CN106279031A - The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone - Google Patents
The method that the MAA crystallization using water soluble method to obtain produces COS dipyrone Download PDFInfo
- Publication number
- CN106279031A CN106279031A CN201610642241.5A CN201610642241A CN106279031A CN 106279031 A CN106279031 A CN 106279031A CN 201610642241 A CN201610642241 A CN 201610642241A CN 106279031 A CN106279031 A CN 106279031A
- Authority
- CN
- China
- Prior art keywords
- maa
- crystallization
- crystallizer
- dipyrone
- valve
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses the method that a kind of MAA using water soluble method to obtain crystallization produces COS dipyrone.The method comprises the following steps: the preparation process of MAA crystallization: add water 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.It is 95% that the inventive method produces COS standard dipyrone one-time success rate, and yield monthly can reach 25 30 tons, and cost saves about 2800 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 water soluble method 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 through formylated
Amino-antipyrine, 4-formyl amino antipyrine to obtain 4-novalgin (i.e. MAA is oily) through methylating, hydrolyze, neutralizing,
4-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 water soluble method 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:
A kind of method that MAA crystallization using water soluble method to obtain produces COS dipyrone, comprises the following steps:
MAA crystallization preparation process: in MAA oil add water, 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 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 crystallization of MAA described in the inventive method substantially uses purified water that MAA oil is carried out remove impurity
Process, thus reach the purpose of purification MAA oil.On the one hand, MAA and amino-antipyrine AA is utilized (to cause COS to mark dipyrone
In the underproof key factor of impurity E) difference of dissolubility in water, reach separate amino-antipyrine AA purpose；Separately
On the one hand, purified water recrystallization is used can also to remove some water-solubility impurities such as inorganic salt；So using purified water that MAA oil is entered
Row purification can preferably realize impurity and separate with MAA.Meanwhile, compared to using ethanol that MAA oil is carried out remove impurity process, use
Purified water is safer.If employing ethanol, will produce containing spirituous mother solution in the preparation process of MAA crystallization, ethanol belongs to
In inflammable and explosive chemicals, MAA produces the link having dehydration in workshop section, so this mother solution can not be in MAA produces workshop section
Apply mechanically, again owing to its mother solution containing substantial amounts of impurity, so being not to be well suited for applying mechanically in condensation workshop section, if in condensation work
Section is applied mechanically and is also needed to numerous and diverse purification procedures, and the effect of purification is the most bad.Therefore, considering, the present invention uses purification
Water carries out remove impurity process to MAA oil.
In the preparation process of the MAA crystallization of the inventive method, the MAA crystalline content >=85wt% prepared is (such as
85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%), major part content, between 87-88wt%, is tied
Brilliant rate is about 88%, and crystalline particle is little, white color, uses the COS one-time success rate of the finished product dipyrone of this MAA crystallization production
95%, product yield 70%, finished product content is qualified, and defects inspecting item unknown impuritie content is low, typically at below 0.035wt%,
Colorimetric is good.
In the preparation process of the MAA crystallization of the inventive method, described MAA oil i.e. 4-novalgin is that dipyrone is raw
An intermediate during product, has the property that brownish red oily liquids, is insoluble in water, be soluble in ethanol, You Jirong
Agent, has alkalescence, and easily crystallizes, and this area conventional method can be used to prepare, such as 4-formyl amino antipyrine
FAA through methylating, hydrolyze, once neutralize, decolouring, secondary neutralizes, dehydration prepares 4-novalgin (i.e. MAA oil), MAA
The content of oil is typically at more than 92wt%.
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described MAA oil
Be 1:(0.4-0.5 with the weight ratio of water) (such as: 1:0.4,1:0.42,1:0.44,1:0.45,1:0.47,1:0.48,1:
0.49).In this step, water consumption is very few, and in MAA crystallization, impurity content is high, and impurity-eliminating effect is bad, thus causes dipyrone finished product
Impurity content is high, does not meets COS standard；Water consumption is too much, and the yield that can cause finished product dipyrone is too low, and cost raises.
