CN106279031B - Using the method for the MAA crystallization production COS analgins that water soluble method obtains - Google Patents
Using the method for the MAA crystallization production COS analgins that water soluble method obtains Download PDFInfo
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- CN106279031B CN106279031B CN201610642241.5A CN201610642241A CN106279031B CN 106279031 B CN106279031 B CN 106279031B CN 201610642241 A CN201610642241 A CN 201610642241A CN 106279031 B CN106279031 B CN 106279031B
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a kind of methods of the MAA crystallization production COS analgins obtained using water soluble method.This approach includes the following steps：The preparation process of MAA crystallizations：Water is added into MAA oil, MAA crystallizations and mother liquor are respectively obtained through standing, crystallization, centrifugation successively after mixing；Step of condensation：Condensation reaction is carried out by MAA crystallizations, with formaldehyde, sodium pyrosulfite, generates analgin feed liquid；Post-processing step：The analgin feed liquid is subjected to decrease temperature crystalline, centrifugation and drying successively, to obtain meeting the analgin of COS standards.It is 95% that the method for the present invention, which produces COS standard analgin one-time success rates, and yield can monthly 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, more particularly to a kind of MAA crystallization production COS peaces obtained using water soluble method are
Close method.
Background technology
Analgin, common prescription medical insurance drug, entitled [(1, the 5- dimethyl -2- phenyl -3- oxos -2,3- bis- of chemistry
Hydrogen -1H- pyrazoles -4- bases) methylamino] Loprazolam sodium salt, structural formula is as shown in formula I, molecular formula：C13H16N3NaO4S, molecule
Amount：333.34, it is soluble easily in water, it is antipyretic, analgesic activity is fast and strong compared with aminopyrine.It is mainly used for bringing down a fever, is also used to treat acute
The diseases such as arthritis, headache, rheumatic pain, toothache and courbature.
The method of industrial production analgin is that antipyrine, antipyrine is made using pyrazolone as starting material at present
By nitrosation, reduction, hydrolysis, obtained 4-AA is neutralized, 4- formyls are made through formylated in 4-AA
Amino-antipyrine, 4- formyl amino antipyrines to obtain 4- novalgins (i.e. MAA is oily) through methylating, hydrolyzing, neutralize,
Analgin is made with formaldehyde, sodium sulfite condensation in 4- novalgins.
In recent ten years, no matter China is presented swift and violent fast-developing trend in terms of the production of analgin or outlet,
Lasting for years export volume crosses ten thousand tons, annual export volume be more than annual total growth more than half.As analgin export volume is held
Continuous to increase, the trend steadily risen is presented in selling price, and benefit has also driven domestic associated production enterprise while raising
Enthusiasm.With the development of market competition, the demand of high standard especially COS standards analgin gradually increases.European Union's COS standards
Tightened up in terms of content and impurity requirement, this requires us to change existing production method, produces purity higher and (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 is white or almost white crystalline powder), to meet COS standards.Existing method
The production of COS analgins is that the above MAA oil of content 92wt% obtained using production directly carries out condensation reaction, thick after reaction
Product weighs molten and is dried to obtain finished product through refining crystallization, wet product, and the molten method of analgin wet product weight packs previous process from product drying
Refining step is started with, and analgin refinement is got rid of the wet fine work of analgin that finishes of material put into be condensed in tank again and use
Alcohol carries out second and dissolves, and activated carbon decolorizing is added, to reduce the impurity wrapped up in analgin wet product, although the method also can
Satisfactory COS products are produced, but the method is cumbersome, working hour, product qualification rate was about compared with long, labor intensity is big
40% or so, it is relatively low, and the one-time success rate of finished product is relatively low, production cost is higher, therefore be badly in need of improving COS analgin finished products
One-time success rate, the yield for reducing production cost and expanding COS analgins.
Invention content
In order to solve the defect of prior art, the object of the present invention is to provide a kind of MAA obtained using water soluble method
The method of crystallization production COS analgins.The one-time success rate that this method produces COS finished products is high, and COS analgins yield is high, reduces
Production cost.
