CN102344384A - Production method of mefenamic acid - Google Patents
Production method of mefenamic acid Download PDFInfo
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- CN102344384A CN102344384A CN2011102584047A CN201110258404A CN102344384A CN 102344384 A CN102344384 A CN 102344384A CN 2011102584047 A CN2011102584047 A CN 2011102584047A CN 201110258404 A CN201110258404 A CN 201110258404A CN 102344384 A CN102344384 A CN 102344384A
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Abstract
The invention discloses a production method of mefenamic acid, which comprises the following steps of: (1) adding water and o-chlorobenzoic acid into a reaction kettle, evenly mixing, and dropwise adding a sodium hydroxide solution while stirring, thereby obtaining a mixed solution; (2) adding solid sodium bicarbonate into the mixed solution in the step (1), adding chalcanthite, 2,3-dimethylaniline and cetyl trimethyl ammonium chloride, and carrying out reflux reaction; (3) after the reflux reaction in the step (2) is finished, dropwise adding hydrochloric acid, and filtering to obtain the crude product; (4) washing the crude product in the step (3) with water, filtering, and drying under reduced pressure to obtain the crude product; and (5) adding dimethyl formamide and water to dissolve the crude product in the step (4), adding activated carbon to carry out reflux decolorization, filtering, cooling to room temperature to crystallize, filtering, recrystallizing, washing with water after the filtration for the last recrystallization, and drying under reduced pressure to obtain the fine mefenamic acid product. The invention can lower the production cost, easily implement industrial production, and overcome the defects in the prior art.
Description
Technical field
The present invention relates to medicine, is a kind of working method of vialidon.
Background technology
Vialidon itself is a kind of antiphlogiston, also is simultaneously the midbody of preparation acridine antimalarial drug and anticarcinogen.Because vialidon has more wide application prospect, therefore, each state was all expanding the scale of production in recent years.Though this area discloses the working method of several kinds of vialidoves, all have some deficiency: for example: CN101475505A is to be reaction solvent with N, toluene etc., and quaternary amine is that phase-transfer catalyst prepares vialidon.The production cost of this method is higher, and environmental pollution is heavier, and it is bigger to handle the difficulty of polluting; The deficiency of CN101704761A working method is, owing to be to react in mutually at profit two, the technology circulation ratio is relatively poor during reaction; Yield is lower, causes wastage of material, simultaneously; Be prone to produce significant foam when feeding intake in the production, be prone to pollute production environment, and production security is lower etc.
Summary of the invention
The objective of the invention is, a kind of working method of vialidon is provided, it can reduce production costs, and is easy to suitability for industrialized production, can solve the deficiency of prior art.
The present invention is for realizing above-mentioned purpose, and realize through following technical scheme: a kind of working method of vialidon comprises the steps:
1. the ratio by weight 1.6:1 adds entry, 0-chloro-benzoic acid in reaction kettle, and after mixing, under agitation condition, dripping concentration is the sodium hydroxide solution 205.7-517.9L of 6.5mol/L, dropwises the back and stirs 30 minutes, obtains mixed solution;
2. in the mixed solution of step in 1., in 30-40 minute, slowly add solid sodium bicarbonate 100-250kg; Stir after 30 minutes; Ratio by weight 5.1:50.5:1 adds cupric sulfate pentahydrate, 2; 3-xylidine and palmityl trimethyl ammonium chloride, be warming up to 95 ℃-105 ℃ back flow reaction 16-22 hour;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 1.5-2.5, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 35 ℃-40 ℃ water 400L washing bullion 3 times, each wash agitation 15-20 minute, the bullion that obtains after the filtration obtained the 300-750kg bullion 80 ℃ of-90 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 700-1750L and water 10-25L dissolving, add 3-7.5kg activated carbon reflux decolour again, filter down at 90 ℃-100 ℃; Reduce to the room temperature crystallization, filter, and then carry out recrystallization 3 times; The stir speed (S.S.) of 3 recrystallizations is 70-80rpm; Rate of temperature fall is 10 ℃-15 ℃/hour, and last recrystallization filters back, water wash, 80 ℃-90 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 227-692kg.
