CN102731531A - Cefmenoxime hydrochloride compound and synthesizing method thereof - Google Patents
Cefmenoxime hydrochloride compound and synthesizing method thereof Download PDFInfo
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- CN102731531A CN102731531A CN2012101917714A CN201210191771A CN102731531A CN 102731531 A CN102731531 A CN 102731531A CN 2012101917714 A CN2012101917714 A CN 2012101917714A CN 201210191771 A CN201210191771 A CN 201210191771A CN 102731531 A CN102731531 A CN 102731531A
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Abstract
The invention relates to the field of pharmacy, and especially related to a cefmenoxime hydrochloride compound and a synthesizing method thereof. The cefmenoxime hydrochloride compound has a formula shown below, and is prepared with a method comprising the steps that: (1) a cefoperazone precursor 7-ATCA.HCl and AE active ester are subjected to a condensation reaction under the existence of CH2Cl2 and an alkalizing agent; and the obtained product is subjected to extraction, decolorization, press-filtration, neutralization, rejection filtration, and drying, such that cefmenoxime acid CMX-H is prepared; (2) the cefmenoxime acid is completely dissolved by using sodium carbonate; the obtained product is subjected to decolorization, press-filtration, neutralization, decolorization, filtration, crystallization, washing, and drying, such that a cefmenoxime hydrochloride half-finished product is prepared; a jet mill is started; and the material is crushed and is filled in aluminum bottles. According to the invention, cefmenoxime acid is prepared into crystals, such that the product purity is greatly improved, and the product quality is ensured. Also, the method provided by the invention is advantaged in small three-waste volume, simple preparation process, and low cost. Therefore, the method is suitable for the industrialized productions of our nation.
Description
Technical field
The present invention relates to relate to pharmacy field, relate in particular to cefmenoxime hydrochloride compound and compound method thereof.
Background technology
Cefmenoxime Hemihydrochloride is the third generation cephalosporin analog antibiotic of Japanese Takede Chemical Industries Ltd in the seventies research; And went on the market in Japan with Bestcall (Bestea) trade(brand)name in 1983; Thereafter respectively in the tw Taiwan, France, Germany, Austria, Korea S, the U.S. etc. are with different trade(brand)name listings, its quality standard has been recorded in USP 24 editions and has been explained orally (version in 1995) with Japanese antibiotics benchmark.
Cefmenoxime Hemihydrochloride is a third generation cephalo, and Gram-negative and male aerophil and anerobes are all had anti-microbial effect.In the Gram-negative bacteria; Anti-microbial effect to intestinal bacteria, pneumobacillus is stronger slightly than cefotiam; Obviously be better than the Kefzol of the first-generation; The anti-microbial effect of influenza being bitten blood bacillus, Bacillus proteus, serratia marcesens, Citrobacter, enterobacter is also more intense, and Bacteroides is also had very strong anti-microbial effect.In gram-positive microorganism, also stronger to micrococcus scarlatinae, pneumococcal anti-microbial effect.Peptococcus, Peptostreptococcus also there is the strong antibiotic effect.Stable to beta lactamase.These article to the effect of Staphylococcus not as first and second cynnematin in generation, poor to Pseudomonas aeruginosa, enterobacteria and faecalis effect.Quiet notes 1g, blood medicine peak value 99.4 mcg/ml, intramuscular injection 0.5g is 10.8 mcg/ml, serum t1/2 is about 1 hour.Metabolism hardly in vivo is mainly through renal excretion.Serum proteins combination rate 85%.These article are good to bile transport, and are higher at body fluid such as sputum, tonsilla, csf, hydrothorax, peritoneal exudate, kidney, bladder wall, uterus, uterine tube, ovary, pelvic cavity transudate, Cord blood, amniotic fluid and tissue distribution concentration.But transhipment seldom in milk.Be applicable to responsive microbial septicemia, meningitis, respiratory tract infection, pyothorax, liver and courage infection, peritonitis, urinary tract infection, genital system infection and burn and surgical wound infection etc.
Comprehensive existing patent, periodical literature and restricted data report, cefmenoxime is that primary amine of C7 of 7-ACA (7 one an amino Cephalosporanic acid) connects ainothiazoly loximate (CEFOTAXIME SODIUM STERILE C
7-position side chain), C
3After connecting desacetoxy ,-position connects first sulphur tetrazole side chain (cefoperazone C
3-position side chain) makes with the hydrochloric acid salify again after.Therefore, can carry out C earlier
7C is carried out after transforming again in-position
3Transform-position, or it is opposite.Early stage document is to C
7-position is transformed and also have been carried out multiple testing program, according to the document analysis of preparation cefmenoxime: early stage C
7The cefotaxime side chain of-position be connect methyl aceto acetate in C7-position of 7-ACA after nitrosification, methylate, polystep reaction such as cyclization forms.This type of is synthetic extremely unreasonable.Synthesizing in recent years all abandoned.And directly get with the direct condensation of cefotaxime acetic acid side chain that has prepared.Compound method mainly contains chloride method and active ester method.Can use for reference at present the synthetic of the CEFOTAXIME SODIUM STERILE of suitability for industrialized production.And C
3Connect first sulphur tetrazole on the-position, compound method mainly contains boron trifluoride method and vitriol oil method.This can use for reference cefoperazone C
3The compound method of-position.
Other confirms 7-ATCAHCl (precursor of cefoperazone) outsourcing to the investigation of the condition of production of domestic cefoperazone and pharmaceutical midbody, can supply for a long time in pharmaceutical factory, Yongning, cefoperazone manufacturer Zhejiang.Pharmaceutical chemistry factory in Dongyang, Zhejiang also can supply for a long time in addition.The prepared AE active ester of ainothiazoly loximate and altax, existing how tame Fine Chemical Works production, ample supply and prompt delivery.Operational path of the present invention for this reason adopts with 7-ATCA HCI and the acid of the synthetic preparation of AE active ester cefmenoxime, processes the aseptic raw material of hydrochloric acid spore first oxime in the sterilisable chamber.
Summary of the invention
Not high in order to solve in the prior art cefmenoxime acid synthesis yield, production cost is high, is not suitable for the technological deficiency of suitability for industrialized production; An object of the present invention is to provide a kind of cefmenoxime hydrochloride compound; Its synthesis yield is high, has reduced production cost, is fit to suitability for industrialized production.Another object of the present invention provides a kind of compound method of cefmenoxime hydrochloride compound.
