CN1803773A - Synthesis and fine purification method of flunixin meglumine - Google Patents
Synthesis and fine purification method of flunixin meglumine Download PDFInfo
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- CN1803773A CN1803773A CN 200610042348 CN200610042348A CN1803773A CN 1803773 A CN1803773 A CN 1803773A CN 200610042348 CN200610042348 CN 200610042348 CN 200610042348 A CN200610042348 A CN 200610042348A CN 1803773 A CN1803773 A CN 1803773A
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- flunixin
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Abstract
The synthesis and extraction and refine method for meglumine flunixin comprises: with p-toluenesulfonic monohydrate as catalyst and 20% KOH as extract, selecting 2-methyl-3- (trifluoromethyl) aniline and 2-chloronicotioyl by mole ratio as 2:1 for reaction with end pH value more than 11.5; cooling and crystallizing the residual aniline to separate and recover; using methanol in extraction and purification for flunixin; static cooling and crystallizing, and separating and cleaning the crystal to obtain the refined product; finally, recrystallizing to prepare the flunixin methylglucamine in water. This invention has high yield.
Description
Technical field:
The present invention relates to method, relate in particular to the synthetic extraction process for purification of flunixin meglumine with 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin and the synthetic flunixin meglumine salt of meglumine.
Background technology:
Prior art is for the elimination reaction of halogenide that has the shuttle base and aminocompound generation; all to protect in general the shuttle base; manage in the reaction process small molecules product that generates is removed again, but adopt the technical process of this technology long, production cost is higher.
Summary of the invention:
The objective of the invention is to, overcome the deficiencies in the prior art part, a kind of synthetic extraction process for purification of flunixin meglumine is provided, adopt the charging capacity that strengthens 2-methyl-3-(trifluoromethyl) aniline and select suitable catalyzer and suitable reaction temperature, feasible reaction is carried out smoothly, then unreacted 2-methyl-3-(trifluoromethyl) aniline is separated again, continue to participate in the reaction of next batch, material finally all is fully used, meet fully in quality under the preceding topic of international standard, production cost is reduced greatly.
The objective of the invention is to realize: 1,2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin fully reaction under catalyst action with following steps; 2, reaction mixture alkalization dissolving; 3, separate unreacted 2-methyl-3-(trifluoromethyl) aniline; 4, the synthetic liquid of alkalescence adds vitriol oil crystallization after gac adds heat decoloring, filtration, gets rid of filter and makes the flunixin crude product; 5, the flunixin crude product is through recrystallizing methanol, and makes the flunixin elaboration after water washing; 6, flunixin elaboration and meglumine reflux synthetic in Virahol; 7, synthetic liquid through decolouring, filtration, crystallization, get rid of filter and make flunixin meglumine salt crude product; 8, flunixin meglumine salt crude product obtains flunixin meglumine salt finished product behind the water recrystallization.The synthetic extraction process for purification important step wherein of flunixin meglumine of the present invention has 3 points: 1, the building-up reactions of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin; 2, the extraction of flunixin and purifying; 3, flunixin meglumine is synthetic and refining.
The synthetic extraction process for purification that uses flunixin meglumine of the present invention uses tosic acid-hydrate to make catalyzer when carrying out the building-up reactions of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin; The mole proportioning of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin is 2: 1; Water is made reaction medium; Temperature is 98 ℃-105 ℃.When the extraction of carrying out flunixin and purifying procedure, employed extracting solution is 20% potassium hydroxide, and the terminal point pH value is 11.5.Unreacted 2-methyl-3-(trifluoromethyl) aniline reuses after the separation by decrease temperature crystalline.When the extraction of carrying out flunixin and purifying procedure, employed strong acid is the vitriol oil, and crystallization terminal point pH value is 4.0-4.5.Employed alcohol is methyl alcohol in the recrystallization process, and the method for recrystallization is static decrease temperature crystalline, and crystallisate is fully washed after separating, and makes elaboration.The media that uses when carrying out flunixin meglumine synthetic is Virahol, and crystallization start temperature is 45 ℃-50 ℃ in the synthetic and refining program of flunixin meglumine, forms static decrease temperature crystalline behind a certain amount of nucleus.The method that the recrystallization of flunixin meglumine is handled is, use water dissolution, filters, and concentrated, crystallization can make finished product.
