, the 6- dichlorophenyl) phenyl acetamide (II-a) of 31.46g (0.1mol) is added to 500mL round bottom
In bottle, 250mL methylene chloride is added, 33.25g (0.25mol) aluminum trichloride (anhydrous) is added in stirring.React 4h.Stop reaction.
Reaction solution is poured into ice water, a large amount of yellow solids are generated.Filtering, by filtrate liquid separation.Water phase 50ml dichloromethane
Alkane extraction is primary.Merge organic phase, washed with the deionized water of 3ml × 2, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure obtains black
Solid.This solid obtains yellowish solid 10.80g, yield 38.9% through column chromatography for separation.
Method three:
The chloro- N- of N- (2, the 6- dichlorophenyl) phenyl acetamide (II-a) of 3.15g (10mmol) is added to 100mL round-bottomed bottle
In, 50mL trifluoroacetic acid, stirring is added.It is cooling in ice-water bath.3.32g (20mmol) aluminum trichloride (anhydrous) is added.Ice-water bath item
8h is reacted under part.Stop reaction, evaporating 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- chlorphenyl) phenyl acetamide (III-b)
Using parachloroanilinum and phenyllacetyl chloride as raw material, N- (4- chlorphenyl) phenylacetyl is prepared according to embodiment 1 (a) method one
Amine (III-b), it is final to obtain white needle-like crystals 23.95g, yield 96.3%.Fusing point: 161.5-163.9 DEG C
(b) preparation of the chloro- N- of N- (4- chlorphenyl) phenyl acetamide (II-b)
With N- (4- chlorphenyl) phenyl acetamide (III-b) for raw material, the chloro- N- of N- is prepared according to embodiment 1 (b) method one
(4- chlorphenyl) phenyl acetamide (II-b), it is final to obtain faint yellow solid 27.98g, yield about 100%.
(c) preparation of 1- (4- chlorphenyl) -2- dihydroindolone (I-b)
With the chloro- N- of N- (4- chlorphenyl) phenyl acetamide (II-b) for raw material, 1- (4- is prepared according to embodiment 1 (c) method one
Chlorphenyl) -2- dihydroindolone (I-b), it is final to obtain faint yellow solid 17.61g, yield 72.3%.Fusing point: 126.6-127.6
℃。ESI-MS m/z 244[M+H]+；1H-NMR (400MHz, CDCl3) δ ppm 7.50 (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 (5)
1. a kind of method for synthesizing 1- aryl -2- indolinone derivative, feature include the following steps: to replace N- aryl
Phenyl-acetamides (III) are dissolved in organic solvent, and chlorination reagent is added, and then reaction obtains the aryl-substituted base acetyl of the chloro- N- of N-
Amine (II)；At a certain temperature by the aryl-substituted yl acetamide of the chloro- N- of N- and a certain amount of Lewis acid and appropriate organic solvent
Reaction, obtains 1- aryl -2- dihydroindolone (I)；Reaction equation are as follows:
Wherein, R1、R2It can separately or concurrently be H, NO2, NH2, F, Cl, Br, I, CN, OH, OCH3, OCH2O, CH3, CF3, COOH,
SO3H, CONH2, CONHR ', COOR '；Wherein R '=C1-10Alkyl；Wherein R1、R2Can be it is single, double or three replace simultaneously, singly,
Position can be adjacent, alternate or opposite when disubstituted；
The certain temperature is 0 DEG C-reflux temperature.
2. according to the method described in claim 1, it is characterized in that the organic solvent are as follows: methylene chloride, chloroform, four chlorinations
Carbon, nitromethane, ether, ethyl acetate, hexamethylene, n-hexane, trifluoroacetic acid, methanol, ethyl alcohol, petroleum ether, acetone, nitro
Benzene, toluene, benzene, acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, carbon disulfide, 1,2- dichloroethanes.
3. according to the method described in claim 1, it is characterized in that the chlorination reagent are as follows: NaOCl, t-BuOCl, NaOCl/HAc,
NaOCl/HAc/t-BuOH、Ca(OCl)2/HAc、Ca(OCl)2/Al2O3、TCCA。
4. according to the method described in claim 1, it is characterized in that the Lewis is sour are as follows: aluminum trichloride (anhydrous), silver nitrate, carbonic acid
Silver, silver sulfate, silver acetate, ferric trichloride, titanium tetrachloride, zinc chloride.
5. according to the method described in claim 1, it is characterized in that the Lewis acid catalyst and the chloro- N- aryl of N- used replace
The molar ratio of phenyl-acetamides (II) is 0.3-1: 1.
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| CN105061291B (en) * | 2015-09-08 | 2017-08-04 | 江俞 | A kind of synthetic method of miscellaneous thick cyclosubstituted indole ketone compound |
| 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 |
Citations (1)
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| CZ280388B6 (en) * | 1990-01-08 | 1996-01-17 | Chemopharma A.S. | Sodium ortho-(2,6-dichloroaniline)-phenylacetate purification method |
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Patent Citations (1)
| 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 |
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| 2-[(2,6-二氯苯基)氨基]苯乙酸钾的合成;李桂英等;《长春工业大学学报(自然科学版)》;20071231;第28卷(第4期);第462页图1和第462-463页1.2 |
| An efficient synthesis of 4-bromo-N-substituted oxindoles by an intramolecular copper-catalyzed amidation reaction;Adri van den Hoogenband et al.,;《Tetrahedron Letters》;20070510;第48卷;第4462页左栏scheme 2，右栏Table 1 |
| Intramolecular Thermal Cyclization Reactions of Diacryloylamines;Alex Alder et al.,;《J. Am. Chem. Soc.》;19831231;第105卷(第22期);第6712页Scheme I和6713页(5) |
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