CN1158248C - Process for preparing diclazuril as veterinary medicine for coccidiosis - Google Patents
Process for preparing diclazuril as veterinary medicine for coccidiosis Download PDFInfo
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Abstract
The present invention relates to a production technology for preparing diclazuril as a veterinary medicine for coccidiosis. The production technology decreases eight process steps in an original process to four process steps, and a diclazuril crude product can be obtained by a one-step reaction of reducing substances. Thus, a reaction process and reaction time are greatly shortened so as to reduce the consumption of reaction materials and lighten the labor intensity. The present invention saves labor and materials; more important, the reaction yield is increased by 10% as compared with the original process; thereby, the production cost is greatly reduced, and the yield is increased.
Description
The present invention relates to the production technique of stud bird poultry coccidiosis medicine diclazuril (Diclazuril).
Diclazuril (Diclazuril) is the anticoccidial drug of a new generation, and the coccidiosis that fowl is raiseeed has fabulous prevention and therapeutic action, does not have loss of weight after the fowl poultry is taken, depilation, chronic poisoning phenomenons such as weak foot are to weightening finish, lay eggs, the quality of fertility rate of hatching egg and meat, egg does not all have influence.At present, the production technique of preparation diclazuril is with 2, and 6-two chloro-4-N-methyl-p-nitroanilines are starting raw material, through diazotization chlorination, condensation, reduction, diazo coupling, cyclization, hydrolysis, decarboxylation, refining eight procedures.Its complex manufacturing, long reaction time, it is many to expend raw material, and labour intensity is big, and cost height and yield are lower.
It is simple to the purpose of this invention is to provide a kind of production technique, and eight procedures in original production technique are reduced to four roads, shortens the reaction times, reduces raw material and expends, and reduces the production technique that labour intensity also can improve the fowl poultry coccidiosis medicine diclazuril of yield
For achieving the above object, production technique of the present invention comprises diazotization chloride process, condensation operation, reduction operation and finished product operation, and feed intake weight proportion and the production technique of each operation are as follows:
One, diazotization chloride process
(1) weight proportion that feeds intake:
2,6-two chloro-4-N-methyl-p-nitroanilines 1 cuprous chloride 0.5-0.7
Vitriol oil 5-7 hydrochloric acid 7-8
Sodium Nitrite 0.3-0.4 frozen water 4-5
Strong phosphoric acid 2.8-3.5 ethanol 2-2.5
(2) production technique step in the following order:
(1) the vacuum suction vitriol oil in the retort, unlatching stir and slowly add Sodium Nitrite, reinforced finishing, and jacket steam is heated to 75 ℃, stirs to make it molten entirely in 15 minutes, turns off steam to keep the jar temperature between 50-60 ℃;
(2) drop into 2,6-two chloro-4-N-methyl-p-nitroanilines, stirring and dissolving 15 minutes, the chuck water coolant is chilled to 35 ℃;
(3) drain jacket water (J.W.), but below the reaction solution to 5 ℃, suction strong phosphoric acid in the recorder jar drops in the retort in the open cold liquid cooling, and the control dropping temperature dropwises and continued insulated and stirred 30 minutes between 3-5 ℃;
(4) add frozen water in retort, temperature control is no more than 25 ℃, finishes, and is cooled to below 15 ℃, and it is standby that the suction test tank continues cooling;
(5) vacuum suction hydrochloric acid in the chlorination reaction jar, stir and drop into cuprous chloride, chuck is cooled to below 15 ℃, slowly drip step (4) gained diazonium liquid, the control dropping temperature finishes and continued insulated and stirred 30 minutes less than 15 ℃, jacket steam heat temperature raising to 70 ℃, be cooled to 50 ℃ again, insulation reaction 1 hour;
(6) be cooled to centrifuging after the room temperature, filter cake is washed to neutrality, weighs after the drying, and control moisture content is less than 5%, the trichloride crude product, the washing sour water is put into the spent acid pond;
(7) suction ethanol in the treatment tank stirs and drops into step (6) gained crude product, open cold condenser, reflux 10 minutes down, be cooled to room temperature, stir insulation 2 hours, blowing is centrifugal, dry back chemical examination weight loss on drying less than 5%, get the trichloride elaboration, the ethanol mother liquor is drawn back treatment tank and is used;
Two, condensation operation
(1) weight proportion that feeds intake:
Trichloride 1 tetrahydrofuran (THF) 1-1.5
Sheet alkali 3-3.5 hydrochloric acid 8.1-8.2
Water 2.5-3 chloroform 10-12
TEBA 0.12-0.15 isopropyl ether 1.2-1.5
Tetrahydrofuran (THF) 2-3 frozen water 20-25
To benzyl chloride nitrile 0.7-0.8 washing water 2.5-3
(2) the following sequential steps of production technique:
(1) suction tap water in the condensation reaction jar drops into sheet alkali, and heating is stirred to dissolving, and chuck advances water coolant, be cooled to room temperature after, suction reacting weight tetrahydrofuran (THF) drops into trichloride and TEBA that above-mentioned operation makes, stirs 10 minutes;
