CN104311469A - Synthetic method of substituted indole-3-acetic acid - Google Patents
Synthetic method of substituted indole-3-acetic acid Download PDFInfo
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- substituted indole
- acetic acid
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- diacetyl
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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
Abstract
A synthetic method of substituted indole-3-acetic acid provided by the invention comprises the following steps: (1) subjecting a starting material substituted indole and an acylation reagent to Friedel-Crafts acylation in the presence of a catalyst to obtain 1,3-diacetyl substituted indole; (2) subjecting an intermediate 1,3-diacetyl substituted indole without refining directly to a Willgerodt-Kindler rearrangement reaction with morpholine and sulfur, hydrolyzing under the catalysis of inorganic alkaline and acidifying to obtain substituted indole-3-acetic acid.
Description
Technical field
The invention belongs to organic chemical synthesis field, particularly a kind of synthetic method of substituted indole-3-acetic acid.
Background technology
Indole-3-acetic acid is the very important natural auxin of a class, has the effect of promotion and coordinate plant growth at low concentrations, shows the effect of hormone weedkiller in higher concentrations.Substituted indole-3-phenylacetic acid compound is also the important chemical intermediate of a class, has vital role in fields such as weedicide, growth hormone, molecular imprinting, biological metabolism researchs.
At present, indole-3-acetic acid can synthesize by the following method:
" Organic Syntheses ", 44 volume 64 pages (1964) reports, take indoles as raw material, the confined reaction under 250 DEG C of conditions with oxyacetic acid and potassium hydroxide aqueous solution, obtains indole-3-acetic acid through cooling, extraction, acidifying, lucifuge drying.Synthetic route is as follows:
This route is a common method preparing indole-3-acetic acid, but the method temperature of reaction is higher, and will use closed reactor, and operation is inconvenient, yield is lower, is not suitable for suitability for industrialized production.
Chinese patent CN102807567A reports, is raw material, reacts with oxalyl chloride at-5 DEG C with indoles, then adds potassium hydroxide aqueous solution and hydrazine hydrate backflow 48h, obtains indole-3-acetic acid.Synthetic route is as follows:
This route uses the hydrazine hydrate that toxicity is larger in a large number, and operating process is dangerous, and environmental pollution is serious, and long reaction time, is not suitable for suitability for industrialized production.
" Phytochemistry ", 72 (volume) 2008-2016 page (2011) reports, is that raw material obtains indole-3-acetic acid through thioglucoside enzyme catalysis with indole-3-acetonitrile.Synthetic route is as follows:
The raw material indole-3-acetonitrile of this route is obtained through polystep reaction by biological enzyme, and process is complicated, and by product is more.
If applied chemistry method is by indoles, dimethylamine, formaldehyde and potassium cyanide Reactive Synthesis indole-3-acetonitrile, then route is longer, and potassium cyanide is highly toxic substance, is not suitable for suitability for industrialized production.
Summary of the invention
Goal of the invention: in order to overcome above-mentioned the deficiencies in the prior art, the object of the present invention is to provide a kind of synthetic method of substituted indole-3-acetic acid, to solve the technical problems such as existing synthetic method Road line length, material toxicity is large, operation is inconvenient.
Technical scheme: the synthetic method of a kind of substituted indole-3-acetic acid provided by the invention, comprises the following steps:
(1) take substituted indole as starting raw material, with acylting agent heating reflux reaction under catalyst action, obtain 1,3-diacetyl substituted indole through Fu-Ke acylations;
(2) intermediate 1 of step (1), 3-diacetyl substituted indole without the need to refining, directly and morpholine and sulphur heating reflux reaction, through Willgerodt-Kindler rearrangement reaction, be hydrolyzed under mineral alkali catalysis, after acidifying, obtain substituted indole-3-acetic acid;
Synthetic route is as follows:
Wherein, R is any substituting group, as fluorine, chlorine, bromine, iodine, alkyl, amino, alkoxyl group, benzyl, cyano group,
Nitro, alkyloyl and carbalkoxy etc. are group arbitrarily, can be the optional position of 4-, 5-, 6-, 7-position on indole ring.
In step (1), described catalyzer is Lewis acid, preferred aluminum chloride, iron trichloride, zinc chloride, most preferably aluminum chloride.
In step (1), acylting agent is Acetyl Chloride 98Min., diacetyl oxide or acetic acid, preferred Acetyl Chloride 98Min..
In step (1), reaction solvent is methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), methyl alcohol, diacetyl oxide, toluene, benzene, preferred methylene dichloride.
In step (1), temperature of reaction is 20 ~ 120 DEG C, preferably 30 ~ 60 DEG C.
