CN118530155B - Method for preparing 7-methylindole under normal temperature condition - Google Patents
Method for preparing 7-methylindole under normal temperature condition Download PDFInfo
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- CN118530155B CN118530155B CN202411004695.0A CN202411004695A CN118530155B CN 118530155 B CN118530155 B CN 118530155B CN 202411004695 A CN202411004695 A CN 202411004695A CN 118530155 B CN118530155 B CN 118530155B
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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
- C07D209/08—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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Abstract
The invention discloses a method for preparing 7-methylindole at normal temperature, belonging to the technical field of application chemistry. The method comprises the following steps: preparing vinyl Grignard reagent in a reaction kettle; slowly dropwise adding titanium tetraisopropoxide into a newly prepared vinyl Grignard reagent at 0 ℃ under the protection of nitrogen, raising the temperature of the system to normal temperature, reacting for 1h, then adding o-nitrotoluene into a vinyl Grignard reagent/titanium tetraisopropoxide mixed solution in batches at 0 ℃, slowly raising the temperature of the system to normal temperature, and reacting overnight; quenching reaction and post-treatment. The invention has the advantages that: under the participation of titanium tetraisopropoxide, the o-nitrotoluene and the vinyl Grignard reagent can react at normal temperature to prepare 7-methylindole, the reaction condition is mild, the operation is simple, and the method is suitable for large-scale preparation of 7-methylindole in actual production.
Description
Technical Field
The invention relates to a method for preparing indole derivatives, in particular to a method for preparing 7-methylindole under normal temperature, belonging to the technical field of application chemistry.
Background
7-Methylindole is an indole derivative. Indole and its derivatives are important organic raw materials and chemical products, and are widely used for preparing pesticides, medicines, dyes, fragrances, plant growth regulators, feed additives and the like. 7-methylindole is a reactant in the synthesis of alpha-aminoamides, which are present in a variety of biologically active compounds.
Currently, the preferred method for synthesizing 7-substituted indoles is the Bartoli Indole synthesis, i.e., the reaction of ortho-substituted nitrobenzene with an excess (typically three times the amount) of alkenyl grignard reagent at low temperature (-40 ℃) followed by post-treatment in aqueous solution to give 7-substituted indoles. Reaction mechanism: firstly, adding a first equivalent of Grignard reagent to an oxygen atom of a nitro group to obtain an O-alkenyl intermediate, then quickly eliminating the generated O-alkenyl intermediate to obtain nitrosoaromatic hydrocarbon, reacting the nitrosoaromatic hydrocarbon with a second equivalent of Grignard reagent to obtain an O-alkenyl hydroxylamine derivative, then carrying out [3,3] -sigma migration on the generated O-alkenyl hydroxylamine derivative, carrying out nucleophilic attack on a ring in a molecule, extracting hydrogen by using a third equivalent of Grignard reagent as a base, cyclizing the aromatic hydrocarbon, and finally acidizing and dehydrating to obtain indole.
The preparation method of Bartoli Indole needs to prepare 7-substituted indole at a low temperature of-40 ℃, so that 7-methylindole is limited in practical production.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a method for preparing 7-methylindole under the normal temperature condition.
In order to achieve the above object, the present invention adopts the following technical scheme:
A method for preparing 7-methylindole under normal temperature conditions, comprising the following steps:
(1) Preparing vinyl Grignard reagent in a reaction kettle;
(2) Under the protection of nitrogen, the temperature of a reaction kettle is reduced to 0 ℃, titanium tetraisopropoxide is slowly dripped into a newly prepared vinyl Grignard reagent, the temperature of the system is increased to normal temperature, the reaction is carried out for 1h, the temperature of the system is reduced to 0 ℃, ortho-nitrotoluene is added into a vinyl Grignard reagent/titanium tetraisopropoxide mixed solution in batches, the temperature of the system is slowly increased to normal temperature, and the reaction is carried out overnight;
(3) Quenching the reaction, removing most of the solvent by rotary evaporation, extracting with dichloromethane, merging organic phases, drying with anhydrous sodium sulfate, filtering, and rotary drying the organic phases to obtain crude products;
(4) Dissolving the crude product in dichloromethane, filtering by using a rapid silica gel column, collecting and spin-drying filtrate, then adding n-heptane, heating to boil, then reducing the system temperature to 0 ℃, pulping, filtering slurry to obtain a filter cake, and drying the filter cake to obtain the 7-methylindole.
