CN108658765B - Preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate - Google Patents
Preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate Download PDFInfo
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- CN108658765B CN108658765B CN201810447817.1A CN201810447817A CN108658765B CN 108658765 B CN108658765 B CN 108658765B CN 201810447817 A CN201810447817 A CN 201810447817A CN 108658765 B CN108658765 B CN 108658765B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C67/00—Preparation of carboxylic acid esters
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention relates to a preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate, belonging to the technical field of chemical reagent synthesis. Firstly, carrying out esterification reaction on maleic anhydride and ethanol, then carrying out transposition reaction to obtain monoethyl fumarate, then reacting the monoethyl fumarate with thionyl chloride to obtain monoethyl fumarate monoacyl chloride, finally reacting the monoethyl fumarate monoacyl chloride with 1, 2-dimethoxybenzene to obtain a target product, namely 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate, and refining to obtain a refined product. The method has the advantages of high yield and purity of the reaction product in each step, high yield and purity of the finally prepared refined product, simple and easily obtained raw materials and low cost. In addition, the preparation method of the invention has simple operation, the impurities in the product are easy to separate and remove, and the purity of the refined product can reach more than 99 percent, thus completely meeting the medical requirements of customers.
Description
Technical Field
The invention belongs to the technical field of chemical reagent synthesis, and particularly relates to a preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate.
Background
4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate is an important product for resisting skin fat spilling, resisting alopecia and protecting skin. Can also be used as an intermediate for synthesizing a series of anti-gastric ulcer and anti-cardiovascular drugs. The preparation method reported in the literature at present is to react 1, 2-dimethoxybenzene with maleic anhydride to obtain 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid, the reaction in the step obtains a mixture which cannot be purified and has a main content of only about 70%, then the prepared mixture is subjected to esterification reaction with ethanol to obtain 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester, the content of the refined mixture is about 80%, and the requirement of 99% for medical use cannot be met.
Aiming at the problems in the prior art, a new process for preparing 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate is researched and developed, so that the purity of the product reaches more than 99 percent, and the method is particularly important for meeting the medical requirements of customers.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester.
In order to achieve the above purpose of the present invention, the present invention adopts the following technical scheme:
a preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate comprises the steps of firstly carrying out esterification reaction on maleic anhydride and ethanol, then carrying out transposition reaction to obtain monoethyl fumarate, then reacting the monoethyl fumarate with thionyl chloride to obtain monoethyl fumarate monoacyl chloride, finally reacting the monoethyl fumarate monoacyl chloride with 1, 2-dimethoxybenzene to obtain a target product of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate, and refining to obtain a product with the purity of more than 99%.
The preparation method of the ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate specifically comprises the following steps:
(1) adding a proper amount of maleic anhydride, absolute ethyl alcohol and a small amount of concentrated sulfuric acid into a first four-mouth bottle in sequence, wherein the mass ratio of the maleic anhydride to the absolute ethyl alcohol is 1: 0.5-1: 1, the mass ratio of concentrated sulfuric acid to maleic anhydride is 0.005: 1-0.015: starting stirring, slowly heating, reacting for 4 hours at 55-65 ℃, then sequentially adding deionized water and thiourea into a bottle, wherein the mass of the deionized water is 0.5-1 time of that of maleic anhydride, and the mass ratio of the thiourea to the maleic anhydride is 0.05: 1-0.15: 1, heating to 80 ℃, continuously carrying out heat preservation reaction for 4 hours at the temperature of 80-85 ℃, carrying out reduced pressure evaporation to obtain water, adding a proper amount of toluene, carrying out reflux dehydration, cooling and filtering, freezing the filtrate, separating out a solid, filtering again to obtain a wet product, and drying to obtain the monoethyl fumarate;
(2) adding the monoethyl fumarate prepared in the step (1) and excessive thionyl chloride into a second four-mouth bottle, wherein the mass ratio of the monoethyl fumarate to the thionyl chloride is 1: 1.5-1: 3, heating to 80 ℃, performing reflux reaction for 4 hours at 80-85 ℃, evaporating excessive thionyl chloride, and performing reduced pressure distillation to obtain fumaric acid monoethyl ester monoacyl chloride;
(3) and (3) sequentially adding 1, 2-dichloroethane and 1, 2-dimethoxybenzene into a third four-mouth bottle to obtain the monoethyl fumarate monoacyl chloride prepared in the step (2), wherein the molar ratio of the 1, 2-dimethoxybenzene to the monoethyl fumarate monoacyl chloride is 1: 1-1: 1.5, then adding anhydrous aluminum trichloride in batches at 35-40 ℃, wherein the mass ratio of the aluminum trichloride to the monoethyl fumarate monoacyl chloride is 1: 1-1.5: 1, heating to 58-62 ℃, carrying out heat preservation reaction for 10 hours, adding the product into a beaker filled with ice and concentrated hydrochloric acid in a fine flow state, stirring, standing, separating an oil layer, evaporating to dryness 1, 2-dichloroethane, adding ethanol, cooling for crystallization, filtering, and drying to obtain refined 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester with the purity of more than 99%.