The purpose of the present invention is what is be achieved through the following technical solutions：
A method of the MAA crystallization production COS analgins obtained using water soluble method are included the following steps：
The preparation process of MAA crystallizations：Water is added into MAA oil, is respectively obtained successively through standing, crystallization, centrifugation after mixing
MAA is crystallized and mother liquor；
Step of condensation：Condensation reaction is carried out by MAA crystallizations, with formaldehyde, sodium pyrosulfite, generates analgin material
Liquid；
Post-processing step：The analgin feed liquid is subjected to decrease temperature crystalline, centrifugation and drying successively, to be met
The analgin of COS standards.
The preparation process of the crystallizations of MAA described in the method for the present invention is substantially to be cleaned to MAA oil using purified water
Processing, to achieve the purpose that purify MAA oil.On the one hand, (COS is caused to mark analgin using MAA and amino-antipyrine AA
In the underproof key factor of impurity E) solubility in water difference, achieve the purpose that detach amino-antipyrine AA；Separately
On the one hand, some water-solubility impurities such as inorganic salts can also be removed using purified water recrystallization；So using purified water to MAA oil into
Row purification can preferably realize impurity and the separation of MAA.Meanwhile removal of impurities processing is carried out to MAA oil compared to using alcohol, it uses
Purified water is safer.If using alcohol, the mother liquor containing alcohol, alcohol category just will produce in the preparation process of MAA crystallizations
There is the link of dehydration in inflammable and explosive chemicals, MAA productions workshop section, so this mother liquor cannot be in MAA produces workshop section
It applies mechanically, and due to containing a large amount of impurity in its mother liquor, so nor being well suited for applying mechanically in condensation workshop section, if in condensation work
Section, which is applied mechanically, also needs to complicated purification procedures, and the effect purified is also bad.Therefore, consider, the present invention is using purifying
Water to MAA oil carries out removal of impurities processing.
In the preparation process of the MAA crystallizations of the method for the present invention, MAA crystalline contents >=85wt% for being prepared (such as
85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%), most of content is between 87-88wt%, knot
For brilliant rate 88% or so, crystalline particle is small, white color, using the COS one-time success rates of the finished product analgin of MAA crystallization productions
95%, product yield 70%, finished product content is qualified, and defects inspecting item unknown impuritie content is low, generally in 0.035wt% hereinafter,
Colorimetric is good.
In the preparation process of the MAA crystallizations of the method for the present invention, the MAA oil, that is, 4- novalgins are analgin lifes
An intermediate during production has following property：Brownish red oily liquids, is insoluble in water, is soluble in alcohol, You Jirong
Agent has alkalescent, and easily crystallizes, and this field conventional method may be used and prepare, such as 4- formyl amino antipyrines
FAA is neutralized through methylating, hydrolyzing, once, is decolourized, secondary neutralization, being dehydrated obtained 4- novalgins (i.e. MAA oil), MAA
The content of oil is generally in 92wt% or more.
In the above-mentioned methods, as a preferred implementation manner, in the preparation process of MAA crystallizations, the MAA oil
Weight ratio with water is 1:(0.4-0.5) (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 impurity content is high in MAA crystallizations, and impurity-eliminating effect is bad, to cause analgin finished product
Impurity content is high, does not meet COS standards；Water consumption is excessive, and the yield of finished product analgin can be caused too low, and cost increases.
In the above-mentioned methods, as a preferred implementation manner, in the preparation process of MAA crystallizations, the crystallization
It is specific as follows：The mixture of MAA oil and purified water after standing is pumped into crystallizing tank, then heating crystalline tank, then by crystallizing tank
Cooling, so that MAA is crystallized.
It is highly preferred that described stand 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 to stand can crystallize to avoid MAA.Standing can complete in the external stainless steel sink with chuck, in order to dwell temperature
Control, naturally it is also possible to select other material and mode of heating to be stood.Standing herein, which can allow in MAA oil, wraps up
Impurity is preferably detached with MAA oil and is dissolved into water.
It is highly preferred that it is described be pumped into crystallizing tank be by the MAA oil pick-up tubes after preheating by after standing MAA oil and water it is mixed
Object is closed to be evacuated in the crystallizing tank.Further, the MAA oil pick-up tubes after the 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 is exactly to block pipeline after preventing the material in pipeline from crystallizing, and extracts MAA oil
Negative-pressure ward may be used with the mixture of water.
