CN105037239B - A kind of preparation method of the acetic acid of 4 chloro-indole 3 - Google Patents
A kind of preparation method of the acetic acid of 4 chloro-indole 3 Download PDFInfo
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- CN105037239B CN105037239B CN201510428781.9A CN201510428781A CN105037239B CN 105037239 B CN105037239 B CN 105037239B CN 201510428781 A CN201510428781 A CN 201510428781A CN 105037239 B CN105037239 B CN 105037239B
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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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses a kind of preparation method of the acetic acid of 4 chloro-indole 3, it is comprised the following steps that：1）Under 80 ~ 120 DEG C of temperature conditionss, in dry DMF solvent, compound I carries out condensation reaction generation compound II with DMFDMA；2）Compound II is dissolved using the mixed solvent of THF and alcohols, under 15 ~ 30 DEG C of temperature conditionss, in inert atmosphere, Raney's nickel is added and hydrazine hydrate is added dropwise and reacted, compound III is obtained after reaction completely；3）Compound III is dissolved using solvent, adds inorganic strong alkali, phase transfer catalyst, compound IV is added dropwise under 20 ~ 35 DEG C of temperature conditionss and carries out substitution reaction, after being added dropwise, temperature rising reflux, compound V is obtained after reaction completely；4）Compound V is hydrolyzed the acetic acid of 4 chloro-indole of target product 3 is made.Raw material employed in this preparation method is without toxic articles, whole course of reaction safety.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of preparation method of 4- chloro-indoles -3- acetic acid.
Background technology
4- chloro-indole -3- acetic acid (4-CIAA), it is a kind of IAA (heteroauxin) class auxin, can promotes to give birth to
It is long, it can also suppress to grow；Can vernalization, also can sprout inhibition；Fruit drop can be prevented, and can flower and fruit thinning, is possessed dual
Property.
The synthetic method of existing 4- chloro-indoles -3- acetic acid has following several：
Masato et al. (Biosci.Biotechnol.Biochem., 64 (4), 808-815,2000) is with the chloro- 6- nitre of 2-
Base benzene is that initiation material has synthesized 4- chloro-indole -3- acetic acid and its ester type compound of correlation, and this method route is longer, and three steps are anti-
It is 58.9% to answer total recovery, and product purity is low, while has used toxic articles cyanide, is unfavorable for the industrialized production of product.Its
Synthetic route is as follows：
Sharon Rossiter et al. (Bioorganici＆Medicinal Chemistry Letters 12 (2002)
Following route 2523-2526) is reported, although the route step is shorter, total recovery is low, only 38.7%, while in technique
Butyl lithium is used, its is expensive and high explosion danger be present, and raw material employs bromoacetate, in process of production can
Large quantity of exhaust gas is discharged, large-scale industrial production can not be realized.
Hiroyuki Ishibashi et al. (J.CHEM.SOC.PERKIN TRANS.1992) reported the conjunction of analog
Into, employ following route, the route reaction step is longer, total recovery be less than 40%, employ a non market-oriented sulfur-bearing
Raw material, its is costly, and simultaneous reactions post processing is cumbersome, can not large-scale production.
Therefore, exploitation one kind is while reaction yield is ensured, it is ensured that reacts the preparation of safe 4- chloro-indole -3- acetic acid
Method is very necessary.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 4- chloro-indoles -3- acetic acid, its operation is simple, uses original
Material is without toxic articles, the safe simultaneous reactions high income of reaction.
