CN101781255A - Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole - Google Patents
Preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole Download PDFInfo
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Abstract
The invention discloses a preparation method of 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole, which comprises the steps of esterification reaction, neutralization reaction, amidinization reaction and preparation of the 2-n-butyl-4(5)-chlor-5(4)-formaldehyde-1H-imidazole. Compared with the prior art, the invention simplifies the technology process, shortens the reaction time, improves the production efficiency, overcomes the step of difficult filtering, removes a compound solvent refining method, has simple, direct and feasible operation and is easy for industrialized production.
Description
Technical field:
The present invention relates to a kind of preparation method of-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles.
Background technology:
Before about the preparation imidazole aldehyde, all be to become penta imidic acid first hydrochloride through ester basically by valeronitrile, again with 1, the 3-otan is generation-n-butyl-5-hydroxy methylimidazole under suitable conditions such as temperature and pressure, through chlorination be oxidized to imidazole aldehyde.As: EP0470795A; JP57 98,270; US 5395,943; Synth.Commun, 1992,22 (20), 2971-2977; Synth.Commun, 1993,23 (18), 2623-2630; China's pharmaceutical chemistry magazine, 1998, Vol.8, No.4,271-276 or the like.
And the preparation method who reported imidazole aldehyde in recent years uses Vilsmeier reagent POCl by N-carboxymethyl penta amidine
3Separate and get through Vilsmeier reaction posthydrolysis in toluene with DMF.As J.Org.Chem.1999,64,8084-8089; WO2006110037 etc.But the present invention has many characteristics, and other documents and materials can't compare with it.
Summary of the invention:
The object of the present invention is to provide a kind of technology simple, the reaction times is short, improved production efficiency-preparation method of n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles.
Technical solution of the present invention is:
1, a kind of preparation method of-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles is characterized in that: comprise the following steps:
(1) esterification:
Valeronitrile under the situation that methyl alcohol exists, is fed the hydrogen chloride gas precursor reactant, obtains penta imidic acid methyl ester hydrochloride:
(2) neutralization reaction:
Penta imidic acid methyl ester hydrochloride in benzene class solution, is added the alkali lye neutralization, makes the pH value be 8-9.5, obtain penta imidic acid methyl esters alkali:
(3) amidineization reaction:
The benzene class solution and the glycine of penta imidic acid methyl esters alkali are carried out the amidineization reaction in the presence of methyl alcohol, obtain N-carboxymethyl penta amidine:
(4) preparation 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
With N-carboxymethyl penta amidine in the presence of toluene or xylene solvent with Phosphorus Oxychloride and N, N dimethyl formamide reaction obtains 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
During esterification, in reactor, add valeronitrile and methyl alcohol, feeding is through the dry inert gas replacement of crossing of sulfuric acid and be cooled to-5--12 ℃ after, remove rare gas element, change the dry hydrogen chloride gas of crossing of the sulfuric acid that stimulates the menstrual flow, after hydrogen chloride gas has led to, improve temperature to 4-15 ℃, stirring reaction 24-48 hour; Valeronitrile, methyl alcohol, hydrogenchloride three's mol ratio is 1.0: 1.5-2.0: 1.2-2.5.
During neutralization reaction, will be through the esterification liquid of esterification, under 30-50 ℃, after removing methyl alcohol under the high vacuum, add the benzene class, under stirring, be cooled to below 0 ℃ then, and be controlled at 0 ℃ of following dripping alkali liquid, neutralization makes pH value to 8-9.5, and static layering is separated the inorganic salt that generate in the neutralization reaction from penta imidic acid methyl esters alkali.
During the amidineization reaction, in reactor, add glycine, first alcohol and water, stir cooling, the control temperature of charge drips the benzene class solution of penta imidic acid methyl esters alkali, after dripping at-10 ℃-0 ℃, transfer pH value, control pH value under the 8.0-10.0 room temperature stirring reaction 15-24 hour; The mol ratio of valeronitrile is in the consumption of glycine and the step (1): valeronitrile: glycine=1.0: 0.93-0.97.