In order to realize first above-mentioned purpose, the technical scheme below the present invention has adopted:
Cefmenoxime hydrochloride compound, this compound has following structural formula:
Above-mentioned cefmenoxime hydrochloride compound is prepared by following method:
1) preparation of cefmenoxime acid
By the precursor 7-ATCAHCl of cephalo croak ketone and AE active ester at CH
2Cl
2With condensation reaction under the condition of basifier, then through extraction, decolouring, press filtration, neutralize, get rid of filter and oven dry, make cefmenoxime acid CMX-H; The chemical equation of condensation reaction is following:
7-ATCAHCl+AE active ester
CMX-H+captax
Wherein: the structural formula of 7-ATCAHCl:
The structural formula of AE active ester:
The structural formula of cefmenoxime acid CMX-H:
The structural formula of captax:
；
2) the half-finished preparation of Cefmenoxime Hemihydrochloride
After above-mentioned cefmenoxime acid adopts yellow soda ash to dissolve fully, pass through decolouring, press filtration, neutralization, decolouring, filtration, crystallization, washing and drying then, make the Cefmenoxime Hemihydrochloride work in-process;
The chemical formula of solubilizing reaction is following:
2CMX-H + Na
2CO
3 2CMX-Na + CO
2 
+ H
2O；
The chemical formula of neutralization reaction is following:
CMX-Na + 3/2HCl
(CMX-H)·HCl
1/2 + NaCl；
3) preparation of Cefmenoxime Hemihydrochloride finished product
Open micronizer mill, with the material that is up to the standards pulverize and the sterilized Aluminum Bottle of packing in.
In order to realize second above-mentioned purpose, the technical scheme below the present invention has adopted:
A kind of compound method of above-mentioned cefmenoxime hydrochloride compound, this method comprises the steps:
1) preparation of cefmenoxime acid
By the precursor 7-ATCAHCl of cephalo croak ketone and AE active ester at CH
2Cl
2With condensation reaction under the condition of basifier, then through extraction, decolouring, press filtration, neutralize, get rid of filter and oven dry, make cefmenoxime acid CMX-H; The chemical equation of condensation reaction is following:
7-ATCAHCl+AE active ester
CMX-H+captax
Wherein: the structural formula of 7-ATCAHCl:
The structural formula of AE active ester:
The structural formula of cefmenoxime acid CMX-H:
The structural formula of captax:
2) the half-finished preparation of Cefmenoxime Hemihydrochloride
After above-mentioned cefmenoxime acid adopts yellow soda ash to dissolve fully,, make the Cefmenoxime Hemihydrochloride work in-process then through once decolouring, press filtration, neutralization, secondary decolourization, filtration, crystallization, washing and drying;
The chemical formula of solubilizing reaction is following:
2CMX-H + Na
2CO
3 
2CMX-Na + CO
2 + H
2O；
The chemical formula of neutralization reaction is following:
CMX-Na + 3/2HCl
(CMX-H)·HCl
1/2 + NaCl；
3) preparation of Cefmenoxime Hemihydrochloride finished product
Open micronizer mill, with the material that is up to the standards pulverize and the sterilized Aluminum Bottle of packing in.
As preferably, the step of the condensation reaction in the above-mentioned step 1) is following:
With CH
2Cl
2Be drawn onto in the condensation jar, control material temperature adds 7-ATCAHCl and AE active ester less than 20 ℃; The weight of AE active ester is 1-1.2 times of 7-ATCAHCl weight; The material temperature drop is after-5 ℃～5 ℃, and stream adds basifier, and the addition of basifier is 0.8-1.0 a times of 7-ATCAHCl weight; The speed control material temperature that adds basifier through adjusting in the reinforced process after basifier adds, is observed feed liquid below 10 ℃, treat feed clarification after ,-5 ℃～10 ℃ insulated and stirred 0.8-1.2 hour.
As preferably, the extraction step in the above-mentioned step 1) is following:
1. in the condensation jar, add purified water, the add-on of purified water is 3-5 a times of 7-ATCAHCl weight, and the material temperature control is at 2-15 ℃; Stirred 3-10 minute, and stopped stirring, left standstill 8-15 minute; Lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin;
2. utilize vacuum to suck purified water in the condensation jar, the soakage of purified water is 3-5 a times of 7-ATCAHCl weight, opens stirring; With vacuum the organic layer in the organic phase basin is drawn into the condensation jar, stops after sucking to stir, close vacuum valve; Emptying; Left standstill 8-15 minute, lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin;
3. repeat 2. to operate, upper aqueous layer is stayed in the condensation jar, opens stirring;
4. utilize vacuum with CH
2Cl
2After sucking the condensation jar, CH
2Cl
2Soakage be 7-ATCAHCl weight 1.5-3 doubly, again the water layer in the water basin is sucked the condensation jar, stop stirring, left standstill 8-15 minute, lower floor's organic layer is put into the organic phase basin;
5. repeat 4. to operate and extract 1 time again.
As preferably, the decolouring step in the above-mentioned step 1) is following: use CH
2Cl
2After the second extraction, build hand hole plate, open stirring, control material temperature is opened vacuum valve on the condensation jar at 2 ~ 15 ℃, takes out true 0.9 ~ 1.2 little space-time and removes CH
2Cl
2Hand hole plate is opened in emptying, in the condensation jar, adds Medicinal Charcoal according to the feed liquid color, builds hand hole plate, opens stirring, and control material temperature is opened vacuum valve on the condensation jar, vacuum decoloration 0.9 ~ 1.2 hour at 2 ~ 15 ℃.
As preferably, the neutralization procedure in the above-mentioned step 1) is following: in neutralization tank, add THF, the add-on of THF is 1.0 ~ 1.5 times of 7-ATCAHCl weight, opens stirring; Control material temperature is at 2 ℃-10 ℃, and stream adds 1.5 ~ 2.5mol/L HCl solution, when pH is 2.4 ~ 2.5; Stop adding HCl solution, stirred crystallization is when the pH bounce-back rises to 2.5 ~ 2.8; Continue stream and add HCl solution, when pH reduces to 2.4 ~ 2.5 once more, stop adding hydrochloric acid; 1 ℃ ~ 5 ℃ are stirred insulation 1 hour.