(2) drip in the bottle suction to benzyl chloride nitrile and tetrahydrofuran (THF), mixedly drop in the retort after evenly, control reaction temperature is below 50 ℃, and reinforced finishing keeps 50 ℃ of reactions of temperature 4 hours;
(3) add frozen water in the acidifying extractor, chuck is cooled to 0 ℃, stirs and slowly be pressed into step (2) gained condensation reaction solution, and ice is separated after 15 minutes dripping hydrochloric acid to pH1～2;
(4) add chloroform, make in the reaction solution solids molten entirely, after static 15 minutes, lower floor's chloroform layer is put into the extracting solution basin, and water layer is with remaining chloroform extraction three times, and each lower floor chloroform layer is put into the extracting solution basin, last water layer discarded, all chloroform extracted solutions are pressed in the jar, add the water agitator treating, discard upper water repeated washing to water layer and are neutrality;
(5) chloroform extracted solution is depressed into concentration tank, normal pressure reclaims chloroform, and the distillation later stage is used water instead towards pump vacuum distilling, steam to the greatest extent chloroform after, stir while hot and slowly add isopropyl ether down, stirred 1 hour, chuck is put into the suction filtration cylinder after being cooled to room temperature, drain condenses;
Three, reduction operation
(1) weight proportion that feeds intake
Condenses 1 reduced iron powder 0.8-1.2
Toluene 8.8-9.2 tetrahydrofuran (THF) 0.3-0.5
Ammonium chloride 0.38-0.42 isopropyl ether 0.45-0.5
Water 9.3-9.8 washing water 5-6
(2) the following sequential steps of production technique:
(1) reduction jar interior suction water adds ammonium chloride, stirring and dissolving, and simultaneously, suction toluene in the test tank drops into last process gained condenses stirring and dissolving;
(2) reduction jar interior aqueous ammonium chloride solution heat temperature raising, the open cold condenser adds reduced iron powder when closely refluxing, continue to be heated to backflow, and reflux state slowly drips the condenses toluene solution that step (1) is prepared down, dropwises back flow reaction 6 hours;
(3) with step (2) gained reaction solution, after the pressure filter press filtration, filtrate is pressed into the layering jar, and filter cake is washed till colourless with tetrahydrofuran (THF);
(4) be pressed into the suitable heating of the interior filtrate of layering jar and avoid crystallization to separate out, layering in 15 minutes is left standstill in insulation, puts sub-cloud water, and upper toluene liquid adds hot water, and agitator treating 15 minutes is incubated standing demix, puts the layer that anhydrates, and repeated washing like this is to emitting water for neutral;
(5) toluene liquid is evacuated to the distillation crystallizer, stirs crystallisation by cooling, and feed liquid is filtered, and filter cake isopropyl ether washed twice is drained the back discharging, oven dry; Filtrate is drawn back crystallizer, and normal pressure reclaims toluene and re-uses, and residue stirs blowing after 1 hour with isopropyl ether, reclaims reduzate;
Four, finished product operation
(1) weight proportion that feeds intake
Reduzate 1 water 5-6
Closed loop agent 0.87-0.9 dimethyl formamide 3.0-3.5
Glacial acetic acid 7.5-8 diatomite 0.06-0.07
Propionic acid 1.3-1.5 ethanol 1.4-1.5
Sodium Nitrite 0.25-0.26 butanols 0.029-0.032
Water 0.42-0.45 washing dimethylformamide 0.5-0.6
Sodium acetate, anhydrous 0.29-0.3 washing ethanol 4.3-4.5
Refining hydrochloric acid 4.0-4.2 washing butanols 0.088-0.09
Thiovanic acid 0.7-0.75
Propionic acid 2-2.2
(2) the following sequential steps of production technique:
The preparation of A, crude product
(1) suction acetic acid, propionic acid in the finished product retort stir down and drop into last process gained reduzate and closed loop agent, continue to stir 30 minutes, drip in the bottle and prepare sodium nitrite in aqueous solution, drip in retort controlled temperature 25 ℃ ± 2, after dripping end, continue to stir 30 minutes;
(2) drop into sodium acetate, anhydrous in the retort, stir open cold condenser after 10 minutes, temperature rising reflux 40 minutes carries out ring-closure reaction;
(3) backflow finishes, and chuck advances water coolant and is chilled to 30 ℃ ± 2, and dripping hydrochloric acid dropwises and continues to stir 10 minutes, and reaction is hydrolyzed;
(4) hydrolysis reaction is finished, and slowly heats up, and normal pressure steams acid, and hydrochloric acid tail gas absorbs through resorber, and temperature rises to 140 ℃ in retort, stops distillation, adds and dredges guanidine-acetic acid, propionic acid, and temperature rising reflux 7 hours carries out decarboxylic reaction;
(5) decarboxylic reaction is finished, and adds entry, and heat temperature raising refluxed 30 minutes, was cooled to room temperature, and blowing is centrifugal, and tap water washs to washings neutrality; Drying materials gets crude product;
B, refining
(1) suction dimethyl formamide in the treatment tank stirs down and drops into last process gained crude product and diatomite, the open cold condenser, and heating for dissolving also refluxed 15 minutes, and material is controlled at 147 ℃;
(2) preheating crystallizer, pressure filter and press filtration pipeline are opened the crystallizer condenser, are incubated press filtration, and filtrate is pressed in the crystallizer, and after filter cake washed with dimethyl formamide, washings was pressed into crystallizer in the lump;