To reach above-mentioned purpose, the technical solution adopted by the present invention is：A kind of preparation method of 4- chloro-indoles -3- acetic acid,
Synthetic route is as follows：
Wherein：X- in compound IV is chlorion or bromide ion；
Comprise the following steps that：
1) under 80~120 DEG C of temperature conditionss, in dry DMF solvent, compound I carries out condensation reaction generation with DMFDMA
Compound II；
2) compound II is dissolved using the mixed solvent of THF and alcohols, under 15~30 DEG C of temperature conditionss, inert atmosphere
In, add Raney's nickel and hydrazine hydrate is added dropwise and reacted, compound III is obtained after reaction completely；
3) compound III is dissolved using solvent, inorganic strong alkali, phase transfer catalyst is added, in 20~35 DEG C of temperature conditionss
Lower dropwise addition compound IV carries out substitution reaction, after being added dropwise, temperature rising reflux, compound V is obtained after reaction completely；Herein,
Reflux temperature is 60~70 DEG C；
4) compound V is hydrolyzed and target product 4- chloro-indole -3- acetic acid is made.
Herein, compound I is the chloro- 6- nitrotoleunes of 2-；Compound II is N, the chloro- 6- nitrobenzene second of N- dimethyl -2-
Enamine；Compound III is 4- chloro-indoles；Compound IV is ethyl chloroacetate or bromoethyl acetate；Compound V is 4- chlorine Yin
Diindyl -3- ethyl acetate；DMFDMA is N,N-dimethylformamide dimethoxym ethane；DMF is dimethylformamide；THF is tetrahydrofuran.
Because the accessory substance in step 1), obtained through condensation reaction is DMF, therefore herein, to reduce in reaction system
Component, used solvent are dry DMF.
In order to improve the molar yield of 4- chloro-indoles, it is used for the solvent for dissolving the compound II herein, in step 2)
For THF and the mixed solvent of alcohols.
In step 2), in order under the premise of ensuring that reaction is complete, reduce the usage amount of catalyst, herein thunder Buddhist nun
Nickel feed intake quality be compound II 5%~20%.
As a kind of specific embodiment, the concrete operations of the step 4) are as follows：Compound V is dissolved in alcohols
With the in the mixed solvent of water, sodium hydroxide is then added, thermal reflow, product 4- chloro-indole -3- acetic acid is obtained after reaction completely.
The hydrolysis of compound V is carried out using this method, its reaction speed is fast, and byproduct of reaction is few.
It is further preferred that the compound V and the mass ratio of sodium hydroxide that are added in the step 4) are 1:0.4~
2。
Preferably, in step 1), compound I and DMFDMA mass ratio are 1：0.9~1.2；In step 2), compound
II, the mass ratio of hydrazine hydrate are 1:1~2；In step 3), compound III, inorganic strong alkali, the mass ratio of compound IV are 1:0.29
~0.5:0.85~1.
It is further preferred that the inorganic strong alkali described in step 3) is one in sodium hydroxide, potassium hydroxide, calcium hydroxide
Kind or a variety of mixtures.
Preferably, be used to dissolving in step 3) solvent of the compound III for toluene, ethylbenzene, one kind in dimethylbenzene or
A variety of mixtures.
It is further preferred that the phase transfer catalyst described in step 3) is triethyl benzyl ammonia chloride, the tetrabutyl is fluorinated
One or more mixtures in ammonium, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate.In order to ensure to react complete premise
Under, the usage amount of catalyst is reduced, herein, feed intake that quality is the compound III the 5% of described phase transfer catalyst
~15%.
Due to the utilization of above-mentioned technical proposal, the present invention has following advantages compared with prior art：The 4- chlorine of the present invention
The preparation method of indole-3-acetic acid, without toxic articles, and reaction raw materials are easy in the reaction raw materials used in this synthetic route
Obtain, be cheap, whole preparation process safety is without danger, suitable for industrialized production.
Brief description of the drawings
Accompanying drawing 1 is the hydrogen nuclear magnetic resonance spectrogram of 4- chloro-indoles, and abscissa is chemical shift；
Accompanying drawing 2 is the mass-spectrogram of 4- chloro-indoles；
Accompanying drawing 3 is the hydrogen nuclear magnetic resonance spectrogram of 4- chloro-indole -3- acetic acid, and abscissa is chemical shift；
Accompanying drawing 4 is the carbon-13 nmr spectra figure of 4- chloro-indole -3- acetic acid, and abscissa is chemical shift；
Accompanying drawing 5 is the mass-spectrogram of 4- chloro-indole -3- acetic acid.