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 purified water, then heating crystalline tank, then by crystallizer
Cooling, so that MAA crystallization.
It is highly preferred that described standing is at 60-75 DEG C (such as 61 DEG C, 63 DEG C, 65 DEG C, 68 DEG C, 71 DEG C, 73 DEG C, 74 DEG C)
Under the conditions of stand 30-60min (such as 31min, 35min, 40min, 48min, 52min, 55min, 58min).At this temperature
Completing standing can avoid MAA to crystallize.Standing can complete in the stainless steel tank with chuck of the outside, in order to dwell temperature
Control, naturally it is also possible to select other material and mode of heating to stand.Standing herein can allow parcel in MAA oil
Impurity is preferably separating of oil with MAA and is dissolved in water.
It is highly preferred that described suction crystallizer be by preheating after MAA oil pick-up tube will stand after MAA oil and water mixed
Compound is evacuated in described 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
Negative pressure-pumping can be used with the mixture of water.
It is highly preferred that described heating crystalline tank be described 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, 74 DEG C, 75 DEG C, 77 DEG C, 79 DEG C), further, by steam, described crystallizer is heated
To 60-75 DEG C.After the mixture of MAA oil and purified water enters crystallizer, temperature can decrease, and has sub-fraction at tank
Crystallize on wall, be at this moment accomplished by material to reheat and make the crystallization on tank skin dissolve, and the material in tank body is all located
After the state dissolved, then carry out the work of decrease temperature crystalline, be so conducive to material Crystal type stably and material homogeneous
Property.
It is highly preferred that the cooling of described crystallizer is described crystallizer to be cooled to less than 20 DEG C (material is at about 20 DEG C
It is fully crystallized) (such as 20 DEG C, 19 DEG C, 18 DEG C, 16 DEG C or 15 DEG C), the most described crystallizer is cooled to 15-20 DEG C, further
Ground, 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 stirring
Device；Chuck, is close to the outer wall of described crystallization tank body, controls by being passed through steam, saline or recirculated water in described chuck
Temperature in described crystallizer body；Steam enters valve, is arranged on the pipeline of described chuck supply steam, is used for controlling steam
Enter the speed of chuck；Exhaust steam dump valve, is arranged on the pipeline discharging exhaust steam in described chuck, is used for controlling exhaust steam and discharges
The speed of described chuck；Enter brine valve, be arranged on the pipeline of described chuck supply saline, be used for controlling saline and enter chuck
Speed；Return brine valve, be arranged on the pipeline discharging saline in described chuck, discharge described chuck for controlling saline
Speed；The cooling of described crystallizer in turn includes the following steps:
Step one, opens agitating device, rotating speed be 25-30 rev/min (such as 26 revs/min, 27 revs/min, 28 revs/min, 29
Rev/min, 30 revs/min), in the duty of described agitating device is continued until crystallizer, material discharging is complete；
Step 2, will heating after crystallizer Temperature fall 110min-130min (such as 112min, 115min,
120min, 125min, 128min), during described Temperature fall, material inlet valve, material outlet valve, steam enter
Valve, exhaust steam dump 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 15-20 DEG C (such as 16 DEG C, 17 DEG C, 18 DEG C, 19 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
The preferable crystallization arrived, 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 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 30/part, MAA crystalline content >=85%
(content of MAA crystallization is to be obtained by chemical titration commonly used in the art, MAA crystalline content is such as 85%, 85.5%,
86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5% or 90%).
In the above-mentioned methods, as a kind of preferred implementation, in the preparation process that described MAA crystallizes, described mother solution
It is back in the corresponding operation of MAA oil preparation process apply mechanically；It is highly preferred that described mother solution is back to the de-of MAA oil preparation process
Color operation is applied mechanically.