(3) temperature drips ethanol, butanol solution while hot in the crystallizer, finish and slowly be cooled to below 20 ℃, stirred crystallization 2 hours, blowing is centrifugal, ethanol, butanols gradation washing, it is colourless that filter cake is washed till filtrate, and mother liquor and washing lotion are put into two ground jars respectively, filter cake dries back discharging oven dry, chemically examine qualified abrasive dust afterwards pack the diclazuril elaboration; If defective need carry out secondary refining with quadrat method;
C, mother liquor reclaim DMF and crude product
With mother liquor suction treatment tank, fraction below 90 ℃ is collected in air distillation, is used for the finished product crystallization; Fraction suction rectifying jar between 90-150 ℃, when steaming to 150 ℃, the beginning underpressure distillation is steamed to the feed liquid thickness and is put into bucket, adds ethanol, concentrates and reclaims crude product, and the decompression fraction is DMF;
D, washing lotion reclaim ethanol
In the washing lotion suction treatment tank, fraction below 90 ℃ is collected in air distillation, fraction C set by step more than 90 ℃, and suction rectifying jar reclaims DMF and ethanol.
The preparation of the raw material closed loop agent in the described finished product operation: propanedioic acid 5kg, urethanum 9kg, aceticanhydride 20kg, drop in the reactor, be heated to 90-100 ℃ and stir 5 hours pressure reducing and steaming acetic acid, the cold crystallization of promptly separating out is put in cooling, washing, alcohol refining product.
Production technique of the present invention and original production technique are relatively, diazo coupling reaction, ring-closure reaction, hydrolysis reaction, decarboxylic reaction, refining five processes are finished by one finished product operation, can make the diclazuril crude product from the reduzate single step reaction, reaction process and reaction times have been shortened greatly, thereby reduced expending and reducing labor intensity of reaction mass, manpower and materials have not only been saved, the more important thing is that reaction yield has improved 10% than original technology, therefore reduce production cost significantly, improved output.
Description of drawings:
Fig. 1 is a diazotization chloride process Production Flow Chart skeleton diagram of the present invention;
Fig. 2 is a condensation operation Production Flow Chart skeleton diagram of the present invention;
Fig. 3 is that the present invention reduces operation Production Flow Chart skeleton diagram;
Fig. 4 is a finished product operation Production Flow Chart skeleton diagram of the present invention.
As shown in Figure 1, the diazotization chloride process is the preparation of carrying out trichloride, the material of required input is 2 in this operation, 6-two chloro-4-N-methyl-p-nitroanilines (industry 〉=98%), sulfuric acid (industry 〉=96%), Sodium Nitrite (industry 〉=95%), phosphoric acid (industry 〉=85%), cuprous chloride (industry 〉=92%), hydrochloric acid (industry 〉=28%), water (ice tap water), ethanol (industry 〉=95%).Raw material is got all the ready, begins to feed intake under equipment operation is normal.Production craft step is as follows:
(1) the vacuum suction 53.45kg vitriol oil in the diazotization reaction jar is opened and is stirred, and slowly adds the 3.23kg Sodium Nitrite, finish, jacket steam is heated to 75 ℃, stirs to make it molten entirely in 15 ℃ minutes, turn off jacket steam, keep the interior temperature of retort between 50-60 ℃;
(2) drop into 8.72kg2,6-two chloro-4-N-methyl-p-nitroanilines, stirring and dissolving 15 minutes, the chuck water coolant is chilled to about 35 ℃;
(3) drain jacket water (J.W.), and open but reaction solution below 5 ℃ of cold liquid cooling; Suction 26.51kg strong phosphoric acid in the recorder jar drops in the retort, and the control dropping temperature notices that the speed of dropping strong phosphoric acid wants slow between 3-5 ℃, and the temperature in the retort must not surpass 5 ℃, dropwises continuation insulated and stirred 30 minutes;
(4) add 38.8kg water in the diazotization reaction jar, controlled temperature is no more than 25 ℃, finishes, and is cooled to below 15 ℃, then in the test tank with the diazonium liquid suction strap clamp layer in the jar, keeps temperature＜15 ℃ standby;
(5) vacuum suction 66.88kg hydrochloric acid in the chlorination reaction jar is opened to stir and is dropped into the 5.23kg cuprous chloride, and chuck is chilled to below 15 ℃, slowly drip at the prepared diazonium liquid of step (4), the control dropping temperature is noted the control rate of addition less than 15 ℃, avoids flash, finish, continued insulated and stirred 30 minutes, the cold hydraulic pressure of chuck goes out, and advances steam heating and is warming up to 70 ℃, be cooled to 50 ℃ again, insulation reaction 1 hour;
(6) reduce to centrifuging after the room temperature, filter cake is washed to neutrality, weighs after the drying, and control moisture content is less than 5%, the crude product trichloride, the washing sour water is put into the spent acid pond and is focused on;
(7) suction 18.6kg ethanol in the treatment tank, stir and drop into step (6) gained trichloride crude product down, the open cold condenser, reflux 10 minutes, the chuck water coolant is chilled to room temperature, stirs insulation 2 hours, and blowing is centrifugal, dry back chemical examination weight loss on drying less than 5%, the ethanol mother liquor is drawn back recovery set usefulness in the treatment tank.