It is highly preferred that the heating crystalline tank be by the crystallizing tank be heated to 60 DEG C or more (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, the crystallizing tank is heated by steam
To 60-75 DEG C.After the mixture of MAA oil and purified water enters crystallizing tank, temperature can decrease, and have sub-fraction in tank
It is crystallized on wall, at this moment just material is needed to reheat that the crystallization on tank skin is made to dissolve, and the material in tank body is all located
After the state of dissolving, then carry out the work of decrease temperature crystalline, be conducive in this way material Crystal type stabilization and material it is uniform
Property.
It is highly preferred that crystallizing tank cooling be by the crystallizing tank be cooled to 20 DEG C or less (material at 20 DEG C or so
It is fully crystallized) (such as 20 DEG C, 19 DEG C, 18 DEG C, 16 DEG C or 15 DEG C), the preferably described crystallizing tank is cooled to 15-20 DEG C, further
Ground, the crystallizing tank include：Tank body is crystallized, top is equipped with material inlet valve, and bottom is equipped with material outlet valve, is internally provided with stirring
Device；Chuck is close to the outer wall of the crystallization tank body, is controlled by being passed through steam, brine or recirculated water into the chuck
Temperature in the crystallizing tank body；Steam enters valve, is set on the pipeline that the chuck supplies steam, for controlling steam
Into the speed of chuck；Steam exhaust dump valve is set to and is discharged on the pipeline of steam exhaust from the chuck, for controlling steam exhaust discharge
The speed of the chuck；Into brine valve, it is set on the pipeline that the chuck supplies brine, enters chuck for controlling brine
Speed；Brine valve is returned, is set to and is discharged on the pipeline of brine from the chuck, the chuck is discharged for controlling brine
Speed；The crystallizing tank cooling in turn includes the following steps：
Step 1, open agitating device, rotating speed be 25-30 revs/min (such as 26 revs/min, 27 revs/min, 28 revs/min, 29
Rev/min, 30 revs/min), the working condition of the agitating device is continued until in crystallizing tank that material discharging finishes；
Step 2, by after heating crystallizing tank Temperature fall 110min-130min (such as 112min, 115min,
120min, 125min, 128min), during the Temperature fall, material inlet valve, material outlet valve, steam enter
Valve, steam exhaust dump valve are in closed state into brine valve, time brine valve；
Step 3, open after Temperature fall it is described return brine valve, while it will be (i.e. small described into brine valve will to open 20-40 degree
Drive brine valve into), it, will when the crystallizing tank 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)
It is described into brine valve open 50-70 degree (driving brine valve in i.e. into), when the crystallizing tank 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) when, described 80-90 degree (driving brine valve into greatly) will be opened into brine valve, until crystallizing
Tank is cooled to 15-20 DEG C (such as 16 DEG C, 17 DEG C, 18 DEG C, 19 DEG C).
The MAA Crystal types that are cooled down using the above method are stable, uniformly, the percent crystallization in massecuite of MAA crystallizations it is stable and
It is efficient, it is suitble to production；The method that the crystallizing tank cooling of the present invention can also use natural cooling cools down, and can also obtain
The preferable crystallization arrived, but the time is too long, efficiency is low, is not suitable for production；And if cooling whole process is quickly cooled down, it obtains
Crystal form appearance it is irregular, crystal form is not of uniform size, uneven, MAA crystallization percent crystallization in massecuite it is also unstable.
Valve used above can be ball valve.
In the above-mentioned methods, as a preferred implementation manner, in the preparation process of MAA crystallizations, the centrifugation
It is to centrifuge the material in the crystallizing tank after cooling, stops centrifugation when the mother liquor being discharged in centrifuge is zero.It is more excellent
Selection of land, centrifugation time are 20-25min (such as 21min, 22min, 23min, 24min, 25min).
Under normal circumstances, MAA is counted after centrifugation and crystallize weight, packed by 30 ㎏/part, MAA crystalline content >=85%
(MAA crystallization content be to be obtained by chemical titration commonly used in the art, MAA crystalline contents such as be 85%, 85.5%,
86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5% or 90%).
In the above-mentioned methods, as a preferred implementation manner, in the preparation process of MAA crystallizations, the mother liquor
It is back in the corresponding process of MAA oil preparation process and applies mechanically；It is highly preferred that the mother liquor is back to the de- of MAA oil preparation process
It is applied mechanically in color process.