Mother solution all returns MAA post bleaching process by pipeline and applies mechanically, and carries out desolventing technology and removes the colloid in mother solution
Impurity.Because containing certain impurity in mother solution, apply mechanically can remove a part of impurity with activated carbon adsorption at bleaching process, pass through
Numerous studies, find to go the removal of impurity can be more than the removal impurity impurity of bringing in finished product after operation operation before
Few.The production of MAA oil includes that procedure below: FAA (formamido phenazone first, hydrolysis, once neutralizes, decolours, in secondary
With, dehydration, MAA oil.Bleaching process is exactly to put into activated carbon the material after once neutralizing carries out the operation that decolouring remove impurity processes,
The best approach of the reuse of mother solution is the MAA being entered by the gross by mother solution and producing common dipyrone (dipyrone of the most non-COS standard)
The bleaching process of preparation is applied mechanically.
In the above-mentioned methods, as a kind of preferred implementation, in described step of condensation, first described MAA is tied
Brilliant put into condensation tank, then according to every kilogram of MAA crystallization add 1.6-1.8L (such as 1.61L, 1.65L, 1.7L, 1.75L,
1.79L) ratio of ethanol 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 is condensed
Reaction, wherein, the scale (i.e. MAA crystallizes total amount × MAA crystalline content) of described MAA crystallization, formaldehyde, the quality of sodium pyrosulfite
Ratio is 1:(0.13-0.15): (0.44-0.46)；Preferably, described ethanol is commercially available edible ethanol, and 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, it is highly preferred that described decrease temperature crystalline is specific as follows: the most certainly
So it is cooled 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 uses circulating water cooling extremely
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).
In the above-mentioned methods, as a kind of preferred implementation, process in the rear in step, described dry concrete ginseng
Number is as follows: inlet temperature 148-165 DEG C (such as 149 DEG C, 150 DEG C, 155 DEG C, 160 DEG C, 164 DEG C), outlet temperature 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).
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 is more than 95%, and yield monthly can reach 25-30 ton, and cost is saved than existing method
About 2800 yuan/ton.Additionally the inventive method product yield can reach more than 70%, and finished product content is qualified, and defects inspecting item is unknown
Impurity is low, and typically below 0.035%, 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 750kg FAA, 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, temperature
Degree control when 135-145 DEG C be incubated 4 hours, after survey percent hydrolysis, percent hydrolysis reach more than 98% be considered as qualified, qualified after
Put into a neutralizing tank.
Once neutralize: open a neutralizing tank air draft and stirring, 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.
Dehydration: separate after mother solution, MAA oil, in suction filtration tank is evacuated to drain sump, opens steam, vacuum carries out dehydrating operations, de-
Coolant-temperature gage is not higher than 95 DEG C, about 1 hour time, prepares 4-novalgin (i.e. MAA oil), and 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 MAA oil and water
The amount that weight ratio is 1:0.4 in MAA oil storage tank, add purified water, the temperature of MAA oil storage tank is controlled 70 by crack steam
(prevent MAA from crystallizing) about DEG C and stand 30 minutes；Open vacuum, use the mode of negative pressure-pumping by being preheated to about 65 DEG C
The upper solution of MAA oil pick-up tube extraction MAA oil storage tank enters in crystallizer；The steam being then turned on crystallizer enters valve 21,
Being risen again by material in crystallizer to 65 DEG C, on inspection crystallizer, the most correctly (other each valves should be at closing each valve switch
State), exhaust steam dump valve 22 now should be at closed mode；Driving agitating device afterwards and start stirring, rotating speed is 27 revs/min, directly
Material in crystallizer is all discharged and is just stopped stirring；By crystallizer Temperature fall 2 hours；Open back brine valve 24 afterwards,
Crystallizer is lowered the temperature by the little brine valve 23 (will enter brine valve 23 and open 30 degree) that drives into, when being cooled to 50 DEG C, in open saline
Valve 23 (will enter brine valve 23 and open 60 degree) is lowered the temperature, and when being cooled to 40 DEG C, opens greatly brine valve 23 and (will enter brine valve 23
Open 90 degree) crystallizer is cooled to 20 DEG C, prepare centrifugally operated；Material in crystallizer is put into centrifuge be centrifuged, observe
When the mother solution amount of outflow is almost nil in the mother solution pipeline being arranged on centrifuge, 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 85.60wt%.