As preferably, above-mentioned step 2) the cefmenoxime acid dissolving step in is following: in enamel pot, add the injection water; Open to stir and add an amount of yellow soda ash, treat that it dissolves fully after, the material temperature is less than 20 ℃ in the controlling tank; Add cefmenoxime acid and skimmer ETHYLE ACETATE, the add-on of ETHYLE ACETATE is 8% ~ 10% of a cefmenoxime acid weight, after cefmenoxime acid adds; Water for injection washing funnel, the sealing hand hole vacuumizes removing carbon dioxide.
As preferably, above-mentioned step 2) the once decolouring in is adopted and is added Medicinal Charcoal and EDTA2Na, opens vacuum, and the material temperature is 1 ℃ ~ 20 ℃ in the controlling tank, decolours 0.8 ~ 1.2 hour; Secondary decolourization adopts Medicinal Charcoal, and the material temperature control was stirred 0.8 ~ 1.2 minute at 1 ℃-10 ℃, left standstill 5 minutes.
As preferably; Above-mentioned step 2) neutralization procedure in is following: feed liquid is opened stirring after completely crossing and stirring after the press filtration; Washing lotion all is pressed into enamel pot; Through 1 ℃-10 ℃ of material temperature in the chuck medium controlling tank, add 2.5 ~ 3.5mol/LHCl solution with fast speed, press cefmenoxime acid: hydrochloric acid=1:3.0-3.5 mol ratio.
As preferably, above-mentioned step 2) crystallisation step in is following: when feed liquid is completely crossed stirring in the crystallizer, open stirring; After feed liquid and washing lotion all were pressed into crystallizer, the crystallizer chuck advanced hot water and heats up, and the material temperature control is at 20 ℃ ~ 25 ℃; Observe the feed liquid changing conditions, feed liquid is complete to pick up counting after white, 20 ℃ ~ 25 ℃ insulated and stirred 0.8 ~ 1.2 hour; Chuck improves the cooling of cooling solvent, and material temperature drop to 0 ℃ ~ 10 ℃ is incubated 1.5 ~ 2.5 hours.
The present invention is through being optimized technology; Crystallization is processed in cefmenoxime acid, and product purity is improved greatly, guarantees final product quality; Through lab scale and pilot scale; C7-position condensation is the preparation of cefmenoxime acid, and yield can be stabilized in 85 % (mol yield) and 120 % (weight yield), and salifiable yield can be stabilized in 73 % (mol yield 75 %) weight yield.The preparation three wastes of this technology are few, and preparation process condition is simple, and solvent is only used a kind of methylene dichloride, and is with low cost, are fit to China's suitability for industrialized production.
Description of drawings
Fig. 1 is the IR figure (KCl method) of Cefmenoxime Hemihydrochloride 20010118 lot numbers of the present invention's preparation.
Fig. 2 is the UV-VIS figure (H of Cefmenoxime Hemihydrochloride 20010118 lot numbers of the present invention's preparation
2O).
Fig. 3 is for Cefmenoxime Hemihydrochloride 20010118 lot numbers of the present invention preparation
1H-NMR figure.
Fig. 4 is the HPLC figure of Cefmenoxime Hemihydrochloride 20010118 lot numbers of the present invention's preparation.
Embodiment
The preparation of embodiment 1 Cefmenoxime Hemihydrochloride
These article are Cefmenoxime Hemihydrochloride, and its structural formula is:
Molecular formula: C
16H
17N
9O
5S
31/2HCl molecular weight: 529.79;
Physico-chemical property: these article be white to faint yellow crystallization or crystalline powder, odorless, or little have special smelly, mildly bitter flavor, have draw moist.
These article are prone to dissolve in methane amide, slightly soluble in methyl alcohol, and soluble,very slightly in water, insoluble in ethanol and ether; At 0.1mol/L
Be prone in the phosphate buffered saline buffer (pH6.8) dissolve.
These article are the semi-synthetic cephalosporins Broad spectrum antibiotics, reach germicidal action through the biosynthesizing that suppresses bacteria cell wall.
In vitro tests shows that these article all have effect to gram-positive microorganism and negative bacterium.
Carry out detailed explanation in the face of the preparation of Cefmenoxime Hemihydrochloride down.
1.1 the preparation of cefmenoxime acid
1.1.1 the preparation of 2mol/LHCl solution: in acid solution preparation bucket, add purified water 108.0kg, add concentrated hydrochloric acid 25.5 ㎏ again, stir, utilize vacuum that it is sucked high level tank, sample examination volumetric molar concentration and proportion, subsequent use.(purified water: concentrated hydrochloric acid=4.2:1) (adjust purified water and concentrated hydrochloric acid consumption by proportioning) according to the need usage quantity
1.1.2 condensation reaction: feed chilled brine in the 1000L condensation enamel pot chuck, open vacuum 750kgCH2Cl2 is drawn onto in the 1000L condensation jar, open stirring.Control material temperature adds 7-ATCAHCl 60.0kg less than 20 ℃, AE active ester 63.3kg, and funnel washs with 45.6kgCH2Cl2.The material temperature drop is after-5 ℃～5 ℃, and stream adds Et3N56.49kg, and the speed control material temperature that adds Et3N through adjusting in the reinforced process after Et3N adds, is observed feed liquid below 10 ℃, treat feed clarification after ,-5 ℃～10 ℃ insulated and stirred 1 hour.
1.1.3 extract
1.1.3.1 in 1000L condensation jar, add purified water 210.0kg, the material temperature control was stirred 5 minutes at 2-15 ℃; Stop stirring; Left standstill 10 minutes, lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin (the basin chuck feeds chilled brine in advance).
1.1.3.2 utilize vacuum to suck purified water 210.0kg in 1000L condensation jar, open stirring, with vacuum the organic layer in the organic phase basin is drawn into 1000L condensation jar; Stop after sucking to stir; Close vacuum valve, emptying was left standstill 10 minutes; Lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin.
1.1.3.3 repeat the 1.1.3.2 operation, upper aqueous layer is stayed in the 1000L condensation jar, opens stirring.
1.1.3.4 after utilizing vacuum that CH2Cl2 120.0kg is sucked 1000L condensation jar, again the water layer in the water basin is sucked 1000L condensation jar, stop stirring, left standstill 10 minutes, lower floor's organic layer is put into the organic phase basin.
