CN106279030A - The method that the MAA crystallization using the molten method of wine to obtain produces COS dipyrone - Google Patents
The method that the MAA crystallization using the molten method of wine to obtain produces COS dipyrone Download PDFInfo
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- CN106279030A CN106279030A CN201610642131.9A CN201610642131A CN106279030A CN 106279030 A CN106279030 A CN 106279030A CN 201610642131 A CN201610642131 A CN 201610642131A CN 106279030 A CN106279030 A CN 106279030A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
- C07D231/48—Oxygen atom in position 3 or 5 and nitrogen atom in position 4 with hydrocarbon radicals attached to said nitrogen atom
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Abstract
The invention discloses the method that a kind of MAA using the molten method of wine to obtain crystallization produces COS dipyrone.The method comprises the following steps: the preparation process of MAA crystallization: add ethanol in MAA oil, after mixing successively through standing, crystallizing, centrifugal, respectively obtain MAA and crystallize and mother solution；Step of condensation: described MAA crystallization and formaldehyde, sodium pyrosulfite are carried out condensation reaction, generates dipyrone feed liquid；Post-processing step: described dipyrone feed liquid is carried out successively decrease temperature crystalline, is centrifuged and is dried, thus obtain meeting the dipyrone of COS standard.The inventive method produces COS standard dipyrone one-time success rate and can reach more than 85%, and yield monthly can reach 20 25 tons, and cost saves about 3000 yuan/ton than existing method.
Description
Technical field
The invention belongs to field of medicine and chemical technology, producing COS peace particularly to a kind of MAA using the molten method of wine to obtain crystallization is
Near method.
Background technology
Dipyrone, common prescription medical insurance medicine, its chemistry entitled [(1,5-dimethyl-2-phenyl-3-oxo-2,3-bis-
Hydrogen-1H-pyrazoles-4-base) methylamino] Loprazolam sodium salt, structural formula as shown in formula I, molecular formula: C13H16N3NaO4S, molecule
Amount: 333.34, soluble in water, antipyretic, analgesic activity is fast and strong compared with aminophenazone.It is mainly used in bringing down a fever, is also used for treating acute
The diseases such as arthritis, headache, rheumatic pain, toothache and myalgia.
The method of current industrial production dipyrone is with pyrazolone as initiation material, prepares phenazone, phenazone
Through nitrosation, reducing, hydrolyze, neutralize prepared 4-AA, 4-AA prepares 4-formyl ammonia through acylated
Base phenazone, 4-formyl amino antipyrine to obtain 4-novalgin (i.e. MAA is oily), 4-through methylating, hydrolyze, neutralizing
Novalgin prepares dipyrone with formaldehyde, sodium sulfite condensation.
In recent ten years, no matter China all presents swift and violent fast-developing trend in terms of the production or outlet of dipyrone,
Lasting for years export volume crosses ten thousand tons, annual export volume exceed annual total growth more than half.Along with dipyrone export volume is held
Continuous increase, its selling price presents the trend of steadily rising, and benefit has also driven domestic associated production enterprise while improving
Enthusiasm.Along with the development of the market competition, the demand of high standard especially COS standard dipyrone gradually increases.European Union's COS standard
In terms of content and impurity requirement tightened up, this just requires that we change existing production method, produces that purity is higher (i.e. rolls over
Dry product content is 99.0%～101.0%), impurity is less (i.e. other any unknown impuritie≤0.05% detected), color
The analgin bulk drug of whiter (i.e. character be white or almost white crystalline powder), to meet COS standard.Existing method
The production of COS dipyrone is to use to produce the content 92wt% above MAA oil that obtains and directly carry out condensation reaction, reacted slightly
Product weighs molten through refining crystallization, wet product and is dried to obtain finished product, the dipyrone wet product molten method of weight, packs previous operation from product drying
Refining step is started with, and dipyrone refinement is got rid of the complete wet fine work of the dipyrone obtained of material and again puts into use in condensation tank
Ethanol carries out second time and dissolves, and adds activated carbon decolorizing, to reduce the impurity of parcel in dipyrone wet product, although the method also can
Produce satisfactory COS product, but the method complex operation, man-hour compared with long, labor intensity big, conforming product rate is about
About 40%, relatively low, and the one-time success rate of finished product is on the low side, production cost is higher, is therefore badly in need of improving COS dipyrone finished product
One-time success rate, reduce production cost and expand the yield of COS dipyrone.