Condensation purification step: MAA crystallization is put in condensation tank, add 1.6L 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 75 DEG C and makes MAA crystallization dissolve, crystallize according still further to MAA
Scale (MAA crystallization content * 85.60wt%), formaldehyde, sodium pyrosulfite the amount that mass ratio is 1:0.14:0.45 to condensation tank in
Carry out condensation reaction, after completion of the reaction by dipyrone feed liquid press-in crystallizer, be naturally cooling to 65 DEG C, open recirculated water valve
Lower the temperature, when being cooled to 25-35 DEG C, close recirculated water valve, prepare centrifugal.By dipyrone wet product input air flow drying machine
In, inlet temperature 152 DEG C, outlet temperature 68 DEG C, it is dried 5.5 hours, obtains dipyrone finished product.Determination of Analgin 99.5%, miscellaneous
Matter E (≤0.15%) is 0.13%, and unknown impuritie (≤0.05%) is 0.032%, meets COS standard.Product yield is 72%.
The statistical result showed that multiple batches of production obtains, according to embodiment 1 process produce COS standard dipyrone, one
Secondary success rate is 96%, i.e. carries out 100 batches productions and can successfully prepare COS standard dipyrone 96 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 MAA oil and water
The amount that weight ratio is 1:0.45 in MAA oil storage tank, add purified water, the temperature of MAA oil storage tank is controlled 70 by crack steam
(prevent MAA from crystallizing) about DEG C and stand 40 minutes；Open vacuum, use the mode of negative pressure-pumping by being preheated to about 65 DEG C
The upper solution of MAA oil pick-up tube extraction MAA oil storage tank enters in crystallizer；The steam being then turned on crystallizer enters valve 21,
Being risen again by material in crystallizer to 65 DEG C, on inspection crystallizer, the most correctly (other each valves should be at closing each valve switch
State), exhaust steam dump valve 22 now should be at closed mode；Driving agitating device afterwards and start stirring, rotating speed is 27 revs/min, directly
Material in crystallizer is all discharged and is just stopped stirring；By crystallizer Temperature fall 2 hours 10 minutes；Open back saline afterwards
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, when being cooled to 50 DEG C, in open
Brine valve 23 (will enter brine valve 23 and open 60 degree) is lowered the temperature, and when being cooled to 40 DEG C, opens greatly brine valve 23 and (will enter saline
Valve 23 opens 90 degree) crystallizer is cooled to 15 DEG C, prepare centrifugally operated；Material in crystallizer is put into centrifuge be centrifuged,
When the mother solution amount of outflow is almost nil in the mother solution pipeline that observation is arranged on centrifuge, stops centrifuge and MAA crystallization taken out,
Carrying out packing for being condensed operation according to 30kg/ part, sample examination, the MAA crystalline content obtained is 87.30wt%.
Condensation purification step: MAA crystallization is put in condensation tank, add 1.7L 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
Scale (MAA crystallization content * 87.30wt%), formaldehyde, sodium pyrosulfite the amount that mass ratio is 1:0.13:0.46 to condensation tank in
Carry out condensation reaction, after completion of the reaction material is pressed in crystallizer, be naturally cooling to 75 DEG C, open recirculated water valve and drop
Temperature, when being cooled to 25-35 DEG C, closes recirculated water valve, prepares centrifugal.By in dipyrone wet product input air flow drying machine, import
Temperature 152 DEG C, outlet temperature 68 DEG C, it is dried 5.5 hours, obtains dipyrone finished product.Determination of Analgin 99.6%, impurity E (≤
0.15%) being 0.11%, unknown impuritie (≤0.05%) is 0.034%, meets COS standard.Product yield is 71%.
