CN104193674A - Synthesis method of flunixin meglumine - Google Patents
Synthesis method of flunixin meglumine Download PDFInfo
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- CN104193674A CN104193674A CN201410428267.0A CN201410428267A CN104193674A CN 104193674 A CN104193674 A CN 104193674A CN 201410428267 A CN201410428267 A CN 201410428267A CN 104193674 A CN104193674 A CN 104193674A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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Abstract
The invention discloses a synthesis method of flunixin meglumine, which comprises the following steps: adding 2-chloronicotinic acid and 2-methyl-3-trifluoromethyl aniline into a sodium hydroxide water solution, stirring, adding toluene and a phase-transfer catalyst, reacting at controlled temperature of 40-45 DEG C for 4-5 hours, regulating the pH value of the solution to 10-11, stirring, standing to stratify, regulating the pH value of the water layer to 5-6, stirring, filtering, washing the filter cake, and drying to obtain flunixin, reacting flunixin and N-methylglucosylamine in isopropanol, heating under reflux for 0.5-1.5 hours, filtering, cooling to 50-60 DEG C, and stirring to crystallize; and when the system temperature drops to 25 DEG C below, continuing stirring for 1 hour, carrying out vacuum filtration on the crystal, and washing with isopropanol to obtain the flunixin meglumine. The method lowers the reaction temperature, saves the energy, shortens the reaction time, and is simple for synthesis operation, low in facility requests and convenient for industrialized operation.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of synthetic method of flunixin meglumine.
Technical background
Flunixin meglumine is a kind of antipyretic and analgesic of novel, nonsteroidal animal specific, belongs to the derivative of nicotinic acid class, is cox-2 inhibitors.Developed the nineties in 20th century by Schering Plough company of the U.S., be now widely used in many countries such as the U.S., France, Switzerland, Germany, Britain.At present, the Ministry of Agriculture of China approved part animal pharmaceutical factory produces flunixin meglumine.On veterinary clinic, this medicine is alleviated inflammation and the pain sensation that muscle abnormality causes for Marko, alleviates the internal organ angina of horse, the diarrhoea for the treatment of colt, tremble, colitis etc.; For ox treatment respiratory system disease, the mazoitis that intracellular toxin causes; Suffer from diarrhoea, tremble and ophthalmology infection for dog treatment of arthritis, heating; Treat diarrhoea etc. for pig, also can be used for the syndromic assisting therapy of sow mastitis, metritis and agalasisa.
At present, bibliographical information mainly contains three kinds of methods about flunixin synthetic: 1, US5484931 report is taking 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine as raw material, and water makees solvent, and tosic acid is catalyzer, reflux obtains flunixin for 24 hours above, and yield is 83%.The method need to be used excessive 2-methyl-3-trifluoromethyl phenylamine, and cost is high, less economical, and the reaction times is longer, and post-processing operation is loaded down with trivial details, and yield is lower.2, US5248781 report is taking 2-chlorine apellagrin ethyl ester and 2-methyl-3-trifluoromethyl phenylamine as raw material, and in 200 DEG C of solvent-free heating or dimethylbenzene, back flow reaction obtains flunixin ethyl ester and obtains flunixin through hydrolysis, and yield is at 43.2%-58.5%.The method temperature of reaction is high, and low conversion rate is difficult for aftertreatment.3, Heterocycles, 38 (10), 1994,2243-2246 report is taking 2-chlorine apellagrin ethyl ester and 2-methyl-3-trifluoromethyl phenylamine as raw material, ethylene glycol is solvent, and 165 DEG C of reactions obtain flunixin ethyl ester for 6 hours, then except desolventizing, in methyl alcohol, hydrolysis obtains flunixin, two yields 77.4%.Two reactions of the method, temperature of reaction is high, need remove high boiling ethylene glycol, hydrolysis reaction aftertreatment complexity, yield is lower.
Chinese patent CN 103694167 A disclose a kind of synthetic method of flunixin meglumine, taking 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine as raw material, and water as solvent, cupric oxide and tosic acid, as catalyzer, react.This preparation method does, under catalyzer prerequisite, to add cupric oxide at the p-methyl benzenesulfonic acid of existing bibliographical information, has greatly increased catalytic efficiency, and reaction is efficiently carried out, and Reaction time shorten, has improved yield.The flunixin obtaining and meglumine salify in acetonitrile solvent, recrystallization obtains flunixin meglumine, and total recovery is about 90%.Synthetic flunixin meglumine in this way, easy to operate simple, not high to equipment requirements, be applicable to industrialized production.But this patent main raw material is 2-methyl-3-trifluoromethyl phenylamine, use the ingredient proportion of 2 times of amounts, it reclaims, and purification and utilization have more highly difficult, and this must cause the rising of whole production cost.