Said 8 steps are mainly concerned with 5 aspects:
1, the synthetic flunixin under catalyst action with 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin;
2, at first with the highly basic dissolving, make the flunixin crude product with the strong acid crystallization then;
3, utilize the first alcohol and water to the flunixin recrystallization, make the particulate state crystal;
4, the dissolving earlier in Virahol with purified flunixin and meglumine, post crystallization obtains the flunixin meglumine crude product;
5, the flunixin meglumine crude product obtains flunixin meglumine salt finished product through the water recrystallization.
The synthetic extraction process for purification of flunixin meglumine of the present invention may further comprise the steps:
(1), the building-up reactions of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin;
(2), the extraction of flunixin and purifying;
(3), flunixin meglumine is synthetic and refining.
Use the synthetic extraction process for purification of flunixin meglumine of the present invention, whole technological process is simple to operate, yield height, not only economy but also be convenient to implement.
Embodiment:
Now in conjunction with the embodiments, synthetic extraction process for purification to flunixin meglumine of the present invention is described in detail as follows: the synthetic extraction process for purification of flunixin meglumine of the present invention may further comprise the steps: the building-up reactions of (1), 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin; (2), the extraction of flunixin and purifying; (3), flunixin meglumine is synthetic and refining.Synthetic extraction process for purification according to flunixin meglumine of the present invention is characterized in that: the building-up reactions of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin uses tosic acid-water and thing to make catalyzer; The mole proportioning of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin is 2: 1; Water is done reaction medium; Temperature is 98-103 ℃.The used extracting solution of the extraction of flunixin and purifying is 20% potassium hydroxide, and terminal point PH is more than 11.5.In the extraction of flunixin and the purifying not 2-methyl-3-(trifluoromethyl) aniline of complete reaction can reuse after the separation by decrease temperature crystalline.The employed strong acid of the extraction of flunixin and purifying is the vitriol oil, and crystallization terminal point PH is 4.0-4.5.The extraction of flunixin and the employed alcohol of purifying recrystallization are methyl alcohol.The method of the extraction of flunixin and purifying recrystallization is static decrease temperature crystalline, and crystallisate is fully washed after separating, and can get elaboration.Flunixin meglumine synthetic and refining in synthetic media be Virahol.Flunixin meglumine synthetic and refining in crystallization start temperature be 45-48 ℃, form static decrease temperature crystalline behind a certain amount of nucleus.The method of the recrystallization of flunixin meglumine is for getting finished product with water dissolution, filtration, concentrated, crystallization.Synthetic extraction process for purification according to flunixin meglumine of the present invention is as follows:
Embodiment (one): at first in 1000 milliliters of reaction flasks that have prolong and an agitator, add 2-methyl-3-(trifluoromethyl) aniline 280 grams, 2-chlorine apellagrin 126.5 grams, 350 milliliters in water and tosic acid-hydrate 12 grams, stir down heating and temperature control at 98-105 ℃ and kept 20 hours.Stop to heat and cooling to below 80 ℃, in reaction solution, drip until making pH value reach more than 11.5 with 20% potassium hydroxide solution, continue stirring and cool to below 30 ℃, obtain not 2-methyl-3-(trifluoromethyl) aniline 110 grams (can continue later on to use) of complete reaction after the filtration; About 500 milliliters of the synthetic extracting solution of red-brown.
Embodiment (two): synthetic extracting solution drips vitriol oil crystallization behind decolorization filtering, to pH value be about 4.5.Filter, the filter cake oven dry is after dissolve with methanol, filtration, the static crystallization of cooling, get rid of filter and water thorough washing, makes flunixin (2-[[2-methyl-3-(trifluoromethyl) phenyl] amido] nicotinic acid) elaboration 150 grams, and yield is about 70%.
Embodiment (three): 100 gram elaboration flunixins, 68 gram meglumines and 700 milliliters of Virahols are put in 2000 milliliters of reaction flasks that have reflux condensing tube and an agitator simultaneously, reflux is dissolved the back fully and is added activated carbon decolorizing, filters the back, cools to 48 ℃ of stirred crystallization, after a large amount of nucleus form, leave standstill, continue to cool to below 20 ℃ and filter, flunixin meglumine salt (2-[[2-methyl-3-(trifluoromethyl) phenyl] amido] meglumine salt of nicotinic acid) crude product, get 150 grams after the crude product drying, yield is 89%.
