CN110615799A - Preparation method of EDOT intermediate - Google Patents
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- CN110615799A CN110615799A CN201910873134.7A CN201910873134A CN110615799A CN 110615799 A CN110615799 A CN 110615799A CN 201910873134 A CN201910873134 A CN 201910873134A CN 110615799 A CN110615799 A CN 110615799A
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Abstract
The invention discloses a preparation method of an EDOT intermediate, which comprises the steps of reacting high-activity reaction substrate 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and 1, 2-dichloroethane which can be used as the reaction substrate and a solvent under a vacuum condition, distilling to remove the solvent, separating out a product through a composite solvent of a benign solvent and a poor solvent, and washing with water to remove salt and impurities to obtain the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. The preparation method solves the problem that the reaction is difficult to complete even under high temperature conditions in the traditional EDOT intermediate preparation process, the reaction product is easy to separate, and the obtained 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene has high purity and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of a medical intermediate, in particular to a preparation method of an EDOT intermediate.
Background
3, 4-Ethylenedioxythiophene (EDOT) is a high-quality conductive polymer material monomer. The synthesis of EDOT was first proposed by Stenger et al in 1998:
a key step reaction of the method is that 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and 1, 2-dihalogen alkane react under the condition of refluxing for 48 hours by taking DMF as a solvent to synthesize the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. The reaction yield is only 50-55%, and the general formula of the reaction in the step is as follows:
wherein X ═ H, M (metal), methyl, or ethyl;
r ═ alkyl of 2 to 4 carbons;
y ═ F, Cl, Br, OH, OR, and the like;
the solvent is DMF, DMSO, Et3N, ROH and the like.
This reaction has the following problems, resulting in a low yield and a large amount of by-products.
1) In the case of an alkylation reaction using a1, 2-dihaloalkane as a raw material, it is necessary to carry out the reaction at a temperature of 115 ℃ or higher to achieve a satisfactory rate, and 1, 2-dichloroethane is a preferable substrate for the reaction, but since it has a boiling point of 83.5 ℃ at normal pressure, it cannot achieve a desired reaction temperature in a reaction system at normal pressure. This is a cause of the long reaction time and the low yield. The reaction condition has no industrial value;
2) N.N-Dimethylformamide (DMF) with high boiling point is used as a solvent, and as an azeotrope is formed with dichloroethane, the reaction temperature can only be increased to 107 ℃, and the alkylation reaction time at the temperature is up to more than 48 hours, so that the industrialization efficiency is severely restricted;
3) the reaction time is shortened by adding 5-20% of quaternary ammonium salt as a phase transfer catalyst under the condition of 1) and 2), certain effect is achieved, but the required amount of the quaternary ammonium salt is large, the product cost is increased, the separation yield of a finished product is only about 75% at most, and the purity is about 92%;
4) the separation of materials in the reaction system of 3) is difficult, and the additive cannot be recycled. The environmental protection pressure is increased to a certain extent;
5) dibromoethane is used as an alkylating reagent, although the reaction speed is improved, the dibromoethane is expensive and too high in cost, so that industrialization is difficult to realize, and in addition, the dibromoethane has more side reactions, so that the quality and the yield of the product are seriously influenced;
6) the microwave reaction is relatively obvious for improving the reaction speed, but the technology is also in the laboratory stage at present and cannot be applied to industrialization;
to solve the above problems, 2008 chenyuan wei et al add phase transfer catalyst tetrabutyl ammonium bromide to the reaction, and after reacting for 4 hours at 135 ℃, remove DMF under reduced pressure to obtain brown solid, with crude product yield of about 99% and unknown purity (CN 10151409A); youguirong in 2017; xia Chengcai et al reflux the desired product (CN102775423,2017, B) in 72% yield for 6-8 hours using ethanol as solvent and tetrabutylammonium bromide as phase transfer catalyst; zhang, Hua; qian, Chao et al, 2011 in 1) using a mixed solvent of triethylamine and DMF and dibromoethane as an alkylating agent to obtain the target product in 52% yield (Journal of Chemical Research,2011, vol.35, #6, p.339-340); coffey; McKellar; reinhardt; nijakowski et al reported in synthetic communications,1996, vol.26, #11, p.2205-2212: 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy thiophene as a substrate, 1, 2-dihaloalkane as an alkylating reagent and potassium carbonate as an acid capturing agent are subjected to reflux reaction in a DMF solvent to obtain a target product with the concentration of 52%. Then, the far east new century company utilizes the microwave to perform the reaction in the same system, and the reaction yield is improved to 83.8 percent. (EP2548875,2013, A1).
The reactions reported in the above documents all require solvents, bases or phase transfer catalysts with high boiling points which are difficult to remove, thus making the isolation of the product difficult.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of an EDOT intermediate, which carries out reaction in a vacuum and airtight environment, can control the reaction temperature below 130 ℃, and has simple and easy separation operation of products.
