CN112898152A - Preparation method of ethoxy diethyl methylene malonate - Google Patents
Preparation method of ethoxy diethyl methylene malonate Download PDFInfo
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- diethyl malonate
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- 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
- C07C67/31—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 functional groups containing oxygen only in singly bound form
Abstract
The invention discloses a preparation method of ethoxy methylene diethyl malonate, which comprises the steps of taking diethyl malonate as a raw material, taking ethyl formate or carbon monoxide as an auxiliary material, introducing formyl under the action of a catalyst, and carrying out condensation reaction with alcohol under the catalysis of acid to obtain the product of ethoxy methylene diethyl malonate. Wherein, the ethyl formate can be replaced by CO, and the cost of raw materials is lower. The method has the advantages of simple operation, easily obtained raw materials, high conversion rate, safety, environmental protection and low cost, and can realize industrial production.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a preparation method of ethoxymethylene diethyl malonate.
Background
The ethoxy methylene diethyl malonate also called EMME contains a plurality of active groups, is an important intermediate of pharmaceutical and chemical engineering, is used for synthesizing decaoxyquinoline, quinolone antibacterial drugs, antitumor drugs tivozanib and the like, has very wide application, and is an important intermediate for preparing heterocyclic compounds.
Various methods for synthesizing ethoxymethylenediethyl malonate exist at present, and the following two methods are more typical:
the first method is Organic Syntheses, col. vol.3, p.395 (1955); vol.28, p.60(1948) and discloses the use of diethyl malonate and triethyl orthoformate as starting materials in ZnCl2And synthesizing the ethoxymethylene diethyl malonate under the catalysis of acetic anhydride.
The chemical reaction formula is as follows:
however, the method takes triethyl orthoformate and a large amount of acetic anhydride as raw materials, so that the method has the advantages of high raw material cost, difficult recovery, poor atom economy and great environmental pollution.
The second method is reported in 2004 chinese patent No. CN 16993300, which discloses that an intermediate is synthesized from hydrocyanic acid, anhydrous alcohol and hydrogen halide, and then reacted with malonic ester to obtain ethoxymethylenemalonic acid diethyl ester.
The chemical reaction formula is as follows:
the method has the advantages that the yield can reach 94 percent, the discharge of three wastes is less, but the method adopts hydrocyanic acid as a raw material which is a highly toxic substance and has high cost.
In summary, the existing process has various disadvantages: (1) the reaction conditions are harsh, and the energy consumption and the time consumption are large; (2) poor atomic economy and high raw material cost; (3) the reaction process is complex and is not easy to be industrially amplified. Therefore, it is highly desired to develop a novel method for preparing ethoxymethylenemalonic acid diethyl ester to meet the industrial demand.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a novel method for synthesizing ethoxymethylenediethyl malonate, which is suitable for industrial production and application. The method has the advantages of low raw material cost, relatively mild reaction conditions, good atom economy, simple operation and high yield, and is suitable for industrial production and application.
The method takes diethyl malonate as a raw material and ethyl formate or carbon monoxide as an auxiliary material, obtains an intermediate compound I under the action of alcohol alkali metal salt and a catalyst, and then the intermediate compound I reacts with ethanol under the action of acid catalysis to obtain a target compound II, namely diethyl ethoxymethylenemalonate.
The synthetic route of the method is as follows:
wherein M is an alkali metal ion, preferably Na and K.
The catalyst is selected from any one of piperidine, quaternary ammonium salt and crown ether, more preferably, the catalyst is dibenzo-24-crown ether-8, and the dosage of the dibenzo-24-crown ether-8 is preferably 0.1-1% of the mass of diethyl malonate. Further preferably 0.1 to 0.4%.