Mother liquor all returns to the posies MAA bleaching process by pipeline and applies mechanically, and carries out the colloid in decolorization removing mother liquor
Impurity.Because containing certain impurity in mother liquor, a part of impurity can be removed with activated carbon adsorption by being applied mechanically in bleaching process, be passed through
Numerous studies, discovery removal impurity before process can bring the impurity in finished product into than removal impurity behind process can be more
It is few.The production of MAA oil includes following procedure：FAA (formamido antipyrine first, hydrolysis, it is primary neutralize, decoloration, it is secondary in
With dehydration, MAA oil.Bleaching process is exactly the process for putting into activated carbon and carrying out decoloration removal of impurities processing to the material after once neutralizing,
The best approach of the reuse of mother liquor is that mother liquor is entered to the MAA for producing common analgin (analgin of i.e. non-COS standards) by the gross
The bleaching process of preparation is applied mechanically.
In the above-mentioned methods, as a preferred implementation manner, in the step of condensation, first the MAA is tied
Crystalline substance input condensation tank, then according to every kilogram of MAA crystallization be added 1.6-1.8L (such as 1.61L, 1.65L, 1.7L, 1.75L,
1.79L) ratio of alcohol is added alcohol into the condensation tank, then by the condensation tank be warming up to 70-80 DEG C (such as 71 DEG C,
72 DEG C, 75 DEG C, 77 DEG C, 79 DEG C), sodium pyrosulfite is added after MAA crystallizations dissolving in the condensation tank and formaldehyde is condensed
Reaction, wherein scale (i.e. MAA crystallizes total amount × MAA crystalline contents), the quality of formaldehyde, sodium pyrosulfite of the MAA crystallizations
Than being 1:(0.13-0.15):(0.44-0.46)；Preferably, the alcohol is commercially available edible alcohol, and ethanol content requires
95wt% or more (such as 95wt%, 95.5wt%, 96wt%, 96.5wt%, 97wt%).
In the above-mentioned methods, as a preferred implementation manner, in the rear in processing step, the decrease temperature crystalline refers to
The decrease temperature crystalline of the analgin feed liquid obtained after to condensation reaction, it is highly preferred that the decrease temperature crystalline is specific as follows：First certainly
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) so are cooled to, then use 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 preferred implementation manner, in the rear in processing step, the specific ginseng of the drying
Number is as follows：148-165 DEG C of inlet temperature (such as 149 DEG C, 150 DEG C, 155 DEG C, 160 DEG C, 164 DEG C), 60-80 DEG C of outlet temperature
(such as 61 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 79 DEG C), time are 5.5-6h (such as 5.6h, 5.7h, 5.8h, 5.9h).
The present invention has the advantages that compared with prior art：
The analgin that the method for the present invention obtains meets COS standards, the one-time success rate for increasing COS finished products, expands COS
The yield of analgin reduces production cost.In the existing method, directly the MAA oil that MAA processes obtain is used to be condensed anti-
It answers, then obtains the analgin finished product for meeting COS standards, existing method production by carrying out repeatedly purifying to analgin feed liquid
The one-time success rate of the analgin of COS standards is 40% hereinafter, product yield is low, and yield is monthly 10 tons, and the method for the present invention
The one-time success rate for producing COS analgins is 95% or more, and yield can monthly reach 25-30 tons, and cost is saved than existing method
About 2800 yuan/ton.In addition the method for the present invention product yield can reach 70% or more, and finished product content is qualified, and defects inspecting item is unknown
Impurity is low, generally 0.035% hereinafter, colorimetric is good.
Description of the drawings
Fig. 1 is the schematic diagram of crystallizing tank 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, steam exhaust dump valve；23, into brine valve；24, brine valve is returned；25、
Compression valve；26, pressure gauge.
Specific implementation mode
The production method of the COS standard analgins of the present invention is illustrated with reference to the accompanying drawings and examples.It should be understood that
These embodiments are only used for explaining the present invention rather than limit the scope of the invention.Externally it should be understood that reading the present invention
Content after, those skilled in the art make various changes or modifications the present invention, and such equivalent forms equally fall within the application
The appended claims limited range.
