CN1187489A - Process for preparing 4-methylimidazole - Google Patents
Process for preparing 4-methylimidazole Download PDFInfo
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- CN1187489A CN1187489A CN97106218A CN97106218A CN1187489A CN 1187489 A CN1187489 A CN 1187489A CN 97106218 A CN97106218 A CN 97106218A CN 97106218 A CN97106218 A CN 97106218A CN 1187489 A CN1187489 A CN 1187489A
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- methylimidazole
- formaldehyde
- ammonium oxalate
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- pyruvic aldehyde
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Abstract
A dewatering cyclization process for synthesizing 4-methyl imidazole from formaldehyde, pyruvaldehyde and ammonium oxalate features that the pH value of ammonium oxalate is first regulated to 1-5, part of formaldehyde is then dropped to it, and the mixture of the rest of formaldehyde and pyruvaldehyde is finally dropped to it at 45-80 deg.C. Its advantages include short holding time, less side-reaction and high output rate of 4-methylimidazole.
Description
The present invention relates to the preparation technology of 4-methylimidazole.
4-methylimidazole is important medicine intermediate, is mainly used in synthetic anti-ulcer medicament Cimitidine Type A/AB.The technology of producing 4-methylimidazole at present mainly contains following several: (a) adopt pyruvic aldehyde, formaldehyde and ammonium sulfate at pH value 1～3, the synthetic 4-methylimidazole of dehydration condensation more than 80 ℃, extract with isopropylcarbinol, the 4-methylimidazole recovery rate reaches 85～88%, but this technological reaction is restive, the poor product quality that makes can not be as the raw material of synthetic Cimitidine Type A/AB; (b) adopt formaldehyde, pyruvic aldehyde to synthesize 4-methylimidazole technology with the ammonium succinate dehydration condensation, the yield of this technology only about 60%, and post-processing step is many, the production cost height; (c) adopt the synthetic 4-methylimidazole of formaldehyde, pyruvic aldehyde and ammonium oxalate dehydration condensation.The good product quality that this technology obtains, and ammonium oxalate can be recycled, so production cost is lower.It is raw material that clear 60-105664 of document and clear 60-104072 have introduced with the ammonium oxalate aqueous solution, formaldehyde, pyruvic aldehyde, the water yield: pyruvic aldehyde is 4～30 (w/w), or adds pyruvic aldehyde in the aqueous solution of ammonium oxalate and formaldehyde; Or in the ammonium oxalate aqueous solution, add the mixed solution of pyruvic aldehyde and formaldehyde; Or in the water, add pyruvic aldehyde, formaldehyde and ammonium oxalate simultaneously respectively.Its reaction times needs 2～5 hours.This technology is compared with other technology in the past, and the molar yield of 4-methylimidazole increases, and is up to 87%.
The preparation technology who the purpose of this invention is to provide a kind of 4-methylimidazole makes formaldehyde, pyruvic aldehyde and ammonium oxalate carry out ring-closure reaction better, reduces side reaction simultaneously, thus the 4-methylimidazole of the high purity of making, high yield.
The objective of the invention is to realize: a kind of preparation technology of 4-methylimidazole by following technical scheme, with the ammonium oxalate aqueous solution, formaldehyde, pyruvic aldehyde is a raw material, by specific order of addition(of ingredients) and reaction pH value adjusting just, promptly at first be adjusted to 1～5 with sour pH value with the ammonium oxalate aqueous solution, in the ammonium oxalate aqueous solution, add part formaldehyde then earlier, under 45～80 ℃ of conditions of temperature of reaction, add the mixed solution of residue reaction again with formaldehyde and pyruvic aldehyde, wherein the weight ratio of water and pyruvic aldehyde is 4～30: 1 in the system, reaction generates the 4-methylimidazole oxalate, adds ammoniacal liquor after reaction finishes and promptly get 4-methylimidazole in this system.
Technique scheme mesoxalic acid ammonium: pyruvic aldehyde: formaldehyde is 1～2: 1～1.5 with molar ratio computing: 1, the weight ratio preferable range of water and pyruvic aldehyde is 5～15: 1, the temperature of reaction preferable range is 50～65 ℃, before adding formaldehyde and pyruvic aldehyde, the pH value preferable range of the ammonium oxalate aqueous solution is 2～4, adjusts the used acid of pH value and can be oxalic acid.The part formaldehyde amount that adds earlier in the ammonium oxalate aqueous solution is for reacting with 10～60% of total formaldehyde amount, and its preferable range is 30～40%.
The present invention since before reaction just with the acidity adjustment of the ammonium oxalate aqueous solution to a suitable scope, and oxalic acid-ammonium oxalate can form buffered soln, entire reaction course all is in the rational acidity scope carries out, reduced the generation of side reaction, help the raising of yield.In addition by adding formaldehyde earlier, after add the feed way of formaldehyde and pyruvic aldehyde mixed solution, the entire reaction time has been shortened greatly, reduced the generation of side reaction product equally, improved the reaction yield of final 4-methylimidazole, obtained good effect.