Preferably, the alcohol alkali metal salt is preferably sodium ethoxide and potassium ethoxide, and the feeding molar ratio of the diethyl malonate to the alcohol alkali metal salt is preferably 0.8-1.2: 1.
the feeding method of the invention has two feeding modes, one mode is that a solvent, alcohol alkali metal salt, diethyl malonate and a catalyst are firstly added into a pressure kettle, and then carbon monoxide gas or ethyl formate is added for heating reaction. In another preferred scheme, the feeding method comprises the steps of firstly adding alcohol alkali metal salt and solvent into a pressure kettle, introducing carbon monoxide or adding ethyl formate, heating, and slowly introducing diethyl malonate till the reaction is finished.
Preferably, the solvent is one of ethanol, toluene and xylene or a miscible mixed solution of two or more. Particularly preferably, the solvent is ethanol, and the mass ratio of the diethyl malonate to the reaction solvent is 1: 1.5-4.
Preferably, the reaction temperature is 80-120 ℃.
Preferably, when carbon monoxide is used as a reaction raw material, the reaction pressure is 2-4 MPa.
Preferably, the acid is hydrogen chloride, sulfuric acid, a solid acid, or a mixture of two thereof, preferably hydrogen chloride.
Preferably, the feeding molar ratio of the acid to the alcohol alkali metal salt is 1-5: 1, preferably 1-2.5: 1.
further preferred technical scheme also comprises the step of product refining: namely, the ethoxymethylene diethyl malonate is refined by reduced pressure distillation under the conditions of-0.1 MPa and 130-140 ℃.
The method for synthesizing the ethoxy methylene diethyl malonate disclosed by the invention has the beneficial effects that:
(1) the reaction conditions are relatively mild, and the pressure required by the reaction is reduced by using the catalyst;
(2) the atom economy is good, the raw material cost is low, and the reactants can be recycled;
(3) the reaction yield is high;
(4) the reaction process is simple and easy to operate and implement.
Drawings
FIG. 1 is a GC diagram of a reaction solution according to an embodiment of the present invention.
FIG. 2 is a GC diagram of the purified product of the example of the present invention.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1
Adding 68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 0.25g of piperidine into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature to be 100 ℃, and reacting for 2 hours when the pressure reaches 2 MPa. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 87.1% and purity of 98%.
Example 2
Adding 68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 0.5g of tetrabutylammonium bromide into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, controlling the pressure to reach 2MPa, and reacting for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 84.7% and purity of 97%.
Example 3
Adding 68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 0.25g of dibenzo-24-crown ether-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, controlling the pressure to reach 2MPa, and reacting for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to obtain compound II with yield of 91.8% and purity of 99%. The GC plot of the reaction solution is shown in fig. 1, corresponding data are shown in table 1, wherein the retention time 5.901 is diethyl malonate, the retention time 12.617 is product, and the GC of the purified product is shown in table 2.
TABLE 1
| Peak number | Retention time | Area of | Height | Concentration unit | Area% |
| 1 | 1.393 | 85116047 | 43227808 | 53.440 | |
| 2 | 1.471 | 22751098 | 13814822 | 14.284 | |
| 3 | 1.652 | 63486 | 32837 | 0.040 | |
| 4 | 2.437 | 56736 | 21548 | 0.036 | |
| 5 | 4.644 | 13811 | 4784 | 0.009 | |
| 6 | 5.901 | 3339868 | 1171991 | 2.097 | |
| 7 | 6.314 | 58899 | 19171 | 0.037 | |
| 8 | 7.315 | 28131 | 6183 | 0.018 | |
| 9 | 8.843 | 24560 | 7729 | 0.015 | |
| 10 | 11.355 | 9863 | 2393 | 0.006 | |
| 11 | 11.459 | 11694 | 2416 | 0.007 | |
| 12 | 11.655 | 10830 | 2158 | 0.007 | |
| 13 | 11.939 | 177295 | 58148 | 0.111 | |
| 14 | 12.617 | 47345875 | 6162008 | 29.726 | |
| 15 | 13.026 | 8332 | 2675 | 0.005 | |
| 16 | 13.257 | 10817 | 2952 | 0.007 | |
| 17 | 13.360 | 9352 | 2832 | 0.006 | |
| 18 | 13.791 | 38478 | 4670 | 0.024 | |
| 19 | 13.851 | 27556 | 4366 | 0.017 | |
| 20 | 14.004 | 14528 | 3919 | 0.009 | |
| 21 | 14.139 | i1914 | 3660 | 0.007 | |
| 22 | 14.548 | 9163 | 1633 | 0.006 | |
| 23 | 15.112 | 19359 | 2795 | 0.012 | |
| 24 | 15.555 | 18993 | 4480 | 0.012 | |
| 25 | 15.976 | 12023 | 1337 | 0.008 | |
| 26 | 16.478 | 77295 | 5839 | 0.049 | |
| 27 | 18.106 | 8946 | 574 | 0.006 | |
| Total of | 159274951 | 64575729 | 100.000 |
TABLE 2
Example 4
Adding 68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 1.5g of dibenzo-24-crown ether-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, and reacting for 2 hours when the pressure reaches 2 MPa. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 500g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 92.3% and purity of 98%.