Embodiment
Technical scheme is further elaborated with reference to specific embodiment and accompanying drawing.
Embodiment 1
A kind of preparation method of 4- chloro-indoles -3- acetic acid, its step are as follows：
1) synthesis of the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2-：By 200g 2- chloro- 6- nitrotoleunes, 183g
DMFDMA is added in 150ml anhydrous DMF solutions, is heated to 80~120 DEG C, insulation reaction 4 hours, is detected using GC detectors
Reaction end, after question response is complete, products therefrom is cooled to room temperature, and 1L toluene solutions are added by product into reaction system
Dissolving, after dissolving, is washed using saturated aqueous common salt, after through anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure to give N, N-
The chloro- 6- nitrostyrolenes amine crude product 290g of dimethyl -2-；
2) synthesis of 4- chloro-indoles：By 290g N, the chloro- 6- nitrostyrolenes amine crude products of N- dimethyl -2- are dissolved in
The in the mixed solvent of 250mlTHF and 250ml methanol, after dissolving, under the conditions of nitrogen protection, 30 DEG C, 40g Raney's nickels are added, and
The purity that 300ml is added dropwise is 80% hydrazine hydrate, by N,-the NO in the chloro- 6- nitrostyrolenes amine of N- dimethyl -2-2Be reduced into-
NH2, the C-N keys fracture in the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2- in-C=C-N-, and carried out in reaction system
Ring closure reaction, synthesis step is as follows, and products therefrom is filtered, and filtrate concentration, vacuum distillation obtain 4- chloro-indole sterling 135g,
Combining step 1) and 2) calculated yield can obtain molar yield obtained by 4- chloro-indoles is 76.4%；
The 4- chloro-indoles of gained are characterized below by infrared spectrum, proton nmr spectra, mass spectrum.
I), ir data is as follows：
IR(v,cm-1)：3372.8,2916.3,1699.0,1399.8,1204.5,732.4s.
II), hydrogen nuclear magnetic resonance modal data is as follows：
1H NMR(300K,CDCl3)：δ=8.3132 (s, 1H), 7.32-7.23 (m, 2H), 7.18-7.10 (m, 2H)
6.6940 (s, 1H)；As shown in Figure 1), it is defined as 4- chloro-indoles by identification, nuclear magnetic resonance hydrogen spectruming determining result.
III), mass spectrograph measurement result is as follows：
EI-MS (m/z, %) 152.0, as shown in Figure 2.
The compound molecular weight is 151.5, occurs 152.0 peak in spectrogram, and the peak at 152.0 is molecular ion peak.
Mass spectroscopy result is defined as 4- chloro-indoles.
3) synthesis of 4- chloro-indoles -3- ethyl acetate：76g 4- chloro-indoles are dissolved in 1L toluene solutions, add 22g's
Sodium hydroxide and 5.7g triethyl benzyl ammonia chlorides, 67g ethyl chloroacetate is added dropwise under 20~35 DEG C of temperature conditionss, drips
Bi Hou, is warming up to 60 DEG C of back flow reactions 16 hours, filters while hot, filtrate decompression is concentrated to give 4- chloro-indole -3- ethyl acetate crude products
130g；
4) synthesis of 4- chloro-indoles -3- acetic acid：By 130g 4- chloro-indole -3- ethyl acetate crude products be dissolved in 500ml water and
The in the mixed solvent of 500ml methanol, 60g sodium hydroxide is added, be heated to 60~70 DEG C of back flow reactions 3 hours.Then will be anti-
Answer liquid to be concentrated under reduced pressure into dry, raffinate is dissolved in 500ml water, add 500ml dichloromethane and washed, be layered, using dense salt
Acid adjusts aqueous phase pH to 1~2, is then extracted using ethyl acetate, merged with organic phase, then entered by anhydrous sodium sulfate
Row drying, 95g 4- chloro-indole -3- acetic acid crude products are concentrated to give, crude product is put into 500ml toluene solutions, stirred 4 hours
Afterwards, filtering, filtration cakes torrefaction, crystallized with alcohol-water after obtain sterling 4- chloro-indole -3- acetic acid 67g.