The reflux time of step in 2. is 20 hours.
Preparing method of the present invention is with 0-chloro-benzoic acid and the water miscible salt of sodium hydroxide production, and is soluble in water, and the significant foam of having avoided with an organic solvent producing aborning is convenient to suitability for industrialized production to the pollution that production environment causes.Adopting sodium hydrogencarbonate in the inventive method is Fu's acid agent, has reduced the side reaction in the reaction process, and has reduced the chance of producing salicylic acid, and product yield is reached about 90%; The cupric sulfate pentahydrate that uses is soluble in water, when having improved catalytic efficiency (, has reduced production cost; Because the 23 dimethyl aniline that adopts and the ratio of 0-chloro-benzoic acid are suitable, improved the utilization ratio of 0-chloro-benzoic acid, simultaneously, 23 dimethyl aniline can be recycled, thereby has further reduced production cost.The phase-transfer catalyst hexadecyl front three ammonium chloride that adopts in the inventive method shortens the reaction times, and has further improved yield.
Embodiment
Vialidon working method of the present invention comprises the steps:
1. the ratio by weight 1.6:1 adds entry, 0-chloro-benzoic acid in reaction kettle, and after mixing, under agitation condition, dripping concentration is the sodium hydroxide solution 205.7-517.9L of 6.5mol/L, dropwises the back and stirs 30 minutes, obtains mixed solution;
2. in the mixed solution of step in 1., in 30-40 minute, slowly add solid sodium bicarbonate 100-250kg; Stir after 30 minutes; Ratio by weight 5.1:50.5:1 adds cupric sulfate pentahydrate, 2; 3-xylidine and palmityl trimethyl ammonium chloride, be warming up to 95 ℃-105 ℃ back flow reaction 16-22 hour;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 1.5-2.5, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 35 ℃-40 ℃ water 400L washing bullion 3 times, each wash agitation 15-20 minute, the bullion that obtains after the filtration obtained the 300-750kg bullion 80 ℃ of-90 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 700-1750L and water 10-25L dissolving, add 3-7.5kg activated carbon reflux decolour again, filter down at 90 ℃-100 ℃; Reduce to the room temperature crystallization, filter, and then carry out recrystallization 3 times; The stir speed (S.S.) of 3 recrystallizations is 70-80rpm; Rate of temperature fall is 10 ℃-15 ℃/hour, and last recrystallization filters back, water wash, 80 ℃-90 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 227-692kg.
The reflux time of step according to the invention in 2. is preferred 20 hours.
One of embodiment of working method of the present invention is:
1. after adding 320L water, 200kg 0-chloro-benzoic acid (1.277kmol) mixed in reaction kettle, under agitation condition, dripping concentration was the sodium hydroxide solution 205.7L of 6.5mol/L, dropwises the back and stirs 30 minutes, obtains mixed solution;
2. in the mixed solution of step in 1., in 30 minutes, slowly add solid sodium bicarbonate 100kg (1.19 kmol); Stir after 30 minutes; Add cupric sulfate pentahydrate 25kg (0.1 kmol), 2; 3-xylidine 247.6kg (2.04 kmol) and palmityl trimethyl ammonium chloride 4.9kg (15.3 2 kmol) were warming up to 95 ℃ of back flow reaction 16 hours;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 1.5, produces a large amount of reddish-brown precipitations during the acidification reaction, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 35 ℃ water 400L washing 3 times, each wash agitation 15 minutes, the bullion that obtains after the filtration obtains the 300kg bullion 80 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 700L and water 10L dissolving, add 3kg activated carbon reflux decolour again, filter down at 90 ℃; Reduce to the room temperature crystallization, refilter, and then carry out recrystallization 3 times; The stir speed (S.S.) of each recrystallization is 70rpm, and rate of temperature fall is 10 ℃/hour, and last recrystallization filters back, water wash; 80 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 227kg, yield is 90.2%.