The purpose of the invention is realized by adopting the following technical scheme:
a method for preparing an EDOT intermediate comprising the following reaction equation:
the method comprises the following steps:
1) placing 0.5mol of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and more than 1mol of 1, 2-dichloroethane in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, and reacting at the temperature of 110-130 ℃;
2) cooling to room temperature, discharging, and recovering 1, 2-dichloroethane by reduced pressure distillation to obtain brown oily solid;
3) adding 200-400mL of mixed solution of isopropanol and water, stirring uniformly at 50-60 ℃, cooling and filtering to obtain a khaki solid; isopropanol is a good solvent of 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene, water is a poor solvent of 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene, and the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene is precipitated by using the coordination of the good solvent and the poor solvent;
4) adding 300-500mL of water for fully washing to obtain a yellowish-brown solid, and drying to obtain the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. The washing in the step has the function of removing NaCl in the product, so that the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene with higher purity is obtained.
Further, in the step 1), the molar ratio of the 1, 2-dichloroethane to the diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is 10-15: 1. namely, under the condition that 1, 2-dichloroethane is used as a reaction substrate or a solvent, and the excessive 1, 2-dichloroethane can achieve a recovery rate of 95% in the recovery process of the 1, 2-dichloroethane in the step 2).
Further, the step 1) further comprises a solvent, wherein the solvent is one or more than two of acetonitrile, tetrahydrofuran and dioxane. Under the conditions, the reaction of 1, 2-dichloroethane and 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene is promoted by a solvent with a low boiling point, the reaction temperature is reduced, and the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene is obtained with high yield.
Further, in the step 1), the molar ratio of the 1, 2-dichloroethane to the diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is 2-3: 1, the amount of solvent was 150-250 mL.
Further, the step 1) further comprises a solvent, wherein the solvent is one or more than two of 2-methylpyrrolidone, DMF and DMSO. That is, under such conditions, the reaction of 1, 2-dichloroethane with diethyl 2, 5-dicarboxylate-3, 4-dihydroxysodium thiophene is promoted by a relatively high-boiling solvent, and the reaction temperature is relatively lowered.
Further, in the step 1), the molar ratio of the 1, 2-dichloroethane to the diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is 2-3: 1, the amount of solvent is 100-200 mL.
Further, in the step 3), the ratio of isopropanol to water is 1: 5-7. So that diethyl 2, 5-dicarboxylate-3, 4-ethylenedioxythiophene is preferably precipitated.
Further, in the step 4), after water is added, stirring and homogenizing for 0.5-2 h. So that the inorganic salt in the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene is fully dissolved in the water, and the purity of the final 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene is improved.
The principle of the invention is as follows: according to the preparation method of the EDOT intermediate, 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene with high reaction activity is used as a reaction substrate, and reacts with 1, 2-dichloroethane which is simultaneously used as the reaction substrate and a solvent in a vacuum and airtight environment, so that the intermolecular collision efficiency and bonding efficiency of the 1, 2-dichloroethane and the substrate 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene are improved; thus obtaining 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene and sodium chloride, separating out in isopropanol and water, and then washing out salt by water, thus obtaining 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene with relatively high purity.
Compared with the prior art, the invention has the beneficial effects that:
compared with the traditional high-temperature high-pressure reaction, the preparation method of the EDOT intermediate provided by the invention has the advantages that the reaction rate is obviously increased, the reaction time is obviously shortened, the reaction can be carried out under the condition of not adding other solvents, and the recovery of the product is simpler;
the preparation method provided by the invention can further increase low-boiling point solvents such as acetonitrile, tetrahydrofuran, dioxane and the like as solvents, so that the reaction is carried out in a high-pressure kettle, and the reaction temperature can be reduced from about 130 ℃ to about 110 ℃, so that the reaction activity is improved; or may be further enhanced by the addition of relatively high boiling solvents such as DMF and the like.
According to the preparation method provided by the invention, the yield of the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene generated by the 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene can reach 95%, and the purity is over 95%.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
The following are specific examples of the present invention, and raw materials, equipments and the like used in the following examples can be obtained by purchasing them unless otherwise specified.
A method for preparing an EDOT intermediate comprising the following reaction equation:
the method comprises the following steps:
1) placing 0.5mol of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and more than 1mol of 1, 2-dichloroethane in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, and reacting at the temperature of 110-130 ℃;
2) cooling to room temperature, discharging, and recovering 1, 2-dichloroethane by reduced pressure distillation to obtain brown oily solid;
3) adding 200-400mL of mixed solution of isopropanol and water, stirring uniformly at 50-60 ℃, cooling and filtering to obtain a khaki solid;
4) adding 300-500mL of water for fully washing to obtain a yellowish-brown solid, and drying to obtain the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene.