Combining step 3) and 4) calculated yield can obtain molar yield obtained by 4- chloro-indole -3- acetic acid is 63.8%；And with
The 200g chloro- 6- nitrotoleunes calculated yields of reaction initiation material 2-, the molar yield obtained by 4- chloro-indole -3- acetic acid are
48.74%, and its purity is more than 99%.
4- chloro-indole -3- the acetic acid of gained is characterized below by proton nmr spectra, carbon-13 nmr spectra.
I), hydrogen nuclear magnetic resonance modal data is as follows：
1H NMR(300K,DMSO)：δ=11.2564 (s, 1H), 7.38-7.32 (m, 2H), 7.08-6.98 (m, 2H),
3.9090(s,2H).As shown in figure 3, by identification, nuclear magnetic resonance hydrogen spectruming determining result is defined as 4- chloro-indole -3- acetic acid.
II), carbon-13 nmr spectra data are as follows：
13C NMR(300K,DMSO)：δ=173.7503,137.9351,126.4700,124.8737,124.0118,
121.8602 119.2866,110.8873,108.1167.It is as shown in figure 4, true by identification, carbon-13 nmr spectra measurement result
It is set to 4- chloro-indole -3- acetic acid.
III), LC-MS measurement results are as follows：
As shown in figure 5, mass spectral molecular ion peak is：(M+1) 211.1, (M+17) 227.1, mass spectroscopy result is defined as
4- chloro-indole -3- acetic acid.
Embodiment 2
A kind of preparation method of 4- chloro-indoles -3- acetic acid, its step are as follows：
1) synthesis of the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2-：With embodiment 1.
2) synthesis of 4- chloro-indoles -3- ethyl acetate：By the N of 290g made from step 1), the chloro- 6- nitre of N- dimethyl -2-
Base styrylamine crude product is dissolved in 500ml methanol solvates, after dissolving, under the conditions of nitrogen protection, 15 DEG C, adds 40g Raney's nickels,
And the hydrazine hydrate that the concentration that 300ml is added dropwise is 80%, by N,-the NO in the chloro- 6- nitrostyrolenes amine of N- dimethyl -2-2Reduction
Into-NH2, the C-N keys fracture in the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2- in-C=C-N-, and enter in reaction system
Row ring closure reaction, products therefrom is filtered, filtrate concentrates, vacuum distillation obtains 4- chloro-indole sterling 112g, combining step 1) and
2) molar yield that calculated yield can obtain obtained by 4- chloro-indoles is 63.5%, and its purity is more than 99%.Being compared with embodiment 1 can
Know：It is good using the mixed solvent of THF and alcohols to be merely not so good as using alcohols as the effect of solvent.
3) synthesis of 4- chloro-indoles -3- ethyl acetate：With embodiment 1.
4) synthesis of 4- chloro-indoles -3- acetic acid：With embodiment 1, with the 200g chloro- 6- nitrotoleunes of reaction initiation material 2-
Calculated yield, the molar yield obtained by 4- chloro-indole -3- acetic acid are 40.51%.
Embodiment 3
A kind of preparation method of 4- chloro-indoles -3- acetic acid, its step are as follows：
1) synthesis of the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2-：With embodiment 1.
2) synthesis of 4- chloro-indoles -3- ethyl acetate：With embodiment 1.
3) synthesis of 4- chloro-indoles -3- ethyl acetate：With embodiment 1.