Summary of the invention
In order to solve the defect of existing technique, object of the present invention is to provide a kind of MAA using the molten method of wine to obtain
Crystallization produces the method for COS dipyrone.The one-time success rate that the method produces COS finished product is high, and COS dipyrone yield is high, reduces
Production cost.
It is an object of the invention to be achieved through the following technical solutions:
The method that a kind of MAA using the molten method of wine to obtain crystallization produces COS dipyrone, comprises the following steps:
The preparation process of MAA crystallization: add ethanol in MAA oil, after mixing successively through standing, crystallizing, centrifugal, respectively must
To MAA crystallization and mother solution；
Step of condensation: described MAA crystallization and formaldehyde, sodium pyrosulfite are carried out condensation reaction, generates dipyrone material
Liquid；
Post-processing step: described dipyrone feed liquid is carried out successively decrease temperature crystalline, is centrifuged and is dried, thus met
The dipyrone of COS standard.
The preparation process of the MAA crystallization of the inventive method substantially uses ethanol that MAA oil is carried out remove impurity process, comes
Purification MAA oil.Utilize MAA and other impurity different solubility in ethanol, by ethanol, MAA oil dissolved, lower the temperature,
Crystallize, be centrifuged, thus realize the separating effect of MAA and partial impurities.
The inventive method MAA crystallization preparation process in, described in prepare MAA crystalline content >=95wt% (ratio
Such as 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%), major part content between 97-98wt%,
Percent crystallization in massecuite is about 75%, and crystalline particle is big, and color HUANGBAI(sic), crystal formation is good, and the one-time success rate of COS standard dipyrone finished product is
More than 85%, product yield is up to more than 80%, and finished product content is qualified.
In the preparation process of the MAA crystallization of the inventive method, described MAA oil i.e. 4-novalgin oil, is that peace is
An intermediate in nearly production process, has the property that brownish red oily liquids, is insoluble in water, is soluble in ethanol, organic
Solvent, has alkalescence, and easily crystallizes, and this area conventional method can be used to prepare, such as 4-formamido group peace for than
Woods FAA through methylating, hydrolyze, once neutralize, decolouring, secondary neutralizes, dehydration prepares 4-novalgin (i.e. MAA oil),
The content (i.e. purity) of MAA oil is general at more than 92wt% (such as 92.5wt%, 93wt%, 93.5wt%, 94wt%).
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described ethanol
The content of middle ethanol more than 95wt% (such as 95wt%, 95.5wt%, 96wt%, 96.5wt%, 97wt%,
97.5wt%).
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, every kilogram of institute
State and MAA oil adds the ethanol of 0.3-0.4L (such as: 0.31L ethanol/kg MAA oil, 0.33L ethanol/kg MAA oil, 0.35L
Ethanol/kg MAA oil, 0.36L ethanol/kg MAA oil, 0.37L ethanol/kg MAA oil, 0.38L ethanol/kg MAA oil, 0.39L
Ethanol/kg MAA oil).
In the preparation process that above-mentioned MAA crystallizes, when ethanol consumption is very few, the content of MAA crystallization is low, and impurity content is high,
The dipyrone finished product simultaneously obtained is defective；When ethanol consumption is too much, cost improves, and the yield of MAA crystallization decreases.
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described crystallization
Specific as follows: the MAA oil after standing and the mixture suction crystallizer of ethanol, then heating crystalline tank, then crystallizer is dropped
Temperature, so that MAA crystallization.
It is highly preferred that described standing is to stand under the conditions of 60-70 DEG C (such as 61 DEG C, 63 DEG C, 65 DEG C, 68 DEG C, 69 DEG C)
30-60min (such as 31min, 35min, 40min, 48min, 52min, 55min, 58min).Completing standing at this temperature can
To avoid MAA to crystallize.Standing can complete in the stainless steel tank with chuck of the outside, in order to the control of dwell temperature, when
Other material and mode of heating so can also be selected to stand.Standing herein can allow the impurity of parcel in MAA oil more preferable
Ground and MAA are separating of oil.
It is highly preferred that described suction crystallizer is the MAA oil after being stood by the MAA oil pick-up tube after preheating and ethanol
Mixture is evacuated in crystallizer.Further, the MAA oil pick-up tube after described preheating have 60-70 DEG C (such as 61 DEG C, 63 DEG C, 65
℃、68℃、70℃)。
The purpose of preheating oil pick-up tube be exactly prevent the material crystallization in pipeline after block pipeline, extraction MAA oil and ethanol
Mixture can use negative pressure-pumping.