The crystallizing tank and be condensed two kinds of equipment that tank is commonly used in the art that the present invention uses, are equipped with folder outside tank body
Set, with the work that the substance to tank interior is heated up, kept the temperature or cooled down, the temperature control principle phase of two kinds of tanks of chuck pair
Together, the crystallization jar structure that the present invention uses simply is introduced below, and referring to Fig. 1, the crystallizing tank includes：Tank body 1 is crystallized,
Top is equipped with material inlet valve 11, is used for the entrance of control material, and bottom is equipped with material outlet valve 12, is used for the row of control material
Go out, is internally provided with agitating device 13, the material for being stirred in crystallizing tank；Chuck 2 is close to crystallize the outer wall of tank body 1, be led to
It crosses and is passed through steam, brine or recirculated water into chuck 2 to control the temperature in crystallization tank body 1；Steam enters valve 21, be set to
Chuck 2 supplies on the pipeline of steam, and the speed of chuck 2 is entered for controlling steam；Steam exhaust dump valve 22 is set to from chuck 2
On the pipeline of middle discharge steam exhaust, the speed of chuck 2 is discharged for controlling steam exhaust；Into brine valve 23, it is set to chuck 2 and supplies salt
On the pipeline of water, the speed of chuck 2 is entered for controlling brine；Brine valve 24 is returned, the pipe that brine is discharged from chuck 2 is set to
On the road, the speed of chuck 2 is discharged for controlling brine；Compression valve 25 and pressure gauge 26, are set to the pipeline being connected to chuck 2
On, by the pressure in the display observation chuck 2 of pressure gauge 26 and the pressure in chuck 2 is adjusted by compression valve 25.
The preparation method of the MAA oil used in following embodiment is as follows：
4- formyl amino antipyrines FAA methylates：900L water is added in the tank that methylates, puts into 750kg FAA, opens
Stirring is added 600kg dimethyl suflfates, while constantly cooling, liquid caustic soda is added when temperature reaches 10 DEG C in tank, surveys pH value 9
When left and right, methylate qualification.
Hydrolysis：The qualified feed liquid that will methylate is squeezed into hydrolytic decomposition pot, and stirring is opened, and 890kg sulfuric acid is added, opens steam, temperature
Degree control keep the temperature 4 hours at 135-145 DEG C, after survey percent hydrolysis, percent hydrolysis reaches 98% or more and is considered as qualification, after qualification
It is put into a neutralizing tank.
It is primary to neutralize：A neutralizing tank air draft and stirring are opened, water of 700L is added, opens steam and is warming up to 80 DEG C, so
Ammonium hydroxide is added afterwards to neutralize, it is that 2.0-2.5 stops adding ammonium hydroxide to be neutralized to pH value, and MAA oil proportions are measured in 1.19-1.22 with densimeter
Between (pycnometric purpose be in order to enable MAA oil smoothly separated from mother liquor provide reference frame).
Decoloration：After primary neutralization, 30kg activated carbons are added in a neutralizing tank, keep 80-90 DEG C of temperature, heat preservation
1 hour.
Secondary neutralization：Feed liquid is pressed by filter in secondary neutralizing tank after decoloration, proportion is adjusted with a water,
When proportion is 1.23 or so, it is passed through liquefied ammonia and adjusts acidity, maintain the temperature at 70-90 DEG C, pH value stops neutralizing when reaching 7.2-7.5,
Stratification.
Dehydration：After detaching mother liquor, MAA oil is evacuated to through suction filtration tank in drain sump, is opened steam, vacuum progress dehydrating operations, is taken off
Coolant-temperature gage is not higher than 95 DEG C, and 4- novalgins (i.e. MAA oil) were made in about 1 hour time, and the content of MAA oil is
92wt%.
The alcohol used in following embodiment is commercially available alcohol, ethanol content 95wt%.