1.1.3.5 repeating 1.1.3.4 extracts 1 time again.
1.1.4 decolouring: after the CH2Cl2 second extraction, build hand hole plate, open stirring, control material temperature is opened vacuum valve on the 1000L condensation jar at 2-15 ℃, vacuumizes except that CH2Cl21 hour.Hand hole plate is opened in emptying, in 1000L condensation jar, adds Medicinal Charcoal 18kg according to the feed liquid color, builds hand hole plate, opens stirring, and control material temperature is opened vacuum valve on the 1000L condensation jar, vacuum decoloration 1 hour at 2-15 ℃.
1.1.5 press filtration: the filter paper in the filter press device is ready; Open compressed air inlet valve on the 1000L condensation jar; Jar internal pressure＜0.1MPa, material gets among the 1000L and enamel pot (1000L neutralization tank chuck feeds chilled brine in advance) through Plate Filtration.After material has been pressed, with being pressed into the 1000L neutralization tank in the lump behind the filter cake in 30.0kg * 3 purified water washing 1000L condensation enamel pot, the frame.
1.1.6 neutralization: in the 1000L neutralization tank, add THF 71.94 ㎏, open stirring, control material temperature is at 2 ℃-10 ℃.Stream adds 2mol/L HCl solution, when pH is 2.4-2.5, stops adding 2mol/L HCl solution, stirred crystallization.When the pH bounce-back rises to 2.6 left and right sides, continue stream and add 2mol/L HCl solution, when pH reduces to 2.4-2.5 once more, stop adding hydrochloric acid.Chuck advances 5 ℃ of chilled brine to material temperature, closes the chuck chilled brine, and 1 ℃-5 ℃ are stirred insulation 1 hour.
1.1.7 get rid of filter: whizzer filter cloth bag is ready.The material insulation finishes, and the crawl whizzer is put into whizzer with material, and blowing limit, limit is centrifugal; After material is all put into two whizzers, close bottom valve, in the 1000L neutralization tank, add purified water 630.0kg; Open stirring, chuck advances chilled brine to washing the purified water temperature below 10 ℃, closes chilled brine.Whizzer gets rid of to be filtered to the absence of liq outflow, stops centrifugal.Every whizzer is put washing purified water 105.0 kg, and material is pinched paste, drives whizzer and gets rid of filter, till absence of liq flows out.Same again repeated washing 2 times.
1.1.8 oven dry: material is transferred to material in two tilting vacuum vibration drying devices after drying.Open the vacuum cold-draw 2 hours, and drove hot water pump (hot water temperature rose 5 ℃ in per 10 minutes, at last to 45 ℃-55 ℃).Continue oven dry about 10 hours, close vacuum valve, drive blow-off valve.Observe the drying regime of material, when material is fit to pulverize, material is taken out pulverizing, again material is put back in the primary dip formula vacuum vibration drying device after the pulverizing.The material temperature control is advanced cooling water temperature to 25 ℃-35 ℃ about 6 hours of 45 ℃ of-55 ℃ of vacuum-dryings.
1.1.9 discharging: close the vacuum valve on the tilting vacuum vibration drying device, open empty valve is designated as zero to vacuum meter.Prepare four polyethylene plastic bags (two bags overlapping), with the material inner bag of packing into separately.Sampling respectively in the discharging process.After inner bag bleeds off inner air, take up sack, fasten with pricking button, outer bag is also fastened with pricking button.Weigh, post label, indicate the name of an article, lot number, date, net weight, send appointed place refrigeration to deposit.
1.2 the half-finished preparation of Cefmenoxime Hemihydrochloride
1.2.1 the preparation of 3mol/L hydrochloric acid soln: in acid solution preparation bucket, add injection water 78.0 kg, add concentrated hydrochloric acid 30.0 kg again, stir.Utilize vacuum that it is sucked high level tank, sample examination volumetric molar concentration and proportion, subsequent use.(water for injection: concentrated hydrochloric acid=2.5-2.8:1) (adjust purified water and concentrated hydrochloric acid consumption by proportioning) according to the need usage quantity
1.2.2 water for injection depyrogenation: in No. 1 enamel pot; Add injection water 500kg; Add Medicinal Charcoal 3.5kg, open stirring, chuck advances the interior water temperature of chilled brine controlling tank less than 10 ℃; Behind the depyrogenation 1 hour, material is pressed into two No. 1 high level tanks in north and south through decarbonization filtering device, 0.8 μ m and 0.22 μ m folder filter.
1.2.3 absolute ethyl alcohol depyrogenation: in No. 1 enamel pot; Add absolute ethyl alcohol 50.0kg; Add Medicinal Charcoal 0.25kg, open stirring, chuck advances the interior water temperature of chilled brine controlling tank less than 10 ℃; Behind the depyrogenation 1 hour, material is pressed into high level tank No. 2 through decarbonization filtering device, 0.8 μ m and 0.22 μ m folder filter.
1.2.4 Aluminum Bottle, aluminium lid, sealing-ring and Stainless Steel Disc (connecting lid) sterilization: clean Aluminum Bottle, aluminium lid, sealing with water for injection
Circle and Stainless Steel Disc and lid, to 100ml washing water achromic point, trichobothrium, choice refreshments≤1.The sealing-ring of washing is put into Stainless Steel Disc, put it into damp and hot baking oven, lid is placed on the upper strata, sterilizes 30 minutes under vapor pressure 0.1 MPa, 121 ℃ of conditions.With Aluminum Bottle of washing and aluminium lid, put into xeothermic baking oven in the lump, sterilization is 2 hours under 180 ℃ of conditions.
1.2.5 cefmenoxime acid dissolving: in the 500L enamel pot; Add injection water 390.0kg, open to stir and add yellow soda ash 6.2kg, treat that it dissolves fully after; Chuck advances to expect in the chilled brine controlling tank that temperature is less than 20 ℃; Add cefmenoxime acid 40.0kg (giving money as a gift) and ETHYLE ACETATE 3.6 ㎏ (skimmer), after cefmenoxime acid adds, with 10kg water for injection washing funnel.The sealing hand hole vacuumizes removing carbon dioxide.
1.2.6 decolouring: after treating the solution all clear, add 100 kg low temperature waters for injection, add Medicinal Charcoal 12.0 ㎏ and EDTA2Na 0.4 ㎏, the sealing hand hole is opened vacuum, and the material temperature is 1 ℃-20 ℃ in the controlling tank, decolours 1 hour.
