CN102417507A - Synthesis method of 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline - Google Patents
Synthesis method of 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline Download PDFInfo
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- CN102417507A CN102417507A CN2010102929546A CN201010292954A CN102417507A CN 102417507 A CN102417507 A CN 102417507A CN 2010102929546 A CN2010102929546 A CN 2010102929546A CN 201010292954 A CN201010292954 A CN 201010292954A CN 102417507 A CN102417507 A CN 102417507A
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- quinoxaline
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Abstract
The invention relates to a synthesis method of 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline, which is mainly used for solving the technical problems of the existing scarce synthetic route, expensive reaction raw materials, difficulty in amplification, narrow application range and the like. The synthesis method comprises the following steps: heating o-phenylenediamine 1 which is a cheap and available chemical raw material and diethyl oxalate for reacting in a solvent to obtain a compound 2 which is 2,3-dihydroxyl quinoxaline; heating the compound 2 and a chloride reagent for reacting to obtain a compound 3 which is 2,3-dichloro-quinoxaline; and reacting the compound 3 with ethyl isocyanoacetate in a solvent in the presence of an alkalization reagent to obtain the final product, namely 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline. By adopting the synthetic route provided by the invention, a large quantity of the 3-ethyl carboxylate-4-chloro imidazole [1,5-a] quinoxaline can be quickly and conveniently prepared.
Description
Technical field
The present invention relates to the compound method of a kind of important medicine intermediate 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline.
Background technology
The imidazo quinoxaline compound; Like imidazoles [1; 2-a] quinoxaline, imidazoles [1,5-a] quinoxaline, 1H-imidazoles [4,5-b] quinoxaline etc. and verivate thereof be one type of important medicine intermediate segment; Wherein imidazoles [1,5-a] quinoxaline and verivate thereof are used particularly extensively, aspect biologic medical, are had vital role.It all shows good biological activity as a plurality of compounds that the molecule parent nucleus is used to prepare, as as GABA receptor stimulant/antagonist (J. Med. Chem.:39:1996:3820); CAMP and cGMP phosphodiesterase inhibitor (J. Med. Chem.:34:1991:2671); A
1-And A
2a-Adenosine receptor agonist (J. Med. Chem.:30:1995:133); The toxicity of inducing to the hippocampus cell has effective restraining effect (J. Med. Chem.:40:1997:2053) etc.Containing the pulsating one type of new compound of imidazoles [1,5-a] quinoxaline, is effective Src family kinase p56Lck suppressor factor like BMS-238497, shows very strong enzyme activity (IC
50And can effectively stop the diffusion (IC of T cell=2 nM),
50=0.67 μ M) (Bioorg. Med. Chem. Lett.:16:2002:1361; Bioorg. Med. Chem. Lett.:12:2002:3153).
Verivate as the imidazo quinoxaline compound; 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1; 5-a] quinoxaline and analogue thereof not only can be used as the compound of the various biologically actives of intermediate preparation; Itself also be proved to be and aspect cardiotonic, had very high researching value, particularly ought reach the ideal myocardial contraction and do the time spent for the influence of heart rate and blood pressure very little (Pat. US4440929A1).
Yet the compound method about 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline has only two pieces of bibliographical informations at present.A kind of is to be starting raw material elder generation and aniline reaction with diformazan sulfenyl-2-nitroethylene; There is ShiShimonoseki ring at POCl3 then; Use the metachloroperbenzoic acid oxidation again; Last and isocyanide ETHYLE ACETATE closes ring and obtains final product (J. Org. Chem.:72:2007:5020-5023), and overall yield is 22%.Its reaction formula is following:
Another kind method is to be starting raw material with imidazole-2-carboxylic acid; Be converted into carboxylicesters later on again with adjacent nitro fluorobenzene generation substitution reaction; Ring is closed in hydrogenation again, and last and chlorination reagent phosphorus oxychloride reaction obtains title product (Pat. US4440929A1), and overall yield is 15.8%; This method is used hydrogenation pass ring, and applicability is wideless.Its reaction formula is following:
。
These two kinds reported method all have expensive raw materials, the problem that is difficult to obtain.The compound method raw material of the present invention's technology is very cheap, three-step reaction, and total recovery reaches 56%.
Summary of the invention
The object of the present invention is to provide the compound method of a kind of important drugs midbody 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline.Technical problems such as the reaction raw materials that mainly solves existing synthetic route shortage and exist is expensive, amplifies difficulty, and suitability is wideless.
Technical scheme of the present invention: the compound method of 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline may further comprise the steps:
The first step: with the O-Phenylene Diamine is raw material, obtains 2 with oxalic acid diethyl ester reacting by heating in solvent, 3-dihydroxyl quinoxaline;
Second step: 2,3-dihydroxyl quinoxaline and chlorination reagent heating obtain 2, the 3-dichloro-quinoxaline;
The 3rd step: 2, the 3-dichloro-quinoxaline obtains the finished product 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline with the isocyanide acetic acid ethyl reaction in the presence of alkalizing agent in solvent.