Trichloride yield calculation formula:
Calculating trichloride output by this formula is 7.55kg, and yield reaches 75%.
As shown in Figure 2, the condensation operation is to carry out the preparation of condenses, and the material of required input is in this operation: last process gained trichloride (mp＞68 ℃, give money as a gift 〉=95%), sheet alkali (industry 〉=95%), water, TEBA (mp＞178 ℃, give money as a gift＞98%), tetrahydrofuran (THF) (industry 〉=95%), hydrochloric acid (industry 〉=28%), chloroform (industry), isopropyl ether (d25250.719-0.723), frozen water, washing water.
Production craft step is as follows:
(1) suction 21.52kg tap water in the condensation reaction jar drops into 23.78kg sheet alkali, opens and stirs, be heated to dissolving, chuck advances water coolant and is chilled to room temperature, suction 21.14kg tetrahydrofuran (THF) in jar, drop into trichloride 7.55kg and TEBA0.98kg that last process makes, stirred 10 minutes;
(2) drip the interior suction of bottle to benzyl chloride nitrile 5.59kg and tetrahydrofuran (THF) 10.57kg, drop to after mixing in the condensation reaction jar, control reaction temperature is below 50 ℃, and reinforced finishing continues to maintain the temperature at 50 ℃ of reactions 4 hours;
(3) add tap water 151kg in the acidifying extractor, chuck is cooled to 0 ℃, stirs slowly to add step (2) gained reaction solution down, and after ice was separated 15 minutes, dripping hydrochloric acid was to ph1-2;
(4) in the acidifying extractor, add chloroform 40kg, make in the reaction solution solids molten entirely, lower floor's chloroform layer is put into the extracting solution basin after static 15 minutes, and water layer is with residue chloroform extraction three times, each adding chloroform amount is 13kg, each lower floor chloroform layer is all put into the extracting solution basin, and last water layer discarded is pressed into all chloroform extracted solutions in the jar, add water washing, and go upper aqueous layer, so repeated washing is to water layer neutrality, general three times;
(5) chloroform solution is depressed into concentration tank, normal pressure reclaims chloroform, the distillation later stage is used water instead towards pump vacuum distilling, noting reclaiming chloroform will eliminate as far as possible, and the later stage is used vacuum distilling instead, when gas phase temperature descends, promptly show and steam to the greatest extent, the chloroform that reclaims can overlap and be used for extracting, and behind the most chloroform of steaming, slowly adds isopropyl ether 9.16kg while hot down, stirred 1 hour, after chuck advances water coolant and is chilled to room temperature, put into the suction filtration cylinder, drain condenses, the chemical examination weight loss on drying is less than 5%, mp 〉=112 ℃, the isopropyl ether mother liquor can be applied mechanically, and generally applies mechanically 5-6 back and concentrates and reclaim.
The yield calculation formula of condenses:
Calculate by this formula, the output of condenses is 8.09kg, yield 75%.
As shown in Figure 3, the reduction operation is carried out the preparation of reduzate, and input material is in this operation: last process gained condenses (mp 〉=112 ℃, give money as a gift 〉=95%), toluene (industrial D
4 200.862--0.868), ammonium chloride (industrial content 〉=99%), water, reduced iron powder (technical grade 80 orders), tetrahydrofuran (THF), isopropyl ether, washing water.