1.2.7 press filtration: the filter paper in the filter press device is ready.Close vacuum valve, blow-off valve is closed in emptying.Open compressed air inlet valve on No. 2 enamel pots, material gets into 1000L enamel pot (pressure＜0.1Mpa) through filter press.After material has been pressed, with being pressed into the 1000L enamel pot in the lump behind depyrogenation water for injection 60kg * No. 2 enamel pots of 3 washings, the interior filter cake of frame.
1.2.8 neutralization: feed liquid is opened stirring after completely cross stirring, and washing lotion all is pressed into the 1000L enamel pot, and through 1 ℃-10 ℃ of material temperature in the chuck medium controlling tank, (it is sour press cefmenoxime: hydrochloric acid=1:3.0-3.5 mol ratio) to add 3mol/LHCl solution with fast speed.Add an amount of 3mol/LHCl solution according to suspension-s sedimentation situation.
1.2.9 decolouring: add Medicinal Charcoal 2.4kg, the material temperature control was stirred 10 minutes at 1 ℃-10 ℃, left standstill 5 minutes.
1.2.10 Sterile Filtration: the notice operator of clean room, confirm that 2 crystallizers sterilize, and before the deadline.Confirm that sterilizing filter bubble point is qualified.Take off the charcoal pressure filter and vacuumize, the supernatant liquid siphon adds nitrogen to taking off the charcoal pressure filter; Require pressure smaller or equal to 0.2MPa; Confirm not have the charcoal of leakage phenomenon, be about to feed liquid and be pressed into crystallizer, the visible foreign matters of the personnel of clean room inspection by sampling filtrating through 0.8 μ m and 0.22 μ m folder filter; Require 100ml feed liquid achromic point, trichobothrium, choice refreshments is smaller or equal to 1.After qualified, continue press filtration.After the supernatant liquid siphon is intact, opens and stir and 1000L enamel pot bottom valve, feed liquid is put into taken off the charcoal pressure filter; After feed liquid has been pressed; Use depyrogenation water for injection 40 ㎏, add 3mol/L hydrochloric acid soln 300ml and be mixed with the washing sour water, with the washing acid water washing 1000L enamel pot of 40 ㎏ * 3.Washing lotion is pressed into crystallizer in the lump.(the Sterile Filtration time is no more than 5 hours).
1.2.11 crystallization: when feed liquid is completely crossed stirring in the crystallizer, open stirring.After feed liquid and washing lotion all were pressed into crystallizer, the crystallizer chuck advanced hot water and heats up, and the material temperature control is at 20 ℃-25 ℃.Observe the feed liquid changing conditions, feed liquid is complete to pick up counting after white, 20 ℃ of-25 ℃ of insulated and stirred 1 hour, and chuck improves the cooling of cooling solvent, and material temperature drop to 0 ℃-10 ℃ is incubated 2 hours.
1.2.12 filtering and washing: affirmation suction filtration jar is sterilized, and before the deadline, opens the vacuum switch on the mother liquor tank.When vacuum tightness reach-when 0.09MPa is above, drive the crystallizer bottom valve.Material is transferred to the suction filtration jar from crystallizer.With depyrogenation water for injection flushing crystallizer in right amount, washing lotion is transferred to the suction filtration jar in the lump.After mother liquor is drained, close vacuum, soaked material 5 minutes with about 40 ㎏ depyrogenation water for injection, suction filtration, repeated washing is 2 times again.Soaked 5 minutes with about 20 ㎏ (material was as the criterion to overflow) depyrogenation ethanol solution, suction filtration, repeated washing is 1 time again.
1.2.13 it is dry: as after washing lotion is drained, material to be packed into sterilize and weigh the stainless steel cask of peeling, build lid, take after the watch-keeping cubicle takes by weighing net weight; Take drying room rapidly, in the vertical vacuum vibration drying device of packing into, the sealing charging opening; Cold-draw 2 hours is driven hot water pump (hot water rose 5 ℃ in per 10 minutes) material is heated, and temperature of charge keeps 38-45 ℃; Vacuum tightness stops heating greater than dry 8-12 hour of-0.095Mpa, and chuck improves cooling water temperature; During material temperature drop to 25 ℃, close water coolant, close vacuum, open empty valve.
1.2.14 discharging, bottling: confirm Aluminum Bottle, sealing-ring and aluminium lid is sterilized, cooled off and before the deadline.Close vibroswitch, under hundred grades of laminar flow hood, open bleeder valve; Drive vibroswitch; Material is packed in the sterilized Aluminum Bottle, and discharging finishes, and covers the aluminium lid (the discharging process is by the regulation sampling) that sealing-ring is installed; Take and roll lid with Cover-rolling machine after weighing in the watch-keeping cubicle, pass to through pass-through and on Aluminum Bottle, indicate the name of an article, lot number, date manufactured, net weight, gross weight etc. between outer packaging.
1.2.15 outer packaging, custody for account of customers: packaging chamber vanning outside, adorn one bottle one the case.Carton indicates the name of an article, lot number, date manufactured, net weight, gross weight etc. outward.Behind the joint sealing, send the warehouse custody for account of customers.
1.3 the preparation of Cefmenoxime Hemihydrochloride finished product
1.3.1 confirm Aluminum Bottle, sealing-ring and aluminium lid is sterilized, cooled off and before the deadline.Open micronizer mill; With the material that is up to the standards pulverize and the sterilized Aluminum Bottle of packing in; Cover the aluminium lid (crushing process is by the regulation sampling) that sealing-ring is installed; Take and roll lid with Cover-rolling machine after weighing in the watch-keeping cubicle, pass to through pass-through and on Aluminum Bottle, post label between outer packaging, indicate the name of an article, lot number, date manufactured, net weight, gross weight, validity period etc.
1.3.2 outer packaging, warehouse-in: packaging chamber vanning outside, put into unit packing list, adorn one bottle one the case.Carton indicates the name of an article, lot number, date manufactured, net weight, gross weight, validity period etc. outward.Behind the joint sealing, send the warehouse custody for account of customers, after the assay was approved warehouse-in.
Test Example
This used test of data prepares lot number: 20010129,20010130,20010131,20010118 by these article Cefmenoxime Hemihydrochloride by embodiment 1 described method by synthetic group with sample.