4) synthesis of 4- chloro-indoles -3- acetic acid：By 130g 4- chloro-indole -3- ethyl acetate crude products be dissolved in 500ml water and
The in the mixed solvent of 500ml methanol, 120g sodium hydroxide is added, be heated to 60~70 DEG C of back flow reactions 3 hours.Then will be anti-
Answer liquid to be concentrated under reduced pressure into dry, raffinate is dissolved in 500ml water, add 500ml dichloromethane and washed, be layered, using dense salt
Acid adjusts aqueous phase pH to 1~2, is then extracted using ethyl acetate, merged with organic phase, then entered by anhydrous sodium sulfate
Row drying, 96g 4- chloro-indole -3- acetic acid crude products are concentrated to give, crude product is put into 500ml xylene solutions, stirring 4 is small
Shi Hou, filtering, filtration cakes torrefaction, sterling 4- chloro-indole -3- acetic acid 66g, combining step 3 are obtained after being crystallized with alcohol-water) and 4) count
The molar yield that calculating yield can obtain obtained by 4- chloro-indole -3- acetic acid is 62.8%, with the 200g chloro- 6- nitre of reaction initiation material 2-
Base toluene calculated yield, the molar yield obtained by 4- chloro-indole -3- acetic acid are 47.98%, and its purity is more than 99%.With embodiment
1 compares, it is known that, the molar yield of 4- chloro-indole -3- acetic acid can be reduced on the contrary by adding excessive highly basic.
Embodiment 4
A kind of preparation method of 4- chloro-indoles -3- acetic acid, its step are as follows：
1) synthesis of the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2-：With embodiment 1.
2) synthesis of 4- chloro-indoles：The chloro- 6- nitre of the N of the 290g as made from the step 1) in embodiment 1, N- dimethyl -2-
Base styrylamine crude product is dissolved in the in the mixed solvent of 250mlTHF and 250ml methanol, after dissolving, in nitrogen protection, 25 DEG C of conditions
Under, add 40g FeCl3/ C, and the hydrazine hydrate that the purity that 300ml is added dropwise is 80%, by N, the chloro- 6- nitros of N- dimethyl -2-
- NO in styrylamine2It is reduced into-NH2, the C-N keys in the chloro- 6- nitrostyrolenes amine of N, N- dimethyl -2- in-C=C-N- break
Split, and ring closure reaction is carried out in reaction system, synthesis step is as follows, and products therefrom is filtered, and filtrate concentration, is evaporated under reduced pressure
Obtain 4- chloro-indole sterling 68g, combining step 1) and 2) calculated yield can obtain molar yield obtained by 4- chloro-indoles is 38.5%,
As known from compared to Example 1, using FeCl3As catalyst preparation 4- chloro-indoles, the molar yield of gained is significantly smaller than to be adopted/C
By the use of the yield obtained by Raney's nickel as catalyst.
3) synthesis of 4- chloro-indoles -3- ethyl acetate：With embodiment 1.
4) synthesis of 4- chloro-indoles -3- acetic acid：With embodiment 1, with the 200g chloro- 6- nitrotoleunes of reaction initiation material 2-
Calculated yield, the molar yield obtained by 4- chloro-indole -3- acetic acid are 24.56%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar can understand present disclosure and be carried out, and it is not intended to limit the scope of the present invention, all according to the present invention
The equivalent change or modification that Spirit Essence is made, it should all cover within the scope of the present invention.