Example 5
Adding 68g of sodium ethoxide, 133g of diethyl malonate, 200g of ethanol and 0.15g of dibenzo-24-crown ether-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, controlling the pressure to reach 2MPa, and reacting for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and vacuum distilling to obtain compound II in 90.1% yield and 98% purity.
Example 6
68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 0.25g of dibenzo-24-crown-8 are added into a pressure kettle, stirred for 1 hour at 0 ℃, 150g of ethyl formate is added, the mixture is sealed and heated, the temperature is controlled at 100 ℃, and the reaction is carried out for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 88.3% and purity of 98%.
Example 7
Adding 68g of sodium ethoxide, 160g of diethyl malonate, 300g of ethanol and 0.25g of dibenzo-24-crown ether-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, controlling the pressure to reach 2MPa, and reacting for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 150g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 76.5% and purity of 98%.
Example 8
Adding 68g of sodium ethoxide, 160g of diethyl malonate and 300g of ethanol into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, controlling the pressure to 2MPa, and reacting for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering and distilling under reduced pressure to obtain the compound II with yield of 61.9% and purity of 98%.
Example 9
Adding 68g of sodium ethoxide, 300g of ethanol and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃ and the pressure to reach 2MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with 95.2% sodium ethoxide yield and 99% purity.
Example 10
Adding 68g of sodium ethoxide, 300g of toluene and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃ and the pressure to reach 2MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 81.3% and purity of 98.5% calculated by sodium ethoxide.
Example 11
Adding 68g of sodium ethoxide, 300g of xylene and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃ and the pressure to reach 2MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 80.1% in terms of sodium ethoxide and purity of 98%.
Example 12
Adding 84g of potassium ethoxide, 300g of ethanol and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃, the pressure at 2MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 93.8% and purity of 98% calculated by potassium ethoxide.
Example 13
Adding 68g of sodium ethoxide, 300g of ethanol and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 100 ℃ and the pressure to reach 4MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 94.3% and purity of 98% in terms of sodium ethoxide.
Example 14
Adding 68g of sodium ethoxide, 300g of ethanol and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature at 120 ℃ and the pressure at 4MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 91.2% and purity of 97% calculated by sodium ethoxide.
Example 15
Adding 68g of sodium ethoxide, 700g of ethanol and 0.25g of dibenzo-24-crown-8 into a pressure kettle, starting stirring, introducing carbon monoxide into the reaction kettle, ventilating for three times, heating, controlling the temperature to be 80 ℃, the pressure to be 2MPa, and introducing 192g of diethyl malonate into the reaction kettle within 2 hours. After the reaction is finished, the temperature is reduced to room temperature, and the pressure is slowly released to normal pressure to obtain a suspension I. The suspension I was added dropwise to 300g of 30% ethanol hydrogen chloride and acidified, and stirred at room temperature for 4 hours. Neutralizing, filtering, and distilling under reduced pressure to recover excessive diethyl malonate to obtain compound II with yield of 89.6% and purity of 98% calculated by sodium ethoxide.