In step (1), the mol ratio of substituted indole and acylting agent is 1:(1 ~ 3), preferred 1:2.
In step (2), the consumption of described intermediate 1,3-diacetyl substituted indole, in starting raw material substituted indole, is 1:(3 ~ 5 with the mol ratio of morpholine and sulphur): (1 ~ 3), preferred 1:3.7:2.5.
In step (2), back flow reaction temperature is 100 ~ 150 DEG C, preferably 110 ~ 130 DEG C.
In step (2), described mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methylate, sodium hydride, preferred sodium hydroxide; Described acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid etc., preferred hydrochloric acid.
Beneficial effect: it is short that the synthetic method of substituted indole-3-acetic acid provided by the invention has route, and yield is high, reaction conditions is gentle, easy to operate, avoids the advantages such as environmental pollution, is suitable for suitability for industrialized production.
Specifically, the inventive method has following outstanding advantage relative to prior art:
(1) synthetic route is short, aftertreatment is easy, and various raw material sources used are extensive and stable, without the need to special processing, is applicable to scale operation;
(2) operational condition is gentle, and without the need to high temperature or low-temp reaction, production cost is low;
(3) avoid using the large raw material of toxic side effect and solvent, operational safety, decreases environmental pollution and harm.
Embodiment
Below in conjunction with specific embodiment; essence of the present invention is understood in exemplary illustration and help further; but embodiment detail is only in order to the present invention is described; do not represent the present invention and conceive lower whole technical scheme; therefore should not be construed as the technical scheme total to the present invention to limit, some are In the view of technician, and the unsubstantiality not departing from the present invention's design increases or changes; such as simply change with the technical characteristic with same or similar technique effect or replace, all belonging to scope.
Synthesis substituted indole-3-acetic acid leads to method:
In the there-necked flask of drying, add 5.0mmol substituted indole successively, 23.0mmol catalyzer, 10.0mL solvent, 10.0mmol acylting agent is slowly dropped in there-necked flask, stirring and refluxing 4 ~ 8h.By in reaction product impouring 15.0mL frozen water, separate organic phase, decompression and solvent recovery, obtain 1,3-diacetyl substituted indole.Directly add 18.5mmol morpholine and 12.5mmol sulphur, stirring and refluxing 3 ~ 9h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% alkaline solution composition, reflux 1 ~ 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with diluted acid, separates out solid.Suction filtration, is washed to neutrality, recrystallization, productive rate 61 ~ 90%.Section Example the results are shown in Table 1.
Embodiment 1
Synthesis 4-chloro-indole-3-acetic acid
Embodiment 1-1
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.9g (4.4mmol) 4-chloro-indole-3-acetic acid, productive rate 87.9%, HPLC >=98%, fusing point 185-187 DEG C.IR(KBr,cm
-1)：3365,3350,1698,1620。
1H?NMR(CD
3OD,ppm)δ：3.88(s,2H),6.80(d,1H,J＝3.6Hz),6.82(d,1H,J＝5.6Hz),7.00(brs,1H),7.12(dd,1H,J＝5.6,3.6Hz)。
Embodiment 1-2
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.7g (23.0mmol) iron trichloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.8g (3.8mmol) 4-chloro-indole-3-acetic acid, productive rate 76.3%.
Embodiment 1-3
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 1.0g (10.0mmol) diacetyl oxide in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4 chloro-indole, directly adds 1.6 (18.5mmol) morpholines and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.7g (3.4mmol) 4-chloro-indole-3-acetic acid, productive rate 68.0%.
Embodiment 1-4
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL tetracol phenixin, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 75 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.8g (3.8mmol) 4-chloro-indole-3-acetic acid, productive rate 75.4%.
Embodiment 1-5
8g (50.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 31g (230.0mmol) aluminum chloride, 100mL methylene dichloride, slowly drops to 4g (50mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 150mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4 chloro-indole, directly adds 16.1g (185mmol) morpholine and 4.0g (125mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 50mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 30mL 70% ethanol and 20mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 6.9g 4-chloro-indole-3-acetic acid, productive rate 66.1%.
Embodiment 1-6
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 1.2g (15.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4 chloro-indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.9g (4.3mmol) 4-chloro-indole-3-acetic acid, productive rate 85.3%.
Embodiment 1-7
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 1.3g (15.0mmol) morpholine and 0.2g (5.0mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.7g (3.1mmol) 4-chloro-indole-3-acetic acid, productive rate 61.8%.
Embodiment 1-8
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 2.2g (25.0mmol) morpholine and 0.5g (15.0mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.9g (4.3mmol) 4-chloro-indole-3-acetic acid, productive rate 85.1%.
