CN102344384B

CN102344384B - Production method of mefenamic acid

Info

Publication number: CN102344384B
Application number: CN 201110258404
Authority: CN
Inventors: 张瑞琛; 李玉刚
Original assignee: DEZHOU BOCHENG PHARMACEUTICAL Co Ltd
Current assignee: DEZHOU BOCHENG PHARMACEUTICAL Co Ltd
Priority date: 2011-09-02
Filing date: 2011-09-02
Publication date: 2013-10-16
Anticipated expiration: 2031-09-02
Also published as: CN102344384A

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 dissolvethe 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 industrialproduction, and overcome the defects in the prior art.

Description

A kind of production method of vialidon

Technical field

The present invention relates to medicine, is a kind of production method of vialidon.

Background technology

Vialidon itself is a kind of antiphlogiston, also is simultaneously the intermediate 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.Although this area discloses the production method of several vialidoves, all there is some deficiency: such as: CN101475505A is that quaternary amine is that phase-transfer catalyst prepares vialidon take dimethyl formamide, toluene etc. as reaction solvent.The production cost of this method is higher, and environmental pollution is heavier, processes the difficulty of polluting larger; The deficiency of CN101704761A production method is, owing to being to react in the profit two-phase, the technique circulation ratio is relatively poor during reaction, yield is lower, causes wastage of material, simultaneously, easily produce a large amount of foams when feeding intake in the production, easily pollute production environment, and production security is lower etc.

Summary of the invention

The objective of the invention is, a kind of production method of vialidon is provided, it can reduce production costs, and is easy to suitability for industrialized production, can solve the deficiencies in the prior art.

The present invention is achieved through the following technical solutions for achieving the above object: a kind of production method of vialidon comprises the steps:

1. the ratio by weight 1.6:1 adds entry, 0-chloro-benzoic acid in the reactor, and after mixing, dripping concentration under agitation condition is the sodium hydroxide solution 205.7-517.9L of 6.5mol/L, dropwises rear stirring 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 be down to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid, to make the pH value of material be 1.5-2.5 again, will obtain crude product behind the material filtering again;

4. with the crude product of step in 3. with 35 ℃-40 ℃ water 400L washing crude product 3 times, each wash agitation 15-20 minute, the crude product that obtains after the filtration obtained the 300-750kg crude product 80 ℃ of-90 ℃ of lower drying under reduced pressure 6 hours;

5. in step crude product 4., add dimethyl formamide 700-1750L and water 10-25L dissolving, add again 3-7.5kg activated carbon reflux decolour, 90 ℃-100 ℃ lower filtrations, be down 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, after last recrystallization filters, 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.

Preparation 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 a large amount of foams of having avoided with an organic solvent producing aborning are convenient to suitability for industrialized production to the pollution that production environment causes.Adopting sodium bicarbonate 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 production method of the present invention comprises the steps:

The reflux time of step of the present invention in 2. is preferred 20 hours.

One of embodiment of production method of the present invention is:

1. add in the reactor after 320L water, 200kg 0-chloro-benzoic acid (1.277kmol) mixes, dripping concentration under agitation condition is the sodium hydroxide solution 205.7L of 6.5mol/L, dropwises rear stirring 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) are warming up to 95 ℃ of back flow reaction 16 hours;

3. after making reacting liquid temperature be down to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid, to make the pH value of material be 1.5 again, produces a large amount of reddish-brown precipitations during the acidification reaction, will obtain crude product behind the material filtering again;

4. with the crude product of step in 3. with 35 ℃ water 400L washing 3 times, each wash agitation 15 minutes, the crude product that obtains after the filtration obtains the 300kg crude product 80 ℃ of lower drying under reduced pressure 6 hours;

5. in step crude product 4., add dimethyl formamide 700L and water 10L dissolving, add again 3kg activated carbon reflux decolour, 90 ℃ of lower filtrations, be down 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 rear, water wash, 80 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 227kg, yield is 90.2%.

Two of production method embodiment of the present invention is:

1. add 480L water, 300KG 0-chloro-benzoic acid (1.916 kmol) in reactor, after mixing, dripping concentration under agitation condition is the sodium hydroxide solution 308.6L of 6.5mol/L, dropwises rear stirring 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) are warming up to 105 ℃ of back flow reaction 20 hours;

3. after making reacting liquid temperature be down to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid, to make the pH value of material be 2 again, produces a large amount of reddish-brown precipitations during the acidification reaction, will obtain crude product behind the material filtering again;

4. with the crude product of step in 3. with 40 ℃ water 400L washing 3 times, each wash agitation 20 minutes, the crude product that obtains after the filtration obtains the 450kg crude product 90 ℃ of lower drying under reduced pressure 6 hours;

5. in step crude product 4., add dimethyl formamide 1050L and water 15L dissolving, add again 4.5kg activated carbon reflux decolour, 100 ℃ of lower filtrations, be down 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 rear, water wash, 90 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 415kg, yield is 90.7%.

Three of production method enforcement of the present invention is: 1. add 800L water, 500kg 0-chloro-benzoic acid (3.193 kmol) in reactor, after mixing, dripping concentration under agitation condition is the sodium hydroxide solution 517.9L of 6.5mol/L, dropwise rear stirring 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) are warming up to 100 ℃ of back flow reaction 22 hours;

3. after making reacting liquid temperature be down to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid, to make the pH value of material be 2.5 again, produces a large amount of reddish-brown precipitations during the acidification reaction, will obtain crude product behind the material filtering again;

4. with the crude product of step in 3. with 37.5 ℃ water 400L washing 3 times, each wash agitation 17.5 minutes, the crude product that obtains after the filtration obtains the 750kg crude product 85 ℃ of lower drying under reduced pressure 6 hours;

5. in step crude product 4., add dimethyl formamide 750L and water 25L dissolving, add again 7.5kg activated carbon reflux decolour, 95 ℃ of lower filtrations, be down 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 rear, water wash, 85 ℃, vacuum tightness≤-the 0.08MPa condition under drying under reduced pressure obtain vialidon elaboration 692kg, yield is 90.8%.

Claims

1. the production method of a vialidon is characterized in that: comprise the steps:

1. after adding entry 800L, 0-chloro-benzoic acid 500kg in the reactor and mixing, dripping concentration under agitation condition is the sodium hydroxide solution 517.9L of 6.5mol/L, dropwises rear stirring 30 minutes, obtains mixed solution;

2. in the mixed solution of step in 1., in 38 minutes, slowly add solid sodium bicarbonate 250kg, stir after 30 minutes, add cupric sulfate pentahydrate 62.5kg, 23 dimethyl aniline 619kg and palmityl trimethyl ammonium chloride 12.25kg, be warming up to 100 ℃ of back flow reaction 22 hours;

3. after making reacting liquid temperature be down to room temperature after the back flow reaction of step in 2. finishes, dripping 20% hydrochloric acid, to make the pH value of material be 2.5 again, and a large amount of reddish-brown precipitation of generation will obtain crude product again during the acidification reaction behind the material filtering;

4. with the crude product of step in 3. with 37.5 ℃ water 400L washing crude product 3 times, each wash agitation 17.5 minutes, the crude product that obtains after the filtration obtains 750 kg crude products 85 ℃ of lower drying under reduced pressure 6 hours;