Preferably, in the step (1), the preparation method of the vinyl grignard reagent specifically comprises the following steps: dissolving bromoethylene in tetrahydrofuran or methyl tertiary butyl ether, adding into a reaction kettle, adding magnesium scraps, raising the temperature of the system to normal temperature, adding 1, 2-dibromoethane for initiating reaction, taking heat preservation measures, and carrying out heat preservation reaction for 2 hours to prepare a vinyl Grignard reagent; wherein the mass ratio of the bromoethylene, the magnesium chips and the 1, 2-dibromoethane is 100:200:1.
Preferably, in step (2), the mass ratio of ortho-nitrotoluene, titanium tetraisopropoxide and vinyl grignard reagent is 0.5:1:2 to 3.
Preferably, in step (3), the reaction is quenched with a saturated solution of ammonium chloride.
Preferably, in step (4), the step of rinsing the filter cake with n-heptane is further included.
The invention has the advantages that: under the participation of titanium tetraisopropoxide, the o-nitrotoluene and the vinyl Grignard reagent can react at normal temperature to prepare 7-methylindole, the reaction condition is mild, the operation is simple, and the method is suitable for large-scale preparation of 7-methylindole in actual production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 7-methylindole;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 7-methylindole;
FIG. 3 is a high performance liquid chromatogram of 7-methylindole.
Detailed Description
The method for preparing 7-methylindole provided by the invention still takes o-nitrotoluene and vinyl Grignard reagent as raw materials, and is different from Bartoli Indole synthesis methods in that titanium tetraisopropoxide (generated by the titanium tetraisopropoxide and the Grignard reagent) is introduced, and the o-nitrotoluene and the vinyl Grignard reagent react under normal temperature under the participation of the titanium tetraisopropoxide to prepare the 7-methylindole.
The invention is described in detail below with reference to the drawings and the specific embodiments.
Example 1
214G of bromoethylene (2.0 mol) is dissolved in 1L of Tetrahydrofuran (THF) and added into a reaction kettle, 96g of magnesium turnings (4.0 mol) is then added, the temperature of the system is raised to normal temperature (25 ℃), 1.7mL of 1, 2-dibromoethane (0.02 mol) is added for initiating reaction, heat preservation measures are taken, and the reaction is carried out for 2 hours, thus preparing the vinyl Grignard reagent (2.0 mol).
Under the protection of nitrogen, the temperature of a reaction kettle is reduced to 0 ℃, 284g of titanium tetraisopropoxide (1.0 mol) is slowly added into the freshly prepared vinyl Grignard reagent in a dropwise manner, the temperature of the system is increased to normal temperature, the reaction is continued for 1h, then the temperature of the system is reduced to 0 ℃, 69g of o-nitrotoluene (0.5 mol) is added into the mixed solution of the vinyl Grignard reagent and the titanium tetraisopropoxide in batches (3 batches, each batch is 23g, the time interval is 15 min), the temperature of the system is slowly increased to normal temperature, and the reaction is carried out overnight.
Adding saturated ammonium chloride solution into the system to quench the reaction, removing most THF by rotary evaporation, extracting with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, and rotary drying the organic phases to obtain crude products.
The crude product is dissolved in methylene dichloride, filtered by a rapid silica gel column (the mass of silica gel is 10 times of that of o-nitrotoluene), the filtrate is collected and dried by spin-drying, then 500mL of n-heptane is added, the system temperature is slowly reduced to 0 ℃ for pulping for 1h, filter cakes are obtained by filtering slurry with filter cloth, the filter cakes are leached twice by the n-heptane, and finally the filter cakes are dried to obtain off-white crystals with the yield of 212g and the yield of 81 percent.