Embodiment 1-9
0.8g (5.0mmol) 4-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) zinc chloride, (reaction solvent can choose reasonable as required for 10.0mL chloroform, methylene dichloride, ethylene dichloride, chloroform, tetrahydrofuran (THF), methyl alcohol, diacetyl oxide, toluene, benzene all can as reaction solvents), solution containing 10.0mmol acetic acid is slowly dropped in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-4-chloro-indole, directly adds 2.2g (25.0mmol) morpholine and 0.5g (15.0mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, add 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filter, cooling, (alkaline solution can choose reasonable as required to add 3.0mL 70% ethanol and 2.0mL 15% potassium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium methylate, sodium hydride all can as alkaline solutions) mixing solutions of solution composition, reflux 2h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2, separates out solid with hydrochloric acid (acid solution can choose reasonable as required, and hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid all can as acid solutions).Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.9g (4.3mmol) 4-chloro-indole-3-acetic acid, productive rate 85.1%.
Embodiment 2
Synthesis 5-methoxy-Indole-3-acetic acid
0.7g (5.0mmol) 5-methoxy-Indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 8h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-5-methoxy-Indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 6h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 80% ethyl alcohol recrystallization, obtains 0.9g (4.3mmol) 5-methoxy-Indole-3-acetic acid, productive rate 85.2%, HPLC >=98%, fusing point 147-149 DEG C.
1H?NMR(CDCl
3,ppm)δ：3.53(s,2H,CH
2COOH)3.67(s,3H,OCH
3),6.63(dd,J＝8.8,2.3Hz,1H,H
6),6.87(d,J＝2.3Hz,1H,H
2),6.98(s,1H,H
4),7.08(d,J＝8.8Hz,1H,H
7),9.33(bs,1H,NH)。
Embodiment 3
Synthesis 6-nitroindoline-3-acetic acid
0.8g (5.0mmol) 6-nitroindoline is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 6h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-6-nitroindoline, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 5h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 95% ethyl alcohol recrystallization, obtains 0.9g (4.1mmol) 6-nitroindoline-3-acetic acid, productive rate 82.5%, HPLC >=97%, fusing point 212-214 DEG C.Ultimate analysis C
10h
8n
2o
4: C, 54.6; H, 3.7.Found:C,54.2；H,3.8。
Embodiment 4
Synthesis 7-chloro-indole-3-acetic acid
0.8g (5.0mmol) 7-chloro-indole is added successively in the there-necked flask of drying, 3.1g (23.0mmol) aluminum chloride, 10.0mL methylene dichloride, slowly drops to 0.8g (10.0mmol) Acetyl Chloride 98Min. in there-necked flask, is heated to 40 DEG C of backflow 7h.By in mixture impouring 15.0mL frozen water, separate organic phase, steaming desolventizes and obtains 1,3-diacetyl-7-chloro-indole, directly adds 1.6g (18.5mmol) morpholine and 0.4g (12.5mmol) sulphur, is heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 5.0mL methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 3.0mL 70% ethanol and 2.0mL 15% sodium hydroxide solution composition, reflux 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 0.9g (4.3mmol) 6-nitroindoline-3-acetic acid, productive rate 85.1%, HPLC >=97%, fusing point 163-165 DEG C.Ultimate analysis C
10h
8nClO
2: C, 57.3; H, 3.8.Found:C,57.2；H,3.9。
Embodiment 5
Synthesis 4-fluoro indole-3-acetic acid
In the there-necked flask of drying, add 6.8kg 4-fluoro indole successively, 30.7kg aluminum chloride, 50.0L methylene dichloride, 7.9kg Acetyl Chloride 98Min. is slowly dropped in there-necked flask, be heated to 40 DEG C of backflow 8h.By in mixture impouring 80.0L frozen water, separate organic phase, recycling design, obtain 1,3-diacetyl-4-fluoro indole, directly add 16.1kg morpholine and 4.0kg sulphur, be heated to 120 DEG C of backflow 8h.Rearrangement reaction is complete, adds 50.0L methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 30.0L 70% ethanol and 20.0L 15% sodium hydroxide solution composition, reflux 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 7.7kg 4-fluoro indole-3-acetic acid, productive rate 79.5%, HPLC >=98%, fusing point 128-129 DEG C.IR(KBr，cm
-1)：3440,1737,1632。
1HNMR(10％CD
3OD?in?CDCl
3，ppm)δ：3.82(s,2H),6.39-7.06(4H，m),8.57(1H,brs，NH)。
Embodiment 6
Synthesis 4-bromo indole-3-acetic acid