Further, in the above technical solution, the cooling filtration temperature after the reflux dehydration in the step (1) is preferably 70 ℃, and the freezing temperature of the filtrate is preferably 0 ℃.
Further, in the step (1) of the technical scheme, the mass of the toluene is 1-2 times that of the maleic anhydride.
Further, in the step (2) of the technical scheme, the temperature of reduced pressure distillation is 133-135 ℃, and the pressure is less than or equal to-0.1 MPa.
Further, in the step (3) of the technical scheme, the mass ratio of the 1, 2-dichloroethane to the monoethyl fumarate monoacyl chloride is 5: 1-10: 1.
further, in the step (3) of the technical scheme, the mass ratio of the concentrated sulfuric acid to the ice is 0.15: 1-0.2: 1.
furthermore, the excess thionyl chloride evaporated in step (2) of the above technical scheme is recycled for reuse.
Further, the 1, 2-dichloroethane evaporated after the oil layer is separated in the step (3) of the technical scheme is dried and reused.
Compared with the prior art, the invention has the following beneficial effects:
(1) the method for preparing 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate has the advantages that the yield and the purity of reaction products in each step are high, the yield and the purity of the finally prepared refined product are also high, and the defects of low purity and low yield of the product prepared by the traditional preparation method are overcome;
(2) the preparation method has the advantages that the adopted raw materials are simple and easy to obtain, the cost is low, and the thionyl chloride and the 1, 2-dichloroethane in the preparation process can be recycled, so that the raw material cost is further reduced, and the economic effect is better;
(3) the preparation method of the invention has simple operation, the impurities in the product are easy to separate and remove, and the purity of the refined product can reach more than 99 percent, thus completely meeting the medical requirements of customers.
Detailed Description
The following is a detailed description of embodiments of the invention. The embodiment is implemented on the premise of the technical scheme of the invention, and a detailed implementation mode and a specific operation process are given, but the protection scope of the invention is not limited to the following embodiment.
Various modifications to the precise description of the invention will be readily apparent to those skilled in the art from the information contained herein without departing from the spirit and scope of the appended claims. It is to be understood that the scope of the invention is not limited to the procedures, properties, or components defined, as these embodiments, as well as others described, are intended to be merely illustrative of particular aspects of the invention. Indeed, various modifications of the embodiments of the invention which are obvious to those skilled in the art or related fields are intended to be covered by the scope of the appended claims.
For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". Accordingly, unless expressly indicated otherwise, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Example 1
The preparation method of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to the embodiment specifically includes the following steps:
(1) adding 200g (2mol) of maleic anhydride into a first 500mL four-neck bottle, then adding 110g (2.4mol) of absolute ethyl alcohol and 1g of concentrated sulfuric acid, starting stirring, slowly heating, reacting for 4 hours at 55-65 ℃, then sequentially adding 100g of deionized water and 20g of thiourea into the bottle, heating to 80 ℃, reacting for 4 hours at 80-85 ℃, evaporating water under reduced pressure, adding 300g of toluene, carrying out reflux dehydration, cooling to 70 ℃, filtering out insoluble substances, freezing the filtrate to 0 ℃, precipitating solids, filtering again to obtain a wet product, and finally drying the wet product to obtain 110g of 95% pure monoethyl fumarate;
the reaction principle of the step is as follows:
(2) adding 110g of monoethyl fumarate and 220g of thionyl chloride prepared in the step (1) into a second 500mL four-necked bottle, heating to 80 ℃, carrying out reflux reaction for 4 hours at 80-85 ℃, distilling out excessive thionyl chloride, drying, repeatedly using, and then distilling out 133-135 ℃ minus 0.1MPa fraction under reduced pressure to obtain 110g of monoethyl fumarate, wherein the purity is 98%, and the yield is 90%;
the reaction principle of the step is as follows:
(3) adding 250g of 1, 2-dichloroethane, 25.4g (0.18mol) of 1, 2-dimethoxybenzene and 30g (0.18mol) of monoethyl fumarate monoacid chloride prepared in the step (2) into a 500mL four-neck flask in sequence, then adding 36.8g of anhydrous aluminum trichloride at 35-40 ℃ for three times, heating to 58-62 ℃, carrying out heat preservation reaction for 10 hours, introducing the product into a beaker filled with 400g of ice and 72g of concentrated sulfuric acid in a fine flow manner, stirring, standing, separating an oil layer, evaporating 1, 2-dichloroethane, recycling, adding 35g of ethanol, cooling to 0 ℃, crystallizing, filtering, and drying to obtain 46g of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester, wherein the purity of the product is 99%, and the yield is 88%;
the reaction principle of the step is as follows:
example 2
The preparation method of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to the embodiment specifically includes the following steps:
(1) adding 200g (2mol) of maleic anhydride into a first 500mL four-neck bottle, then adding 100g (2.2mol) of absolute ethyl alcohol and 2g of concentrated sulfuric acid, starting stirring, slowly heating, reacting for 4 hours at 55-65 ℃, then sequentially adding 150g of deionized water and 10g of thiourea into the bottle, heating to 80 ℃, reacting for 4 hours at 80-85 ℃, evaporating water under reduced pressure, adding 200g of toluene, carrying out reflux dehydration, cooling to 70 ℃, filtering out insoluble substances, freezing the filtrate to 0 ℃, precipitating solids, filtering again to obtain a wet product, and finally drying the wet product to obtain 106g of 96% pure monoethyl fumarate;
(2) adding 106g of monoethyl fumarate and 160g of thionyl chloride prepared in the step (1) into a second 500mL four-necked bottle, heating to 80 ℃, carrying out reflux reaction at 80-85 ℃ for 4 hours, evaporating excessive thionyl chloride, drying, repeatedly using, and then evaporating fractions at 133-135 ℃/-0.1MPa under reduced pressure to obtain 107g of monoethyl fumarate, wherein the purity is 98.6%, and the yield is 90.4%;
(3) and (3) adding 218.5g of 1, 2-dichloroethane, 25.4g (0.18mol) of 1, 2-dimethoxybenzene and 43.7g (0.27mol) of monoethyl fumarate monoacyl chloride prepared in the step (2) into a 500mL four-neck flask in sequence, then adding 43.7g of anhydrous aluminum trichloride three times at the temperature of 35-40 ℃, heating to 58-62 ℃, carrying out heat preservation reaction for 10 hours, introducing the product into a beaker filled with 400g of ice and 60g of concentrated sulfuric acid in a fine flow manner, stirring, standing, separating out an oil layer, evaporating 1, 2-dichloroethane, recycling and reusing, adding 50g of ethanol, cooling to 0 ℃, crystallizing, filtering, and drying to obtain 54g of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester, wherein the purity of the product is 99.4%, and the yield is 88.7%.
Example 3
The preparation method of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to the embodiment specifically includes the following steps:
(1) adding 200g (2mol) of maleic anhydride into a first 500mL four-neck bottle, then adding 200g (4.35mol) of absolute ethyl alcohol and 3g of concentrated sulfuric acid, starting stirring, slowly heating, reacting for 4 hours at 55-65 ℃, then sequentially adding 200g of deionized water and 30g of thiourea into the bottle, heating to 80 ℃, reacting for 4 hours at 80-85 ℃, evaporating water under reduced pressure, adding 400g of toluene, carrying out reflux dehydration, cooling to 70 ℃, filtering out insoluble substances, freezing the filtrate to 0 ℃, precipitating solids, filtering again to obtain a wet product, and finally drying the wet product to obtain 112g of 97.6% pure monoethyl fumarate;
(2) adding 112g of monoethyl fumarate and 220g of thionyl chloride prepared in the step (1) into a second 500mL four-necked bottle, heating to 80 ℃, carrying out reflux reaction for 4 hours at 80-85 ℃, distilling out excessive thionyl chloride, drying, repeatedly using, and then distilling out 133-135 ℃ minus 0.1MPa fraction under reduced pressure to obtain 112g of monoethyl fumarate, wherein the purity is 98.2%, and the yield is 91.4%;
(3) and (3) sequentially adding 350g of 1, 2-dichloroethane, 25.4g (0.18mol) of 1, 2-dimethoxybenzene and 35g (0.216mol) of monoethyl fumarate monoacyl chloride prepared in the step (2) into a 500mL fourth bottle, then adding 52.5g of anhydrous aluminum trichloride at 35-40 ℃ for four times, heating to 58-62 ℃, carrying out heat preservation reaction for 10 hours, introducing the product into a beaker filled with 400g of ice and 80g of concentrated sulfuric acid in a fine flow manner, stirring, standing, separating an oil layer, evaporating 1, 2-dichloroethane, recycling, adding 45g of ethanol, cooling to 0 ℃, crystallizing, filtering, and drying to obtain 49g of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-crotonate with the purity of 99.2% and the yield of 94%.