The data of the nuclear magnetic resonance hydrogen spectrum (figure 1), the nuclear magnetic resonance carbon spectrum (figure 2) and the mass spectrum of the off-white crystal are specifically as follows:
1 H NMR (400 MHz, chloroform -d）δ7.54（d,J=7.7Hz,1H）,7.20（dd,J=3.2,2.5Hz,1H）,7.08（t,J=7.4Hz,1H）,7.03（dt,J=7.2,1.0Hz,1H）,6.59（dd,J=3.2,2.0Hz,1H）,2.51（s,3H）;)
13 C NMR (101 MHz, chloroform-d) delta 135.66, 127.67, 124.37, 122.76, 120.65, 120.34, 118.77, 103.17, 16.87;
ESI-MS: c 9H9N（[M-H] +) calculated molecular weight 131.0708, theoretical 131.1825.
The data of the above-mentioned nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum confirm that the off-white crystal is 7-methylindole.
The purity of the product 7-methylindole was 99.9% as determined by high performance liquid chromatography (FIG. 3).
Example 2
Substantially the same as in example 1, the only difference is that: the amount of vinyl grignard reagent was reduced to 1.0mol so that the mass ratio of titanium tetraisopropoxide to the vinyl grignard reagent was 1:1, wherein the preparation method of the vinyl Grignard reagent specifically comprises the following steps: 107g of bromoethylene (1.0 mol) is dissolved in 1L of Tetrahydrofuran (THF) and added into a reaction kettle, 48g of magnesium turnings (2.0 mol) is added, the temperature of the system is raised to normal temperature (25 ℃), 0.8mL of 1, 2-dibromoethane (0.01 mol) is added for initiating reaction, heat preservation measures are taken, and the reaction is carried out for 2 hours, thus preparing the vinyl Grignard reagent (1.0 mol).
Finally, 88g of 7-methylindole was produced in a yield of 34% and with a purity of 98.2%.
Example 3
Substantially the same as in example 1, the only difference is that: the amount of vinyl grignard reagent was increased to 3.0mol so that the mass ratio of titanium tetraisopropoxide to the vinyl grignard reagent was 1:3, wherein the preparation method of the vinyl Grignard reagent specifically comprises the following steps: 321g of bromoethylene (3.0 mol) is dissolved in 1L of Tetrahydrofuran (THF) and added into a reaction kettle, then 144g of magnesium turnings (6.0 mol) are added, the temperature of the system is raised to normal temperature (25 ℃), 2.5mL of 1, 2-dibromoethane (0.03 mol) is added for initiating reaction, heat preservation measures are taken, and the reaction is carried out for 2 hours, thus preparing the vinyl Grignard reagent (3.0 mol).
Finally, 196g of 7-methylindole was produced in a yield of 75% and with a purity of 99.1%.
Example 4
Substantially the same as in example 1, the only difference is that: the amount of vinyl grignard reagent was increased to 4.0mol so that the mass ratio of titanium tetraisopropoxide to the vinyl grignard reagent was 1:4, the preparation method of the vinyl Grignard reagent specifically comprises the following steps: 428g of bromoethylene (4.0 mol) is dissolved in 1L of Tetrahydrofuran (THF) and added into a reaction kettle, 192g of magnesium turnings (8.0 mol) is added, the temperature of the system is raised to normal temperature (25 ℃), 3.2mL of 1, 2-dibromoethane (0.04 mol) is added for initiating reaction, heat preservation measures are taken, and the reaction is carried out for 2 hours, so that vinyl Grignard reagent (4.0 mol) is prepared.
Finally, 41.5g of 7-methylindole was prepared in a yield of 16% and a purity of 98.4%.
From examples 1 to 4, it can be seen that: the addition ratio of the vinyl grignard reagent to the titanium tetraisopropoxide has a great influence on the formation of 7-methylindole, wherein when the addition ratio of the titanium tetraisopropoxide to the vinyl grignard reagent (the mass ratio of substances) is 1:2, the yield of 7-methylindole is highest and reaches 81%, and when the addition amount of vinyl grignard reagent is continuously increased, the generation of byproducts is obviously increased, and analysis is probably due to the fact that the conversion efficiency of titanium tetraisopropoxide is insufficient, and the residual high-activity vinyl grignard reagent reacts with nitro on o-nitrotoluene.