Embodiment 1
The preparation of MAA crystallizations：MAA oil is added in the external MAA oil storage tanks equipped with chuck, then according to MAA oil and water
Weight ratio be 1:Purified water is added into MAA oil storage tanks for 0.4 amount, and crack steam controls the temperature of MAA oil storage tanks 70
DEG C or so (preventing MAA from crystallizing) stand 30 minutes；Vacuum is opened, by being preheated to 65 DEG C or so by the way of negative-pressure ward
The upper solution that MAA oil pick-up tubes extract MAA oil storage tanks enters in crystallizing tank；The steam being then turned on crystallizing tank enters valve 21,
Material in crystallizing tank is risen again to 65 DEG C, checks whether correctly (other each valves should be at closing each valve switch on crystallizing tank
State), steam exhaust dump valve 22 should be at closed state at this time；It opens agitating device later to start to stir, rotating speed is 27 revs/min, directly
All discharge just stops stirring to material in crystallizing tank；By crystallizing tank Temperature fall 2 hours；Brine valve 24 is opened back later,
It is small drive into brine valve 23 (i.e. will into brine valve 23 open 30 degree) cool down to crystallizing tank, when being cooled to 50 DEG C, in open brine
Valve 23 (will open 60 degree into brine valve 23) cools down, and when being cooled to 40 DEG C, opening brine valve 23 greatly (i.e. will be into brine valve 23
Open 90 degree) crystallizing tank is cooled to 20 DEG C, prepare centrifugally operated；Material in crystallizing tank is put into centrifuge and is centrifuged, is observed
When the mother liquor amount flowed out in the mother liquor pipeline being set on centrifuge is almost nil, stops centrifuge and MAA is crystallized into taking-up, according to
30 ㎏/part is packed for being condensed process, sample examination, and obtained MAA crystalline contents are 85.60wt%.
It is condensed purification step：MAA is crystallized in input condensation tank, 1.6L alcohol amounts are added to contracting according to 1kg MAA crystallizations
It closes in tank and commercially available 95wt% alcohol is added, condensation tank, which is then warming up to 75 DEG C, makes MAA crystallization dissolvings, is crystallized according still further to MAA
Scale (MAA crystallization content * 85.60wt%), formaldehyde, sodium pyrosulfite mass ratio be 1:0.14:0.45 amount is into condensation tank
Condensation reaction is carried out, analgin feed liquid is pressed into crystallizing tank after completion of the reaction, is naturally cooling to 65 DEG C, opens recirculated water valve
Cool down, when being cooled to 25-35 DEG C, closes recirculated water valve, prepare centrifugation.By analgin wet product input air flow drying machine
In, 152 DEG C of inlet temperature, 68 DEG C of outlet temperature is 5.5 hours dry, obtains analgin finished product.Determination of Analgin 99.5%, it is miscellaneous
Matter E (≤0.15%) is 0.13%, and unknown impuritie (≤0.05%) is 0.032%, meets COS standards.Product yield is 72%.
It is multiple batches of to produce obtained statistical result showed, produce COS standard analgins according to 1 process of embodiment, one
Secondary success rate is 96%, that is, COS standards analgin can successfully be prepared 96 times by carrying out the production of 100 batches.
Embodiment 2
The preparation of MAA crystallizations：MAA oil is added in the external MAA oil storage tanks equipped with chuck, then according to MAA oil and water
Weight ratio be 1:Purified water is added into MAA oil storage tanks for 0.45 amount, and crack steam controls the temperature of MAA oil storage tanks 70
DEG C or so (preventing MAA from crystallizing) stand 40 minutes；Vacuum is opened, by being preheated to 65 DEG C or so by the way of negative-pressure ward
The upper solution that MAA oil pick-up tubes extract MAA oil storage tanks enters in crystallizing tank；The steam being then turned on crystallizing tank enters valve 21,
Material in crystallizing tank is risen again to 65 DEG C, checks whether correctly (other each valves should be at closing each valve switch on crystallizing tank
State), steam exhaust dump valve 22 should be at closed state at this time；It opens agitating device later to start to stir, rotating speed is 27 revs/min, directly
All discharge just stops stirring to material in crystallizing tank；By crystallizing tank Temperature fall 10 minutes 2 hours；Brine is opened back later
Valve 24, it is small drive into brine valve 23 (i.e. will into brine valve 23 open 30 degree) cool down to crystallizing tank, when being cooled to 50 DEG C, in open
Brine valve 23 (will open 60 degree into brine valve 23) cools down, and when being cooled to 40 DEG C, opening brine valve 23 greatly (i.e. will be into brine
Valve 23 opens 90 degree) crystallizing tank is cooled to 15 DEG C, prepare centrifugally operated；Material in crystallizing tank is put into centrifuge and is centrifuged,
When the mother liquor amount flowed out in the mother liquor pipeline that observation is set on centrifuge is almost nil, stops centrifuge and MAA is crystallized into taking-up,
It is packed according to 30kg/ parts for being condensed process, sample examination, obtained MAA crystalline contents are 87.30wt%.