During step (4) preparation 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles, the consumption mol ratio of N-carboxymethyl penta amidine, Phosphorus Oxychloride, DMF and toluene or dimethylbenzene is: N-carboxymethyl penta amidine: Phosphorus Oxychloride: DMF: toluene or dimethylbenzene=1.0: 2.0-3.2: 1.5-8: 7.0-9.5; Drip temperature 20-50 ℃ of Phosphorus Oxychloride, the temperature that drips DMF is at 70-90 ℃; Batching finishes, and material after the stirring and refluxing reaction finishes, is cooled to 70-30 ℃ 97-101 ℃ of stirring and refluxing reaction 3-4 hour, and impouring is cooled to be hydrolyzed in the frozen water below 20 ℃ in advance, and hydrolysis temperature must not surpass 30 ℃, and hydrolysis time must not be less than at 1 o'clock; With the alkali neutralization, regulate the ph value to 1.2-2.0 after the hydrolysis, tell organic layer, condensing crystal is separated out crude product 2-n-butyl-4 (5)-chloro-5 (4) formaldehyde-1H-imidazoles.
Advantage of the present invention has:
1. in valeronitrile and methyl alcohol behind the logical hydrogenchloride during esterification, use temperature adapts to and improves, and makes the reaction times shorten to more than 20 hour by a couple of days, has shortened reaction time greatly;
2. penta imidic acid first hydrochloride, in sodium hydroxide solution or potassium hydroxide solution and the time, adopted in toluene solution and carried out, the imidic acid methyl esters of generation is extracted in the toluene layer, and the sodium-chlor (potassium) that neutralization generates is dissolved in the water, and is easily separated, avoided filtering difficult problem;
3. penta imidic acid methyl esters toluene solution can directly drop into down the step amidineization, and N-carboxymethyl penta amidine is insoluble to toluene, easily layering separation, and the toluene that branches away can directly be got back to back and applies mechanically;
4.N-carboxymethyl penta amidine, has the cyclization of carrying out, chlorination and hydrolysis oxidation and becomes one step of amidine azoles aldehyde to finish characteristics through Vilsmeier reaction with Vilsmeier agent;
5. the crude product imidazole aldehyde is refining utilizes this product in the aqueous solution, and the characteristics of dissolving under the different ph values and separating out adopt deionized water to make solvent, can overcome double solvents and reclaim difficult problem.
The present invention prepares the method for 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles and compares with conventional art, simplified technological process, shortened the reaction times, improved production efficiency, overcome and filtered difficult step, removed the double solvents process for purification, easy row simple to operation is easy to suitability for industrialized production.
The invention will be further described below in conjunction with embodiment:
Embodiment:
Embodiment 1:
One, the preparation of N-carboxymethyl penta amidine
Step 1.
The preparation of penta imidic acid methyl ester hydrochloride:
Stirring is being housed, thermometer (± 50 ℃), the Y pipe, on the Y pipe reflux exchanger is housed, upper end of condenser dress calcium chloride tube, another of Y pipe mouthful dress gas introduction tube, the gas introduction tube lower end requires to be inserted in the subsurface 250ml there-necked flask of reaction mass, before feeding intake, after feeding nitrogen replacement air carried out air displacement in about 15 minutes earlier, begin to feed intake, in there-necked flask, add positive valeronitrile 83.5g (1.0mol), methyl alcohol 40g (1.28mol) stirs and is cooled to-10 ℃, and beginning is fed after vitriol oil drying by the hydrogen chloride gas that the sodium chloride salt acid solution drips the sulfuric acid generation, temperature remains between-5 ∽-10 ℃ when leading to hydrogen chloride gas, about about 6 hours of the time of logical hydrogen chloride gas, valeronitrile, the two mol ratio of hydrogenchloride is 1.0: 1.2-2.5, weightening finish (the hydrogen chloride gas scale of construction) 66 ∽ 70g.After 2 hours, be warming up to 15 ± 1 ℃ at stirring reaction under this temperature at leisure, continue the insulated and stirred reaction after 24 hours, sampling, GC detects, and valeronitrile runs out of and is terminal point.
After adorning stirring, thermometer, Ke Shi still head on the there-necked flask with last reaction mass, temperature is no more than under 30 ℃ in remaining on, and methyl alcohol is reclaimed in underpressure distillation, until evaporate to dryness.Weigh again, generally increase weight still at 56 ∽ 60g (HCl).The about 155 ∽ 170g of material gross weight.
Step 2.