Summary of the invention
Object of the present invention is exactly the synthetic method for a kind of flunixin meglumine is provided, and its reaction times shortens, temperature of reaction reduces, yield improves.
To achieve these goals, the present invention adopts following technical scheme:
A synthetic method for flunixin meglumine, comprises the following steps:
(1) first 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine are added in aqueous sodium hydroxide solution and stirred, 2-chlorine apellagrin can better be dissolved in buck like this, add toluene and aqueous sodium hydroxide solution to form two-phase solvent, and phase-transfer catalyst, control temperature at 40-45 DEG C, react after 4-5 hour, regulator solution PH to 10-11 (preferably regulating with sodium hydroxide solution), stir 10-15min, stratification, water layer PH is adjusted to 5-6 (preferably regulating with sulfuric acid), stirs after 1 hour and filters, filter cake washs by purified water, is dried to obtain flunixin;
(2) gained flunixin in step (1) is reacted in Virahol with N-methyl glucoside amine, after reflux 0.5-1.5 hour (preferably 1 hour), reacting liquor while hot is filtered, being cooled to 50-60 DEG C now has crystal to separate out, stirred crystallization, being down to 25 DEG C of following continuation until system temperature stirred after 1 hour, so that crystal is thoroughly separated out, crystal suction filtration can obtain quality through washed with isopropyl alcohol and meet the flunixin meglumine that American Pharmacopeia 35 (USP35) requires completely, and two overall yield of reaction reach more than 85%.
The mol ratio of described 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine is 1:1.05-1:1, the mol ratio of described 2-chlorine apellagrin and sodium hydroxide solution sodium hydroxide used is 1:1, the quality of 2-chlorine apellagrin and the volume ratio of water are 1:6-10, and water is 1:1 with volume of toluene ratio; Described phase-transfer catalyst is; Chlorinating benzyl triethylamine (TEBAC), consumption is the feed intake 0.5%-1% of quality of 2-chlorine apellagrin.
In step (2), the mol ratio of flunixin and N-methyl glucoside amine is 1:1.02-1.20, and the quality of flunixin and the volume ratio of Virahol are 1:5-7.
Compared with prior art, the synthetic feature of flunixin meglumine of the present invention is as follows:
1. the synthetic application phase-transfer-catalyzed reactions of flunixin, reacts more thorough, and product yield improves, and total recovery can reach more than 85%.
2. the inventive method has reduced temperature of reaction, when saving the energy, has shortened the reaction times.
3. synthetic operation is easy, lower to equipment requirements, is convenient to industrialization operation.
Embodiment
Embodiment 1
(1) 4g sodium hydroxide is dissolved in 95ml water, until sodium hydroxide dissolve completely cooling after, 18.4g 2-methyl-3-trifluoromethyl phenylamine and 15.7g 2-chlorine apellagrin are added after sodium hydroxide solution stirring and dissolving, add 95ml toluene, and 0.157gTEBAC, control temperature 40 DEG C of stirring reactions 4 hours; Reaction solution uses 3mol/L NaOH solution to regulate after PH to 10 after being down to normal temperature, stirs 10min, removes upper organic phase, then gained water is adjusted to PH to 5 with 4mol/L sulfuric acid after standing 20min, stirs after 1 hour, and after suction filtration, filter cake washs by purified water, dries.Obtain product 28.4g, yield 95.9%.
(2) get 20.0g (1) products obtained therefrom flunixin and 14.5gN-methyl glucoside amine joins in 120ml Virahol, be heated to reflux after 1 hour, filtered while hot obtains filtrate leaving standstill, treat that filtrate is cooled to 50 DEG C of stirred crystallization, system temperature is down to 25 DEG C of following continuation and is stirred after 1 hour, and crystal suction filtration is through washed with isopropyl alcohol, dry, obtain flunixin meglumine 30.5g, yield is 92%, purity 99.8% (according to the detection method of American Pharmacopeia 35).