Production craft step:
(1) reduction jar interior suction water 76.86kg adds ammonium chloride 3.24kg, stirring and dissolving; Suction toluene 72.81kg in the proportion meter measuring tank drops into last process gained condenses 8.09kg simultaneously, fully stirs and makes its dissolving;
(2) reduction jar interior aqueous ammonium chloride solution heat temperature raising, the open cold condenser adds reduced iron powder 7.28kg when closely refluxing, continue to be heated to backflow, under reflux state, the condenses toluene solution in the test tank slowly is added dropwise in the reduction jar, after dropping finishes, continued back flow reaction 6 hours; Note adding iron powder when aqueous ammonium chloride solution is heated to fast boiling, under boiling state, drip the condenses toluene solution, with the thoroughness that guarantees to react;
(3) be incubated press filtration after reaction finishes, preheating awl bottom slice jar, pressure filter and each pipeline of press filtration before the press filtration, warm up time must be more than 15 minutes, in order to avoid separate out crystallization and blocking pipe during press filtration; Open layering jar double-pipe condenser, according to the press filtration rules reaction solution is pressed into the layering jar, after binder finished, to colourless, filtrate was pressed into the layering jar with the tetrahydrofuran (THF) washing leaching cake;
(4) being pressed into the interior filtrate of layering jar should suitably heat, and avoids crystallization to separate out, and is incubated layering in static 15 minutes, puts the sub-cloud water layer, toluene layer is put into the hot water by the sleeve pipe heating, and agitator treating 15 minutes is after the insulation static layering, put the layer that anhydrates, repeated washing is to washing out water neutrality, general three times;
(5) toluene liquid is evacuated to the distillation crystallizer, stirs crystallisation by cooling, stirs 2 hours below 20 ℃, feed liquid is put into the suction filtration bucket and is filtered, and filter cake is drained discharging with isopropyl ether 3.88kg washed twice, send chemical examination behind the drying materials, weight loss on drying less than 1%mp＞184 ℃ reduzate; Filtrate is drawn back the distillation crystallizer, and normal pressure recovery toluene can overlap and be used for reaction, and residue is an amount of with isopropyl ether, stirs blowing after 1 hour, and it is concentrated refining to reclaim reduzate, and the isopropyl ether mother liquor is concentrated to be reclaimed.
The yield calculation formula of reduzate:
The output of by formula calculating reduzate is 5.46kg, and yield is 74%.
As shown in Figure 4, the finished product operation is last procedure of the present invention, and the material of required input is in this procedure: last process gained reduzate (mp＞184 ℃, weight loss on drying is less than 1%), closed loop agent, Glacial acetic acid (industry 〉=95%).Propionic acid (industrial content 〉=92%), Sodium Nitrite (industry 〉=95%), water, sodium acetate, anhydrous (〉=98%), refining hydrochloric acid (industry) is dredged guanidine-acetic acid (content 〉=85%), propionic acid (〉=92%), and dimethyl formamide (bp152-156 ℃, content 〉=95%, moisture content is less than 0.3%), (weight loss on drying is less than 2%, pH≤10 for diatomite, acetone solution is less than 0.2%), ethanol (industry 〉=95%), and butanols (d20 ℃, 0.809-0.813).
The preparation of closed loop agent: propanedioic acid 5kg, urethanum 9kg, aceticanhydride 20kg in the input reactor, heats 90-100 ℃ and stirred 5 hours, pressure reducing and steaming acetic acid, the cold crystallization of promptly separating out is put in cooling, washing, alcohol is refining, gets product 6.2kg, and yield is 52%.
Production craft step:
The preparation of A, crude product
(1) suction acetic acid 42.95kg in the finished product retort, propionic acid 7.15kg stirs down and drops into reduzate 5.46kg and closed loop agent 4.75kg, continues to stir 30 minutes; Drip adding Sodium Nitrite 1.39kg and water 2.29kg in the bottle, prepare sodium nitrite in aqueous solution, drip in retort, controlled temperature 25 ℃ ± 2 after dropping finishes, continues to stir 30 minutes; Notice that this step doazo reaction is crucial, directly influences the crude product quality, and is even at a slow speed when dripping sodium nitrite in aqueous solution, prevents that the Sodium Nitrite partial concn is too high, mixing effect will be got well;
(2) drop into sodium acetate, anhydrous 1.58kg in the retort, stir open cold condenser after 10 minutes, temperature rising reflux 40 minutes carries out ring-closure reaction;
(3) backflow finishes, and chuck advances water coolant and is chilled to 30 ℃ ± 2, and dripping hydrochloric acid 22kg finishes and stirred 10 minutes, and reaction is hydrolyzed;
(4) hydrolysis reaction is finished, and slowly heats up, and normal pressure steams acid, and hydrochloric acid tail gas absorbs through resorber, and temperature rises to 140 ℃ and stops distillation in retort, adds and dredges guanidine-acetic acid 3.93kg, propionic acid 11.14kg, and temperature rising reflux 7 hours carries out decarboxylic reaction; Notice that when steaming acid, emit hydrochloric acid tail gas and want the water absorption, decontamination is also reclaimed hydrochloric acid, 104 ℃ of diluted acids that steams discard after focusing on foreshot, sell with the after cut collection storage for 104 ℃;
(5) decarboxylic reaction is finished, and adds entry 31.18kg, and heat temperature raising refluxed 30 minutes, be cooled to about 25 ℃ after, blowing is centrifugal, tap water washs to washings neutrality, behind the drying materials, chemical examination moisture content is less than 1%, the about 17.15kg of crude product.
