CN111606838A - Preparation method of bis-indolyl methane compound - Google Patents
Preparation method of bis-indolyl methane compound Download PDFInfo
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- CN111606838A CN111606838A CN202010564172.7A CN202010564172A CN111606838A CN 111606838 A CN111606838 A CN 111606838A CN 202010564172 A CN202010564172 A CN 202010564172A CN 111606838 A CN111606838 A CN 111606838A
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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
- C07D209/12—Radicals substituted by oxygen atoms
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- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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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
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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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- 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
- C07D209/20—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 substituted additionally by nitrogen atoms, e.g. tryptophane
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Abstract
The invention discloses a preparation method of a bis-indolyl methane compound, which comprises the following steps: (1) adding aromatic aldehydes, indoles and a trace amount of catalyst water serving as reaction substrate raw materials into a reaction kettle respectively; (2) heating to 110-180 ℃ in a sealed state, and keeping for a certain time; (3) stopping heating, cooling the reaction kettle to room temperature to 80 ℃, and adding an organic solvent to flush the materials into a collecting tank; (4) carrying out solid-liquid separation, washing and recrystallization to obtain a target product bis-indolyl methane compound; (5) collecting the solvent mother liquor, recovering the product, and recovering the solvent for reuse. Compared with the prior art, the invention has the advantages that: low cost and environmental protection.
Description
Technical Field
The invention relates to the technical field of bis-indolyl methane compounds, in particular to a preparation method of a bis-indolyl methane compound.
Background
The bis-indolyl methane (BIMs) derivatives have wide application in the fields of essence, perfume, dye, medicine and agriculture, and are very important basic organic raw materials. The general synthesis method is an alkylation reaction of indole compounds and aldehydes or ketones in a solvent under the catalysis of a catalyst. Wherein the catalyst comprises acidic catalysts such as protonic acid, Lewis acid-surfactant, solid acid and the like; the solvent is dichloroethane, etc., or water and surfactant in water phase system. These processes are all carried out in open vessels, requiring stirring or milling; the catalyst is difficult to recycle and is easy to cause water pollution in general; or the catalyst preparation is complicated; or preparing organic waste liquid containing a large amount of toxic metals and surfactants due to demulsification and washing in a Lewis acid-surfactant combination (LASCs) catalyst system in an aqueous phase, and particularly generating toxic waste water containing a large amount of surfactant sodium dodecyl sulfate which is difficult to treat. Generally, the yield of various catalytic reactions is not high, the subsequent purification waste is large in production amount, and a large amount of waste liquid is generated due to the fact that a large amount of organic solvent participates in the reaction, the atom economy of the whole process is poor, the cost is high, the pollution is serious, and therefore the industrial large-scale application is difficult. Therefore, the present invention is to overcome or solve the above problems and to provide a new technical method of high efficiency, cleanness and greenness under thermal catalysis without catalyst and non-toxic solvent and trace amount of water.
Disclosure of Invention
The invention aims to overcome the technical defects and provide a preparation method of a bis-indolyl methane compound with low cost and environmental protection.
In order to solve the technical problems, the technical scheme provided by the invention is as follows: a preparation method of bis-indolyl methane compounds comprises the following steps:
(1) adding aromatic aldehydes, indoles and a trace amount of catalyst water serving as reaction substrate raw materials into a reaction kettle respectively;
(2) heating to 110-180 ℃ in a sealed state, and keeping for a certain time;
(3) stopping heating, cooling the reaction kettle to room temperature to 80 ℃, and adding an organic solvent to flush the materials into a collecting tank;
(4) carrying out solid-liquid separation, washing and recrystallization to obtain a target product bis-indolyl methane compound;
(5) collecting the solvent mother liquor, recovering the product, and recovering the solvent for reuse.
Compared with the prior art, the invention has the advantages that: when the preparation method of the bis-indolyl methane compound is used, other catalysts are not needed for reaction, only water is needed, the use of the catalysts in the preparation reaction process can be eliminated, a large number of resources are saved, the use cost is reduced, the pollution of a toxic solvent in the preparation reaction process can be reduced through the high-efficiency mass transfer and the self-solvent thermal catalytic effect of a reaction system, the high-efficiency and clean production of the bis-indolyl methane derivative is realized, the phenomena that the catalysts are difficult to recycle and pollute the environment are avoided, and the preparation method is more environment-friendly.