Example 1:
a preparation method of an EDOT intermediate comprises the following steps:
1) placing 130mL (0.5mol) of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and 675g (6.8mol) of 1, 2-dichloroethane in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, keeping for 2min, heating until the temperature in the container reaches 130 ℃, and carrying out heat preservation reaction for 2 h;
2) cooling to room temperature, discharging, distilling under reduced pressure to recover 1, 2-dichloroethane, wherein the recovery rate of excess 1, 2-dichloroethane reaches 98%, and obtaining brown oily solid;
3) adding a mixed solution of 50mL of isopropanol and 300mL of water, stirring uniformly at 60 ℃, cooling and filtering to obtain a yellowish-brown solid;
4) adding 400mL of water, stirring, pulping for 1h to obtain a yellowish-brown solid, and drying to obtain 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. 136g of target product is obtained after drying, the yield is 95.3%, and the purity is as high as more than 97%.
Example 2:
a preparation method of an EDOT intermediate comprises the following steps:
1) placing 130mL (0.5mol) of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene, 100g (1.01mol) of 1, 2-dichloroethane and 200mL of acetonitrile in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, keeping for 2min, heating to the temperature of 115 ℃ in the container, and carrying out heat preservation reaction for 2 h;
2) cooling to room temperature, discharging, and recovering the solvent by reduced pressure distillation to obtain brown oily solid;
3) adding a mixed solution of 50mL of isopropanol and 300mL of water, stirring uniformly at 60 ℃, cooling and filtering to obtain a yellowish-brown solid;
4) 400mL of water was added, stirred and slurried for 1h to obtain 275g of a wet yellowish solid, which was dried to obtain 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. After drying, 137.3g of target product is obtained, the yield is 95.9%, and the purity is as high as more than 97%.
Example 3:
a preparation method of an EDOT intermediate comprises the following steps:
1) placing 130mL (0.5mol) of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene, 100g (1.01mol) of 1, 2-dichloroethane and 100mL of DMF in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, keeping for 2min, heating to the temperature of 115 ℃ in the container, and carrying out heat preservation reaction for 2 h;
2) cooling to room temperature, discharging, and recovering the solvent by reduced pressure distillation to obtain brown oily solid;
3) adding a mixed solution of 50mL of isopropanol and 300mL of water, stirring uniformly at 60 ℃, cooling and filtering to obtain a yellowish-brown solid;
4) adding 400mL of water, stirring and pulping for 1h to obtain 263g of wet earthy yellow solid, and drying to obtain 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene. Drying to obtain 136.2g of target product, with yield 95.1% and purity over 96%.
The reaction temperature in example 2 can be lowered by 15 ℃ compared to that in example 1 to achieve similar yield and purity, and the reaction temperature in example 3 can be lowered accordingly, but when the separation is performed in step 2), the solvent is likely to remain in the product, so that example 2 is preferred.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (8)
1. A preparation method of an EDOT intermediate is characterized by comprising the following reaction equation:
the method comprises the following steps:
1) placing 0.5mol of 2, 5-dicarboxylic acid diethyl ester-3, 4-dihydroxy sodium thiophene and more than 1mol of 1, 2-dichloroethane in an airtight container, vacuumizing to the vacuum degree of 0.1MPa, and reacting at the temperature of 110-130 ℃;
2) cooling to room temperature, discharging, and recovering 1, 2-dichloroethane by reduced pressure distillation to obtain brown oily solid;
3) adding 200-400mL of mixed solution of isopropanol and water, stirring uniformly at 50-60 ℃, cooling and filtering to obtain a khaki solid;
4) adding 300-500mL of water for fully washing to obtain a yellowish-brown solid, and drying to obtain the 2, 5-dicarboxylic acid diethyl ester-3, 4-ethylenedioxythiophene.
2. The process for the preparation of EDOT intermediates of claim 1 wherein in step 1), the molar ratio of 1, 2-dichloroethane to diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is from 10 to 15: 1.
3. the process for producing EDOT intermediates of claim 1, wherein step 1) further comprises a solvent, said solvent being one or more of acetonitrile, tetrahydrofuran and dioxane.
4. The process for the preparation of EDOT intermediates of claim 3 wherein in step 1), the molar ratio of 1, 2-dichloroethane to diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is from 2 to 3: 1, the amount of solvent was 150-250 mL.
5. The process for the preparation of EDOT intermediates of claim 1 wherein step 1) further comprises a solvent, said solvent being one or more of 2-methylpyrrolidone, DMF and DMSO.
6. The process for the preparation of EDOT intermediates of claim 5 wherein in step 1), the molar ratio of 1, 2-dichloroethane to diethyl 2, 5-dicarboxylate-3, 4-dihydroxy sodium thiophene is from 2 to 3: 1, the amount of solvent is 100-200 mL.
7. The process for the preparation of EDOT intermediates of claim 1 wherein in step 3) the ratio of isopropanol to water is 1: 5-7.
8. The process for the preparation of EDOT intermediates of claim 1 wherein in step 4), after the addition of water, the homogenate is stirred for 0.5 to 2 hours.
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