B, refining
(1) suction dimethyl formamide 16.38kg in the treatment tank stirs and drops into previous step rapid gained crude product 7.15kg and diatomite 0.36kg down, and the open cold condenser is heated to dissolving and refluxed 15 minutes, and feed temperature is controlled at more than 147 ℃;
(2) preheating crystallizer, pressure filter and press filtration pipeline stop up when avoiding press filtration, open the crystallizer condenser, are incubated press filtration, and filtrate pushes back in the crystallizer, and after filter cake washed with dimethyl formamide, washings pushed back crystallizer in the lump;
(3) drip ethanol 7.71kg, butanols 0.16kg in the crystallizer while hot, finish and slowly be cooled to below 20 ℃, stirred crystallization 2 hours, blowing is centrifugal, washing ethanol, butanols gradation washing, it is colourless to be washed till filtrate, and mother liquor and washing lotion are put into two ground cylinders respectively; Qualified back abrasive dust packing is chemically examined in the discharging oven dry of drying back, gets the diclazuril finished product; If defective, need to carry out secondary refining with quadrat method, (highly finished product: DMF=1: 24).Drip ethanol and cooling rate when this step should be noted crystallization and want slow, to guarantee crystalline quality.
C, mother liquor reclaim DMF and diclazuril crude product
In mother liquor suction treatment tank, air distillation is collected fraction below 90 ℃ and is used for the finished product crystallization; Fraction suction rectifying jar reclaims DMF and ethanol between 90-150 ℃, and when steaming to 150 ℃, the beginning underpressure distillation is during underpressure distillation, should lower the temperature in advance, prevent to dash material, steam to the feed liquid thickness, put into bucket, add an amount of ethanol, concentrate and reclaim the diclazuril crude product, the decompression fraction is DMF, recyclable utilization.
D, washing lotion reclaim ethanol
In the washing lotion suction treatment tank, normal pressure reclaims ethanol, collects fraction below 90 ℃, more than 90 ℃ fraction again rectifying reclaim DMF and ethanol.
The product yield calculation formula:
By formula calculating finished product output is 4kg, and yield is 56%.
Claims (2)
1, the production technique of stud bird poultry coccidiosis medicine diclazuril comprises diazotization chloride process, condensation operation, reduction operation and finished product operation, it is characterized in that:
One, diazotization chloride process
(1) weight proportion that feeds intake:
2,6-two chloro-4-N-methyl-p-nitroanilines 1 cuprous chloride 0.5-0.7
Vitriol oil 5-7 hydrochloric acid 7-8
Sodium Nitrite 0.3-0.4 frozen water 4-5
Strong phosphoric acid 2.8-3.5 ethanol 2-2.5
(2) production technique step in the following order:
(1) the vacuum suction vitriol oil in the retort, unlatching stir and slowly add Sodium Nitrite, reinforced finishing, and jacket steam is heated to 75 ℃, stirs to make it molten entirely in 15 minutes, turns off steam to keep the jar temperature between 50-60 ℃;
(2) drop into 2,6-two chloro-4-N-methyl-p-nitroanilines, stirring and dissolving 15 minutes, the chuck water coolant is chilled to 35 ℃;
(3) drain jacket water (J.W.), but below the reaction solution to 5 ℃, suction strong phosphoric acid in the recorder jar drops in the retort in the open cold liquid cooling, and the control dropping temperature dropwises and continued insulated and stirred 30 minutes between 3-5 ℃;
(4) add frozen water in retort, temperature control is no more than 25 ℃, finishes, and is cooled to below 15 ℃, and it is standby that the suction test tank continues cooling;
(5) vacuum suction hydrochloric acid in the chlorination reaction jar, stir and drop into cuprous chloride, chuck is cooled to below 15 ℃, slowly drip step (4) gained diazonium liquid, the control dropping temperature finishes and continued insulated and stirred 30 minutes less than 15 ℃, jacket steam heat temperature raising to 70 ℃, be cooled to 50 ℃ again, insulation reaction 1 hour;
(6) be cooled to centrifuging after the room temperature, filter cake is washed to neutrality, weighs after the drying, and control moisture content is less than 5%, the trichloride crude product, the washing sour water is put into the spent acid pond;
(7) suction ethanol in the treatment tank stirs and drops into step (6) gained crude product, open cold condenser, reflux 10 minutes down, be cooled to room temperature, stir insulation 2 hours, blowing is centrifugal, dry back chemical examination weight loss on drying less than 5%, get the trichloride elaboration, the ethanol mother liquor is drawn back treatment tank and is used;
Two. the condensation operation