It is highly preferred that described heating crystalline tank be crystallizer is heated to more than 60 DEG C (such as 61 DEG C, 63 DEG C, 65 DEG C, 68
DEG C, 70 DEG C, 72 DEG C, 73 DEG C), further, crystallizer is heated to 60-70 DEG C (due to molten in ethanol of MAA by steam
Xie Du is higher than MAA dissolubility in water, and temperature here refers to ensure that MAA all dissolves in ethanol).When MAA oil and
After the mixture of ethanol enters crystallizer, temperature can decrease, and has sub-fraction and crystallizes on tank skin, is at this moment accomplished by handle
After material reheats and makes the crystallization on tank skin dissolve, and the material in tank body is all in the state of dissolving, then carry out
The work of decrease temperature crystalline, is so conducive to the stable of material Crystal type and the homogeneity of material.
It is highly preferred that the cooling of described crystallizer is described crystallizer to be cooled to less than 10 DEG C (cool to 10 DEG C the following is
In order to ensure the percent crystallization in massecuite that MAA crystallizes, small part MAA when more than 10 DEG C, is also had not crystallize complete or MAA knot
Brilliant crystal formation is also unstable) (such as 10 DEG C, 9 DEG C, 8 DEG C, 7 DEG C, 6 DEG C, 5 DEG C, 4 DEG C), the most described crystallizer is cooled to 5-10
DEG C, further, described crystallizer includes: crystallization tank body, top is provided with material inlet valve, and bottom is provided with material outlet valve, interior
Portion is provided with agitating device；Chuck, is close to the outer wall of described crystallization tank body, by being passed through steam, saline in described chuck or following
Ring water controls the temperature in described crystallizer body；Steam enters valve, is arranged on the pipeline of described chuck supply steam, uses
In the speed controlling steam entrance chuck；Exhaust steam dump valve, is arranged on the pipeline discharging exhaust steam in described chuck, is used for controlling
The speed of described chuck is discharged in exhaust steam processed；Enter brine valve, be arranged on the pipeline of described chuck supply saline, be used for controlling salt
Water enters the speed of chuck；Return brine valve, be arranged on the pipeline discharging saline in described chuck, be used for controlling saline and discharge
The speed of described chuck；The cooling of described crystallizer in turn includes the following steps:
Step one, opens agitating device, rotating speed be 15-20 rev/min (such as 16 revs/min, 17 revs/min, 18 revs/min, 19
Rev/min, 20 revs/min), in the duty of described agitating device is continued until described crystallizer, material discharging is complete；
Step 2, will heating after crystallizer Temperature fall 80min-100min (such as 82min, 85min, 90min,
95min, 98min), during described Temperature fall, material inlet valve, material outlet valve, steam enter valve, exhaust steam is discharged
Valve, enter brine valve, return brine valve be in closed mode；
Step 3, opens the described brine valve that returns after Temperature fall, simultaneously by described enter brine valve to open 20-40 degree (the least
Drive brine valve into), when described crystallizer is cooled to 45-55 DEG C (such as 46 DEG C, 48 DEG C, 50 DEG C, 52 DEG C, 53 DEG C, 54 DEG C), will
Described enter brine valve open 50-70 degree (in i.e., driving brine valve into), when described crystallizer be cooled to 35-45 DEG C (such as 36 DEG C, 38
DEG C, 40 DEG C, 42 DEG C, 43 DEG C, 44 DEG C) time, by described enter brine valve open 80-90 degree (driving the most greatly brine valve into), until crystallization
Tank is cooled to less than 10 DEG C (such as 10 DEG C, 9 DEG C, 8 DEG C, 7 DEG C, 6 DEG C, 5 DEG C, 4 DEG C).
Use said method carry out lowering the temperature the MAA Crystal type obtained percent crystallization in massecuite stable, uniform, MAA crystallization stable and
Efficiency is high, is suitable for producing；The crystallizer cooling of the present invention can also use the method for natural cooling to lower the temperature, and it can also obtain
To preferably crystallization, but the time is oversize, and efficiency is low, is not suitable for producing；And if whole process of lowering the temperature the most quickly cools down, then obtained
Crystal formation outward appearance is irregular, crystal formation is not of uniform size, uneven, MAA crystallization percent crystallization in massecuite the most unstable.
Valve used above can be ball valve.
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described centrifugal
It is that the material in the crystallizer after lowering the temperature is centrifuged, until stopping centrifugal when the mother solution discharged in centrifuge is zero.More excellent
Selection of land, centrifugation time is 20-25min (such as 21min, 22min, 23min, 24min, 25min).