It is condensed purification step：MAA is crystallized in input condensation tank, 1.7L alcohol amounts are added to contracting according to 1kg MAA crystallizations
It closes in tank and commercially available 95wt% alcohol is added, condensation tank, which is then warming up to 70 DEG C, makes MAA crystallization dissolvings, is crystallized according still further to MAA
Scale (MAA crystallization content * 87.30wt%), formaldehyde, sodium pyrosulfite mass ratio be 1:0.13:0.46 amount is into condensation tank
Condensation reaction is carried out, material is pressed into crystallizing tank after completion of the reaction, is naturally cooling to 75 DEG C, recirculated water valve is opened and is dropped
Temperature when being cooled to 25-35 DEG C, closes recirculated water valve, prepares centrifugation.By in analgin wet product input air flow drying machine, import
152 DEG C of temperature, 68 DEG C of outlet temperature is 5.5 hours dry, obtains analgin finished product.Determination of Analgin 99.6%, impurity E (≤
0.15%) it is 0.11%, unknown impuritie (≤0.05%) is 0.034%, meets COS standards.Product yield is 71%.
It is multiple batches of to produce obtained statistical result showed, produce COS standard analgins according to 1 process of embodiment, one
Secondary success rate is 98%, that is, COS standards analgin can successfully be prepared 98 times by carrying out the production of 100 batches.
Comparative example
MAA oil is put into condensation tank, alcohol is added into condensation tank according to 1kg MAA oil addition 2.6L alcohol amounts, then
Mass ratio according to MAA oil scale (MAA oil total amount * 92wt%), formaldehyde, sodium pyrosulfite is 1:0.14:0.45 amount is to contracting
It closes in tank and carries out condensation reaction, material is pressed into refining crystallization tank after completion of the reaction, be naturally cooling to 70 DEG C, open circulating-water valve
Door cools down, and when being cooled to 25 DEG C, closes recirculated water valve, prepares centrifugation.The analgin wet product that centrifugation obtains is thrown again
Enter to be condensed in tank, 2.6L alcohol amounts, which are added, according to 1kg MAA oil is added alcohol dissolving, and activated carbon is added.It opens steam and is warming up to 80
DEG C, 30 minutes are kept the temperature, binder is filtered after decoloration and enters refining crystallization tank, repeats the work of crystallization cooling centrifugation, obtaining peace is
Nearly wet product, by analgin wet product input air flow drying machine, 162 DEG C of inlet temperature, 78 DEG C of outlet temperature is 5.5 hours dry, obtains
To analgin finished product.Determination of Analgin 99.5%, impurity E (≤0.15%) are 0.13%, and unknown impuritie (≤0.05%) is
0.032%, meet COS standards.Product yield is 66.5%.
It is multiple batches of to produce obtained statistical result showed, produce COS standard analgins according to 1 process of embodiment, one
Secondary success rate is 40%, that is, COS standards analgin can successfully be prepared 40 times by carrying out the production of 100 batches.
From the foregoing, it will be observed that the effect and haveing an advantage that of the present invention provides a kind of MAA crystallization productions obtained using water soluble method
The method of COS analgins, the method increase the one-time success rate of COS finished products, expand the yield of COS analgins, reduce
Production cost.
Claims (13)
1. a kind of method of the MAA crystallization production COS analgins obtained using water soluble method, which is characterized in that include the following steps：
The preparation process of MAA crystallizations：Water is added into MAA oil, MAA is respectively obtained through standing, crystallization, centrifugation successively after mixing
Crystallization and mother liquor；
Step of condensation：Condensation reaction is carried out by MAA crystallizations, with formaldehyde, sodium pyrosulfite, generates analgin feed liquid；
Post-processing step：The analgin feed liquid is subjected to decrease temperature crystalline, centrifugation and drying successively, to obtain meeting COS marks
Accurate analgin；Wherein,
In the preparation process of MAA crystallizations, the weight ratio of the MAA oil and water is 1:0.4-0.5；
The standing is to stand 30-60min under the conditions of 60-75 DEG C.
2. according to the method described in claim 1, it is characterized in that, in the preparation process of MAA crystallizations, the crystallization has
Body is as follows：The mixture of MAA oil and purified water after standing is pumped into crystallizing tank, then heating crystalline tank, then crystallizing tank is dropped
Temperature, so that MAA is crystallized.