(1) weight proportion that feeds intake:
Trichloride 1 tetrahydrofuran (THF) 1-1.5
Sheet alkali 3-3.5 hydrochloric acid 8.1-8.2
Water 2.5-3 chloroform 10-12
TEBA 0.12-0.15 isopropyl ether 1.2-1.5
Tetrahydrofuran (THF) 2-3 frozen water 20-25
To benzyl chloride nitrile 0.7-0.8 washing water 2.5-3
(2) the following sequential steps of production technique:
(1) suction tap water in the condensation reaction jar drops into sheet alkali, and heating is stirred to dissolving, and chuck advances water coolant, be cooled to room temperature after, suction reacting weight tetrahydrofuran (THF) drops into trichloride and TEBA that above-mentioned operation makes, stirs 10 minutes;
(2) drip in the bottle suction to benzyl chloride nitrile and tetrahydrofuran (THF), mixedly drop in the retort after evenly, control reaction temperature is below 50 ℃, and reinforced finishing keeps 50 ℃ of reactions of temperature 4 hours;
(3) add frozen water in the acidifying extractor, chuck is cooled to 0 ℃, stirs and slowly be pressed into step (2) gained condensation reaction solution, and ice is separated after 15 minutes dripping hydrochloric acid to pH1～2;
(4) add chloroform, make in the reaction solution solids molten entirely, after static 15 minutes, lower floor's chloroform layer is put into the extracting solution basin, and water layer is with remaining chloroform extraction three times, and each lower floor chloroform layer is put into the extracting solution basin, last water layer discarded, all chloroform extracted solutions are pressed in the jar, add the water agitator treating, discard upper water repeated washing to water layer and are neutrality;
(5) chloroform extracted solution is depressed into concentration tank, normal pressure reclaims chloroform, and the distillation later stage is used water instead towards pump vacuum distilling, steam to the greatest extent chloroform after, stir while hot and slowly add isopropyl ether down, stirred 1 hour, chuck is put into the suction filtration cylinder after being cooled to room temperature, drain condenses;
Three, reduction operation
(1) weight proportion that feeds intake
Condenses 1 reduced iron powder 0.8-1.2
Toluene 8.8-9.2 tetrahydrofuran (THF) 0.3-0.5
Ammonium chloride 0.38-0.42 isopropyl ether 0.45-0.5
Water 9.3-9.8 washing water 5-6
(2) the following sequential steps of production technique:
(1) reduction jar interior suction water adds ammonium chloride, stirring and dissolving, and simultaneously, suction toluene in the test tank drops into last process gained condenses stirring and dissolving;
(2) reduction jar interior aqueous ammonium chloride solution heat temperature raising, the open cold condenser adds reduced iron powder when closely refluxing, continue to be heated to backflow, and reflux state slowly drips the condenses toluene solution that step (1) is prepared down, dropwises back flow reaction 6 hours;
(3) with step (2) gained reaction solution, after the pressure filter press filtration, filtrate is pressed into the layering jar, and filter cake is washed till colourless with tetrahydrofuran (THF);
(4) be pressed into the suitable heating of the interior filtrate of layering jar and avoid crystallization to separate out, layering in 15 minutes is left standstill in insulation, puts sub-cloud water, and upper toluene liquid adds hot water, and agitator treating 15 minutes is incubated standing demix, puts the layer that anhydrates, and repeated washing like this is to emitting water for neutral;
(5) toluene liquid is evacuated to the distillation crystallizer, stirs crystallisation by cooling, and feed liquid is filtered, and filter cake isopropyl ether washed twice is drained the back discharging, oven dry; Filtrate is drawn back crystallizer, and normal pressure reclaims toluene and re-uses, and residue stirs blowing after 1 hour with isopropyl ether, reclaims reduzate;
Four, finished product operation
(1) weight proportion that feeds intake
Reduzate 1 water 5-6
Closed loop agent 0.87-0.9 dimethyl formamide 3.0-3.5
Glacial acetic acid 7.5-8 diatomite 0.06-0.07
Propionic acid 1.3-1.5 ethanol 1.4-1.5
Sodium Nitrite 0.25-0.26 butanols 0.029-0.032
Water 0.42-0.45 washing dimethylformamide 0.5-0.6
Sodium acetate, anhydrous 0.29-0.3 washing ethanol 4.3-4.5
Refining hydrochloric acid 4.0-4.2 washing butanols 0.088-0.09
Thiovanic acid 0.7-0.75 propionic acid 2-2.2
(2) the following sequential steps of production technique:
The preparation of A, crude product
(1) suction acetic acid, propionic acid in the finished product retort stir down and drop into last process gained reduzate and closed loop agent, continue to stir 30 minutes, drip in the bottle and prepare sodium nitrite in aqueous solution, drip in retort controlled temperature 25 ℃ ± 2, after dripping end, continue to stir 30 minutes;