7.1 physicochemical constant and character
7.1.1 appearance character and stink
Confirm and visual inspection that through the powder x-ray diffraction spectrum these article are white or off-white color crystallization or crystalline powder.Hear odorless, mouth is tasted mildly bitter flavor, or special odor is arranged slightly.
7.1.2 solubleness
Solubility test method by two note on the use regulations of Chinese Pharmacopoeia version in 2000 is measured, and the result lists in table 7-1.
Test-results and the bibliographical information of table 7-l meet.These article are prone to dissolve in 0.lmol/L phosphoric acid buffer (PH6.8), methane amide, dissolve in the 0.1mol/LNaOH part omitted, and slightly soluble in methyl alcohol, soluble,very slightly in water, almost insoluble in ethanol, ether.
7.1.3 fusing point
Undertaken by Chinese Pharmacopoeia two appendix VIC melting point determinations in 2000.Select for use silicone oil do to pass warm liquid, heat-up rate is controlled about 3 ℃/minute, and three batches of pilot scales and highly finished product are all in about 160 ℃ of flavescence, and browning look gradually 190 ℃ of left and right sides charings, is not seen fusing point or decomposition point then.
7.1.4 draw moist
Several parts of these article of getting, about 0.1g, the accurate title, decide, and in the moisture eliminator of different humidity (25 ℃), placed 24 hours, takes out accurate the title again and decide, and its determination data is seen table 7-2.
Test-results show these article have draw moist.
7.1.5 ultraviolet absorption spectrum
Make an experiment by two appendix IV of Chinese Pharmacopoeia version in 2000 A spectrophotometry, the aqueous solution, 0.lmol/L sodium hydroxide solution, 0.lmol/L hydrochloric acid soln, 0.lmol/LPH6.8 phosphoric acid buffer and the assay item current downflow phase solution of preparing the about 15 μ g/ml of these article respectively make an experiment.Test shows that the uv absorption spectrum of these article 0.lmol/L phosphate buffer solution (PH6.8) is presented at 230 places the absorption peak position is arranged, and in 0.lmol/LNaOH, absorbing peak position has obvious change, and absorption peak ranks in table 7-3.
7.1.6 uptake factor
These article have the absorption peak position at the 230nm place, and 257 ~ 259nm has bigger absorption, and the absorption of 230nm place is bigger; But consider that it is near the ultraviolet end absorption; Be prone to produce and do sorrow, explain orally (day anti-base) version Cefmenoxime Hemihydrochloride quality standard regulation in 1998, select 257nm for use with reference to Japanese antibiotics benchmark; Press the specified requirement of Chinese Pharmacopoeia version two appendix IV A in 2000 and new drug (Western medicine) study of pharmacy governing principle, carry out the mensuration of this wavelength absorption coefficient.
Make in instrument: UV one 2401PC day island proper Tianjin.
The quartzy cuvette of cuvette: lcm is used preceding pair correlation.
Slit width is to the influence of optical density: get the sample P H6.8 phosphate buffer solution of about 15 μ g/ml, at the 257nm place, measure its optical density with different slit width, the result sees table 7-4.
The maximum absorption band position finding: fixed block seam degree 1.0nm, above-mentioned solution is measured optical density near the 257nm place, measure the result and see table 7-5.
The maximum absorption coefficient determination: get the about 16mg of these article, the accurate title, decide, and puts in the 100ml measuring bottle, uses PH6.8; 0.lmol/L the slow liquid dissolving of phosphoric acid also is diluted to scale, mixing, and precision pipettes this solution 5.0ml again, puts in 50ml and the 100ml measuring bottle; Add PH6.5, the 0.lmol/L phosphoric acid buffer is diluted to scale, mixing; Process the test liquid of two kinds of concentration, measure optical density, calculate its uptake factor with dry product in the 257nm wavelength.The result sees table 7-6.
Simultaneously above-mentioned solution is measured optical density and calculated uptake factor with method on other four different ultraviolet spectrometry light justice appearance, the result sees table 7-7.
The Cefmenoxime Hemihydrochloride clinical study is measured the results list 7-8 with the uptake factor of product.
Table 7-8 Cefmenoxime Hemihydrochloride uptake factor
7.2 purity test
7.2.1HPLC the impurity that possibly exist in the synthesis technique Cefmenoxime Hemihydrochloride product of methodological study according to these article of inspection impurity has raw material 7-amino-3-［ (l-methyl-IH-tetrazolium-5 one base) thiomethyl ］ Cephalosporanic acid hydrochloride (being called for short 7-ATCAHCI); 1-methyl-5-sulfenyl one tetrazole; (being called for short MMTE), 7-amino-Cephalosporanic acid (being called for short 7-ACA) etc., these all have uv-absorbing; With reference to day anti-base version in 1998; USP 24 editions selects for use HPLC that it is studied and controls, to guarantee this quality.
7.2.1.1HPLC determination of foreign matter condition
Regulation by under Chinese Pharmacopoeia version appendix in 2000 the VD HPLC item detects.
(1) test apparatus:
Day island proper Tianjin LC of company one 6A liquid chromatograph, with SPD one 6AV uv-spectrophotometric detector, C one R3A chromatographic data processor, and 20 μ, 1 automatic sampling valve.
(2) chromatographic column:
Selecting the most general octadecylsilane chemically bonded silica for use is weighting agent.Diamonsil C18 4.6x200nm 5um chromatographic column on probation.
(3) selection of moving phase
This research methyl alcohol once on probation is made organic phase, and 0.5%, 1% glacial acetic acid solution is made water respectively, but separate impurities degree before Cefmenoxime Hemihydrochloride main peak and the main peak; All not as good as USP 24 editions; Day, anti-base was made organic phase with acetonitrile in the version quality standard in 1998, and the separating size that 2% Glacial acetic acid min. 99.5 is made water is big, therefore still selected for use water-Glacial acetic acid min. 99.5-second eyeball (850:17:150) to be moving phase; The RT of main peak is about 10 minutes, can the impurity that possibly exist separated to detect in 20 minutes to finish.
(4) detect wavelength
The ultraviolet absorption spectrum of Cefmenoxime Hemihydrochloride in moving phase, its maximum absorption band is considered 7-ATCAHCl at 265nm, 7-ACA and detecting of MMTZ altogether with reference to the method for day anti-base version in 1998 and USP 24 editions, select for use 254nm to make to detect wavelength.