3. according to the method described in claim 2, it is characterized in that,
The suction crystallizing tank be the mixture of MAA oil and water after standing is evacuated to by the MAA oil pick-up tubes after preheating it is described
In crystallizing tank, the MAA oil pick-up tubes after the preheating have 60-70 DEG C of temperature；
The heating crystalline tank is that the crystallizing tank is heated to 60 DEG C or more；
The crystallizing tank cooling is that the crystallizing tank is cooled to 20 DEG C or less.
4. according to the method described in claim 3, it is characterized in that, the crystallizing tank is heated to 60-75 DEG C by steam；Institute
It is that the crystallizing tank is cooled to 15-20 DEG C to state crystallizing tank cooling.
5. method according to claim 3 or 4, which is characterized in that the crystallizing tank includes：
Tank body is crystallized, top is equipped with material inlet valve, and bottom is equipped with material outlet valve, is internally provided with agitating device；
Chuck is close to the outer wall of the crystallization tank body, by being passed through steam, brine or recirculated water into the chuck to control
State the temperature in crystallizing tank body；
Steam enters valve, is set on the pipeline that the chuck supplies steam, the speed of chuck is entered for controlling steam；
Steam exhaust dump valve is set to and is discharged on the pipeline of steam exhaust from the chuck, the chuck is discharged for controlling steam exhaust
Speed；
Into brine valve, it is set on the pipeline that the chuck supplies brine, the speed of chuck is entered for controlling brine；
Brine valve is returned, is set to and is discharged on the pipeline of brine from the chuck, the speed of the chuck is discharged for controlling brine
Degree.
6. according to the method described in claim 5, it is characterized in that, crystallizing tank cooling in turn includes the following steps：
Step 1 opens agitating device, and rotating speed is 25-30 revs/min, and the working condition of the agitating device is continued until crystallization
Material discharging finishes in tank；
Step 2, by the crystallizing tank Temperature fall 110min-130min after heating, during the Temperature fall, material
Inlet valve, material outlet valve, steam enter valve, steam exhaust dump valve, are in closed state into brine valve, time brine valve；
Step 3, open after Temperature fall it is described return brine valve, while opening 20-40 degree, that is, small by described into brine valve and drive salt into
Water valve drives described opened during 50-70 degree is into brine valve into brine valve, works as institute when the crystallizing tank is cooled to 45-55 DEG C
When stating crystallizing tank and being cooled to 35-45 DEG C, opens 80-90 degree by described into brine valve and drive brine valve into greatly, until crystallizing tank drops
Temperature is to 15-20 DEG C.
7. according to the method described in claim 1, it is characterized in that, in the preparation process of MAA crystallizations, the centrifugation is
Material in crystallizing tank after cooling is centrifuged, stops centrifugation when the mother liquor being discharged in centrifuge is zero.
8. the method according to the description of claim 7 is characterized in that in the preparation process of MAA crystallizations, centrifugation time is
20-25min。
9. according to the method described in claim 1, it is characterized in that, in the preparation process of MAA crystallizations, the mother liquor returns
It is back in the corresponding process of MAA oil preparation process and applies mechanically.
10. according to the method described in claim 1, it is characterized in that, the MAA crystallization preparation process in, the mother liquor
It is back in the bleaching process of MAA oil preparation process and applies mechanically.
11. according to the method described in claim 1, it is characterized in that, in the step of condensation, first the MAA is tied
Wine is added into the condensation tank in crystalline substance input condensation tank, the ratio that 1.6-1.8L alcohol then is added according to every kilogram of MAA crystallization
Essence, then the condensation tank is warming up to 70-80 DEG C, sodium pyrosulfite and first is added after MAA crystallizations dissolving in the condensation tank
Aldehyde carries out condensation reaction, wherein the scale of MAA crystallization, formaldehyde, sodium pyrosulfite mass ratio be 1:0.13-0.15:
0.44-0.46。
12. according to the method for claim 11, which is characterized in that in the step of condensation, second in the alcohol
The content of alcohol is in 95wt% or more.
13. according to the method described in claim 1, it is characterized in that, in the rear in processing step, the decrease temperature crystalline refers to
The decrease temperature crystalline of the analgin feed liquid obtained after to condensation reaction, it is specific as follows：It is first naturally cooling to 65-75 DEG C, then
Using circulating water cooling to 25-35 DEG C；The design parameter of the drying is as follows：148-165 DEG C of inlet temperature, outlet temperature 60-
80 DEG C, the time is 5.5-6 hours.
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| 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 |
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| 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 |
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