Claims (3)
1. a kind of preparation method of 4- chloro-indoles -3- acetic acid, it is characterised in that synthetic route is as follows：
Wherein：X- in compound IV is chlorine or bromine；
Comprise the following steps that：
1) under 80~120 DEG C of temperature conditionss, in dry DMF solvent, compound I carries out condensation reaction generation chemical combination with DMFDMA
Thing II, wherein, the compound I and DMFDMA mass ratio are 1：0.9~1.2；
2) compound II is dissolved using the mixed solvent of THF and alcohols, under 15~30 DEG C of temperature conditionss, in inert atmosphere,
Add Raney's nickel and hydrazine hydrate is added dropwise and reacted, compound III is obtained after reaction completely, wherein, the compound II, hydration
The mass ratio of hydrazine is 1:1~2；
3) compound III is dissolved using solvent, adds inorganic strong alkali, phase transfer catalyst, dripped under 20~35 DEG C of temperature conditionss
Add compound IV to carry out substitution reaction, after being added dropwise, temperature rising reflux, compound V is obtained after reaction completely, wherein, describedization
Compound III, inorganic strong alkali, the mass ratio of compound IV are 1:0.29~0.5:0.85~1, described inorganic strong alkali is hydroxide
One or more mixtures in sodium, potassium hydroxide, calcium hydroxide, for dissolve the solvent of the compound III for toluene,
One or more mixtures in ethylbenzene, dimethylbenzene, described phase transfer catalyst are triethyl benzyl ammonia chloride, the tetrabutyl
One or more mixtures in ammonium fluoride, tetrabutylammonium iodide, 4-butyl ammonium hydrogen sulfate, described phase transfer catalyst
The quality that feeds intake is the 5%~15% of the compound III；
4) compound V is dissolved in the in the mixed solvent of alcohols and water, then adds sodium hydroxide, thermal reflow, reaction is completely
After obtain product 4- chloro-indole -3- acetic acid.
2. the preparation method of 4- chloro-indoles -3- acetic acid according to claim 1, it is characterised in that:Institute in the step 4)
The compound V and the mass ratio of sodium hydroxide added is 1:0.4~2.
3. the preparation method of 4- chloro-indoles -3- acetic acid according to claim 1, it is characterised in that：It is described in step 2)
Raney's nickel feed intake quality be the compound II 5%~20%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002110A1 (en) * | 2000-06-30 | 2002-01-10 | Cancer Research Technology Limited | Use of indole-3-acetic acid derivatives in medicine |
| RU2430513C2 (en) * | 2009-12-04 | 2011-10-10 | Николай Михайлович Пржевальский | Plant growth stimulator based on 3-indolylacetic acid and production method thereof |
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2015
- 2015-07-21 CN CN201510428781.9A patent/CN105037239B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002110A1 (en) * | 2000-06-30 | 2002-01-10 | Cancer Research Technology Limited | Use of indole-3-acetic acid derivatives in medicine |
| RU2430513C2 (en) * | 2009-12-04 | 2011-10-10 | Николай Михайлович Пржевальский | Plant growth stimulator based on 3-indolylacetic acid and production method thereof |
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| Title |
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| Halogenated Indole-3-acetic Acids as Oxidatively Activated Prodrugs with Potential for Targeted Cancer Therapy;S. Rossiter et al.;《Bioorganic & Medicinal Chemistry Letters》;20020815;第12卷(第18期);第2523-2526页 * |
| Synthesis and Biological Activities of 4-Chloroindole-3-acetic Acid and Its Esters;Masato Katayama;《Biosci. Biotechnol. Biochem.》;20140522;第64卷(第4期);第808-815页 * |
| Synthesis and Evaluation of Some Substituted Indole Derivatives for Cardiovascular Activity;Navneet Singh et al.;《International Journal of Pharmaceutical Sciences and Drug Research》;20130331;第5卷(第1期);第14-17页 * |
| Synthesis of 2-[2"-carbomyl-5"-(heteroarylinomethylene)-1",3",4"-thiadiazol-2"-yl/oxadiazol-2"-yl)]-4,5-dihydroimidazolines as hypotensive agents;Mirdual Tyagi and Ashok Kumar;《Oriental Journal of Chemistry》;20021231;第18卷(第1期);第125-130页 * |
| Synthesis of new indole congeners as promising anti-inflammatory agents;DEEPAK KUMAR et al.;《Oriental Journal of Chemistry》;20101231;第26卷(第2期);第455-466页 * |
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