The statistical result showed that multiple batches of production obtains, according to embodiment 1 process produce COS standard dipyrone, one
Secondary success rate is 98%, i.e. carries out 100 batches productions and can successfully prepare COS standard dipyrone 98 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 70 DEG C, opens circulating-water valve
Door is lowered the temperature, and when being cooled to 25 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 1kg MAA oil and add ethanol dissolving, add activated carbon.Open steam and be warming up to 80
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 162 DEG C, outlet temperature 78 DEG C, it is dried 5.5 hours,
To 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 66.5%.
The statistical result showed that multiple batches of production obtains, according to embodiment 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 water soluble method 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 water soluble method to obtain produces COS dipyrone, it is characterised in that comprise the following steps:
MAA crystallization preparation process: in MAA oil add water, 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, described MAA oil
It is 1:0.4-0.5 with the weight ratio of water.
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 purified water, then heating crystalline tank, then is dropped by crystallizer
Temperature, so that MAA crystallization.
Method the most according to claim 3, it is characterised in that described standing is standing 30-under the conditions of 60-75 DEG C
60min；Described suction crystallizer is that the mixture of the MAA oil after being stood by the MAA oil pick-up tube after preheating and water is evacuated to institute
State in crystallizer；Preferably, the MAA oil pick-up tube after described preheating has 60-70 DEG C；Described heating crystalline tank is by described crystallization
Tank is heated to more than 60 DEG C, it is preferable that by steam, described crystallizer is heated to 60-75 DEG C；Described crystallizer cooling be by
Described crystallizer is cooled to less than 20 DEG C, and the most described crystallizer is cooled to 15-20 DEG C.
5. according to the method described in claim 3 or 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 3, it is characterised in that the cooling of described crystallizer in turn includes the following steps:
Step one, opens agitating device, and rotating speed is 25-30 rev/min, and the duty of described agitating device is continued until crystallization
In tank, material discharging is complete；
Step 2, by the crystallizer Temperature fall 110min-130min after heating, during described Temperature fall, material
Inlet valve, material outlet valve, steam enter valve, exhaust steam dump 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 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 15-20 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；Preferably,
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 returns
It is back in the corresponding operation of MAA oil preparation process apply mechanically；Preferably, described mother solution is back to the decolouring work of MAA oil preparation process
Sequence 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 1.6-1.8L 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；Preferably, in described ethanol ethanol content 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
Decrease temperature crystalline to the dipyrone feed liquid obtained after condensation reaction, specific as follows: to be first naturally cooling to 65-75 DEG C, then
Use circulating water cooling to 25-35 DEG C；Described dry design parameter is as follows: inlet temperature 148-165 DEG C, outlet temperature 60-
80 DEG C, the time is 5.5-6 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610642241.5A CN106279031B (en) | 2016-08-08 | 2016-08-08 | Using the method for the MAA crystallization production COS analgins that water soluble method obtains |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610642241.5A CN106279031B (en) | 2016-08-08 | 2016-08-08 | Using the method for the MAA crystallization production COS analgins that water soluble method obtains |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106279031A true CN106279031A (en) | 2017-01-04 |
| CN106279031B CN106279031B (en) | 2018-07-31 |
Family