Generally, count MAA after being centrifuged and crystallize weight, packed by 30kg/ part, MAA crystalline content >=95%
(content of MAA crystallization is to be obtained by chemical titration commonly used in the art, MAA crystalline content is such as 95%, 95.5%,
96%, 96.5%, 97%, 97.5%, 98%, 98.5%).
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described mother solution
The condensation operation being back to produce common dipyrone (dipyrone of the most non-COS standard) after activated carbon decolorizing adsorbs is applied mechanically.
The mother solution of MAA crystallization is more due to impurity, it is impossible to apply mechanically in the batch producing COS material, can only produce commonly
Through desolventing technology rear enclosure use during dipyrone material, in order to ensure that common dipyrone (i.e. meets Chinese Pharmacopoeia version first in 2010 to augment
This standard-required) quality, for every batch produces 1500kg dipyrone, the mother solution amount that every batch can be applied mechanically is about 200 liters.
In the above-mentioned methods, as a kind of preferred implementation, in described step of condensation, first described MAA is tied
Brilliant input is condensed tank, then according to the ratio of every kilogram of MAA crystallization addition 2.2-2.3L (such as 2.21L, 2.25L, 2.29L) ethanol
Example adds ethanol in described condensation tank, more described condensation tank is warming up to 70-80 DEG C (such as 71 DEG C, 72 DEG C, 75 DEG C, 77 DEG C,
79 DEG C), after MAA crystallization is dissolved in described condensation tank, add sodium pyrosulfite and formaldehyde carries out condensation reaction, wherein, described
The scale (gross mass × MAA crystalline content of the MAA crystallization i.e. added) of MAA crystallization, formaldehyde, the mass ratio of sodium pyrosulfite are
1:(0.13-0.15): (0.44-0.46), it is preferable that described ethanol is commercially available edible ethanol, ethanol content requires
More than 95wt% (such as 95wt%, 95.5wt%, 96wt%, 96.5wt%, 97wt%).
In the above-mentioned methods, as a kind of preferred implementation, processing in step in the rear, described decrease temperature crystalline refers to
Decrease temperature crystalline to the dipyrone feed liquid obtained after condensation reaction, described dry design parameter is as follows: inlet temperature is
148-165 DEG C (such as 149 DEG C, 150 DEG C, 155 DEG C, 160 DEG C, 164 DEG C), outlet temperature be 60-80 DEG C (such as 61 DEG C, 65 DEG C,
70 DEG C, 75 DEG C, 79 DEG C), the time is 5.5-6h (such as 5.6h, 5.7h, 5.8h, 5.9h).It is highly preferred that process step in the rear
In Zhou, described decrease temperature crystalline is specific as follows: be first naturally cooling to 65-75 DEG C (such as 66 DEG C, 67 DEG C, 68 DEG C, 70 DEG C, 72 DEG C, 73
DEG C, 74 DEG C), then use circulating water cooling to 25-35 DEG C (such as 26 DEG C, 27 DEG C, 28 DEG C, 29 DEG C, 31 DEG C, 32 DEG C, 34 DEG C).
The present invention has the advantages that compared to existing technology
The dipyrone that the inventive method obtains meets COS standard, the one-time success rate adding COS finished product, expands COS
The yield of dipyrone, reduce production cost.In existing method, directly it is used for the MAA oil that MAA operation obtains being condensed instead
Should, then obtaining meeting the dipyrone finished product of COS standard by dipyrone feed liquid being carried out repeatedly purification, existing method produces
The one-time success rate of the dipyrone of COS standard is less than 40%, and product yield is low, and yield is monthly 10 tons, and the inventive method
The one-time success rate producing COS dipyrone can reach more than 85%, and yield monthly can reach 20-25 ton, and cost is than existing method
Save about 3000 yuan/ton.Additionally the inventive method product yield can reach more than 80%, and finished product content is qualified, defects inspecting item
Unknown impuritie is low, and typically 0.035%～0.05%, colorimetric is good.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of crystallizer of the present invention, wherein, 1, crystallization tank body；11, material inlet valve；12, material outlet
Valve；13, agitating device；2, chuck；21, steam enters valve；22, exhaust steam dump valve；23, brine valve is entered；24, brine valve is returned；25、
Compression valve；26, Pressure gauge.
Detailed description of the invention
With embodiment, the production method of the COS standard dipyrone of the present invention is illustrated below in conjunction with the accompanying drawings.Should be understood that
These embodiments are only used for explaining the present invention rather than limiting the scope of the present invention.Externally should be understood that and reading the present invention
Content after, the present invention is made various changes or modifications by those skilled in the art, and these equivalent form of values fall within the application equally
Appended claims limited range.