The invention will be further elaborated by the following examples.[embodiment 1]
With 67.2 gram ammonium oxalate dispersing and dissolvings in 129 ml waters, with oxalic acid the pH value of ammonium oxalate is adjusted into 2 then.Formaldehyde 9.4 grams that in above-mentioned solution, add 37% (weight) earlier, under 55 ℃ of conditions of temperature, add formaldehyde 22 grams of 37% (weight) and the mixed solution of pyruvic aldehyde 73.8 gram (0.43 mole) compositions of 42% (weight), the joining day is 1 hour, be incubated 0.5 hour, reaction finishes the back decompression dehydration, recycle-water 170 grams, and at this moment the water yield also has 0.7 times of 4-methylimidazole oxalate total amount in the system, become pasty state, with the washing of 45 ml methanol, then this solution is cooled to 5 ℃, filter.In the 4-methylimidazole oxalate that above-mentioned steps obtains, add 70 ml water furnishing solution, drip ammoniacal liquor 59 grams of 25% (weight) again.Drip off the back and be cooled to 5 ℃ again after 1 hour, filter in insulation under 50 ℃ of conditions.With the above-mentioned 4 Methylimidazole filtrates that obtain, through decompression dehydration, underpressure distillation again gets 29.6 gram 4-methylimidazole products, purity 99.2%, and the yield of 4-methylimidazole is 83.1%.
Gas chromatographic analysis is adopted in data analysis; Instrument HP-5890 gas chromatographicanalyzer.Chromatographic condition, 250 ℃ of column temperatures, 320～350 ℃ of gasification temperatures, 280 ℃ of detector temperatures, thermal conductivity detector is done carrier gas with hydrogen, flow velocity 60 ml/min.Chromatographic column is 3 meters stainless steel columns.In fill out 60/80 order TANAX stationary phase.Adopt inner mark method ration, internal standard substance is a Diethylene Glycol.[embodiment 2]
Each step according to embodiment 1, just adding the water yield in the ammonium oxalate is 491 milliliters, temperature of reaction is 65 ℃, the pH value of regulating with oxalic acid is 4, and the formaldehyde amount that adds 37% (weight) in advance is 12.5 grams, and the formaldehyde amount of 37% (weight) that the back adds is 18.9 grams, all the other conditions are with embodiment 1, obtain 32.0 gram 4-methylimidazole products at last, purity 99.2%, the yield of 4-methylimidazole is 89.9%.[embodiment 3]
Each step according to embodiment 1, just adding the water yield in the ammonium oxalate is 80 milliliters, temperature of reaction is 45 ℃, the pH value of regulating with oxalic acid is 5, and the formaldehyde amount that adds 37% (weight) in advance is 3.2 grams, and the formaldehyde amount that the back adds 37% (weight) is 28.2 grams, all the other conditions are with embodiment 1, obtain 27.0 gram 4-methylimidazole products at last, the yield of purity 98.5%, 4～Methylimidazole is 75.4%.[embodiment 4]
Each step according to embodiment 1, just amount of water is 867 milliliters in the ammonium oxalate, and the ammonium oxalate add-on is 48 grams, pyruvic aldehyde 99.7 grams of 42% (weight), temperature of reaction is 80 ℃, the pH value of regulating with oxalic acid is 1, and the formaldehyde amount that adds 37% (weight) in advance is 18.8 grams, and the formaldehyde amount that the back adds 37% (weight) is 12.6 grams, all the other conditions are with embodiment 1, obtain 30.4 gram 4-methylimidazole products at last, purity 99.0%, the yield of 4-methylimidazole is 85.2%.[embodiment 5]
According to each step of embodiment 1, just the ammonium oxalate add-on is 96 grams, and temperature of reaction is 50 ℃, the pH value of regulating with oxalic acid is 3, and all the other conditions obtain 29.5 gram 4-methylimidazole products at last with embodiment 1, purity 99.2%, the yield of 4-methylimidazole are 82.9%.[comparative example 1]
With 67.2 gram ammonium oxalate dispersing and dissolving in 129 ml waters.Formaldehyde 31.4 grams that in this system, add 37% (weight) earlier, under 55 ℃ of temperature condition, add pyruvic aldehyde 73.8 grams (0.43 mole) of 42% (weight), under 55～60 ℃ of conditions, dripped 1 hour, be incubated 2 hours, reaction finishes the back decompression dehydration, recycle-water 170 grams, and at this moment the water yield also has 0.7 times of 4-methylimidazole oxalate total amount in the system, become pasty state, with the washing of 45 ml methanol, then this solution is cooled to 5 ℃, filter.In the 4-methylimidazole oxalate that above-mentioned steps obtains, add 70 ml waters, drip ammoniacal liquor 59 grams of 25% (weight) again.Drip off the back and be cooled to 5 ℃ again after 1 hour, filter in insulation under 50 ℃ of conditions.With the above-mentioned 4-methylimidazole filtrate that obtains, through decompression dehydration, underpressure distillation again gets 28.7 gram 4-methylimidazoles, purity 99.2%, and the yield of 4-methylimidazole is 80.6%.[comparative example 2]
With 67.2 gram ammonium oxalate dispersing and dissolving in 129 ml waters, under 55 ℃ of conditions, in this system, add formaldehyde 31.4 grams of 37% (weight) and the pyruvic aldehyde 73.8 of 42% (weight) and restrain the mixed solution that (0.43 mole) is formed, under 55～60 ℃ of conditions, in 1 hour, drip off, insulation is 2 hours under this temperature, later step is with comparative example 1, get 27.8 gram 4-methylimidazoles at last, purity 99.2%, the yield of 4-methylimidazole is 78.0%.