The preparation of penta imidic acid methyl esters alkali toluene solution
In the above-mentioned material that removes methyl alcohol, add toluene 200ml, stirring makes its whole dissolvings, be cooled to then below-10 ℃, sodium hydroxide solution with 6M neutralizes then, transfer ph to 8.0, stirring reaction reaffirmed that ph is 8 more than 1 hour under the former temperature, and must not be, otherwise to continue to be transferred to requirement with the 6M sodium hydroxide solution less than 8.
Standing demix, water layer are used toluene 50ml * 2 extractions again, and the combining methylbenzene layer is penta inferior sour methyl esters alkali toluene solution.
Step 3.
The preparation of N-carboxymethyl penta amidine
Dress stirs on the 1000ml there-necked flask, thermometer (± 50 ℃), tail pipe etc., add glycine 70.5g therein, methyl alcohol 220ml, water 30ml, under stirring, be cooled to-2 ∽-5 ℃, begin to drip penta imidic acid methyl esters toluene solution, guarantee, drip with 1 hour time below 0 ℃, after waiting to dropwise, transfer ph8.5-9.5 with 6M sodium hydroxide solution gob, and, slowly be warmed up to 30 ± 2 ℃ then and stir after anti-15-20 hour stirring reaction below 0 ℃ 2 hours, crystallisation by cooling is separated out, filter, get crystallization (1), filtrate is told toluene, concentrating under reduced pressure, reclaim the methyl alcohol post crystallization and separate out, filter, drain crystallization (2), altogether wet product 136-144g, dry product 120-122g, [HPLC] 〉=98%, yield 77.21% (based on valeronitrile).Fusing point 197.5-200.5 ℃.
Two, the preparation of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
Step 1:
(1) cyclization, chlorination and the formylation of .N-carboxymethyl penta amidine (Vilsmeier reagent):
Add N-carboxymethyl penta amidine 50g in the there-necked flask of 500ml, toluene 300ml is cooled to below 5 ℃, under brute force stirs, drip phosphorus oxychloride 117g, in the dropping process, temperature has the phenomenon that rises gradually, dropwises, and continues to stir to be raised to 70 ℃, drip DMF, the consumption mol ratio of N-carboxymethyl penta amidine and DMF is: N-carboxymethyl penta amidine: DMF=1.0: 1.5-8, about 15 minutes dropping time, in the dropping process, temperature can automatically rise, and has hydrogen chloride gas to produce and drain into outdoor.Dropwise, rise to 97 ℃ at leisure, 97-101 ℃ of following stirring reaction 3 hours, insulation was cooled to below 30 ℃ after finishing, and joined at leisure in the 350ml ice cold water in stirring down.But water temperature must be lower than 30 ℃, and is last, with the 150ml frozen water material in the reaction flask rinsed well again, and material is all gone in the beaker, stirs 2 hours at 15-30 ℃, reaches with abundant hydrolysis and finishes.
(2). neutralization:
Material after the hydrolysis cools to 10-15 ℃, and the Asia remains under this temperature, transfers ph with 30% sodium hydroxide solution, from the ph negative value, transfers to 1.5.Purpose is to be dissolved in material in the water toluene layer of emanating.
(3). layering and extraction:
Material in the beaker is transferred in the separating funnel, standing demix (leaving standstill at least 5 minutes), tell toluene layer, water layer is used toluene 50ml * 3 extractions again, and extraction temperature can be brought up to 40 ℃, closes the And toluene solution, use pure washing more once, time of repose is slightly long a bit to make moisture clean, uses anhydrous magnesium sulfate (sodium) drying again.
(4). concentrate and reclaim toluene, crystallization is separated out:
Underpressure distillation concentrates, and the liquid temperature is no more than 60 ℃, and the top temperature is no more than 40 ℃, reclaims toluene, material residue cumulative volume about 1/3 to 1/4.Then thing is cooled to-2 ℃, kept 2 hours, crystallization is separated out, and suction filtration is once drained with reclaiming colourless dry toluene or toluene (giving first cooling) rinsing, gets crude product 45g.Mother liquor also will reclaim crude product once more.(meter weight is surveyed content, calculated yield), if throw 50g, N-carboxymethyl penta amidine, about the wet product 45g of 2-n-butyl-4-chloro-5-formyl imidazoles crude product (about dry product 40g, [HPLC] more than 99%, yield 67.78%).