Crystallizer and condensation tank that the present invention uses are commonly used in the art two kind equipment, are all provided with folder outside tank body
Set, the work heating up with the material to tank interior, be incubated or lowering the temperature, the chuck temperature control principle phase to two kinds of tanks
With, to introduce the crystallizer structure that the present invention uses the most simply, see Fig. 1, described crystallizer includes: crystallization tank body 1,
Top is provided with material inlet valve 11, and for controlling the entrance of material, bottom is provided with material outlet valve 12, for controlling the row of material
Going out, inside is provided with agitating device 13, for stirring the material in mixed crystallization tank；Chuck 2, is close to the outer wall crystallizing tank body 1, logical
Cross and in chuck 2, be passed through steam, saline or recirculated water control to crystallize the temperature in tank body 1；Steam enter valve 21, be arranged to
Chuck 2 supplies on the pipeline of steam, enters the speed of chuck 2 for controlling steam；Exhaust steam dump valve 22, is arranged at from chuck 2
On the pipeline of middle discharge exhaust steam, discharge the speed of chuck 2 for controlling exhaust steam；Enter brine valve 23, be arranged at and supply salt to chuck 2
On the pipeline of water, enter the speed of chuck 2 for controlling saline；Return brine valve 24, be arranged at the pipe discharging saline in chuck 2
Lu Shang, discharges the speed of chuck 2 for controlling saline；Compression valve 25 and Pressure gauge 26, be arranged at the pipeline connected with chuck 2
On, observe the pressure in chuck 2 by the display of Pressure gauge 26 and regulate the pressure in chuck 2 by compression valve 25.
The preparation method of the MAA oil used in following example is as follows:
4-formyl amino antipyrine FAA methylates: adds 900L water in the tank that methylates, puts into 750kgFAA, opens
Stirring, adds 600kg dimethyl sulfate, the most constantly cooling, when in tank, temperature adds liquid caustic soda when reaching 10 DEG C, surveys pH value 9
During left and right, methylate qualified.
Hydrolysis: qualified feed liquid is squeezed in hydrolytic decomposition pot by methylating, opens stirring, adds 890kg sulphuric acid, opens steam heating
Hydrolytic decomposition pot, temperature control when 135-145 DEG C be incubated 4 hours, after survey percent hydrolysis, percent hydrolysis reach more than 98% be considered as close
Lattice, qualified after put into a neutralizing tank.
Once neutralize: open a neutralizing tank air draft and stir, add water of 700L, open steam and be warming up to 80 DEG C, so
Rear addition ammonia neutralizes, and being neutralized to pH value is that 2.0-2.5 stops adding ammonia, records MAA oil proportion at 1.19-1.22 with gravimeter
Between (pycnometric purpose is to make MAA oil can separate smoothly offer reference frame from mother solution).
Decolouring: after once neutralizing, adds 30kg activated carbon in a neutralizing tank, keeps temperature 80-90 DEG C, insulation
1 hour.
Secondary neutralizes: decolouring terminate after by feed liquid in filter press-in secondary neutralizing tank, regulate proportion with water,
When proportion is about 1.23, being passed through liquefied ammonia regulation acidity, maintain the temperature at 70-90 DEG C, pH value stops neutralizing when reaching 7.2-7.5,
Stratification afterwards.
Dehydration: the mother solution after layering is separated, then through suction filtration tank, MAA oil is evacuated in drain sump, opens steam and add
Heat, carries out dehydrating operations under vacuum, and dehydration temperaturre is 95 DEG C, about 1 hour time.Prepare 4-novalgin
(i.e. MAA oil), the content of MAA oil is 92wt%.
The ethanol used in following example is commercially available ethanol, and ethanol content is 95wt%.
Embodiment 1
The preparation of MAA crystallization: MAA oil is added outside being provided with in the MAA oil storage tank of chuck, then according to every kilogram of MAA
Oil adds the amount of ethanol 0.3L and adds ethanol to MAA oil storage tank, and the temperature of MAA oil storage tank is controlled at about 65 DEG C by crack steam
(preventing MAA from crystallizing) stands 30 minutes；Open vacuum, use the mode of negative pressure-pumping to pump by being preheated to the MAA of about 65 DEG C
The upper solution of pipe extraction MAA oil storage tank enters in crystallizer；The steam being then turned on crystallizer enters valve 21, by crystallizer
Interior material is risen again to 65 DEG C, checks that on crystallizer, each valve switch is the most correct (other each valves should be at closed mode), weary
Vapour dump valve 22 now should be at closed mode；Driving agitating device afterwards and start stirring, rotating speed is 18 revs/min, until crystallizer
Interior material is all discharged and is just stopped stirring；By crystallizer Temperature fall 1.5 hours；Open back brine valve 24 afterwards, little drive into
Crystallizer is lowered the temperature by brine valve 23 (will enter brine valve 23 and open 30 degree), when being cooled to 50 DEG C, in open brine valve 23 (i.e.