As an improvement, the feeding ratio of the aromatic aldehydes and the indoles as the reaction substrate raw materials in the step (1) is 1:2 mol.
As an improvement, the catalyst used in the step (1) is water, and the using amount of the catalyst is 0.185-1.85 mol% of the raw materials of the reaction substrates.
As an improvement, the reaction pressure in the step (2) is 1-10 atm.
As an improvement, the reaction time in the step (2) is 20 to 180 minutes.
As a modification, the temperature distribution of the reaction apparatus in (3) is measured by using an infrared measuring instrument.
As an improvement, the organic solvent added into the washing material in the step (3) is one of polar solvents or a mixed solvent with any proportion.
Detailed Description
The present invention is further described in the following by specific examples, which are illustrative only and not limiting, and should not be construed as limiting the scope of the present invention.
Example 1
P-nitrobenzaldehyde (0.25mmol, 0.0418 g) and indole (0.5mmol, 0.0585 g) are respectively added into a pressure-resistant closed hydrothermal reaction kettle with the volume of 10 ml, and the kettle is placed in a heater. Measuring the temperature of the reaction kettle from room temperature to 160 ℃ by infrared rays, keeping heating at the temperature for 1 hour, and stopping heating; after the temperature of the reaction kettle is reduced to room temperature (about 25 ℃), opening the reaction kettle, tracking and monitoring the reaction result by TLC thin-layer chromatography (a solvent with a volume ratio of petroleum ether to ethyl acetate of 3:1 is used as a developing agent), after preliminarily confirming that the reaction basically tends to be completed, adding dichloromethane (5mL multiplied by 2) in batches, stirring and dispersing, transferring the mixture into a suction filtration device, carrying out suction filtration, and washing until the mixture is dried to obtain the target product, wherein the yield of the product is 90%; the collected dichloroethane mother liquor is reused after solvent is recovered by evaporation. And determining the product as a target product through nuclear magnetism.
Example 2
The reaction substrate feed ratio and feed amount, reaction vessel, and basic operation were the same as in example 1 except that a small amount of water was added, the temperature and time of the reaction were changed, and the yield of the reaction was followed and monitored as shown in Table 1. The results show that the external trace water has obvious thermal catalytic effect at the temperature of 160 ℃ and 180 ℃.
TABLE 1 results of influence of reaction temperature on yield of reaction product
Example 3
P-nitrobenzaldehyde (1mol, 16.713 g), indole (2mol,23.430 g) and 8 ml of water were put in a pressure-resistant closed reaction vessel having a volume of 1 l, respectively, and placed in a heater. Measuring the temperature of the reaction kettle from room temperature to 160 ℃ by infrared rays, keeping heating at the temperature for 1 hour, and stopping heating; after the temperature of the reaction vessel was lowered to room temperature (about 25 ℃), the reaction vessel was opened, the solids in the reaction vessel were taken out into a 1-liter open vessel, and the reaction result was monitored by TLC thin layer chromatography (a solvent in a volume ratio of petroleum ether to ethyl acetate 3:1 as a developing solvent) with follow-up, and it was preliminarily confirmed that the content of the reaction product was close to 98%. Then adding dichloromethane (300mL multiplied by 3) in batches into a container containing the crude product, stirring and dispersing, transferring to a suction filtration device for suction filtration and washing till the crude product is dry; the obtained light yellow solid is a product with the purity of more than 99.9 percent, and the yield is 96 percent. The collected dichloroethane mother liquor is evaporated to recover the solvent and then reused. And determining the product as a target product through nuclear magnetism.
Example 4
The basic procedure, i.e.the reaction conditions, are as in example 1, except that the substrate aromatic aldehyde 1 is different from that of Ar-R1(R1Is a substituent, substituted indole compound 2 (R)2Is a substituent). No catalyst and no solvent were added. The yields after isolation and purification are shown in Table 2.
