CN111662233A - Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method - Google Patents
Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method Download PDFInfo
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- CN111662233A CN111662233A CN202010588302.0A CN202010588302A CN111662233A CN 111662233 A CN111662233 A CN 111662233A CN 202010588302 A CN202010588302 A CN 202010588302A CN 111662233 A CN111662233 A CN 111662233A
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- C07—ORGANIC CHEMISTRY
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention belongs to a medical intermediate, and particularly relates to a method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method. The invention provides a synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester for the first time, provides a synthetic route for the synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester, and has the advantages of short synthetic route, reasonable design, simple operation and easy control; the compound A (1H-imidazole-2-carboxylic acid ethyl ester) is used as a raw material, a better polarization environment is provided for N-chlorosuccinimide molecules by organic acid under the environment of low temperature and organic acid, the electrophilic activity of a substrate is improved, the reaction is promoted, the generation of byproducts is reduced, and the yield and the purity of the product are improved.
Description
Technical Field
The invention belongs to a medical intermediate, and particularly relates to a method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method.
Background
The synthesis method of the compound 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the existing problems, the method for synthesizing the 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by the one-step method is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester has the following chemical reaction formula:
compound a compound B;
the synthesis comprises the following steps:
and (2) uniformly mixing the compound A and a solvent, adding organic acid, cooling, dropwise adding an N-chlorosuccinimide solution, and stirring for reaction to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.
Preferably, the solvent is any one of dimethylformamide and N-methylpyrrolidone.
Preferably, the solid-liquid ratio g/mL of the compound A to the solvent is 1: 30-35.
Preferably, the organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.
Preferably, the solid-to-liquid ratio g/mL of the compound A and the organic acid is 5-9: 1.
Preferably, the mass ratio of the compound A to the N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing the N-chlorosuccinimide and a solvent according to the solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.
Preferably, the end point of the temperature reduction is-5-0 ℃.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester for the first time, and provides a synthetic route for the synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester;
(2) the synthetic method of the 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester provided by the invention is short in route, reasonable in design, simple to operate and easy to control;
(3) the compound A (1H-imidazole-2-carboxylic acid ethyl ester) is used as a raw material, a better polarization environment is provided for N-chlorosuccinimide molecules by organic acid under the environment of low temperature and organic acid, the electrophilic activity of a substrate is improved, the reaction is promoted, the generation of byproducts is reduced, and the yield and the purity of the product are improved.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
The solvent is any one of dimethylformamide and N-methylpyrrolidone.
The organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.
The mass ratio of the compound A to the N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing the N-chlorosuccinimide and a solvent according to the solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.
A method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method, which comprises the following steps: uniformly mixing the compound A and the solvent according to the solid-liquid ratio g/mL of the compound A and the solvent of 1: 30-35, adding the organic acid according to the solid-liquid ratio g/mL of the compound A and the organic acid of 5-9: 1, cooling to-5-0 ℃, dropwise adding an N-chlorosuccinimide solution, stirring and reacting for 15-20 hours to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.
Example 1
The solvent is any one of dimethylformamide and N-methylpyrrolidone.
The organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.
(1) A method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method, which comprises the following steps: uniformly mixing 50g of the compound A with 1L of solvent, adding 10mL of organic acid, cooling to 0 ℃, dropwise adding 500 mLN-chlorosuccinimide solution, and stirring for reacting for 17 hours;
(2) and (3) detecting by TLC (thin layer chromatography), adding 3 liters of water into the reaction solution, extracting by ethyl acetate, concentrating the extract, performing column chromatography, concentrating to obtain a crude product, pulping the crude product by using 500mL of acetonitrile, filtering, washing a filter cake by using water for three times, and drying the filter cake to obtain 32.5g of white solid, namely the compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester, wherein the purity is 98.6 percent, and the yield is 52.18 percent.
1H NMR（CD3OD）:7.28(s, 1H), 4.35(q, J=7.2Hz, 2H), 1.38(t, J=7.2Hz, 3H)
Example 2
The solvent is any one of dimethylformamide and N-methylpyrrolidone.
The organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.
