CN110698352B - Synthetic method of 3-bromo-5-aminocatechol dimethyl ether - Google Patents
Synthetic method of 3-bromo-5-aminocatechol dimethyl ether Download PDFInfo
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- CN110698352B CN110698352B CN201911038687.7A CN201911038687A CN110698352B CN 110698352 B CN110698352 B CN 110698352B CN 201911038687 A CN201911038687 A CN 201911038687A CN 110698352 B CN110698352 B CN 110698352B
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Abstract
The invention relates to a synthesis method of 3-bromine-5-amino-catechol dimethyl ether, which comprises three steps of reactions: s1: 2-methoxy-4-nitrophenol is taken as an initial raw material, and 2-methoxy-4-nitro-6-bromophenol is obtained through bromination; s2: methylating the phenolic group on the 2-methoxy-4-nitro-6-bromophenol to obtain 3-bromo-5-nitro-catechol dimethyl ether; s3, reducing the nitro group on the 3-bromo-5-nitro-catechol dimethyl ether into amino group to prepare the 3-bromo-5-amino-catechol dimethyl ether. The invention provides a new synthesis path of 3-bromo-5-aminocatechol dimethyl ether, which is characterized in that 2-methoxy-4-nitrophenol is used as an initial raw material to synthesize a final product through 3 steps of reactions such as bromination, methylation and reduction, the reaction steps are simple, intermediate products and target products are easy to separate, the environmental pollution is less, the cost is low, the total yield is high (more than 75 percent), and the industrial production is easy to realize.
Description
Technical Field
The invention relates to a synthetic method of an organic chemical intermediate, in particular to a synthetic method of 3-bromine-5-amino catechol dimethyl ether.
Background
The organic chemical intermediate is an important part in chemical production, is not only a product of a basic raw material, but also a raw material of fine chemical engineering, and has a profound influence on the application aspect of chemical production. China classifies fine chemicals into 11 categories such as dyes, catalysts, additives and the like according to actual conditions, wherein intermediates or raw materials for producing the fine chemicals are collectively called chemical intermediates. Organic chemical intermediates are often used in the fields of medicine, dyes, resins, plasticizers, and the like. Therefore, the synthesis research of the organic chemical intermediate with a specific structure has important significance.
The 3-bromo-5-amino catechol dimethyl ether has a unique chemical structure and good reaction activity, and amino groups in molecules can be further converted into various derivatives after diazotization, so that the 3-bromo-5-amino catechol dimethyl ether has potential application values in the fields of medicines, dyes and the like.
Disclosure of Invention
Technical problem to be solved
In order to solve the problems in the prior art, the invention provides a method for synthesizing 3-bromo-5-aminocatechol dimethyl ether.
(II) technical scheme
In order to achieve the purpose, the invention adopts the main technical scheme that:
the invention provides a synthetic method of 3-bromine-5-amino-catechol dimethyl ether, which comprises three steps of reactions:
s1: 2-methoxy-4-nitrophenol is taken as an initial raw material, and 2-methoxy-4-nitro-6-bromophenol is obtained through bromination;
s2: methylating the phenolic group on the 2-methoxy-4-nitro-6-bromophenol to obtain 3-bromo-5-nitro-catechol dimethyl ether;
s3, reducing the nitro group on the 3-bromo-5-nitro-catechol dimethyl ether into amino group to prepare 3-bromo-5-amino-catechol dimethyl ether;
the reaction sequence of the above steps S1-S3 is described as follows:
according to a preferred embodiment of the present invention, step S1: reacting 2-methoxy-4-nitrophenol with a brominating agent in a solvent to generate 2-methoxy-4-nitro-6-bromophenol; the brominating reagent is selected from one or more of bromine, N-bromosuccinimide and sodium bromate, and the solvent is selected from one or more of carbon tetrachloride, trichloromethane, acetic acid and water.
Further preferably, the brominating reagent is bromine, and the solvent is chloroform.
The reaction is carried out at room temperature, and the reaction time is more than 4 hours; and after the reaction is finished, cooling to room temperature, quenching unreacted bromine by using sodium bisulfite, washing to be neutral, removing trichloromethane by rotary evaporation, and drying to obtain an intermediate product 2-methoxy-4-nitro-6-bromophenol.
According to the preferred embodiment of the present invention, step S2: reacting 2-methoxy-4-nitro-6-bromophenol with a methylating agent and an acid-binding agent in a solvent to generate 3-bromo-5-nitro-catechol dimethyl ether; the methylation reagent is methyl iodide or dimethyl sulfate, the acid-binding agent is one or more selected from sodium carbonate, potassium carbonate, sodium hydroxide and triethylamine, and the solvent is one or more selected from acetonitrile, acetone, ethyl acetate, chloroform, ethanol and methanol.