The reaction mechanism is presumed to be as follows: the Grignard reagent and the titanium tetraisopropoxide are firstly prepared into dialkyl titanium, one vinyl group in the dialkyl titanium is nucleophilic to attack nitro to generate a nitroso intermediate, the other vinyl group in the dialkyl titanium is then to attack nitroso to generate intramolecular cyclization, and then the construction of indole ring is completed after [3, 3] rearrangement and dehydration.
。
Example 5
Substantially the same as in example 1, the only difference is that: in the preparation of vinyl grignard reagent, tetrahydrofuran was replaced with methyl tert-butyl ether in equal volumes.
Finally, 193g of 7-methylindole was prepared in 74% yield with a purity of 99.2%.
It should be noted that the above examples are only examples for clearly illustrating the present invention, and are not limiting to the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. Not all embodiments are exhaustive. Obvious changes and modifications which are extended by the technical proposal of the invention are still within the protection scope of the invention.
Claims (5)
1. A method for preparing 7-methylindole under normal temperature conditions, which is characterized by comprising the following steps:
(1) Preparing vinyl Grignard reagent in a reaction kettle;
(2) Under the protection of nitrogen, the temperature of a reaction kettle is reduced to 0 ℃, titanium tetraisopropoxide is slowly dripped into a newly prepared vinyl grignard reagent, the temperature of a system is increased to normal temperature, the reaction is carried out for 1h, the temperature of the system is reduced to 0 ℃, ortho-nitrotoluene is added into a vinyl grignard reagent/titanium tetraisopropoxide mixed solution in batches, and the mass ratio of the ortho-nitrotoluene, the titanium tetraisopropoxide and the vinyl grignard reagent is 0.5:1: 2-3, slowly increasing the temperature of the system to normal temperature, and reacting overnight;
(3) Quenching the reaction, removing most of the solvent by rotary evaporation, extracting with dichloromethane, merging organic phases, drying with anhydrous sodium sulfate, filtering, and rotary drying the organic phases to obtain crude products;
(4) Dissolving the crude product in dichloromethane, filtering by using a rapid silica gel column, collecting and spin-drying filtrate, then adding n-heptane, heating to boil, then reducing the system temperature to 0 ℃, pulping, filtering slurry to obtain a filter cake, and drying the filter cake to obtain the 7-methylindole.
2. The method according to claim 1, wherein in step (1), the vinyl grignard reagent is prepared by the following method:
and (3) dissolving bromoethylene in tetrahydrofuran or methyl tertiary butyl ether, adding the solution into a reaction kettle, adding magnesium chips, raising the temperature of the system to normal temperature, adding 1, 2-dibromoethane for initiating reaction, taking heat preservation measures, and carrying out heat preservation reaction for 2 hours to prepare the vinyl Grignard reagent.
3. The method according to claim 2, wherein the mass ratio of the substances of vinyl bromide, magnesium turnings and 1, 2-dibromoethane is 100:200:1.
4. The process according to claim 1, wherein in step (3), the reaction is quenched with a saturated solution of ammonium chloride.
5. The method of claim 1, further comprising the step of rinsing the filter cake with n-heptane in step (4).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011111675A1 (en) * | 2010-03-08 | 2011-09-15 | 大日本住友製薬株式会社 | Novel indole derivative |
| CN110922404A (en) * | 2019-11-22 | 2020-03-27 | 南京正济医药研究有限公司 | Process for preparing 5-hydroxy-7-azaindoles |
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| FR1357604A (en) * | 1959-06-26 | 1964-04-10 | Roussel Uclaf | Process for the preparation of a disubstituted typtamine and resulting products |
| CN103755622A (en) * | 2013-12-25 | 2014-04-30 | 华东理工大学 | Method for synthesizing 4,5,6-7-D4indole-3-acetic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011111675A1 (en) * | 2010-03-08 | 2011-09-15 | 大日本住友製薬株式会社 | Novel indole derivative |
| CN110922404A (en) * | 2019-11-22 | 2020-03-27 | 南京正济医药研究有限公司 | Process for preparing 5-hydroxy-7-azaindoles |
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