In the there-necked flask of drying, add 98.0kg 4-bromo indole successively, 307.0kg aluminum chloride, 500L methylene dichloride, 79.0kg Acetyl Chloride 98Min. is slowly dropped in there-necked flask, be heated to 40 DEG C of backflow 8h.By in mixture impouring 800L frozen water, separate organic phase, recycling design, obtain 1,3-diacetyl-4-bromo indole, directly add 161kg morpholine and 40.0kg sulphur, be heated to 120 DEG C of backflow 5h.Rearrangement reaction is complete, adds 500L methyl alcohol, heating for dissolving, activated carbon decolorizing, filters, cooling, adds the mixing solutions of 300L 70% ethanol and 200L 15% sodium hydroxide solution composition, reflux 4h.Reaction is finished, and filter, decompression and solvent recovery, adds suitable quantity of water, is adjusted to pH=1 ~ 2 with dilute hydrochloric acid, separates out solid.Suction filtration, is washed to neutrality, uses 60% ethyl alcohol recrystallization, obtains 102.2kg 4-bromo indole-3-acetic acid, productive rate 85.2%, HPLC >=98%, fusing point 185-187 DEG C.IR(KBr，cm
-1)：3360,3050,1697。
1HNMR(50％CD
3OD?in?CDCl
3，ppm)δ：3.96(s,2H),6.78(t,1H，J＝7.5Hz),7.01(brs,1H),7.05(dd,1H,J＝7.5,1.6Hz),7.09(dd,1H,J＝5.6,1.6Hz)。
Table 1 section Example result
To those skilled in the art, under this patent design and specific embodiment enlightenment, some distortion that can directly derive from this patent disclosure and general knowledge or associate, or in prior art, commonly use substituting of known technology, and the mutual various combination between feature, such as change the substituting group on indole ring or change substituent position, the solvent do not pointed out in reaction solvent specification sheets substitutes, temperature of reaction, the change of time, acid, the change of alkali, etc. unsubstantiality change, can be employed equally, this patent representation function and effect can be realized, expansion of illustrating no longer is one by one described in detail, all belong to this patent protection domain.
Claims (7)
1. a synthetic method for substituted indole-3-acetic acid, is characterized in that comprising the following steps:
(1) take substituted indole as starting raw material, with acylting agent heating reflux reaction under catalyst action, obtain 1,3-diacetyl substituted indole through Fu-Ke acylations;
(2) intermediate 1 of step (1); 3-diacetyl substituted indole without the need to refining, directly and morpholine and sulphur heating reflux reaction, through Willgerodt-Kindler rearrangement reaction; be hydrolyzed under mineral alkali catalysis, after acidifying, obtain substituted indole-3-acetic acid.
2. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1, it is characterized in that: in step (1), described catalyzer is Lewis acid, preferred aluminum chloride, iron trichloride, zinc chloride, most preferably aluminum chloride.
3. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1, it is characterized in that: in step (1), acylting agent is Acetyl Chloride 98Min., diacetyl oxide or acetic acid, preferred Acetyl Chloride 98Min..
4. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1, it is characterized in that: in step (1), reaction solvent is methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), methyl alcohol, diacetyl oxide, toluene, benzene, preferred methylene dichloride.
5. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1, is characterized in that: in step (1), and the mol ratio of described substituted indole and acylting agent is 1:(1 ~ 3), preferred 1:2.
6. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1; it is characterized in that: in step (2); described intermediate 1; 3-diacetyl substituted indole is without the need to refining; in starting raw material substituted indole; be 1:(3 ~ 5 with the mol ratio of morpholine, sulphur): (1 ~ 3), preferred 1:3.7:2.5.
7. the synthetic method of a kind of substituted indole-3-acetic acid according to claim 1, it is characterized in that: in step (2), described mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methylate, sodium hydride, preferred sodium hydroxide; Described acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid etc., preferred hydrochloric acid.
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| WO2018164214A1 (en) * | 2017-03-08 | 2018-09-13 | 国立大学法人名古屋大学 | Plant growth regulator |
| CN114573496A (en) * | 2022-04-08 | 2022-06-03 | 贵州大学 | Preparation method of 4-chloroindole-3-acetic acid |
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Cited By (5)
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| WO2018164214A1 (en) * | 2017-03-08 | 2018-09-13 | 国立大学法人名古屋大学 | Plant growth regulator |
| JPWO2018164214A1 (en) * | 2017-03-08 | 2020-01-23 | 国立大学法人名古屋大学 | Plant growth regulator |
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| CN114573496B (en) * | 2022-04-08 | 2023-11-07 | 贵州大学 | Preparation method of 4-chloroindole-3-acetic acid |
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