CN103694167A - Method for synthesizing flunixin meglumine - Google Patents
Method for synthesizing flunixin meglumine Download PDFInfo
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- CN103694167A CN103694167A CN201310683096.1A CN201310683096A CN103694167A CN 103694167 A CN103694167 A CN 103694167A CN 201310683096 A CN201310683096 A CN 201310683096A CN 103694167 A CN103694167 A CN 103694167A
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- Prior art keywords
- flunixin
- meglumine
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- methyl
- flunixin meglumine
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- PMIMPBYTPPRBGD-UHFFFAOYSA-N CCOC(c1cccnc1Cl)=O Chemical compound CCOC(c1cccnc1Cl)=O PMIMPBYTPPRBGD-UHFFFAOYSA-N 0.000 description 1
- TWLDBACVSHADLI-UHFFFAOYSA-N Cc(c(C(F)(F)F)ccc1)c1N Chemical compound Cc(c(C(F)(F)F)ccc1)c1N TWLDBACVSHADLI-UHFFFAOYSA-N 0.000 description 1
- NOOCSNJCXJYGPE-UHFFFAOYSA-N Cc(c(C(F)(F)F)ccc1)c1Nc1ncccc1C(O)=O Chemical compound Cc(c(C(F)(F)F)ccc1)c1Nc1ncccc1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for synthesizing flunixin meglumine. According to the method, reaction is carried out in a manner that 2-chloronicotinic acid and 2-methyl-3-trifluoromethylaniline serve as raw materials, water serves as a solvent and cupric oxide and para-toluenesulfonic acid serve as catalysts. According to the method, on the premise that the condition that para-toluenesulfonic acid serves as a catalyst is reported in the existing literature, cupric oxide is added, so that the catalysis efficiency is increased greatly, the reaction can be carried out efficiently, the reaction time is shortened, and the yield is increased; obtained flunixin and meglumine are salified in an acetonitrile solvent and are recrystallized, so as to obtain flunixin meglumine, and the total yield is about 90%; through synthesizing flunixin meglumine by the method, the operation is convenient and simple, and the requirements for equipment are low, so that the method is applicable to industrial large-scale production.
Description
Technical field:
The present invention relates to a kind of synthetic method of flunixin meglumine, belong to the synthetic field of veterinary drug.
Background of invention:
Flunixin meglumine, belongs to class anti-inflammation analgesia medicine for animals, has antipyretic, anti-inflammatory and analgesic activity, separately or can obviously improve clinical symptom with Antibiotic combination medication, and can strengthen antibiotic activity.On veterinary clinic, be usually used in alleviating pain and anti-inflammatory that internal organ angina, muscle and the bone disorder of horse cause; The various diseases of ox infects the acutely inflamed control causing, as laminitis, sacroiliitis etc., also can be used in addition the syndromic assisting therapy of sow mastitis, metritis and agalasisa:
At present, the preparation method of the flunixin meglumine of bibliographical information is mainly divided into two steps, and the first step is the synthetic of flunixin, and second step is flunixin and meglumine salify, obtains flunixin meglumine.Meglumine is chemical industry or the medical material that market is easy to get, and synthesizing of flunixin becomes the key intermediate in flunixin meglumine preparation process.
Synthetic for flunixin, bibliographical information mainly contain three kinds of methods:
It is raw material that method one US5484931 report be take 2-chlorine apellagrin and 2-methyl-3-trifluoromethyl phenylamine, and water is made solvent, and tosic acid is catalyzer, and reflux obtains flunixin, and yield is 83%:
The method needs 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.
It is raw material that method two US5248781 report be take 2-chlorine apellagrin ethyl ester and 2-methyl-3-trifluoromethyl phenylamine, and in 200 ℃ of solvent-free heating or dimethylbenzene, back flow reaction obtains flunixin ethyl ester, through hydrolysis, obtains flunixin, and yield is 43.2%～58.5%:
The method temperature of reaction is high, and low conversion rate is difficult for aftertreatment.
Method three Heterocycles, 38 (10), 1994, it is raw material that 2243-2246 report be take 2-chlorine apellagrin ethyl ester and 2-methyl-3-trifluoromethyl phenylamine, ethylene glycol is solvent, and 165 ℃ of reactions obtain flunixin ethyl ester for 6 hours, then except desolventizing, in methyl alcohol, hydrolysis obtains flunixin, two step yields 77.4%:
The method two-step reaction, temperature of reaction is high, need to remove high boiling ethylene glycol, and hydrolysis reaction aftertreatment is complicated, and yield is lower.
Summary of the invention:
Main purpose of the present invention is to provide the synthetic method of the flunixin meglumine that a kind of reaction times shortens, yield improves.