Step 2
Making with extra care of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
Crude product 100g, add deionized water 1300ml, agitation and dropping concentrated hydrochloric acid (reagent, 36-37%) 200ml, crude product 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H imidazoles all dissolves, temperature is more than 15 ℃, stir half an hour after, check once more confirm dissolving fully (otherwise adding hydrochloric acid) until dissolving fully after, add gac 5g, stir decolouring, be warming up to 40-50 ℃, stir decolouring about 1 hour, be cooled to room temperature, suction filtration, filter Pie gac is used 30-50ml hot water (more than 40-50 ℃) to soak again and is drained, and this moment, material ph value should be negative.
Filtrate is closed And, at room temperature, stir on one side, one side drips 30% sodium hydroxide solution, transfer material ph value from negative to positive 1.5, with the about 250ml of 30% sodium hydroxide solution, stirring is surveyed the ph value after half an hour once more, stir crystallisation by cooling and analyse the mountain, stir down more than 2 hours at 0-2 ℃, suction filtration, drain, steep with 0-2 ℃ of deionized water 50ml again and wash once, drain, the about 98g of product that must wet, dry 93.5g.Survey 96.5-98.5 ℃ of .[HPLC of fusing point] 99.95%, yield 93.5%.
Embodiment 2:
During the preparation of penta imidic acid methyl esters alkali toluene solution, toluene with benzene or dimethylbenzene replace, sodium hydroxide replaces with potassium hydroxide; Toluene is replaced with dimethylbenzene in cyclization, chlorination and the formylation step of N-carboxymethyl penta amidine during the preparation of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles, and sodium hydroxide is replaced with potassium hydroxide, yellow soda ash or sodium bicarbonate during neutralization reaction during the preparation of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles.During esterification, valeronitrile, methyl alcohol, hydrogenchloride three's mol ratio is 1.0: 1.5-2.0: 1.2-2.5 (example 1: 1.6: 2.4,1: 1.9: 1.3,1: 1.7: 2.0); The consumption of glycine and the mol ratio of valeronitrile are: valeronitrile: glycine=1.0: 0.93-0.97 (example 1: 0.94,1: 0.95,1: 0.97); In cyclization, chlorination and the formylation step of N-carboxymethyl penta amidine during preparation 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles, the consumption mol ratio of N-carboxymethyl penta amidine, Phosphorus Oxychloride, DMF and dimethylbenzene is: N-carboxymethyl penta amidine: Phosphorus Oxychloride: DMF: dimethylbenzene=1.0: 2.0-3.2: 1.5-8: 7.0-9.5 (1: 2: 5: 9,1: 3: 2: 8,1: 2.5: 8: 7).All the other are with embodiment 1.
Claims (5)
1. the preparation method of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles is characterized in that: comprise the following steps:
(1) esterification:
Valeronitrile under the situation that methyl alcohol exists, is fed the hydrogen chloride gas precursor reactant, obtains penta imidic acid methyl ester hydrochloride:
(2) neutralization reaction:
Penta imidic acid methyl ester hydrochloride in benzene class solution, is added the alkali lye neutralization, makes the pH value be 8-9.5, obtain penta imidic acid methyl esters alkali:
(3) amidineization reaction:
The benzene class solution and the glycine of penta imidic acid methyl esters alkali are carried out the amidineization reaction in the presence of methyl alcohol, obtain N-carboxymethyl penta amidine:
(4) preparation 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
With N-carboxymethyl penta amidine in the presence of toluene or xylene solvent with Phosphorus Oxychloride and N, dinethylformamide reaction obtains 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles:
2. the preparation method of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde according to claim 1-1H-imidazoles, it is characterized in that: during esterification, in reactor, add valeronitrile and methyl alcohol, feeding is through the dry inert gas replacement of crossing of sulfuric acid and be cooled to-5--12 ℃ after, remove rare gas element, change the dry hydrogen chloride gas of crossing of the sulfuric acid that stimulates the menstrual flow, after hydrogen chloride gas has led to, improve temperature to 4-15 ℃, stirring reaction 24-48 hour; Valeronitrile, methyl alcohol, hydrogenchloride three's mol ratio is 1.0: 1.5-2.0: 1.2-2.5.
