CN1442410A - Improved method of preparing secnidazole - Google Patents
Improved method of preparing secnidazole Download PDFInfo
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- CN1442410A CN1442410A CN 02106825 CN02106825A CN1442410A CN 1442410 A CN1442410 A CN 1442410A CN 02106825 CN02106825 CN 02106825 CN 02106825 A CN02106825 A CN 02106825A CN 1442410 A CN1442410 A CN 1442410A
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- flagentyl
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Abstract
An improved process for preparing flagentyl (2-dimethyl-5-nitro-1H-imidazole-1-ethanol) as efficient antiamebic and antiprotozoal includes reaction of 2-dimethyl-5-nitro-imidazole and propane oxide under existance of lewis acid and searating. Its advantages are high purity and high output rate.
Description
Technical field
The present invention relates to improving one's methods of preparation flagentyl (being 2-dimethyl-5-nitro-1H-imidazoles-1 ethanol).Has structure shown in general formula I by the flagentyl of the inventive method preparation; It is anti-efficiently amoeba and antigen bio-pharmaceutical.
General formula I
Technical background
Flagentyl is that biological its demand of medicine of anti-efficiently amoeba and antigen increases fast.Therefore, be necessary to develop a kind of novel high yield low cost method.
The synthetic of flagentyl reported (consulting French Patent 1427627 (October 10 1963 applying date) and French Patent M3270 (December 30 1963 applying date)) by Rhone-poulec S.A at first, and they relate to 2-methyl-5-nitro-imidazoles (1mol) is dissolved in (85%) in a large amount of formic acid (7.88 parts).In surpassing 1.5 hours, in being cooled to-14 degrees centigrade above-mentioned solution, add a large amount of propylene oxides (5mol).Mixed solution is placed and is spent the night, and vacuum is removed unnecessary formic acid.Add entry in the residuum, stir, filter, remove unreacted 2-methyl-5-nitro-imidazoles (0.5945mol).Filtrate is handled with the NaOH of 10M, makes pH≤9.00.Mixture is placed in ice-water bath and is spent the night, and gets thick product.The toluene recrystallization gets pure flagentyl (0.1944mol), yield 47.94%.
Aforesaid method has many shortcomings.One of topmost shortcoming is to deep-etching, and the operation of deleterious formic acid and its reclaim under reduced pressure are handled.Product toluene recrystallization, toluene are that potential is poisonous, flammable solvent.In addition, aforesaid method needs a large amount of propylene oxide (for example, using the 5mol propylene oxide with 1mol 2-methyl-5-nitro-imidazoles reaction needed).
In other selectable method, by Claude Jeanmart and Mayer NaoumMesser (Rhone-poulec S.A) report (German Patent, grant number 2,107,423; On September 2nd, 1971 and British Patent No. 1278758; On June 21st, 1972) 2-methyl-imidazoles, monochloroacetone and Anhydrous potassium carbonate are suspended in the acetone, come nitrated production 2-methyl-5-nitro-imidazoles-acetone with nitrosonitric acid.Do at methyl alcohol with sodium borohydride to reduce under the condition of solvent, the total recovery of flagentyl is 3.62%.
Aforesaid method has following shortcoming:
A) yield is low, only is 3.62%.
B) need three-step approach.
C) use expensive sodium borohydride and monochloroacetone.
Described by Claude Jeanmart and Mayer Naoum Messer (Rhone-poulec S.A), (English Patent, grant number 1,278,757; On June 2nd, 1972 and English Patent, grant number 1278758; On June 21st, 1972) 2-methyl-imidazoles is done under the condition of solvent and the propylene oxide reaction at ethanol, obtains 1-(2-hydroxypropyl)-2-methyl-imidazoles.Hydroxyl by the Acetyl Chloride 98Min. acetylize protect 1-(2-acetylize propyl group)-2-methyl-5-nitro-imidazoles, by nitrated and hydrolysis afterwards, obtain 1-(2-hydroxypropyl)-2-methyl-5-nitro-imidazoles.Yield 6.25%.
According to Lavigne, Michel etc. (Rhone-poulec Rorer S.A), (PCT application number WO91/13877, on September 19th, 1991), 1-acetoxyl methyl-2-methyl-4-nitro-imidazoles is dissolved in methylene dichloride, uses oleum and propylene oxide 20 degrees centigrade of processing.After further handling, the yield with 14.5% obtains flagentyl.
Because flagentyl is the biological medicine of anti-efficiently amoeba and antigen, its demand increases fast.Be necessary to develop a kind of novel high yield low cost method, overcome above-mentioned shortcoming.
Therefore, we are through deep research and development, and in order to overcome the shortcoming of prior art, main purpose of the present invention is to provide a kind of high yield effectively to prepare the method for flagentyl cheaply.
Summary of the invention
In order to finish above-mentioned and other purposes of the present invention, use a kind of new solvent systems.The present invention is based on a beyond thought discovery, if Lewis acid is suspended in a kind of solvent, ester solvent preferably, be used among the reaction of (general formula I I) 2-methyl-5-nitro-imidazoles and propylene oxide, flagentyl is compared with 14.5% yield of report in the past, can produce the high yield of 48-50%.
Thus, the invention provides a kind of improved preparation method who prepares the flagentyl shown in the general formula I, comprising the 2-dimethyl-5-nitro shown in the general formula I I--imidazoles and propylene oxide react under the condition that Lewis acid exists, be under 0-5 degree centigrade the situation in temperature range, be suspended in the organic ester solvent, separate the flagentyl that forms with ordinary method.
General formula I I general formula I
In a preferred embodiment of the invention, can use for example Lewis acid such as Aluminum chloride anhydrous, the used organic solvent of this reaction can be selected from ethyl acetate butylacetate etc.