Technical scheme of the present invention is a kind of synthetic method of flunixin meglumine, it is characterized in that, reaction is carried out in two steps:
It is raw material that the first step be take 2-methyl-3-trifluoromethyl phenylamine and 2-chlorine apellagrin, water as solvent, cupric oxide and tosic acid are made catalyzer, wherein, 2-methyl-3-trifluoromethyl phenylamine: 2-chlorine apellagrin: tosic acid: the mol ratio of cupric oxide is 2: 1: 0.01～0.1: 0.01～0.1, optimum molar ratio is 2-methyl-3-trifluoromethyl phenylamine: 2-chlorine apellagrin: tosic acid: cupric oxide=2: 1: 0.05: 0.05, reaction system is heated to reflux, maintains reflux state reaction 2～4 hours.When in HPL ℃ of monitoring system, 2-chlorine apellagrin content is lower than 0-5%, reduce temperature, when system temperature is during lower than 50 ℃, add alkali, if the aqueous solution adjust pH of potassium hydroxide or sodium hydroxide is to 10-0～11-0, filter the excessive unreacted raw material of filtering, filtrate uses hydrochloric acid adjust pH to 5-0～6.0, filter the purified water washing of filter cake, the dry flunixin that obtains.
Second step reacts with the meglumine of 1.02～1.2 equivalents with the flunixin that the first step reaction obtains in acetonitrile, and keeping system temperature is 70～80 ℃, reacts 2 hours.Reacting liquor while hot is filtered, filtrate naturally cooling, standing crystallization, while having crystal to separate out, starts mechanical stirring, when system temperature is down to 20 ℃, continues to stir 1 hour.Crystal, through suction filtration, acetonitrile washing, can obtain quality and meet the flunixin meglumine that EP7.5 requires, two-step reaction total recovery approximately 90%.
The invention has the beneficial effects as follows that take 2-chlorine apellagrin and 2-methyl-3-(trifluoromethyl) aniline is raw material, water as solvent, cupric oxide and tosic acid, as catalyzer, react synthetic flunixin.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, obtains flunixin meglumine, and total recovery is about 90%.Synthetic flunixin meglumine, easy to operate simple in this way, not high to equipment requirements, is applicable to industrialized production.
Embodiment:
Embodiment 1:
The preparation of flunixin:
(1) in being equipped with the reaction flask of return line, 1000mL adds 500g purified water, 55.1g2-chlorine apellagrin, 122.6g2-methyl-3-trifluoromethyl phenylamine, 0.6g tosic acid, and 0.28g cupric oxide, stirs and is warming up to backflow, insulation reaction 4 hours.
(2) reaction solution is cooled to below 50 ℃, in reaction solution, drip 25% potassium hydroxide solution, regulate pH value to 10.0～11.0, regulating complete continuation to stir is cooled to below 20 ℃, fully stir 1 hour, suction filtration, filter cake is mainly excessive 2-methyl-3-trifluoromethyl phenylamine, and recyclable continuation is used.
(3) in filtrate, drip 30% sulfuric acid adjust pH to 5.0～6.0, fully stirring and crystallizing is 1 hour, suction filtration, and filter cake is used 300g purified water agitator treating 30 minutes, filters, and dries.Obtain 94.5g product, yield 91%, HPLC purity 99.1%.
The preparation of flunixin meglumine:
(1) in being equipped with the reaction flask of return line, 1000mL adds 680mL acetonitrile, 90g flunixin, and 71.6g meglumine, stirs and is warming up to 75 ℃, and reaction solution clarification, continues insulated and stirred 2 hours.
(2) heat filtering, temperature control is not less than 70 ℃, with the strainer of abundant preheating, reacting liquor while hot is filtered, insolubles in filtering system, filtrate is refunded in reaction flask, starts standing, naturally cooling, starts after crystallize out to stir, and is down to 20 ℃, growing the grain 1h, suction filtration, washs with acetonitrile, dry, obtain flunixin meglumine 138.8g, yield 93%, HPLC is greater than 99.9%, and quality product meets EP7.5 requirement.
Embodiment 2:
The preparation of flunixin:
(1) in being equipped with the reaction flask of return line, 1000mL adds 500g purified water, 55.1g2-chlorine apellagrin, 122.6g2-methyl-3-trifluoromethyl phenylamine, 3.0g tosic acid, and 1.4g cupric oxide, stirs and is warming up to backflow, insulation reaction 2.5 hours.
(2) reaction solution is cooled to below 50 ℃, in reaction solution, drip 25% potassium hydroxide solution, regulate pH value to 10.0～11.0, regulating complete continuation to stir is cooled to below 20 ℃, fully stir 1 hour, suction filtration, filter cake is mainly excessive 2-methyl-3-trifluoromethyl phenylamine, and recyclable continuation is used.
(3) in filtrate, drip 30% sulfuric acid adjust pH to 5.0～6.0, fully stirring and crystallizing is 1 hour, suction filtration, and filter cake is used 300g purified water agitator treating 30 minutes, filters, and dries.Obtain 98.5g product, yield 95%, HPLC purity 99.7%.
The preparation of flunixin meglumine:
(1) in being equipped with the reaction flask of return line, 1000mL adds 680mL acetonitrile, 90g flunixin, and 62.6g meglumine, stirs and is warming up to 80 ℃, and reaction solution clarification, continues insulated and stirred 2 hours.