ID=57666190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610642241.5A Active CN106279031B (en) | 2016-08-08 | 2016-08-08 | Using the method for the MAA crystallization production COS analgins that water soluble method obtains |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106279031B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110172038A (en) * | 2018-06-12 | 2019-08-27 | 武汉武药制药有限公司 | The technique that one kettle way prepares analgin magnesium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584707A (en) * | 2012-01-18 | 2012-07-18 | 河北冀衡（集团）药业有限公司 | Production method of analgin bulk drug |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN103012270A (en) * | 2012-12-31 | 2013-04-03 | 河北冀衡（集团）药业有限公司 | Method for recovering antipyrine from mother solution after crystallization of antipyrine crude oil |
-
2016
- 2016-08-08 CN CN201610642241.5A patent/CN106279031B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584707A (en) * | 2012-01-18 | 2012-07-18 | 河北冀衡（集团）药业有限公司 | Production method of analgin bulk drug |
| CN102627608A (en) * | 2012-03-31 | 2012-08-08 | 武汉武药制药有限公司 | Preparation method for analgesic and antipyretic drug-analgin |
| CN103012270A (en) * | 2012-12-31 | 2013-04-03 | 河北冀衡（集团）药业有限公司 | Method for recovering antipyrine from mother solution after crystallization of antipyrine crude oil |
Non-Patent Citations (4)
| Title |
|---|
| TORIZO TAKAHASHI等: "Syntheses of analgesics. XVII. Antipyrine derivatives", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| 周炳琪: "以双(4-甲胺基安替比林)甲烷合成安乃近", 《中国医药工业杂志》 * |
| 杨成顺: "安乃近工艺改进", 《山东大学硕士学位论文》 * |
| 江济章等: "还原烃化法制备安乃近", 《医药工业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110172038A (en) * | 2018-06-12 | 2019-08-27 | 武汉武药制药有限公司 | The technique that one kettle way prepares analgin magnesium |
| CN110172038B (en) * | 2018-06-12 | 2022-10-18 | 武汉武药制药有限公司 | Process for preparing analgin magnesium by one-pot method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106279031B (en) | 2018-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101643226B (en) | Method for producing nitrate and ammonium chloride with double decomposition circulation method | |
| CN207591325U (en) | A kind of industrial hemp extraction cannabidiol isolates and purifies device | |
| WO2020187169A1 (en) | Device for preparing xylitol by integrating evaporation, crystallization and centrifugal separation, and control method therefor | |
| CN102516806A (en) | Method for extracting capsorubin and capsaicine by utilizing continuous countercurrent ultrasonic extracting machine | |
| CN112158865A (en) | Method for recycling lithium element in lithium precipitation mother liquor | |
| CN107619426A (en) | A kind of preparation method of Fluocinonide | |
| CN106279030A (en) | The method that the MAA crystallization using the molten method of wine to obtain produces COS dipyrone | |
| CN102391189A (en) | Preparation method of sulfadoxine | |
| CN106279031B (en) | Using the method for the MAA crystallization production COS analgins that water soluble method obtains | |
| CN106748847A (en) | A kind of extracting method of L alanine | |
| CN105771304A (en) | Double-effect countercurrent evaporation crystallization system for monosodium glutamate and working process thereof | |
| CN210711829U (en) | System for utilize citric acid gypsum production gypsum whisker | |
| CN104577122B (en) | Lithium iron phosphate solvothermal preparation device | |
| CN107216264A (en) | A kind of processing method of L alanine waste liquor | |
| CN106883202A (en) | A kind of preparation method of L ascorbyl palmitates | |
| CN102516183A (en) | Method for preparing sulfadoxine and its intermediate | |
| CN102746134A (en) | Method for decreasing content of sodium chloride impurities in recovered sodium formate | |
| CN111825120A (en) | Method for preparing battery-grade manganese sulfate from manganese metal | |
| CN110105195A (en) | A method of extracting dihydroartemisinic acid from sweet wormwood wax oil | |
| CN205616574U (en) | Use coking desulfurization waste liquid to carry device of salt extraction filter residue as raw materials purification sodium hyposulfite | |
| CN104610385A (en) | Refining method of D-glucosamine hydrochloride | |
| CN104725402B (en) | A kind of method of 6 aminopenicillanic acid continuous crystallization | |
| CN107244756A (en) | A kind of post-processing approach of phenylenediamine hydrolyzate | |
| CN102863470A (en) | Method for coproducing egg yolk lecithin, cephalin, yolk oil and low-denatured protein flour | |
| CN105906475A (en) | Production method and production device of crystal mannite |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 053000 No.1, Weiwu street, high tech Zone, Hengshui City, Hebei Province Patentee after: Hebei Jiheng Pharmaceutical Co.,Ltd. Address before: 053000 No.368 Jianshe North Street, Hengshui City, Hebei Province Patentee before: HEBEI JIHENG (Group) PHARMACEUTICAL Co.,Ltd. |