Claims (9)
1. A method for synthesizing ethoxy methylene diethyl malonate uses diethyl malonate as raw material, ethyl formate or carbon monoxide as auxiliary material, and under the action of alcohol alkali metal salt and catalyst, an intermediate compound I is obtained, and then the intermediate compound I reacts with alcohol solution under the action of acid to obtain ethoxy methylene diethyl malonate.
2. The preparation method according to claim 1, wherein the alcoholic alkali metal salt is potassium salt or sodium salt, preferably sodium ethoxide, the reaction solvent is one or a mixture of ethanol, toluene and xylene, preferably ethanol, and the mass ratio of the diethyl malonate to the reaction solvent is 1: 1.5-4.
3. The preparation method according to claim 2, wherein the feeding molar ratio of the diethyl malonate to the alcohol alkali metal salt is 0.8-1.2: 1.
4. the method according to claim 1, wherein the catalyst is any one of piperidine, quaternary ammonium salt and crown ether.
5. The process according to claim 4, wherein the catalyst is dibenzo-24-crown-8, and the amount of dibenzo-24-crown-8 is 0.1-1%, preferably 0.1-0.4% by mass of diethyl malonate.
6. The method according to claim 1, wherein the acid is hydrogen chloride, sulfuric acid, a solid acid, or a mixture of two thereof, preferably hydrogen chloride.
7. The process according to claim 1, wherein the reaction pressure for preparing the compound I is 2 to 4MPa and the reaction temperature is 80 to 120 ℃.
8. The preparation method of claim 1, wherein the molar ratio of the acid to the alcohol alkali metal salt is 1-5: 1, preferably 1 to 2.5: 1.
9. the method according to claim 1, wherein the process for synthesizing diethyl ethoxymethylenemalonate comprises the following steps:
s1: adding a solvent, an alcohol alkali metal salt, diethyl malonate and a catalyst into a pressure kettle in proportion, introducing carbon monoxide gas to a certain pressure, or adding ethyl formate, and heating for reacting for 2-6 hours to obtain a compound I; in another preferred scheme, firstly adding alcohol alkali metal salt and solvent into a pressure kettle, introducing carbon monoxide or adding ethyl formate, heating, and slowly introducing diethyl malonate until the reaction is finished to obtain a compound I;
s2: the solution of diethyl formyl malonate reacts with ethanol for 4 to 8 hours under the action of acid catalysis;
s3: filtering, and distilling the filtrate under reduced pressure at-0.1 MPa and 140 ℃ to obtain the ethoxymethylenediethyl malonate.
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| CN114181149A (en) * | 2021-12-30 | 2022-03-15 | 浙江本立科技股份有限公司 | Synthetic method of 3, 4-dimethylpyrazole |
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| CN109111363A (en) * | 2018-09-11 | 2019-01-01 | 常州大学 | A kind of preparation method of ethoxy methylene diethyl malonate |
| CN111153799A (en) * | 2020-01-20 | 2020-05-15 | 浙江本立科技股份有限公司 | Preparation method of methyl 3-methoxyacrylate |
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| US4665218A (en) * | 1984-04-26 | 1987-05-12 | Dynamit Nobel Ag | Method for the preparation of alkoxymethylene compounds of acetic esters and substituted acetic esters |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114181149A (en) * | 2021-12-30 | 2022-03-15 | 浙江本立科技股份有限公司 | Synthetic method of 3, 4-dimethylpyrazole |
| CN114181149B (en) * | 2021-12-30 | 2024-04-02 | 浙江本立科技股份有限公司 | Synthesis method of 3, 4-dimethylpyrazole |
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