(2) heat filtering, temperature control is not less than 70 ℃, with the strainer of abundant preheating, reacting liquor while hot is filtered, insolubles in filtering system, filtrate is refunded in reaction flask, starts standing, naturally cooling, starts after crystallize out to stir, and is down to 20 ℃, growing the grain 1h, suction filtration, washs with acetonitrile, dry, obtain flunixin meglumine 141.6g, yield 95%, HPLC is greater than 99.9%, and quality product meets EP7.5 requirement.
Embodiment 3:
(1) in being equipped with the reaction flask of return line, 2000mL adds 1000g purified water, 110.2g2-chlorine apellagrin, 245.2g2-methyl-3-trifluoromethyl phenylamine, 12.0g tosic acid, and 5.6g cupric oxide, stirs and is warming up to backflow, insulation reaction 2 hours.
(2) reaction solution is cooled to below 50 ℃, in reaction solution, drip 25% potassium hydroxide solution, regulate pH value to 10.0～11.0, regulating complete continuation to stir is cooled to below 20 ℃, fully stir 1 hour, suction filtration, filter cake is mainly excessive 2-methyl-3-trifluoromethyl phenylamine, and recyclable continuation is used.
(3) in filtrate, drip 30% sulfuric acid adjust pH to 5.0～6.0, fully stirring and crystallizing is 1 hour, suction filtration, and filter cake is used 300g purified water agitator treating 30 minutes, filters, and dries.Obtain 196.4g product, yield 94.5%, HPLC purity 99.6%.
The preparation of flunixin meglumine:
(1) in being equipped with the reaction flask of return line, 1000mL adds 680mL acetonitrile, 90g flunixin, and 60.8g meglumine, stirs and is warming up to 70 ℃, and reaction solution clarification, continues insulated and stirred 2 hours.
(2) heat filtering, temperature control is not less than 70 ℃, with the strainer of abundant preheating, reacting liquor while hot is filtered, insolubles in filtering system, filtrate is refunded in reaction flask, starts standing, naturally cooling, starts after crystallize out to stir, and is down to 20 ℃, growing the grain 1h, suction filtration, washs with acetonitrile, dry, obtain flunixin meglumine 140.4g, yield 94%, HPLC is greater than 99.9%, and quality product meets EP7.5 requirement.
Claims (5)
1. a synthetic method for flunixin meglumine, comprises the synthesis step of following order:
(1) 2-methyl-3-trifluoromethyl phenylamine and 2-chlorine apellagrin are with water as solvent, and reaction generates flunixin;
(2) flunixin and meglumine are made solvent at acetonitrile, and 70～80 ℃ of synthetic flunixin meglumines, is characterized in that, it is catalyzer that synthesis step (1) be take tosic acid and cupric oxide.
2. synthetic method according to claim 1, is characterized in that, in described synthesis step (1), and 2-methyl-3-trifluoromethyl phenylamine: the mol ratio of 2-chlorine apellagrin is 2: 1.
3. synthetic method according to claim 1, is characterized in that, in described synthesis step (1), and tosic acid: the mol ratio of cupric oxide is 1: 1.
4. synthetic method according to claim 1, is characterized in that, in described synthesis step (1), and 2-chlorine apellagrin: the mol ratio of tosic acid is 1: 0.01～0.1.
5. according to the synthetic method described in arbitrary claim in claim 1～4, it is characterized in that, in described synthesis step (2), flunixin: the mol ratio of meglumine is 1: 1.02～1.2.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310683096.1A CN103694167A (en) | 2013-12-11 | 2013-12-11 | Method for synthesizing flunixin meglumine |
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| CN201310683096.1A CN103694167A (en) | 2013-12-11 | 2013-12-11 | Method for synthesizing flunixin meglumine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193674A (en) * | 2014-08-27 | 2014-12-10 | 济南久隆医药科技有限公司 | Synthesis method of flunixin meglumine |
| 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 |
| CN113372264A (en) * | 2021-06-16 | 2021-09-10 | 宁夏常晟药业有限公司 | Synthetic method of 2- [ 2-methyl-3- (trifluoromethyl) phenylamino ] nicotinic acid |
| 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 |
| CN116813537A (en) * | 2023-06-09 | 2023-09-29 | 深圳市绿诗源生物技术有限公司 | Preparation method and application of novel flunixin hapten |
-
2013
- 2013-12-11 CN CN201310683096.1A patent/CN103694167A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104193674A (en) * | 2014-08-27 | 2014-12-10 | 济南久隆医药科技有限公司 | Synthesis method of flunixin meglumine |
| CN104193674B (en) * | 2014-08-27 | 2016-05-25 | 济南久隆医药科技有限公司 | A kind of synthetic method of flunixin meglumine |
| 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 |
| CN113372264A (en) * | 2021-06-16 | 2021-09-10 | 宁夏常晟药业有限公司 | Synthetic method of 2- [ 2-methyl-3- (trifluoromethyl) phenylamino ] nicotinic acid |
| 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 |
| CN116813537A (en) * | 2023-06-09 | 2023-09-29 | 深圳市绿诗源生物技术有限公司 | Preparation method and application of novel flunixin hapten |
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