In other embodiments of the present invention, 2-methyl-5-nitro-imidazoles: Aluminum chloride anhydrous: the mol ratio of propylene oxide is 1: 1.90: 1.75.
After having reacted, reactant can separate the flagentyl that forms under conventional situation.But for example in the hydrochloric acid soln of reactant impouring dilution, filtering is the 2-methyl-5-nitro-imidazoles of reaction, with caustic alkali filtrate being basified to pH is 12.8-13.0, use ethyl acetate extraction, concentrate and obtain reddish-brown oily matter, water comes recrystallization to obtain the crude product flagentyl, and the water recrystallization obtains pure product flagentyl, yield 48-50% again.
Preparation method's of the present invention advantage:
1) single step reaction makes method simple.
2) the high yield of product, yield is 48-50%
3) propylene oxide consumption few (comparing only 1.75 moles with the 4-5 molar equivalent) makes and implements present method very economical.
4) water comes recrystallization to obtain crude product, makes present method not only simply but also economical.
The detail of the inventive method specifically describes in the following embodiments, and the example of this method only is provided here, but should not be construed as the scope of the present invention that limits.
Embodiment
The preparation method of embodiment 12-dimethyl-5-nitro-1H-imidazoles-1-ethanol (being flagentyl)
In 5 liter of four neck flask that has in refrigerating unit and the band cover dropping funnel, add the 1600ml anhydrous ethyl acetate, be cooled to 0-5 degree centigrade under stirring, slowly add 400g (3.0mol) Aluminum chloride anhydrous, maintain the temperature between 0-5 degree centigrade.In the settled solution that obtains, add 200g (1.5748mol) 2-methyl-5-nitro-imidazoles.Observe dense soup compound.Maintain the temperature at 0-5 degree centigrade, drip the propylene oxide of 160g (2.75mol), rate of addition was controlled at about 1 hour.Reactant continues to stir 3 hours under 0-5 degree centigrade condition in temperature, in the hydrochloric acid of impouring dilution, continues to stir 15 minutes then.Reacting liquid filtering, remove unreacted 2-methyl-5-nitro-imidazoles.-80 degrees centigrade of dryings 24 hours reclaim 30g (0.2363mol) 2-methyl-5-nitro-imidazoles.
It is 12.8-13.0 that filtrate is basified to pH with 48% alkali lye, maintains the temperature between 25-30 degree centigrade.Separate new aspect, keep ethyl acetate, water layer extracts 3 times with ethyl acetate 500ml.Ethyl acetate layer is merged, and ethyl acetate is removed in distillation, and last residual solvent is removed under vacuum condition, obtains 318g reddish-brown oily matter.These oily matter waters come recrystallization to obtain 140g exsiccant flagentyl crude product, and the water recrystallization obtains the pure product of 120g flagentyl again, (the 2-methyl-5-nitro-imidazoles according to reaction is measured yield=48.41% only) chemical examination=99.71%.
Claims (6)
1, a kind ofly prepares improving one's methods of the flagentyl shown in the general formula I (being 2-dimethyl-5-nitro-1H-imidazoles-1-ethanol), under the condition that exists at Lewis acid, with the 2-dimethyl-5-nitro shown in the general formula I I--imidazoles and propylene oxide reaction, in temperature range is that reactant is suspended in the organic ester solvent under 0-5 degree centigrade the situation, separates the flagentyl that forms from reaction mixture.
General formula I general formula I I
2, method according to claim 1, it is characterized in that described flagentyl is to separate from reaction mixture, it is the hydrochloric acid of reactant impouring dilution, filter unreacted 2-methyl-5-nitro-imidazoles, with caustic alkali filtrate being basified to pH is 12.8-13.0, uses ethyl acetate extraction, concentrate and obtain reddish-brown oily matter, water comes these oily matter usefulness of recrystallization, obtains the flagentyl crude product, and the water recrystallization obtains the pure product of flagentyl (48-50%) again.
3, method according to claim 1 and 2 is characterized in that described Louis comprises Aluminum chloride anhydrous.
4, according to each described method among the claim 1-3, it is characterized in that 2-methyl-5-nitro-imidazoles: Aluminum chloride anhydrous: the mol ratio of propylene oxide is 1: 1.90: 1.75.
5,, it is characterized in that described solvent is selected from ethyl acetate and butylacetate according to the described method of aforementioned any claim.
6, a kind of preparation flagentyl (being 2-dimethyl-5-nitro-1H-imidazoles-1-ethanol) shown in embodiment 1 improves one's methods.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02106825 CN1279025C (en) | 2002-03-05 | 2002-03-05 | Improved method of preparing secnidazole |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02106825 CN1279025C (en) | 2002-03-05 | 2002-03-05 | Improved method of preparing secnidazole |
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| Publication Number | Publication Date |
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| CN1442410A true CN1442410A (en) | 2003-09-17 |
| CN1279025C CN1279025C (en) | 2006-10-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 02106825 Expired - Fee Related CN1279025C (en) | 2002-03-05 | 2002-03-05 | Improved method of preparing secnidazole |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
| US11253501B2 (en) | 2015-06-01 | 2022-02-22 | Lupin Inc. | Secnidazole formulations and use in treating bacterial vaginosis |
-
2002
- 2002-03-05 CN CN 02106825 patent/CN1279025C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
| CN103539745B (en) * | 2013-10-11 | 2015-09-02 | 黄冈赛康药业有限公司 | A kind of preparation method of secnidazole |
| US11253501B2 (en) | 2015-06-01 | 2022-02-22 | Lupin Inc. | Secnidazole formulations and use in treating bacterial vaginosis |
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| Publication number | Publication date |
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| CN1279025C (en) | 2006-10-11 |
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