Brine valve 23 will be entered and open 60 degree) lower the temperature, when being cooled to 40 DEG C, open greatly brine valve 23 and (brine valve 23 will be entered and open 90
Degree) crystallizer is cooled to 10 DEG C, prepare centrifugally operated；Material in crystallizer being put into centrifuge be centrifuged, observation is arranged at
When the mother solution amount that flows out in mother solution pipeline on centrifuge is almost nil, stops centrifuge and MAA crystallization is taken out, according to 30/
Part carries out packing for being condensed operation, sample examination, and the MAA crystalline content obtained is 97.90wt%.
Condensation purification step: MAA crystallization is put in condensation tank, add 2.25L alcohol amount to contracting according to 1kg MAA crystallization
Closing and add ethanol in tank, then condensation tank is warming up to 75 DEG C and makes MAA crystallization dissolve, (MAA ties the scale crystallized according still further to MAA
Brilliant total amount * 97.90wt%), formaldehyde, the amount that mass ratio is 1:0.14:0.45 of sodium pyrosulfite be condensed in condensation tank
Reaction, after completion of the reaction by dipyrone feed liquid press-in crystallizer, is naturally cooling to 65 DEG C, opens recirculated water valve and drop
Temperature, when being cooled to 25-35 DEG C, closes recirculated water valve, prepares centrifugal.By dipyrone wet product input air flow drying machine after Li Xin
In, inlet temperature 150 DEG C, outlet temperature 60 DEG C, it is dried 5.5 hours, obtains dipyrone finished product.Determination of Analgin 99.9%, miscellaneous
Matter E (≤0.15%) is 0.13%, and unknown impuritie (≤0.05%) is 0.038%, meets COS standard.Product yield is 82%.
The statistical result showed that multiple batches of production obtains, according to embodiment 1 process produce COS standard dipyrone, one
Secondary success rate is 86%, i.e. carries out 100 batches productions and can successfully prepare COS standard dipyrone 86 times.
Embodiment 2
The preparation of MAA crystallization: MAA oil is added outside being provided with in the MAA oil storage tank of chuck, then according to every kilogram of MAA
Oil adds the amount of commercially available 95wt% ethanol 0.35L and adds ethanol to MAA oil storage tank, and crack steam is by the temperature of MAA oil storage tank
Control to stand 45 minutes about 65 DEG C (preventing MAA from crystallizing)；Open vacuum, use the mode of negative pressure-pumping by being preheated to 65 DEG C
The upper solution of the MAA oil pick-up tube extraction MAA oil storage tank of left and right enters in crystallizer；The steam being then turned on crystallizer enters
Valve 21, rises again material in crystallizer to 70 DEG C, and on inspection crystallizer, the most correctly (other each valves should be at each valve switch
Closed mode), exhaust steam dump valve 22 now should be at closed mode；To drive agitating device afterwards and start stirring, rotating speed is 18 turns/
Point, until the material in crystallizer is all discharged just stops stirring；By crystallizer Temperature fall 1 hour 20 minutes；Open afterwards
Returning brine valve 24, crystallizer is lowered the temperature by the little brine valve 23 (will enter brine valve 23 and open 30 degree) that drives into, is cooled to 50 DEG C
Time, in open brine valve 23 (brine valve 23 will be entered and open 60 degree) and lower the temperature, when being cooled to 40 DEG C, open greatly brine valve 23 (i.e.
Brine valve 23 will be entered and open 90 degree) crystallizer is cooled to 8 DEG C, prepare centrifugally operated；Material in crystallizer is put into centrifuge
Interior centrifugal, when the mother solution amount of outflow is almost nil in the mother solution pipeline that observation is arranged on centrifuge, stop centrifuge by MAA knot
Brilliant taking-up, carries out packing for being condensed operation according to 30/part, sample examination, and the MAA crystalline content obtained is 98.2wt%.