(5) to the requirement of chromatographic column number of theoretical plate
Pressing two appendix VD of Chinese Pharmacopoeia version in 2000 method, is 4962 by cefmenoxime peak theory of computation plate number, and main peak was adjacent the impurity peaks separating size and met the requirements this moment.
(6) assay method
The about 10mg of these article of getting, the accurate title, decide, and adds 0.lmol/L PH6.8 phosphoric acid buffer 2ml dissolving; Add assay item current downflow again and process the need testing solution that contains 0.2mg among every lml mutually, other gets and supplies examination solution lml to put in the 10Oml volumetric flask, adds moving phase and is diluted to scale; Shake up the effect contrast solution.Chromatographic condition according under the assay item makes an experiment, and gets contrast solution 20ul and injects liquid chromatograph, regulates detection sensitivity, makes the height at principal constituent peak reach 10% of registering instrument full scale.Get each 20ul of need testing solution and contrast solution again and inject liquid chromatograph, the twice of record color atlas to principal constituent peak RT.As showing impurity, measure each impurity peak area sum in the need testing solution color atlas; Must not be greater than 4 times (4.0%) of contrast solution main peak area.
7.2.1.2 HPLC determination of foreign matter result
Aforesaid method is learned research and is shown; The HPLC method of selected relative substance inspection; Can be used for the related substance inspection of Cefmenoxime Hemihydrochloride product; 2 times of record color atlas to principal constituent peak RT, the impurity that exists in the intact product of sufficient inspected, present method also can be used as the method for degraded product chromatogram inspection in this article stability study.
Can confirm that 2.2 are divided into 7-ACA, 2.4 are divided into 7-ATCAHCI, and 5.6 are divided into MMTZ, and all the other are unknown impuritie.The Cefmenoxime Hemihydrochloride impurity number of middle trial production is 14 to 15, and total amount is 1.00 ~ 1.58%, and its check result is seen table 7-11.
Table 7-11 Cefmenoxime Hemihydrochloride determination of foreign matter result
7.3 the selection of content assaying method
7.3.1 the selection of content assaying method considers that Cefmenoxime Hemihydrochloride contains more impurity (about 1.2%); And to light, wet responsive, be prone to produce impurity, therefore do not consider to adopt volumetry to carry out assay; And with reference to USP 24 editions; Day anti-base version in 1998 is selected for use highly sensitively, and the strong HPLC HPLC method of specificity is as content assaying method.
7.3.2HPLC the methodological study of assay
7.3.2.1HPLC the optimization test of condition determination test
Instrument, chromatographic column, the selection of moving phase is seen under the HPLC purity test item (7.2.1).
7.3.2.2HPLC the reliability test of measuring method
(1) stability of trial-product in moving phase sees that test liquid was placed about 2 hours under the table 7-10 sample introduction precision item, and the Cefmenoxime Hemihydrochloride peak area changes less.Its RSD% is 0.41.
(2) with the separate impurities degree by aforementioned chromatographic condition, does not disturb the assay of these article through calculating equal two the appendix VD of Chinese Pharmacopoeia version in 2000 that can meet to separating the regulation greater than 1.5 the strict peak of hydrochloric acid cephalo first and the front and back separating size of portion's impurity peaks mutually.
(3) linear relationship of these article sample size and peak area application Cefmenoxime Hemihydrochloride reference substance (20010118) carries out the linear relationship test; The result lists in table 7-19; Test liquid is at 500 ~ 0.06ug/ml; Concentration and peak area linear relationship are better in the scope, still clear detecting when test liquid concentration is 0.06ug/ml, and lower limit of detectability is 0.0012ug.
(4) precision of measuring method
Same need testing solution is carried out several measures, by the test of calculated by peak area sample introduction precision, the weighing for several times on the same day of same sample or not the same date weighing measure, calculate by percentage composition and carry out in a few days and measuring method microtest in the daytime, the result lists in table 7-20.Test shows that the precision of method can satisfy the assay requirement.
7.4 assay is used reference substance
7.4.1 assay is with the preparation of reference substance
The reference substance lot number is 20010118.
7.4.2 assay with reference substance markization
Send Chinese medicine bioassay alleged fixed 20010118 highly finished product, its content is with C
16H
17N
9O
5S
3Show and count 93.5%.
7.6 preparing product assay result adopts above-mentioned definite content assaying method, is that assay is used reference substance with reference substance 20010118, the pilot scale preparing product of mensuration is pressed anhydride and is calculated, the percentage of hydrochloric cefmenoxime, and the result sees table 7-20.
Table 7-20 assay result
Claims (10)
1. cefmenoxime hydrochloride compound is characterized in that this compound has following structural formula:
Above-mentioned cefmenoxime hydrochloride compound is prepared by following method:
1) preparation of cefmenoxime acid
Precursor 7-ATCAHCl and the AE active ester of embracing croak ketone by head are at CH
2Cl
2With condensation reaction under the condition of basifier, then through extraction, decolouring, press filtration, neutralize, get rid of filter and oven dry, make cefmenoxime acid CMX-H; The chemical equation of condensation reaction is following:
7-ATCAHCl+AE active ester
CMX-H+captax
Wherein: the structural formula of 7-ATCAHCl:
The structural formula of AE active ester:
The structural formula of cefmenoxime acid CMX-H:
The structural formula of captax:
2) the half-finished preparation of Cefmenoxime Hemihydrochloride
After above-mentioned cefmenoxime acid adopts yellow soda ash to dissolve fully, pass through decolouring, press filtration, neutralization, decolouring, filtration, crystallization, washing and drying then, make the Cefmenoxime Hemihydrochloride work in-process;
The chemical formula of solubilizing reaction is following:
2CMX-H + Na
2CO
3 
2CMX-Na + CO
2 
+ H
2O；
The chemical formula of neutralization reaction is following:
CMX-Na + 3/2HCl
(CMX-H)·HCl
1/2 + NaCl；
3) preparation of Cefmenoxime Hemihydrochloride finished product
Open micronizer mill, with the material that is up to the standards pulverize and the sterilized Aluminum Bottle of packing in.