(2) drop into sodium acetate, anhydrous in the retort, stir open cold condenser after 10 minutes, temperature rising reflux 40 minutes carries out ring-closure reaction;
(3) backflow finishes, and chuck advances water coolant and is chilled to 30 ℃ ± 2, and dripping hydrochloric acid dropwises and continues to stir 10 minutes, and reaction is hydrolyzed;
(4) hydrolysis reaction is finished, and slowly heats up, and normal pressure steams acid, and hydrochloric acid tail gas absorbs through resorber, and temperature rises to 140 ℃ in retort, stops distillation, adds and dredges guanidine-acetic acid, propionic acid, and temperature rising reflux 7 hours carries out decarboxylic reaction;
(5) decarboxylic reaction is finished, and adds entry, and heat temperature raising refluxed 30 minutes, was cooled to room temperature, and blowing is centrifugal, and tap water washs to washings neutrality; Drying materials gets crude product;
B, refining
(1) suction dimethyl formamide in the treatment tank stirs down and drops into last process gained crude product and diatomite, the open cold condenser, and heating for dissolving also refluxed 15 minutes, and the material temperature control is at 147 ℃;
(2) preheating crystallizer, pressure filter and press filtration pipeline are opened the crystallizer condenser, are incubated press filtration, and filtrate is pressed in the crystallizer, and after filter cake washed with dimethyl formamide, washings was pressed into crystallizer in the lump;
(3) drip ethanol, butanol solution in the crystallizer while hot, finish and slowly be cooled to below 20 ℃, stirred crystallization 2 hours, blowing is centrifugal, ethanol, butanols gradation washing, it is colourless that filter cake is washed till filtrate, and mother liquor and washing lotion are put into two ground cylinders respectively, filter cake dries back discharging oven dry, chemically examine qualified abrasive dust afterwards pack the diclazuril elaboration; If defective need carry out secondary refining with quadrat method;
C, mother liquor reclaim DMF and crude product
With mother liquor suction treatment tank, fraction below 90 ℃ is collected in air distillation, is used for the finished product crystallization; Fraction suction rectifying jar between 90-150 ℃, when steaming to 150 ℃, the beginning underpressure distillation is steamed to the feed liquid thickness and is put into bucket, adds ethanol, concentrates and reclaims crude product, and the decompression fraction is DMF;
D, washing lotion reclaim ethanol
In the washing lotion suction treatment tank, fraction below 90 ℃ is collected in air distillation, fraction C set by step more than 90 ℃, and suction rectifying jar reclaims DMF and ethanol.
2, the production technique of raiseeing coccidiosis medicine diclazuril according to the described stud bird of claim 1, it is characterized in that: the preparation of the raw material closed loop agent in the described finished product operation: propanedioic acid 5kg, urethanum 9kg, aceticanhydride 20kg, drop in the reactor, be heated to 90-100 ℃ and stir 5 hours pressure reducing and steaming acetic acid, the cold crystallization of promptly separating out is put in cooling, washing, alcohol refining product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011028173A CN1158248C (en) | 2001-01-12 | 2001-01-12 | Process for preparing diclazuril as veterinary medicine for coccidiosis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011028173A CN1158248C (en) | 2001-01-12 | 2001-01-12 | Process for preparing diclazuril as veterinary medicine for coccidiosis |
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| CN1158248C true CN1158248C (en) | 2004-07-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447597A (en) * | 2014-10-26 | 2015-03-25 | 威海普瑞森医药技术开发有限公司 | Preparation method for diclazuril |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883148A (en) * | 2017-03-29 | 2017-06-23 | 浙江国邦药业有限公司 | A kind of restoring method of (2,6 dichloro-4,4 amido) a (4 ' chlorphenyl) benzene acetonitrile |
| CN110074134A (en) * | 2019-06-05 | 2019-08-02 | 河南科技大学 | Foamaseptic of coccidian oocyst and preparation method thereof is killed in a kind of suppression |
| CN117510426B (en) * | 2024-01-04 | 2024-04-19 | 山东国邦药业有限公司 | Synthesis method of anticoccidial veterinary drug triazine ring |
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2001
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447597A (en) * | 2014-10-26 | 2015-03-25 | 威海普瑞森医药技术开发有限公司 | Preparation method for diclazuril |
| CN104447597B (en) * | 2014-10-26 | 2018-07-31 | 威海迪素制药有限公司 | A kind of preparation method of diclazuril |
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| CN1343654A (en) | 2002-04-10 |
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