Condensation purification step: MAA crystallization is put in condensation tank, add 2.3L alcohol amount to contracting according to 1kg MAA crystallization
Close in tank and add commercially available 95wt% ethanol, then condensation tank is warming up to 70 DEG C and makes MAA crystallization dissolve, crystallize according still further to MAA
The scale total amount * 96wt% of crystallization (MAA), formaldehyde, sodium pyrosulfite the amount that mass ratio is 1:0.14:0.44 in condensation tank
Carry out condensation reaction, after completion of the reaction by dipyrone feed liquid press-in crystallizer, be naturally cooling to 75 DEG C, open recirculated water valve
Lower the temperature, when being cooled to 25-35 DEG C, close recirculated water valve, prepare centrifugal.After Li Xin, dipyrone wet product input air flow is done
In dry machine, inlet temperature 160 DEG C, outlet temperature 75 DEG C, it is dried and obtains dipyrone finished product in 6 hours.Determination of Analgin 99.8%, miscellaneous
Matter E (≤0.15%) is 0.13%, and unknown impuritie (≤0.05%) is 0.040%, meets COS standard.Product yield is 81%.
The statistical result showed that multiple batches of production obtains, according to embodiment 2 process produce COS standard dipyrone, one
Secondary success rate is 85%, i.e. carries out 100 batches productions and can successfully prepare COS standard dipyrone 85 times.
Comparative example
MAA oil is put in condensation tank, add 2.6L alcohol amount according to 1kg MAA oil and add ethanol in condensation tank, then
According to MAA oil scale (MAA oil total amount * 92wt%), formaldehyde, sodium pyrosulfite the amount that mass ratio is 1:0.14:0.45 to contracting
Close in tank and carry out condensation reaction, after completion of the reaction material is pressed into refining crystallization tank, is naturally cooling to 75 DEG C, opens circulating-water valve
Door is lowered the temperature, and when being cooled to 30 DEG C, closes recirculated water valve, prepares centrifugal.The centrifugal dipyrone wet product obtained is thrown again
Enter and be condensed in tank, add 2.6L alcohol amount according to 1kgMAA oil and add ethanol dissolving, add activated carbon.Open steam and be warming up to 85
DEG C, it being incubated 30 minutes, decolouring is filtered binder after terminating and is entered refining crystallization tank, repeats the work that crystallization cooling is centrifugal, and obtaining peace is
Nearly wet product, by dipyrone wet product input air flow drying machine, inlet temperature 155 DEG C, outlet temperature 70 DEG C, it is dried 6 hours, obtains
Dipyrone finished product.Determination of Analgin 99.5%, impurity E (≤0.15%) is 0.13%, and unknown impuritie (≤0.05%) is
0.032%, meet COS standard.Product yield is 65%.
The statistical result showed that multiple batches of production obtains, according to comparative example 1 process produce COS standard dipyrone, one
Secondary success rate is 40%, i.e. carries out 100 batches productions and can successfully prepare COS standard dipyrone 40 times.
From the foregoing, it will be observed that the effect of the present invention provides a kind of MAA using the molten method of wine to obtain crystallization production with haveing an advantage that
The method of COS dipyrone, described method adds the one-time success rate of COS finished product, expands the yield of COS dipyrone, reduces
Production cost.
Claims (10)
1. the method that the MAA crystallization that a kind uses the molten method of wine to obtain produces COS dipyrone, it is characterised in that comprise the following steps:
MAA crystallization preparation process: in MAA oil add ethanol, after mixing successively through standing, crystallizing, be centrifuged, respectively obtain
MAA crystallization and mother solution；
Step of condensation: described MAA crystallization and formaldehyde, sodium pyrosulfite are carried out condensation reaction, generates dipyrone feed liquid；
Post-processing step: described dipyrone feed liquid is carried out successively decrease temperature crystalline, is centrifuged and is dried, thus obtain meeting COS mark
Accurate dipyrone.
Method the most according to claim 1, it is characterised in that in the preparation process that described MAA crystallizes, in described ethanol
The content of ethanol is at more than 95wt%.
Method the most according to claim 1, it is characterised in that in the preparation process that described MAA crystallizes, described in every kilogram
MAA oil adds the ethanol of 0.3-0.4L.
Method the most according to claim 1, it is characterised in that in the preparation process that described MAA crystallizes, described crystallization tool
Body is as follows: the MAA oil after standing and the mixture suction crystallizer of ethanol, then heating crystalline tank, then is lowered the temperature by crystallizer,
So that MAA crystallization；Preferably, described standing is standing 30-60min under the conditions of 60-70 DEG C；Preferably, described suction crystallization
Tank is that the mixture of the MAA oil after being stood by the MAA oil pick-up tube after preheating and ethanol is evacuated in crystallizer, further preferably
Ground, the MAA oil pick-up tube after described preheating has 60-70 DEG C；Preferably, described heating crystalline tank is that crystallizer is heated to 60 DEG C
Above, further, by steam, crystallizer is heated to 60-70 DEG C；Preferably, the cooling of described crystallizer is by described crystallization
Tank is cooled to less than 10 DEG C, and the most described crystallizer is cooled to 5-10 DEG C.