(1) A method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method, which comprises the following steps: uniformly mixing 50g of the compound A with 1L of solvent, adding 10mL of organic acid, cooling to 0 ℃, dropwise adding 400 mLN-chlorosuccinimide solution, and stirring for reacting for 15 hours;
(2) and (3) detecting by TLC (thin layer chromatography), adding 3 liters of water into the reaction solution, extracting by ethyl acetate, concentrating the extract, performing column chromatography, concentrating to obtain a crude product, pulping the crude product by using 500mL of acetonitrile, filtering, washing a filter cake by using water for three times, and drying the filter cake to obtain 30.6g of white solid, namely the compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester, wherein the purity is 97.9 percent, and the yield is 49.13 percent.
1H NMR（CD3OD）:7.28(s, 1H), 4.35(q, J=7.2Hz, 2H), 1.38(t, J=7.2Hz, 3H)
Comparative example
The solvent is any one of dimethylformamide and N-methylpyrrolidone.
(1) A method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method, which comprises the following steps: uniformly mixing 50g of the compound A with 1L of solvent, cooling to 0 ℃, dropwise adding 500 mLN-chlorosuccinimide solution, and stirring for reacting for 17 hours;
(2) and (3) detecting by TLC (thin layer chromatography), adding 3 liters of water into the reaction solution, extracting by ethyl acetate, concentrating the extract, performing column chromatography, concentrating to obtain a crude product, pulping the crude product by using 500mL of acetonitrile, filtering, washing a filter cake by using water for three times, and drying the filter cake to obtain 25.8g of white solid, namely the compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester, wherein the purity is 94.6 percent, and the yield is 41.42 percent.
1H NMR（CD3OD）:7.28(s, 1H), 4.35(q, J=7.2Hz, 2H), 1.38(t, J=7.2Hz, 3H)
The present invention has been further described with reference to specific embodiments, but it should be understood that the detailed description should not be construed as limiting the spirit and scope of the present invention, and various modifications made to the above-described embodiments by those of ordinary skill in the art after reading this specification are within the scope of the present invention.
Claims (7)
1. A one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester is characterized in that the chemical reaction formula of the synthesis is as follows:
compound a compound B;
the synthesis comprises the following steps:
and (2) uniformly mixing the compound A and a solvent, adding organic acid, cooling, dropwise adding an N-chlorosuccinimide solution, and stirring for reaction to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.
2. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solvent is any one of dimethylformamide and N-methylpyrrolidone.
3. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound A to the solvent is 1: 30-35.
4. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.
5. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound A to the organic acid is 5-9: 1.
6. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the mass ratio of the compound A to N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing N-chlorosuccinimide and a solvent according to a solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.
7. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the end point of the temperature reduction is-5 to 0 ℃.
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Citations (5)
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| CN102417507A (en) * | 2010-09-27 | 2012-04-18 | 上海药明康德新药开发有限公司 | Synthesis method of 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline |
| CN102464661A (en) * | 2010-11-16 | 2012-05-23 | 上海药明康德新药开发有限公司 | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester |
| CN104177296A (en) * | 2014-08-11 | 2014-12-03 | 蒋军荣 | Preparation method of 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester |
| CN105218550A (en) * | 2015-09-29 | 2016-01-06 | 山东友帮生化科技有限公司 | The synthetic method of 3-chlorine imidazo [1,2-b] pyridazine |
| CN106632351A (en) * | 2016-11-18 | 2017-05-10 | 山东友帮生化科技有限公司 | Method for preparing 6-bromine imidazo [1,2-a]pyrazine-3-nonanoic acid-ethyl ester |
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- 2020-06-24 CN CN202010588302.0A patent/CN111662233B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102417507A (en) * | 2010-09-27 | 2012-04-18 | 上海药明康德新药开发有限公司 | Synthesis method of 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline |
| CN102464661A (en) * | 2010-11-16 | 2012-05-23 | 上海药明康德新药开发有限公司 | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester |
| CN104177296A (en) * | 2014-08-11 | 2014-12-03 | 蒋军荣 | Preparation method of 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester |
| CN105218550A (en) * | 2015-09-29 | 2016-01-06 | 山东友帮生化科技有限公司 | The synthetic method of 3-chlorine imidazo [1,2-b] pyridazine |
| CN106632351A (en) * | 2016-11-18 | 2017-05-10 | 山东友帮生化科技有限公司 | Method for preparing 6-bromine imidazo [1,2-a]pyrazine-3-nonanoic acid-ethyl ester |
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