Reaction formula is following:
。
The first step is reflected in the solvent carries out, and solvent is a kind of in methyl alcohol, ethanol or the glycol dimethyl ether, is optimum condition with ethanol; Temperature of reaction is 65 ℃～85 ℃; Reaction times is 12～24 hours.
The reaction of second step can add N, and dinethylformamide is optimum condition as catalyzer to add catalyzer; Chlorination reagent is thionyl chloride or POCl3, is optimum condition with the thionyl chloride; Temperature of reaction is 78～110 ℃; Reaction times is 4～18 hours.
Solvent in the three-step reaction is N, dinethylformamide or methyl-sulphoxide; Alkalizing agent is 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine or diisopropylethylamine, and with 1,8-diazacyclo [5,4,0] hendecene-7 is an optimum condition, temperature of reaction is-10～20 ℃; Reaction times is 1～18 hour.
The invention has the beneficial effects as follows: 1, starting raw material very cheaply is easy to get; 2, step is short, and yield is high; 3, purifying is simple, is easy to amplify.
Embodiment
Following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content.
Embodiment 1:
2,3-dihydroxyl quinoxalineSynthesis technique:
In 1 liter reaction flask of reflux condensing tube is housed, O-Phenylene Diamine (50 grams, 0.46 mole) is dissolved in ethanol (500 milliliters), stirs adding oxalic acid diethyl ester (135.1 grams, 0.92 mole) down.Reaction slowly is heated to reflux state (78 ℃), and afterreaction finished in 12 hours, will react in the ice-water bath and cool off; With the solid filtering of separating out, filter cake is with cold ethanol (100 milliliters of x 2) washing, and dried in vacuum obtains title product 2; 3-dihydroxyl quinoxaline (67 grams, 87%).
Proton nmr spectra (DMSO-
d 6 , 400 MHz), δ ppm:11.91 (s, 2 H), 7.11-7.06 (m, 4 H).
Embodiment 2:
2,3-dihydroxyl quinoxalineSynthesis technique:
Solvent is a methyl alcohol, and temperature of reaction is reflux (65 ℃).Reaction times is 12 hours.All the other are identical with embodiment 1.Yield is 74%.
Embodiment 3:
2,3-dihydroxyl quinoxalineSynthesis technique:
Solvent is a glycol dimethyl ether, and temperature of reaction is reflux (85 ℃).Reaction times is 24 hours.All the other are identical with embodiment 1.Yield is 52%.
Embodiment 4:
2, the 3-dichloro-quinoxalineSynthesis technique:
, 2 liters reaction flask of reflux condensing tube adds 2 in being housed; 3-dihydroxyl quinoxaline (48.9 grams, 0.3 mole) adds sulfur oxychloride (500 milliliters) then carefully; Stir and add N down; Dinethylformamide (2 milliliters) slowly is heated to backflow (78 ℃) then as catalyzer, reacts 12 hours.After the reaction cooled reaction solution is concentrated into driedly, the bullion that obtains obtains title product 2 with cold water (100 milliliters of x 2) washing after the drying, 3-dichloro-quinoxaline (59.5 grams, 99%).
Proton nmr spectra (DMSO-
d 6 , 400 MHz), δ ppm:8.11 (dd,
J 1 =6.4 Hz,
J 2 =3.2 Hz, 2 H), 7.97 (dd,
J 1 =6.4 Hz,
J 2 =3.2 Hz, 2 H).
Embodiment 5:
2, the 3-dichloro-quinoxalineSynthesis technique:
Reaction times is 18 hours.All the other are identical with embodiment 4.Yield is 83%.
Embodiment 6:
2, the 3-dichloro-quinoxalineSynthesis technique:
With 2,3-dihydroxyl quinoxaline (5 grams, 0.031 mole) is dissolved in N, dinethylformamide (50 milliliters); Slowly add POCl3 (12.5 milliliters, 0.12 mole) again, then reaction system slowly is heated to 110 ℃, react and after 4 hours reaction system is cooled to room temperature; Pour into again in the frozen water,, use cold water washing the solid filtering of separating out; Drying obtains product 2,3-dichloro-quinoxaline (4.8 grams, 79%).
Embodiment 7:
3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxalineSynthesis technique:
In being equipped with, add 2 in the there-necked flask of temperature thermometer, 3-dichloro-quinoxaline (10 grams, 0.05 mole) and N, dinethylformamide (50 milliliters); Be cooled to-15 ℃ with the cryosel bath, add 1 again, 8-diazacyclo [5; 4,0] hendecene-7 (11.2 milliliters, 0.075 mole).Stir after 10 minutes, slowly drip isocyanide ETHYLE ACETATE (5.1 grams, 0.045 mole) through constant pressure funnel, about 2 hours of dropping time, the control rate of addition makes temperature be no more than-10 ℃.After dripping, reaction system is warming up to 20 ℃ and stirred 18 hours naturally.In reaction system, add methylene dichloride (150 milliliters); Water (50 milliliters of x 2) and saturated aqueous common salt (50 milliliters of x 2) washing is again used anhydrous sodium sulfate drying with organic phase, removes by filter siccative; Filtrating concentrating obtains thick product; (dichloromethane/ethyl acetate=5:1) separation obtains product 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline (8 grams, 65%) to silica gel column chromatography.