2. the compound method of the described cefmenoxime hydrochloride compound of claim 1 is characterized in that this method comprises the steps:
1) preparation of cefmenoxime acid
Precursor 7-ATCAHCl and the AE active ester of embracing croak ketone by head are at CH
2Cl
2With condensation reaction under the condition of basifier, then through extraction, decolouring, press filtration, neutralize, get rid of filter and oven dry, make cefmenoxime acid CMX-H; The chemical equation of condensation reaction is following:
7-ATCAHCl+AE active ester
CMX-H+captax
Wherein: the structural formula of 7-ATCAHCl:
The structural formula of AE active ester:
The structural formula of cefmenoxime acid CMX-H:
The structural formula of captax:
；
2) the half-finished preparation of Cefmenoxime Hemihydrochloride
After above-mentioned cefmenoxime acid adopts yellow soda ash to dissolve fully,, make the Cefmenoxime Hemihydrochloride work in-process then through once decolouring, press filtration, neutralization, secondary decolourization, filtration, crystallization, washing and drying;
The chemical formula of solubilizing reaction is following:
2CMX-H + Na
2CO
3 
2CMX-Na + CO
2 
+ H
2O；
The chemical formula of neutralization reaction is following:
CMX-Na + 3/2HCl
(CMX-H)·HCl
1/2 + NaCl；
3) preparation of Cefmenoxime Hemihydrochloride finished product
Open micronizer mill, with the material that is up to the standards pulverize and the sterilized Aluminum Bottle of packing in.
3. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that the step of condensation reaction is following:
With CH
2Cl
2Be drawn onto in the condensation jar, control material temperature adds 7-ATCAHCl and AE active ester less than 20 ℃; The weight of AE active ester is 1-1.2 times of 7-ATCAHCl weight; The material temperature drop is after-5 ℃～5 ℃, and stream adds basifier, and the addition of basifier is 0.8-1.0 a times of 7-ATCAHCl weight; The speed control material temperature that adds basifier through adjusting in the reinforced process after basifier adds, is observed feed liquid below 10 ℃, treat feed clarification after ,-5 ℃～10 ℃ insulated and stirred 0.8-1.2 hour.
4. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that the extraction step in the step 1) is following:
1. in the condensation jar, add purified water, the add-on of purified water is 3-5 a times of 7-ATCAHCl weight, and the material temperature control is at 2-15 ℃; Stirred 3-10 minute, and stopped stirring, left standstill 8-15 minute; Lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin;
2. utilize vacuum to suck purified water in the condensation jar, the soakage of purified water is 3-5 a times of 7-ATCAHCl weight, opens stirring; With vacuum the organic layer in the organic phase basin is drawn into the condensation jar, stops after sucking to stir, close vacuum valve; Emptying; Left standstill 8-15 minute, lower floor's organic layer is put into the organic phase basin, with vacuum with upper aqueous layer suction water basin;
3. repeat 2. to operate, upper aqueous layer is stayed in the condensation jar, opens stirring;
4. utilize vacuum with CH
2Cl
2After sucking the condensation jar, CH
2Cl
2Soakage be 7-ATCAHCl weight 1.5-3 doubly, again the water layer in the water basin is sucked the condensation jar, stop stirring, left standstill 8-15 minute, lower floor's organic layer is put into the organic phase basin;
5. repeat 4. to operate and extract 1 time again.
5. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that the decolouring step in the step 1) is following: use CH
2Cl
2After the second extraction, build hand hole plate, open stirring, control material temperature is opened vacuum valve on the condensation jar at 2-15 ℃, takes out the little space-time of true 0.9-1.2 and removes CH
2Cl
2Hand hole plate is opened in emptying, in the condensation jar, adds Medicinal Charcoal according to the feed liquid color, builds hand hole plate, opens stirring, and control material temperature is opened vacuum valve on the condensation jar, vacuum decoloration 0.9-1.2 hour at 2-15 ℃.
6. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that the neutralization procedure in the step 1) is following: in neutralization tank, add THF, the add-on of THF be 7-ATCAHCl weight 1.0-1.5 doubly; Open stirring, control material temperature is at 2 ℃-10 ℃, and stream adds 1.5-2.5mol/L HCl solution; When pH is 2.4-2.5, stop adding HCl solution, stirred crystallization; When the pH bounce-back rises to 2.5-2.8; Continue stream and add HCl solution, when pH reduces to 2.4-2.5 once more, stop adding hydrochloric acid; 1 ℃-5 ℃ are stirred insulation 1 hour.
7. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that step 2) in cefmenoxime acid dissolving step following: in enamel pot, add the injection water; Open to stir and add an amount of yellow soda ash, treat that it dissolves fully after, the material temperature is less than 20 ℃ in the controlling tank; Add cefmenoxime acid and skimmer ETHYLE ACETATE; The add-on of ETHYLE ACETATE is the 8%-10% of cefmenoxime acid weight, after cefmenoxime acid adds, and water for injection washing funnel; The sealing hand hole vacuumizes removing carbon dioxide.
8. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that step 2) in once decolouring adopt to add Medicinal Charcoal and EDTA2Na, open vacuum, the material temperature is 1 ℃-20 ℃ in the controlling tank, decolours 0.8-1.2 hour; Secondary decolourization adopts Medicinal Charcoal, and the material temperature control was stirred 0.8-1.2 minute at 1 ℃-10 ℃, left standstill 5 minutes.
9. the compound method of cefmenoxime hydrochloride compound according to claim 2; It is characterized in that step 2) in neutralization procedure following: feed liquid is opened stirring after completely cross stirring after the press filtration; Washing lotion all is pressed into enamel pot; Through 1 ℃-10 ℃ of material temperature in the chuck medium controlling tank, add 2.5-3.5mol/LHCl solution with fast speed, press cefmenoxime acid: hydrochloric acid=1:3.0-3.5 mol ratio.
10. the compound method of cefmenoxime hydrochloride compound according to claim 2 is characterized in that step 2) in crystallisation step following: when feed liquid is completely crossed stirring in the crystallizer, open stirring; After feed liquid and washing lotion all were pressed into crystallizer, the crystallizer chuck advanced hot water and heats up, and the material temperature control is at 20 ℃-25 ℃; Observe the feed liquid changing conditions; Pick up counting after feed liquid is complete white, 20 ℃-25 ℃ insulated and stirred 0.8-1.2 hour, chuck improves the cooling of cooling solvent; Material temperature drop to 0 ℃-10 ℃ is incubated 1.5-2.5 hour.
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