Further preferably, the methylating agent is dimethyl sulfate, the acid-binding agent is potassium carbonate, and the solvent is acetonitrile.
Heating to 40-60 deg.C, reacting for 4 hr or more, adding excessive dimethyl sulfate, and adding Na 2 CO 3 Removing excessive dimethyl sulfate from the aqueous solution, transferring the mixture into distilled water after the reaction is finished, standing, performing vacuum filtration after solid is separated out, and drying the filtrate to obtain an intermediate product 3-bromo-5-nitro-catechol dimethyl ether.
According to the preferred embodiment of the present invention, step S3: 3-bromine-5-nitro-catechol dimethyl ether reacts with a reducing agent in a solvent to generate 3-bromine-5-amino-catechol dimethyl ether; the reducing agent is selected from one or more of iron powder, sodium sulfide, stannous chloride and hydrogen, and the solvent is selected from one or more of methanol, ethanol, water and dilute hydrochloric acid.
Further preferably, the reducing agent is iron powder, and the solvent is diluted hydrochloric acid.
The reaction temperature is heated to 70-90 ℃, the reaction is carried out in dilute hydrochloric acid, and the reaction time is more than 5 hours; after the reaction is finished, unreacted iron is removed by filtration, and Na is added 2 CO 3 Neutralizing the filtrate, standing, performing vacuum filtration after solid is separated out, and drying the filtrate to obtain the target product 3-bromo-5-amino-catechol dimethyl ether.
(III) advantageous effects
The invention has the beneficial effects that:
the invention provides a new synthesis path of 3-bromo-5-aminocatechol dimethyl ether, which is characterized in that 2-methoxy-4-nitrophenol is used as an initial raw material, and a final product is synthesized by total 3 steps of reactions such as bromination, methylation and reduction, wherein the reaction steps are simple, intermediate products and target products are easy to separate, the environmental pollution is less, the cost is low, the total yield is high (more than 75 percent), and the industrial production is easy.
Drawings
FIG. 1 is a NMR spectrum of 2-methoxy-4-nitro-6-bromophenol produced in the first step of example 1.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of 3-bromo-5-nitro-catechol dimethyl ether produced in the second step of example 1.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of 3-bromo-5-amino-catechol dimethyl ether produced in the third step of example 1.
Detailed Description
For the purpose of better explaining the present invention and to facilitate understanding, the present invention will be described in detail below with reference to specific embodiments.
Example 1
The first step is as follows: preparation of 2-methoxy-4-nitro-6-bromophenol
4g (0.024 mol) of 2-methoxy-4-nitrophenol was weighed into a 100mL distillation flask, 40mL of chloroform was added thereto and dissolved, and after the starting material was completely dissolved, a dropping funnel containing 16mL of chloroform was added to the flask, and about 1.3mL (0.028 mol) of liquid bromine was added to the dropping funnel to dissolve the bromine in chloroform. Slowly dripping the mixed solution in the dropping funnel into a distillation flask, reacting for about 4 hours after dripping at room temperature, cooling to room temperature after reaction, quenching unreacted bromine by using saturated sodium bisulfite, washing to be neutral, removing chloroform by rotary evaporation, and drying the concentrated solution at 50 ℃ by using a drying oven to obtain 5.5g of a product 2-methoxy-4-nitro-6-bromophenol, wherein the yield is 93%. The reaction process in the step is represented as follows:
the product was analyzed by nmr and the results are shown in fig. 1:
1 H-NMR(MHz,CHCl 3 )δ:8.13(s,1H),7.33(s,1H),6.57(s,1H),4.03(s,3H)，MS:MH + ＝249。
the second step is that: preparation of 3-bromo-5-nitro-catechol dimethyl ether
5g (0.020 mol) of 2-methoxy-4-nitro-6-bromophenol was weighed into a 100mL distillation flask, 50mL of acetonitrile was added to completely dissolve the starting material, and 5.52g (0.081 mol) of K was added 2 CO 3 3mL (0.024 mol) of dimethyl sulfate SO was added with stirring for a while 2 (OCH 3 ) 2 The reaction was completed by heating to 50 ℃ for about 4 hours. Pre-preparing Na with a certain concentration 2 CO 3 Adding the aqueous solution into a distillation flask after the reaction is finished and stirring to remove excessive SO 2 (OCH 3 ) 2 . And then transferring the mixture in the flask to distilled water, standing, separating out solids, carrying out vacuum filtration, and drying the filtrate in an oven at 50 ℃ to obtain 4.8g of the product 3-bromo-5-nitrophthalic acid dimethyl ether with the yield of about 90.9%. The reaction process in the step is represented as follows:
the product was subjected to nmr spectroscopy, and the results are shown in fig. 2:
1 H-NMR(MHz,CHCl 3 )δ:8.09(d,1H),7.44(d,1H),3.97(d,6H)，MS:MH + ＝263。
the third step: preparation of 3-bromo-5-amino-catechol dimethyl ether
Weighing 4g (0.015 mol) of 3-bromo-5-nitrophthalic dimethyl ether into a 100mL distillation flask, adding 30mL of hydrochloric acid solution (diluted by 35wt% of concentrated hydrochloric acid by 3 times with water) to dissolve, heating to 80 ℃, adding 1.75g (0.031 mol) of Fe powder until complete dissolution, and keeping the temperature at 80 ℃ for about 5 hours to finish the reaction. After the reaction is finished, the unreacted iron mud is removed by filtration. Neutralizing the filtered mixed solution to neutrality by using a sodium carbonate solution, standing, separating out solids, filtering under reduced pressure, and drying the solids by using an oven at 50 ℃ to obtain 3.2g of 3-bromine-5-amino catechol dimethyl ether with the yield of about 90.4%. The reaction process in the step is represented as follows:
the product was analyzed by nmr and the results are shown in fig. 3:
1 H-NMR(MHz,CHCl 3 )δ:6.45(d,1H),6.20(d,1H),3.81(s,3H),3.76(s,3H),3.58(s,br,2H)。MS:MH + =233. Thus, the synthesis method of the invention can indeed prepare the target product.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (1)
1. A synthetic method of 3-bromine-5-amino-catechol dimethyl ether is characterized by comprising three steps of reactions:
s1: 2-methoxy-4-nitrophenol is used as an initial raw material, and the 2-methoxy-4-nitro-6-bromophenol is obtained through bromination; reacting 2-methoxy-4-nitrophenol with a brominating agent in a solvent to generate 2-methoxy-4-nitro-6-bromophenol; the brominating reagent is bromine, and the solvent is trichloromethane; the reaction is carried out at room temperature, and the reaction time is more than 4 hours; after the reaction is finished, cooling to room temperature, quenching unreacted bromine by sodium bisulfite, washing to neutrality by water, removing trichloromethane by rotary evaporation, and drying to obtain an intermediate product 2-methoxy-4-nitro-6-bromophenol;
s2: methylating the phenolic group on the 2-methoxy-4-nitro-6-bromophenol to obtain 3-bromo-5-nitro-catechol dimethyl ether; the method comprises the following steps of reacting 2-methoxy-4-nitro-6-bromophenol with a methylating agent and an acid-binding agent in a solvent to generate 3-bromo-5-nitro-catechol dimethyl ether; the methylation reagent is dimethyl sulfate, the acid-binding agent is potassium carbonate, and the solvent is acetonitrile;
heating to 40-60 deg.C, reacting for 4 hr or more, adding excessive dimethyl sulfate, and adding Na 2 CO 3 Removing excessive dimethyl sulfate from the aqueous solution, transferring the mixture into distilled water after the reaction is finished, standing, performing vacuum filtration after solid is separated out, and drying the filtrate to obtain an intermediate product, namely 3-bromo-5-nitro-catechol dimethyl ether;
s3, reducing the nitro group on the 3-bromo-5-nitro-catechol dimethyl ether into amino group to prepare 3-bromo-5-amino-catechol dimethyl ether;
the step is that 3-bromine-5-nitro-catechol dimethyl ether reacts with a reducing agent in a solvent to generate 3-bromine-5-amino-catechol dimethyl ether; the reducing agent is iron powder, and the solvent is dilute hydrochloric acid; the reaction temperature is heated to 70-90 ℃, the reaction is carried out in dilute hydrochloric acid, and the reaction time is more than 5 hours; after the reaction is finished, unreacted iron is removed by filtration, and Na is added 2 CO 3 Neutralizing the filtrate, standing, performing vacuum filtration after solid is separated out, and drying the filtrate to obtain a target product 3-bromo-5-amino-catechol dimethyl ether;
the reaction sequence of the above steps S1-S3 is described as follows:
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| WO2003042164A1 (en) * | 2001-11-13 | 2003-05-22 | Theravance, Inc | Aryl aniline beta-2 adrenergic receptor agonists |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
| CN109134204A (en) * | 2018-11-16 | 2019-01-04 | 白银棓诺新材料有限公司 | The synthetic method of the fluoro- 5- chlorophenol of the bromo- 4- of intermediate 2- |
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| WO2003042164A1 (en) * | 2001-11-13 | 2003-05-22 | Theravance, Inc | Aryl aniline beta-2 adrenergic receptor agonists |
| CN102241621A (en) * | 2010-05-11 | 2011-11-16 | 江苏恒瑞医药股份有限公司 | 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof |
| CN109134204A (en) * | 2018-11-16 | 2019-01-04 | 白银棓诺新材料有限公司 | The synthetic method of the fluoro- 5- chlorophenol of the bromo- 4- of intermediate 2- |
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