Proton nmr spectra (CDCl3,400 MHz), δ ppm:8.73 (s, 1 H), 7.99 (dd,
J 1 =7.6 Hz,
J 2 =1.2 Hz, 2 H), 7.70-7.61 (m, 2 H), 4.5 1 (q,
J=7.2 Hz, 2 H), 1.48 (t,
J=7.2 Hz, 3 H).
Embodiment 8:
3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxalineSynthesis technique:
20 ℃ drip isocyanide ETHYLE ACETATE down, and temperature of reaction is 20 ℃, and the reaction times is 1 hour.All the other are identical with embodiment 7.Yield is 32%.
Embodiment 9:
3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxalineSynthesis technique:
Alkalizing agent is a triethylamine, and temperature of reaction is 20 ℃, and the reaction times is 12 hours.All the other are identical with embodiment 7.Yield is 12%.
Embodiment 10:3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxalineSynthesis technique:
Alkalizing agent is a diisopropylethylamine, and temperature of reaction is 20 ℃, and the reaction times is 16 hours.All the other are identical with embodiment 7.Yield is 20%.
Claims (8)
1.3-the compound method of carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline may further comprise the steps:
The first step reaction is a raw material with the O-Phenylene Diamine, obtains 2 with oxalic acid diethyl ester reacting by heating in solvent, 3-dihydroxyl quinoxaline;
The reaction of second step, 2,3-dihydroxyl quinoxaline and chlorination reagent heating obtain 2, the 3-dichloro-quinoxaline;
Three-step reaction, 2, the 3-dichloro-quinoxaline obtains the finished product 3-carboxylic acid, ethyl ester-4-chlorine imidazoles [1,5-a] quinoxaline with the isocyanide acetic acid ethyl reaction in the presence of alkalizing agent in solvent.
2. the compound method of 3-carboxylic acid, ethyl ester according to claim 1-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that, the first step reaction solvent is a kind of in methyl alcohol, ethanol or the glycol dimethyl ether, and temperature of reaction is 65 ℃～85 ℃; Reaction times is 12～24 hours.
3. the compound method of 3-carboxylic acid, ethyl ester according to claim 2-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that solvent is an ethanol.
4. the compound method of 3-carboxylic acid, ethyl ester according to claim 1-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that, the reaction of second step adds N, and dinethylformamide is as catalyzer.
5. the compound method of 3-carboxylic acid, ethyl ester according to claim 1-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that, second step reaction chlorination reagent is thionyl chloride or POCl3, and temperature of reaction is 78 ℃～110 ℃; Reaction times is 4～18 hours.
6. the compound method of 3-carboxylic acid, ethyl ester according to claim 5-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that chlorination reagent is a thionyl chloride.
7. the compound method of 3-carboxylic acid, ethyl ester according to claim 1-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that the solvent in the three-step reaction is N, dinethylformamide or DMSO 99.8MIN.; Alkalizing agent is 1,8-diazacyclo [5,4,0] hendecene-7, triethylamine or diisopropylethylamine, and temperature of reaction is-10 ℃～20 ℃; Reaction times is 1～18 hour.
8. the compound method of 3-carboxylic acid, ethyl ester according to claim 7-4-chlorine imidazoles [1,5-a] quinoxaline is characterized in that the three-step reaction alkalizing agent is 1,8-diazacyclo [5,4,0] hendecene-7.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111662233A (en) * | 2020-06-24 | 2020-09-15 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
| CN101407519A (en) * | 2007-10-12 | 2009-04-15 | 天津药明康德新药开发有限公司 | Method for synthesizing 5,6,7,8-tetrahydrochysene- imidazo [1,5-alpha] pyrazine |
-
2010
- 2010-09-27 CN CN2010102929546A patent/CN102417507A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
| CN101407519A (en) * | 2007-10-12 | 2009-04-15 | 天津药明康德新药开发有限公司 | Method for synthesizing 5,6,7,8-tetrahydrochysene- imidazo [1,5-alpha] pyrazine |
Non-Patent Citations (1)
| Title |
|---|
| G. S. M. SUNDARAM，等: "Dipolar Cycloaddition of Ethyl Isocyanoacetate to 3-Chloro-2-(methylthio)/ 2-(methylsulfonyl) quinoxalines: Highly Regio and Chemoselective Synthesis of Substituted Imidazo[1,5-a]quinoxaline-3-carboxylates", 《J.ORG.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111662233A (en) * | 2020-06-24 | 2020-09-15 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method |
| CN111662233B (en) * | 2020-06-24 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method |
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Application publication date: 20120418 |