Two of working method embodiment of the present invention is:
1. in reaction kettle, add 480L water, 300KG 0-chloro-benzoic acid (1.916 kmol), after mixing, under agitation condition, dripping concentration is the sodium hydroxide solution 308.6L of 6.5mol/L, dropwises the back and stirs 30 minutes, obtains mixed solution;
2. in the mixed solution of step in 1., in 40 minutes, slowly add solid sodium bicarbonate 150kg (1.19 kmol); Stir after 30 minutes; Add cupric sulfate pentahydrate 37.5kg (0.15 kmol), 2; 3-xylidine 371.4kg (3.06 kmol) and palmityl trimethyl ammonium chloride 7.35kg (22.98 kmol) were warming up to 105 ℃ of back flow reaction 20 hours;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 2, produces a large amount of reddish-brown precipitations during the acidification reaction, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 40 ℃ water 400L washing 3 times, each wash agitation 20 minutes, the bullion that obtains after the filtration obtains the 450kg bullion 90 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 1050L and water 15L dissolving, add 4.5kg activated carbon reflux decolour again, filter down at 100 ℃; Reduce to the room temperature crystallization, filter, and then carry out recrystallization 3 times; The stir speed (S.S.) of each recrystallization is 80rpm, and rate of temperature fall is 15 ℃/hour, and last recrystallization filters back, water wash; 90 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 415kg, yield is 90.7%.
Three of working method enforcement of the present invention is: 1. in reaction kettle, add 800L water, 500kg 0-chloro-benzoic acid (3.193 kmol); After mixing; Under agitation condition, dripping concentration is the sodium hydroxide solution 517.9L of 6.5mol/L; Dropwise the back and stirred 30 minutes, obtain mixed solution;
2. in the mixed solution of step in 1., in 38 minutes, slowly add solid sodium bicarbonate 250kg (2.975 kmol); Stir after 30 minutes; Add cupric sulfate pentahydrate 62.5kg (0.25 kmol), 2; 3-xylidine 619kg (5.1 kmol) and palmityl trimethyl ammonium chloride 12.25kg (38.3 kmol) were warming up to 100 ℃ of back flow reaction 22 hours;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 2.5, produces a large amount of reddish-brown precipitations during the acidification reaction, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 37.5 ℃ water 400L washing 3 times, each wash agitation 17.5 minutes, the bullion that obtains after the filtration obtains the 750kg bullion 85 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 750L and water 25L dissolving, add 7.5kg activated carbon reflux decolour again, filter down at 95 ℃; Reduce to the room temperature crystallization, filter, and then carry out recrystallization 3 times; The stir speed (S.S.) of each recrystallization is 75rpm, and rate of temperature fall is 12.5 ℃/hour, and last recrystallization filters back, water wash; 85 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 692kg, yield is 90.8%.
Claims (2)
1. the working method of a vialidon is characterized in that: comprise the steps:
1. the ratio by weight 1.6:1 adds entry, 0-chloro-benzoic acid in reaction kettle, and after mixing, under agitation condition, dripping concentration is the sodium hydroxide solution 205.7-517.9L of 6.5mol/L, dropwises the back and stirs 30 minutes, obtains mixed solution;
2. in the mixed solution of step in 1., in 30-40 minute, slowly add solid sodium bicarbonate 100-250kg; Stir after 30 minutes; Ratio by weight 5.1:50.5:1 adds cupric sulfate pentahydrate, 2; 3-xylidine and palmityl trimethyl ammonium chloride, be warming up to 95 ℃-105 ℃ back flow reaction 16-22 hour;
3. after making reacting liquid temperature reduce to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid again, to make the pH value of material be 1.5-2.5, again with obtaining bullion behind the material filtering;
4. with the bullion of step in 3. with 35 ℃-40 ℃ water 400L washing bullion 3 times, each wash agitation 15-20 minute, the bullion that obtains after the filtration obtained the 300-750kg bullion 80 ℃ of-90 ℃ of following drying under reduced pressure 6 hours;
5. in step bullion 4., add N 700-1750L and water 10-25L dissolving, add 3-7.5kg activated carbon reflux decolour again, filter down at 90 ℃-100 ℃; Reduce to the room temperature crystallization, filter, and then carry out recrystallization 3 times; The stir speed (S.S.) of 3 recrystallizations is 70-80rpm; Rate of temperature fall is 10 ℃-15 ℃/hour, and last recrystallization filters back, water wash, 80 ℃-90 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 227-692kg.