Get this product 0.175g, accurately weighed, add after Glacial acetic acid 50ml dissolving, with perchloric acid titration liquid (0.1mol/L) titration, and the result of titration is proofreaied and correct with blank test.Every 1ml perchloric acid titration liquid (0.1mol/L) is equivalent to the C of 24.57mg
14h
11f
3n
2o
2c
7h
17nO
5.Calculation formula:
V
0: the blank volume that consumes titrating solution, ml;
V: sample consumes titrating solution volume, ml;
F: correction factor (titrating solution is demarcated concentration and the ratio that indicates concentration);
T: every 1ml titrating solution is equivalent to the weight of measured matter, mg;
W: the weight of trial-product, g;
| Trial-product numbering | 1 | 2 | Blank |
| Trial-product g | 0.1749 | 0.1751 | 0.00 |
| Titrating solution initial reading ml | 0.00 | 0.00 | 0.00 |
| Titrating solution final reading ml | 7.14 | 7.15 | 0.05 |
| Titrating solution consumes ml | 7.14 | 7.15 | 0.05 |
ω％＝(ω1％+ω2％)/2＝99.8％
According to literature query, present method, with respect to the method for US5484931 and US5248781 introduction, has been avoided reflux in the preparation process of flunixin, the gentleer saving energy of reaction conditions, and the reaction times shortens, and reaction whole process can be controlled in about 7 hours; The method of introducing with respect to CN103694167A, 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine feed ratio are 1:2, reflux, present method 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine feed ratio 1:1.05-1:1,40-50 DEG C of reaction, reaction conditions gentleness, and production cost is lower, avoid a large amount of recovery of raw material 2-methyl-3-trifluoromethyl phenylamine, simple to operate.
Embodiment 2
(1) 4g sodium hydroxide is dissolved in 95ml water, until sodium hydroxide dissolve completely cooling after, 18.5g 2-methyl-3-trifluoromethyl phenylamine and 15.7g 2-chlorine apellagrin are added after sodium hydroxide solution stirring and dissolving, add 95ml toluene, and 0.157gTEBAC, control temperature 45 DEG C of stirring reactions 4 hours; Reaction solution uses 3mol/L NaOH solution to regulate after PH to 10 after being down to normal temperature, stirs 10min, removes upper organic phase, then gained water is adjusted to PH to 6 with 4mol/L sulfuric acid after standing 20min, stirs after 1 hour, and after suction filtration, filter cake washs by purified water, dries.Obtain product 28.2g, yield 95.3%
(2) get 20.0g (1) products obtained therefrom flunixin and 14.5gN-methyl glucoside amine joins in 120ml Virahol, be heated to reflux after 1 hour, filtered while hot obtains filtrate leaving standstill, treat that filtrate is cooled to 50 DEG C of stirred crystallization, system temperature is down to 25 DEG C of following continuation and is stirred after 1 hour, and crystal suction filtration is through washed with isopropyl alcohol, dry, obtain flunixin meglumine 30.2g, yield is 91%, purity 99.9%.
Embodiment 3
(1) 4g sodium hydroxide is dissolved in 106ml water, until sodium hydroxide dissolve completely cooling after, 18.4g 2-methyl-3-trifluoromethyl phenylamine and 15.7g 2-chlorine apellagrin are added after sodium hydroxide solution stirring and dissolving, add 106ml toluene, and 0.157gTEBAC, control temperature 40 DEG C of stirring reactions 4 hours; Reaction solution uses 3mol/L NaOH solution to regulate after PH to 11 after being down to normal temperature, stirs 10min, removes upper strata organic layer, then gained water layer is adjusted to PH to 5 with 4mol/L sulfuric acid after standing 20min, stirs after 1 hour, and after suction filtration, filter cake washs by purified water, dries.Obtain product 27.9g, yield 94.3%.
(2) get 20.0g (1) products obtained therefrom flunixin and 14.5gN-methyl glucoside amine joins in 130ml Virahol, be heated to reflux after 1 hour, filtered while hot obtains filtrate leaving standstill, treat that filtrate is cooled to 55 DEG C of stirred crystallization, system temperature is down to 25 DEG C of following continuation and is stirred after 1 hour, and crystal suction filtration is through washed with isopropyl alcohol, dry, obtain flunixin meglumine 30.4g, yield is 91.7%, purity 99.9%.
Embodiment 4
(1) 4g sodium hydroxide is dissolved in 100ml water, until sodium hydroxide dissolve completely cooling after, 18.4g 2-methyl-3-trifluoromethyl phenylamine and 15.7g 2-chlorine apellagrin are added after sodium hydroxide solution stirring and dissolving, add 100ml toluene, and 0.157gTEBAC, control temperature 43 DEG C of stirring reactions 4 hours; Reaction solution uses 3mol/L NaOH solution to regulate after PH to 11 after being down to normal temperature, stirs 10min, removes upper organic phase, then gained water is adjusted to PH to 5 with 4mol/L sulfuric acid after standing 20min, stirs after 1 hour, and after suction filtration, filter cake washs by purified water, dries.Obtain product 28.1g, yield 94.9%
(2) get 20.0g (1) products obtained therefrom flunixin and 14.5gN-methyl glucoside amine joins in 120ml Virahol, be heated to reflux after 1 hour, filtered while hot obtains filtrate leaving standstill, treat that filtrate is cooled to 60 DEG C of stirred crystallization, system temperature is down to 25 DEG C of following continuation and is stirred after 1 hour, and crystal suction filtration is through washed with isopropyl alcohol, dry, obtain flunixin meglumine 30.9g, yield is 93%, purity 99.9%.