3. the preparation method of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde according to claim 1 and 2-1H imidazoles, it is characterized in that: during neutralization reaction, will be under 30-50 ℃ through the esterification liquid of esterification, after removing methyl alcohol under the high vacuum, add the benzene class, under stirring, be cooled to below 0 ℃ then, and be controlled at 0 ℃ of following dripping alkali liquid, neutralization makes pH value to 8-9.5, and static layering is separated the inorganic salt that generate in the neutralization reaction from penta imidic acid methyl esters alkali.
4. the preparation method of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde according to claim 1 and 2-1H-imidazoles, it is characterized in that: during the amidineization reaction, in reactor, add glycine, first alcohol and water, stir cooling, the control temperature of charge drips the benzene class solution of penta imidic acid methyl esters alkali, after dripping at-10 ℃-0 ℃, transfer pH value, control pH value under the 8.0-10.0 room temperature stirring reaction 15-24 hour; The consumption mol ratio of valeronitrile is in the consumption of glycine and the step (1): valeronitrile: glycine=1.0: 0.93-0.97.
5. the preparation method of 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde according to claim 1 and 2-1H-imidazoles, it is characterized in that: during step (4) preparation 2-n-butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles, the consumption mol ratio of N-carboxymethyl penta amidine, Phosphorus Oxychloride, DMF and toluene or dimethylbenzene is: N-carboxymethyl penta amidine: Phosphorus Oxychloride: DMF: toluene or dimethylbenzene=1.0: 2.0-3.2: 1.5-8: 7.0-9.5; Drip temperature 20-50 ℃ of Phosphorus Oxychloride, the temperature that drips DMF is at 70-90 ℃; Batching finishes, and material after the stirring and refluxing reaction finishes, is cooled to 70-30 ℃ 97-101 ℃ of stirring and refluxing reaction 3-4 hour, and impouring is cooled to be hydrolyzed in the frozen water below 20 ℃ in advance, and hydrolysis temperature must not surpass 30 ℃, and hydrolysis time must not be less than at 1 o'clock; With the alkali neutralization, regulate the ph value to 1.2-2.0 after the hydrolysis, tell organic layer, condensing crystal is separated out crude product 2-n butyl-4 (5)-chloro-5 (4)-formaldehyde-1H-imidazoles.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102584628A (en) * | 2011-12-30 | 2012-07-18 | 江苏科本医药化学有限公司 | Method for synthesizing N-carboxymethyl pentamidine |
| CN105061321A (en) * | 2015-08-27 | 2015-11-18 | 滨海三甬药业化学有限公司 | Method for preparing drug intermediate 2-n-butyl-4(5)-chlorine-5(4)-formaldehyde-1H-imidazole |
| CN106995411A (en) * | 2017-05-02 | 2017-08-01 | 滨海三甬药业化学有限公司 | A kind of preparation method of the formyl imidazoles of 2 normal-butyl, 4 chlorine 5 |
| CN109942495A (en) * | 2019-04-19 | 2019-06-28 | 江西三元药业有限公司 | A kind of production technology of imidazole aldehyde |
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| JP4103149B2 (en) * | 1996-01-05 | 2008-06-18 | ロンザ リミテッド | Process for producing 2-substituted 5-chloroimidazole-4-carbaldehyde |
| CN101163680A (en) * | 2005-04-15 | 2008-04-16 | 迪士曼药品和化学品有限公司 | Preparation of 2-substituted 4-chloro-5-formylimidazoles by vilsmeier reaction of the condensation product of glycine and an imido ester with a formamide in the presence of a triflate (trifluormethane |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102584628A (en) * | 2011-12-30 | 2012-07-18 | 江苏科本医药化学有限公司 | Method for synthesizing N-carboxymethyl pentamidine |
| CN102584628B (en) * | 2011-12-30 | 2015-04-22 | 浙江外国语学院 | Method for synthesizing N-carboxymethyl pentamidine |
| CN105061321A (en) * | 2015-08-27 | 2015-11-18 | 滨海三甬药业化学有限公司 | Method for preparing drug intermediate 2-n-butyl-4(5)-chlorine-5(4)-formaldehyde-1H-imidazole |
| CN106995411A (en) * | 2017-05-02 | 2017-08-01 | 滨海三甬药业化学有限公司 | A kind of preparation method of the formyl imidazoles of 2 normal-butyl, 4 chlorine 5 |
| CN109942495A (en) * | 2019-04-19 | 2019-06-28 | 江西三元药业有限公司 | A kind of production technology of imidazole aldehyde |
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