Table 2 preparation of bis-indolylmethane derivatives for different substituent classes without catalyst and solvent the nuclear magnetic spectra of some representative compounds are shown in figure 1:
FIG. 1 NMR spectra
Therefore, the reaction process of the preparation method of the bis-indolyl methane compound provided by the invention is as follows: aromatic aldehydes, indole compounds and trace water which are raw materials of a reaction substrate are respectively added into a pressure-resistant reactor, then the pressure-resistant reactor is heated to be below 200 ℃ in a closed state, and the substrates in the reactor are liquefied and gasified, so that the hydrothermal synthesis reaction of a target product is realized under the thermal catalysis of a little water generated by reaction and water vapor added with fresh water; part of raw materials are used as solvents to play the role of the solvents in the whole process, and no additional solvent is needed; a small amount of water as a byproduct generated by the reaction forms a high-efficiency diffusion conduction hydrothermal system with a substrate at the temperature of more than 110 ℃ and less than 200 ℃, and the high-efficiency synthesis of a target product is realized within 3 hours; subsequently, the heating was stopped, the reactor was allowed to cool to room temperature to 80 ℃ and the material was discharged for subsequent separation and purification. Or adding an organic solvent to wash the materials into a collecting tank, and then continuing to carry out solid-liquid separation, washing and recrystallization to obtain the target product bis-indolyl methane compound. Collecting the solvent mother liquor, recovering the product, and recovering the solvent for reuse. Compared with the known synthetic method, the solvothermal synthetic method has the advantages of high substrate conversion rate, easy separation and purification of the target product bis-indolyl methane derivative, easy mass production, simple equipment, easy operation and simple post-treatment. Therefore, the preparation method of the bis-indolyl methane compound provided by the invention is low in cost and environment-friendly.
Claims (7)
1. The preparation method of the bis-indolyl methane compound is characterized by comprising the following steps:
(1) adding aromatic aldehydes, indoles and a trace amount of catalyst water serving as reaction substrate raw materials into a reaction kettle respectively;
(2) heating to 110-180 ℃ in a sealed state, and keeping for a certain time;
(3) stopping heating, cooling the reaction kettle to room temperature to 80 ℃, and adding an organic solvent to flush the materials into a collecting tank;
(4) carrying out solid-liquid separation, washing and recrystallization to obtain a target product bis-indolyl methane compound;
(5) collecting the solvent mother liquor, recovering the product, and recovering the solvent for reuse.
2. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: the feeding proportion of the reaction substrate raw material aromatic aldehyde and the indole in the step (1) is 1:2 mol.
3. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: the catalyst used in the step (1) is water, and the using amount of the catalyst is 0.185-1.85 mol% of the reaction substrate raw material.
4. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: the reaction pressure in the step (2) is 1-10 atmospheric pressure.
5. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: the reaction time in the step (2) is 20-180 minutes.
6. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: and (3) measuring the temperature distribution of the reaction device by using an infrared measuring instrument.
7. The method for preparing bis-indolylmethane compounds according to claim 1, wherein the method comprises the following steps: the organic solvent added in the step (3) is one of polar solvents or a mixed solvent with any proportion.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706829A (en) * | 2005-05-12 | 2005-12-14 | 苏州大学 | Double indolyl derivative synthesizing process |
| CN105732466A (en) * | 2016-04-27 | 2016-07-06 | 上海应用技术学院 | Preparation method of 4-hydroxy phenyl bis(indolyl) methane |
| CN106999610A (en) * | 2014-12-11 | 2017-08-01 | Rf 医疗公司 | Include the targeted contrast agent of hydrazides functional group |
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2020
- 2020-06-19 CN CN202010564172.7A patent/CN111606838B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706829A (en) * | 2005-05-12 | 2005-12-14 | 苏州大学 | Double indolyl derivative synthesizing process |
| CN106999610A (en) * | 2014-12-11 | 2017-08-01 | Rf 医疗公司 | Include the targeted contrast agent of hydrazides functional group |
| CN105732466A (en) * | 2016-04-27 | 2016-07-06 | 上海应用技术学院 | Preparation method of 4-hydroxy phenyl bis(indolyl) methane |
Non-Patent Citations (2)
| Title |
|---|
| FEI HE,ET.: ""Glycerol as a promoting medium for electrophilic activation of aldehydes:catalyst-free synthesis of di(indolyl)methanes, xanthene-1,8(2H)-diones and 1-oxo-hexahydroxanthenes"", 《GREEN CHEMISTRY》 * |
| 刘雄伟等: ""双吲哚烷基类化合物在无催化剂和无溶剂条件下的高效合成"", 《应用化学》 * |
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