Claims (8)
1. A preparation method of 4- (3, 4-dimethoxyphenyl) -4-oxo-2-ethyl crotonate is characterized by comprising the following steps: firstly, carrying out esterification reaction on maleic anhydride and ethanol, then carrying out transposition reaction to obtain fumaric acid monoethyl ester, then reacting the fumaric acid monoethyl ester with thionyl chloride to obtain fumaric acid monoethyl ester monoacyl chloride, finally reacting the fumaric acid monoethyl ester monoacyl chloride with 1, 2-dimethoxybenzene to obtain a target product, namely 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester, and refining to obtain a product with the purity of more than 99%; the method specifically comprises the following steps:
(1) adding a proper amount of maleic anhydride, absolute ethyl alcohol and a small amount of concentrated sulfuric acid into a first four-mouth bottle in sequence, wherein the mass ratio of the maleic anhydride to the absolute ethyl alcohol is 1: 0.5-1: 1, the mass ratio of concentrated sulfuric acid to maleic anhydride is 0.005: 1-0.015: starting stirring, slowly heating, reacting for 4 hours at 55-65 ℃, then sequentially adding deionized water and thiourea into a bottle, wherein the mass of the deionized water is 0.5-1 time of that of maleic anhydride, and the mass ratio of the thiourea to the maleic anhydride is 0.05: 1-0.15: 1, heating to 80 ℃, continuously carrying out heat preservation reaction for 4 hours at the temperature of 80-85 ℃, carrying out reduced pressure evaporation to obtain water, adding a proper amount of toluene, carrying out reflux dehydration, cooling and filtering, freezing the filtrate, separating out a solid, filtering again to obtain a wet product, and drying to obtain the monoethyl fumarate;
(2) adding the monoethyl fumarate prepared in the step (1) and excessive thionyl chloride into a second four-mouth bottle, wherein the mass ratio of the monoethyl fumarate to the thionyl chloride is 1: 1.5-1: 3, heating to 80 ℃, performing reflux reaction for 4 hours at 80-85 ℃, evaporating excessive thionyl chloride, and performing reduced pressure distillation to obtain fumaric acid monoethyl ester monoacyl chloride;
(3) and (3) sequentially adding 1, 2-dichloroethane and 1, 2-dimethoxybenzene into a third four-mouth bottle to obtain the monoethyl fumarate monoacyl chloride prepared in the step (2), wherein the molar ratio of the 1, 2-dimethoxybenzene to the monoethyl fumarate monoacyl chloride is 1: 1-1: 1.5, then adding anhydrous aluminum trichloride in batches at 35-40 ℃, wherein the mass ratio of the aluminum trichloride to the monoethyl fumarate monoacyl chloride is 1: 1-1.5: 1, heating to 58-62 ℃, carrying out heat preservation reaction for 10 hours, adding the product into a beaker filled with ice and concentrated hydrochloric acid in a fine flow state, stirring, standing, separating an oil layer, evaporating to dryness 1, 2-dichloroethane, adding ethanol, cooling for crystallization, filtering, and drying to obtain refined 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoic acid ethyl ester with the purity of more than 99%.
2. The process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: in the step (1), the cooling and filtering temperature is 70 ℃ after the reflux dehydration, and the freezing temperature of the filtrate is 0 ℃.
3. The process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: the mass of the toluene in the step (1) is 1-2 times of that of maleic anhydride.
4. The process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: in the step (2), the temperature of reduced pressure distillation is 133-135 ℃, and the pressure is less than or equal to-0.1 MPa.
5. The process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: the mass ratio of the 1, 2-dichloroethane to the monoethyl fumarate monoacyl chloride in the step (3) is 5: 1-10: 1.
6. the process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: the mass ratio of the concentrated hydrochloric acid to the ice in the step (3) is 0.15: 1-0.2: 1.
7. the process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: and (3) recovering the excessive thionyl chloride evaporated in the step (2) for reuse.
8. The process for the preparation of ethyl 4- (3, 4-dimethoxyphenyl) -4-oxo-2-butenoate according to claim 1, characterized in that: and (3) separating out an oil layer, and drying the 1, 2-dichloroethane evaporated out for reuse.
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