Claims (8)
1, a kind of preparation technology of 4-methylimidazole, with the ammonium oxalate aqueous solution, formaldehyde and pyruvic aldehyde are raw material, wherein the weight ratio of water and pyruvic aldehyde is 4～30: 1, under 45～80 ℃ of conditions of temperature of reaction, reaction generates the 4-methylimidazole oxalate, reaction finishes the back and add ammoniacal liquor acquisition 4-methylimidazole in this system, it is characterized in that before adding formaldehyde and pyruvic aldehyde, by specific order of addition(of ingredients) and reaction pH value adjusting just, promptly be adjusted to 1～5 with sour pH value with the ammonium oxalate aqueous solution, the adding step of formaldehyde and pyruvic aldehyde is to add part formaldehyde earlier in the ammonium oxalate aqueous solution, and then adds the mixed solution of residue reaction with formaldehyde and pyruvic aldehyde.。
2, according to the preparation technology of the described 4-methylimidazole of claim 1, it is characterized in that ammonium oxalate: pyruvic aldehyde: formaldehyde is 1～2: 1～1.5 with molar ratio computing: 1.
3, according to the preparation technology of the described 4-methylimidazole of claim 1, the weight ratio that it is characterized in that water and pyruvic aldehyde is 5～15: 1.
4,, it is characterized in that temperature of reaction is 50～65 ℃ according to the preparation technology of the described 4-methylimidazole of claim 1.
5, according to the preparation technology of the described 4-methylimidazole of claim 1, it is characterized in that before adding formaldehyde and pyruvic aldehyde, be adjusted into 2～4 with sour pH value with the ammonium oxalate aqueous solution.
6, according to the preparation technology of the described 4-methylimidazole of claim 1, it is characterized in that regulating the acid that the ammonium oxalate aqueous ph value uses is oxalic acid.
7, according to the preparation technology of the described 4-methylimidazole of claim 1, the part formaldehyde amount that it is characterized in that adding earlier in the ammonium oxalate aqueous solution is for reacting with 10～60% of total formaldehyde amount.
8, according to the preparation technology of the described 4-methylimidazole of claim 1, the part formaldehyde amount that it is characterized in that adding earlier in the ammonium oxalate aqueous solution is for reacting with 30～40% of total formaldehyde amount.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97106218A CN1060471C (en) | 1997-01-10 | 1997-01-10 | Process for preparing 4-methylimidazole |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97106218A CN1060471C (en) | 1997-01-10 | 1997-01-10 | Process for preparing 4-methylimidazole |
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| CN1187489A true CN1187489A (en) | 1998-07-15 |
| CN1060471C CN1060471C (en) | 2001-01-10 |
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| CN97106218A Expired - Fee Related CN1060471C (en) | 1997-01-10 | 1997-01-10 | Process for preparing 4-methylimidazole |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199126A (en) * | 2010-03-25 | 2011-09-28 | 中国石油化工股份有限公司 | Preparation method of dialkyl imidazoles |
| CN108794402A (en) * | 2018-07-16 | 2018-11-13 | 南京雪郎化工科技有限公司 | A kind of preparation method of 4-methylimidazole |
| CN110988175A (en) * | 2019-12-17 | 2020-04-10 | 南京正济医药研究有限公司 | Method for determining genotoxic impurity methylglyoxal in cimetidine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0244468B2 (en) * | 1983-11-12 | 1990-10-04 | Taoka Chemical Co Ltd | 44MECHIRUIMIDAZOORUNOSEIZOHO |
| JPH0244469B2 (en) * | 1983-11-12 | 1990-10-04 | Taoka Chemical Co Ltd | 44MECHIRUIMIDAZOORUNOSEIZOHOHO |
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1997
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199126A (en) * | 2010-03-25 | 2011-09-28 | 中国石油化工股份有限公司 | Preparation method of dialkyl imidazoles |
| CN102199126B (en) * | 2010-03-25 | 2013-06-05 | 中国石油化工股份有限公司 | Preparation method of dialkyl imidazoles |
| CN108794402A (en) * | 2018-07-16 | 2018-11-13 | 南京雪郎化工科技有限公司 | A kind of preparation method of 4-methylimidazole |
| CN110988175A (en) * | 2019-12-17 | 2020-04-10 | 南京正济医药研究有限公司 | Method for determining genotoxic impurity methylglyoxal in cimetidine |
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| CN1060471C (en) | 2001-01-10 |
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