Embodiment (four): in the water with 100 gram flunixin meglumine salt (2-[[2-methyl 3-(trifluoromethyl) phenyl] amido] meglumine salt of nicotinic acid) dissolving crude product to 800 milliliter, enter after the filtration that the heating in water bath negative pressure concentrates in the reaction flask that 2000 milliliters of bands stir, be concentrated into and stop heating when liquid color deepens, add smart the kind and continue to stir cooling simultaneously, when a large amount of sperm nucleus produce, stop to stir, continue to cool to below 20 degree, filtration drying obtains flunixin meglumine salt finished product 80 grams.Quality meets the 5th edition standard of European Pharmacopoeia fully.
Claims (8)
1, a kind of synthetic extraction process for purification of flunixin meglumine is characterized in that may further comprise the steps:
(1), the building-up reactions of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin;
(2), the extraction of flunixin and purifying;
(3), flunixin meglumine is synthetic and refining.
2, the synthetic extraction process for purification of flunixin meglumine according to claim 1, it is characterized in that: the synthesis reaction temperature of 2-methyl-3-(trifluoromethyl) aniline and 2-chlorine apellagrin is 98-103 ℃.
3, the synthetic extraction process for purification of flunixin meglumine according to claim 1 is characterized in that: the used extracting solution of the extraction of flunixin and purifying is 20% potassium hydroxide, and terminal point PH is more than 11.5.
4, the synthetic extraction process for purification of flunixin meglumine according to claim 1 is characterized in that: in the extraction of flunixin and the purifying not 2-methyl-3-(trifluoromethyl) aniline of complete reaction can reuse after the separation by decrease temperature crystalline.
5, the synthetic extraction process for purification of flunixin meglumine according to claim 1 is characterized in that: the extraction of flunixin and purifying use strong acid, and crystallization terminal point PH is 4.0-4.5.
6, the synthetic extraction process for purification of flunixin meglumine according to claim 1, it is characterized in that: the method for the extraction of flunixin and purifying recrystallization is static cooling, crystallization.
7, the synthetic extraction process for purification of flunixin meglumine according to claim 1 is characterized in that: the synthetic and refining middle crystallization start temperature of flunixin meglumine is 45-48 ℃.
8, the synthetic extraction process for purification of flunixin meglumine according to claim 1 is characterized in that: the method for the recrystallization of flunixin meglumine is for getting finished product with water dissolution, filtration, concentrated, crystallization.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610042348 CN1803773A (en) | 2006-01-24 | 2006-01-24 | Synthesis and fine purification method of flunixin meglumine |
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| CN 200610042348 CN1803773A (en) | 2006-01-24 | 2006-01-24 | Synthesis and fine purification method of flunixin meglumine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769827A (en) * | 2016-03-09 | 2016-07-20 | 金陵科技学院 | Heat clearing and pain alleviating veterinary flunixin meglumine coating agent for animals and preparation method thereof |
| CN108586327A (en) * | 2018-04-25 | 2018-09-28 | 山东久隆恒信药业有限公司 | A kind of synthetic method of Flunixin |
| CN110483389A (en) * | 2019-09-18 | 2019-11-22 | 山东久隆恒信药业有限公司 | A kind of refining methd of Flunixin |
| CN115710218A (en) * | 2022-12-15 | 2023-02-24 | 山东久隆恒信药业有限公司 | Crystallization method for improving fluidity of flunixin meglumine |
-
2006
- 2006-01-24 CN CN 200610042348 patent/CN1803773A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105769827A (en) * | 2016-03-09 | 2016-07-20 | 金陵科技学院 | Heat clearing and pain alleviating veterinary flunixin meglumine coating agent for animals and preparation method thereof |
| CN105769827B (en) * | 2016-03-09 | 2018-07-17 | 金陵科技学院 | For animal clearing away heat and alleviating pain flunixin meglumine plastics and preparation method thereof |
| CN108586327A (en) * | 2018-04-25 | 2018-09-28 | 山东久隆恒信药业有限公司 | A kind of synthetic method of Flunixin |
| CN110483389A (en) * | 2019-09-18 | 2019-11-22 | 山东久隆恒信药业有限公司 | A kind of refining methd of Flunixin |
| CN115710218A (en) * | 2022-12-15 | 2023-02-24 | 山东久隆恒信药业有限公司 | Crystallization method for improving fluidity of flunixin meglumine |
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