The specific embodiment of the present invention is described although above-mentioned in conjunction with the embodiments; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendments that creative work can make or distortion still in protection scope of the present invention.
Claims (8)
1. a synthetic method for flunixin meglumine, is characterized in that, comprises the following steps:
(1) 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine are added in aqueous sodium hydroxide solution and stirred, add toluene and phase-transfer catalyst, control temperature at 40-45 DEG C, react after 4-5 hour regulator solution PH to 10-11, stratification after stirring, water layer PH is adjusted to 5-6, after stirring, filter, washing leaching cake, is dried to obtain flunixin;
(2) gained flunixin in step (1) is reacted in Virahol with N-methyl glucoside amine, after reflux 0.5-1.5 hour, filter, be cooled to 50-60 DEG C, stirred crystallization, be down to 25 DEG C of following continuation until system temperature and stir after 1 hour, crystal suction filtration obtains flunixin meglumine through washed with isopropyl alcohol;
The mol ratio of described 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine is 1:1.05-1:1, the mol ratio of described 2-chlorine apellagrin and sodium hydroxide solution sodium hydroxide used is 1:1, the mass volume ratio of chlorine apellagrin and water is 1:6-10, and water is 1:1 with volume of toluene ratio; Described phase-transfer catalyst is; Chlorinating benzyl triethylamine, consumption is the feed intake 0.5%-1% of quality of 2-chlorine apellagrin.
In described step (2), the mol ratio of flunixin and N-methyl glucoside amine is 1:1.02-1.20, and the quality of flunixin and the volume ratio of Virahol are 1:5-7.
2. synthetic method as claimed in claim 1, is characterized in that, uses the sodium hydroxide solution regulator solution PH to 10-11 of 3mol/L in described step (1).
3. synthetic method as claimed in claim 1, is characterized in that, stirs 10-15min, stratification in described step (1).
4. synthetic method as claimed in claim 1, is characterized in that, in described step (1), water layer is adjusted to 5-6 with 4mol/L sulphuric acid soln PH.
5. synthetic method as claimed in claim 1, is characterized in that, in described step (1), stirs after 1-2 hour and filters.
6. synthetic method as claimed in claim 1, is characterized in that, uses purified water washing leaching cake in described step (1).
7. synthetic method as claimed in claim 1, is characterized in that, reflux 1 hour in described step (2).
8. synthetic method as claimed in claim 1, is characterized in that, described step (2) is after reflux 0.5-1.5 hour, and reacting liquor while hot is filtered.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109206365A (en) * | 2018-09-13 | 2019-01-15 | 龙岩台迈三略制药有限公司 | A kind of preparation method of flunixin meglumine |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965735A (en) * | 1991-12-20 | 1999-10-12 | Schering Corporation | Process for preparing flunixin and intermediates thereof |
| CN102442944A (en) * | 2011-12-14 | 2012-05-09 | 齐鲁动物保健品有限公司 | Preparation method of flunixin |
| CN103694167A (en) * | 2013-12-11 | 2014-04-02 | 威海雅瑞生物科技有限公司 | Method for synthesizing flunixin meglumine |
-
2014
- 2014-08-27 CN CN201410428267.0A patent/CN104193674B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965735A (en) * | 1991-12-20 | 1999-10-12 | Schering Corporation | Process for preparing flunixin and intermediates thereof |
| CN102442944A (en) * | 2011-12-14 | 2012-05-09 | 齐鲁动物保健品有限公司 | Preparation method of flunixin |
| CN103694167A (en) * | 2013-12-11 | 2014-04-02 | 威海雅瑞生物科技有限公司 | Method for synthesizing flunixin meglumine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109206365A (en) * | 2018-09-13 | 2019-01-15 | 龙岩台迈三略制药有限公司 | A kind of preparation method of flunixin meglumine |
| CN109206365B (en) * | 2018-09-13 | 2019-11-26 | 龙岩台迈三略制药有限公司 | A kind of preparation method of flunixin meglumine |
| 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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