2. the working method of a kind of vialidon according to claim 1 is characterized in that: the reflux time of step in 2. is 20 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201110258404 CN102344384B (en) | 2011-09-02 | 2011-09-02 | Production method of mefenamic acid |
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| CN 201110258404 CN102344384B (en) | 2011-09-02 | 2011-09-02 | Production method of mefenamic acid |
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| CN102344384B CN102344384B (en) | 2013-10-16 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420863A (en) * | 2013-03-25 | 2013-12-04 | 江苏海佳化工有限公司 | Mefenamic acid short-process synthesis preparation and refining method |
| CN104193639A (en) * | 2014-09-16 | 2014-12-10 | 德州博诚制药有限公司 | Mefenamic acid refining system |
| CN105949075A (en) * | 2016-06-24 | 2016-09-21 | 江苏倍合德化工有限公司 | Synthesis method of mefenamic acid |
| CN106380414A (en) * | 2016-08-30 | 2017-02-08 | 西安利君精华药业有限责任公司 | Mefenamic acid and synthesis technology thereof |
| CN107382754A (en) * | 2017-07-10 | 2017-11-24 | 江苏倍合德化工有限公司 | A kind of quick high-efficiency synthesis method for preparing mefenamic acid |
| CN110256375A (en) * | 2019-06-11 | 2019-09-20 | 天津大学 | Mefenamic acid-piperazine salt type and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475505A (en) * | 2009-02-09 | 2009-07-08 | 宝鸡天新医药化工有限公司 | Process for preparing mefenamic acid |
| CN101704761A (en) * | 2009-10-23 | 2010-05-12 | 宁波斯迈克制药有限公司 | Synthesis method of mefenamic acid |
-
2011
- 2011-09-02 CN CN 201110258404 patent/CN102344384B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475505A (en) * | 2009-02-09 | 2009-07-08 | 宝鸡天新医药化工有限公司 | Process for preparing mefenamic acid |
| CN101704761A (en) * | 2009-10-23 | 2010-05-12 | 宁波斯迈克制药有限公司 | Synthesis method of mefenamic acid |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420863A (en) * | 2013-03-25 | 2013-12-04 | 江苏海佳化工有限公司 | Mefenamic acid short-process synthesis preparation and refining method |
| CN104193639A (en) * | 2014-09-16 | 2014-12-10 | 德州博诚制药有限公司 | Mefenamic acid refining system |
| CN105949075A (en) * | 2016-06-24 | 2016-09-21 | 江苏倍合德化工有限公司 | Synthesis method of mefenamic acid |
| CN106380414A (en) * | 2016-08-30 | 2017-02-08 | 西安利君精华药业有限责任公司 | Mefenamic acid and synthesis technology thereof |
| CN106380414B (en) * | 2016-08-30 | 2018-07-03 | 西安利君精华药业有限责任公司 | A kind of mefenamic acid and its synthesis technology |
| CN107382754A (en) * | 2017-07-10 | 2017-11-24 | 江苏倍合德化工有限公司 | A kind of quick high-efficiency synthesis method for preparing mefenamic acid |
| CN110256375A (en) * | 2019-06-11 | 2019-09-20 | 天津大学 | Mefenamic acid-piperazine salt type and preparation method thereof |
| CN110256375B (en) * | 2019-06-11 | 2022-03-29 | 天津大学 | Mefenamic acid-piperazine salt type and preparation method thereof |
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| CN102344384B (en) | 2013-10-16 |
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