Method the most according to claim 4, it is characterised in that described crystallizer includes:
Crystallization tank body, top is provided with material inlet valve, and bottom is provided with material outlet valve, and inside is provided with agitating device；
Chuck, is close to the outer wall of described crystallization tank body, controls institute by being passed through steam, saline or recirculated water in described chuck
State the temperature in crystallizer body；
Steam enters valve, is arranged on the pipeline of described chuck supply steam, enters the speed of chuck for controlling steam；
Exhaust steam dump valve, is arranged on the pipeline discharging exhaust steam in described chuck, discharges described chuck for controlling exhaust steam
Speed；
Enter brine valve, be arranged on the pipeline of described chuck supply saline, enter the speed of chuck for controlling saline；
Return brine valve, be arranged on the pipeline discharging saline in described chuck, discharge the speed of described chuck for controlling saline
Degree.
Method the most according to claim 4, it is characterised in that the cooling of described crystallizer in turn includes the following steps:
Step one, opens described agitating device, and rotating speed is 15-20 rev/min, and the duty of described agitating device is continued until
In described crystallizer, material discharging is complete；
Step 2, by the crystallizer Temperature fall 80min-100min after heating, during described Temperature fall, material enters
Mouthful valve, material outlet valve, steam enter valve, exhaust steam dump valve, enter brine valve, return brine valve and be in closed mode；
Step 3, opens the described brine valve that returns after Temperature fall, simultaneously by described enter brine valve open that 20-40 degree is the least drives salt into
Water valve, when described crystallizer is cooled to 45-55 DEG C, by described enter brine valve open 50-70 degree be in drive brine valve into, work as institute
State crystallizer when being cooled to 35-45 DEG C, by described enter brine valve open 80-90 degree and drive the most greatly brine valve into, until crystallizer fall
Temperature is to less than 10 DEG C.
Method the most according to claim 1, it is characterised in that in the preparation process that described MAA crystallizes, described being centrifuged is
Material in crystallizer after cooling is centrifuged, until stopping centrifugal when the mother solution discharged in centrifuge is zero, it is preferable that
Centrifugation time is 20-25min.
Method the most according to claim 1, it is characterised in that in the preparation process that described MAA crystallizes, described mother solution warp
The condensation operation being back to produce common dipyrone after activated carbon decolorizing absorption is applied mechanically.
Method the most according to claim 1, it is characterised in that in described step of condensation, first crystallizes described MAA
Put into condensation tank, then according to the ratio of every kilogram of MAA crystallization addition 2.2-2.3L ethanol adds ethanol in described condensation tank,
Again described condensation tank is warming up to 70-80 DEG C, after MAA crystallization is dissolved in described condensation tank, adds sodium pyrosulfite and formaldehyde enters
Row condensation reaction, wherein, the scale of described MAA crystallization, formaldehyde, the mass ratio of sodium pyrosulfite are 1:0.13-0.15:0.44-
0.46, it is preferable that in described ethanol, ethanol content is at more than 95wt%.
Method the most according to claim 1, it is characterised in that processing in step in the rear, described decrease temperature crystalline refers to
The decrease temperature crystalline of the dipyrone feed liquid obtained after condensation reaction, specific as follows: to be first naturally cooling to 65-75 DEG C, then adopt
With circulating water cooling to 25-35 DEG C；Described dry design parameter is as follows: inlet temperature is 148-165 DEG C, and outlet temperature is
60-80 DEG C, the time is 5.5-6h.
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| CN108440413A (en) * | 2018-04-26 | 2018-08-24 | 山东新华制药股份有限公司 | The preparation method of high quality analgin |
| CN109897002A (en) * | 2017-12-07 | 2019-06-18 | 武汉武药制药有限公司 | The hexahydrated preparation of 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium |
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| CN109897002A (en) * | 2017-12-07 | 2019-06-18 | 武汉武药制药有限公司 | The hexahydrated preparation of 1- phenyl -2,3- dimethyl -4- methylamino pyrazolin-5-one-N- methane sulfonic acid magnesium |
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| CN106279030B (en) | 2018-08-17 |
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